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OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 1
LEUKEMIA COMMITTEE
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 2
CONTENTS
S0919 Phase II ............................................................................................................................................................... 6
S1204 Surveillance ...................................................................................................................................................... 12
S1312 Phase I .............................................................................................................................................................. 13
S1318 Phase II ............................................................................................................................................................. 19
S1612 Phase II-III ........................................................................................................................................................ 25
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 3
Patient Registrations to Studies
By 12 Month Intervals
LEUKEMIA COMMITTEE
Screening registrations and registrations to Biologic only studies are excluded.
SWOG LAPS MEMBER NCORP NON-SWOG
183
280
564549
244
88
0
100
200
300
400
500
600
Time of Registration
Jul 2011Jun 2012
Jul 2012Jun 2013
Jul 2013Jun 2014
Jul 2014Jun 2015
Jul 2015Jun 2016
Jul 2016Jun 2017
40
76
33
34
46
66
36
132
139
106
61
258
125
140
73
211
45
101
48
50
46
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 4
Patient Registrations by Study and Arm LEUKEMIA COMMITTEE
Jan 2017
Jun 2017
Jul 2016
Dec 2016
Jan 2016
Jun 2016
All
Patients
S0919 Rel AML: Pravastatin+Ida+Ara-C
Induction
Pravastatin+Idarubicin+Ara-C 1 10 4 115
Consolidation
Pravastatin+Idarubicin+Ara-C 0 1 0 15
S1312 ALL, CD22+, REL/REF, Inotuzumab+CVP
Initial Registration
CVP + Inotuzumab dose level 1 0 0 0 5
CVP + Inotuzumab dose level 2 0 0 0 5
CVP + Inotuzumab dose level 3 0 0 2 11
CVP + Inotuzumab dose level 4 0 4 1 5
CVP + Inotuzumab dose level 5 6 4 0 10
6 8 3 36
S1318 ALL, Age 65+, Ph±, Blinatumomab
Initial registration
Induction: Ph- 14 6 4 27
Induction: Ph+/Ph-like 9 5 2 16
23 11 6 43
A041202 CLL, 65+, Ben+Rtx vs Ibrut±Rtx*
Total Registrations 0 0 4 99
E1910 BCR-ABL-neg, B ALL, Blinatumomab*
Total Registrations 16 9 8 62
E1912 CLL, Age 18-70, Ibrutinib vs FCR*
Total Registrations 0 0 37 130
E2905 MDS, Len vs Len + Epo*
Total Registrations 0 0 9 81
NHLBIMDS LEUK, National MDS Study*
Total Registrations 3 1 0 4
* For non-SWOG coordinated studies only SWOG registrations are shown.
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 5
Non-SWOG Studies with SWOG-Credited Registrations LEUKEMIA COMMITTEE
Studies with Accrual from January 2016 - June 2017
SWOG
Champion
Date
Activated
Date
Closed
Total
Accrued
A041202 CLL, 65+, Ben+Rtx vs Ibrut±Rtx S Coutre 12/15/13 05/16/16 548
Most Recent Progress Report
E1910 BCR-ABL-neg, B ALL, Blinatumomab M Liedtke 12/23/13 227
Most Recent Progress Report
E1912 CLL, Age 18-70, Ibrutinib vs FCR S O’Brien 02/07/14 06/09/16 529
Most Recent Progress Report
E2905 MDS, Len vs Len + Epo C Schiffer 02/09/09 05/13/16 240
Most Recent Progress Report
NHLBIMDS LEUK, National MDS Study D Hill, C Yi 04/05/16 216
No Progress Report Available
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 6
S0919/II
S0919 Phase II
Coordinating Group: SWOG
A Phase II Study of Idarubicin and Ara-C in Combination with Pravastatin
for Poor-risk Acute Myelogenous Leukemia (AML)
Participants:
SWOG, CTSU (Supported by ECOG-ACRIN)
Study Chairs:
A Advani, L Michaelis, E Attallah (ECOG-ACRIN)
Statisticians:
M Othus, A Moseley
Data Coordinator:
L Highleyman
Date Activated:
08/15/2009
Objectives To test whether the complete remission (CR) rate
(including CR with incomplete recovery [CRi]) in
poor-risk patients with acute myeloid leukemia
(AML) treated with a combination of chemotherapy
and pravastatin is sufficiently high to warrant Phase
III investigation. This will be tested independently in
two groups of patients: (1) patients with MDS
transformed to AML, and (2) refractory or relapsed
patients with previous remission < 6 months.
To estimate relapse-free survival and overall survival
rates in these two groups of patients.
To estimate the frequency and severity of toxicities
of this regimen in these two groups of patients.
To evaluate in a preliminary manner whether
prestudy cytogenetic features correlate with response
in these two groups of patients.
Patient Population MDS transformed to AML cohort (Cohort 1):
Patients must have a previous morphologically
confirmed diagnosis of MDS/CMML. Patients may
have received previous non-intensive therapy (e.g.
azacitidine, decitabine, low-dose cytarabine (LDAC),
lenalidomide) given for treatment of MDS/CMML
(with up to 20% blasts). At the time of registration
patients must have a morphologically confirmed
diagnosis of acute myeloid leukemia (AML).
Relapsed/Refractory Cohort (Cohort 2):
Patients must have a previous morphologically
confirmed diagnosis of acute myeloid leukemia
(AML). Relapse or refractory disease must be
documented by a bone marrow examination
demonstrating > 5% blasts in the bone marrow not
attributable to another cause.
Patients must have received at least one prior
induction chemotherapy regimen for their AML and
they may have received any type of chemotherapy.
Patients must not have received chemotherapy within
14 days prior to registration. Relapsed patients must
have achieved CR or CRi, lasting less than six
months with their last induction regimen. Primary
refractory patients are eligible if, on Day 14 of their
previous chemotherapy regimen, they have
significant residual disease. Refractory patients who
received only hypomethylating agent or low dose
therapy for induction are not eligible.
All patients:
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 7
S0919/II
Patients with acute promyelocytic leukemia (APL,
FAB M3) or blastic transformation of chronic
myelogenous leukemia are not eligible.
Patients who have received autologous or allogeneic
stem cell transplantation are not eligible.
Patients must have adequate cardiac function as
defined in the protocol. Patients must be at least 18
years of age, must have a Zubrod performance status
of 0, 1, or 2, and must have adequate renal and
hepatic function. Patients must not have clinical
evidence of leptomeningeal disease and must not
have a systemic fungal, bacterial, viral or other
infection that is not controlled. Patients who are
known to be HIV+ may be eligible providing they
meet all of the criteria in the protocol.
Stratification/Descriptive Factors Patients will be stratified according to disease status:
patients with MDS transformed to AML vs refractory
or relapsed patients with previous remission less than
6 months.
Accrual Goals Seventy-four eligible patients will be accrued to the
two additional poor-risk cohorts, 37 in each cohort.
Summary Statement On July 1, 2012, the study was temporarily closed to
accrual to relapsed patients with previous remission
of longer than three months. Final results for this
cohort of 36 patients were reported in the Spring
2013 Report of Studies and are not included in this
report. On April 1, 2013, the study was re-opened to
two additional poor-risk cohorts: patients with MDS
transformed AML, and refractory or relapsed patients
with previous remission less than six months. The
following tables, other than 'Registration by
Institution' show accrual for these two poor-risk
cohorts only.
Relapsed/Refractory Cohort:
The study was closed to accrual for
refractory/relapsed AML patients on November 24,
2014, after meeting the accrual goal with 50 patients
registered. Three patients are ineligible: one due to
prior stem cell transplantation and two due to
previous remission longer than six months. One
patient had a cardiac event prior to starting treatment
causing a decline in performance status. This patient
did not receive any protocol therapy and is not
included in any analyses. A major protocol deviation
is coded for one patient who received an extra dose
of Ara-C.
Forty-six relapsed/refractory AML patients have been
assessed for adverse events. Four treatment-related
deaths occurred: one due to sepsis (reported as Inf,
Unk ANC: blood), another due to hypotension, a
third due to beta strep Group B (reported as Inf, 3-4
ANC: blood), and a fourth due to respiratory failure
(reported as DLCO). An additional 11 patients
experienced treatment-related Grade 4 non-
hematologic toxicities.
Two patients accrued to the refractory/relapsed
cohort were ineligible for consolidation therapy
because they were ineligible for induction. An
additional patient who relapsed prior to consolidation
treatment began is not evaluable for toxicities. No
Grade 3 or higher treatment-related non-hematologic
toxicity has been reported during consolidation
therapy.
MDS Transformed to AML Cohort:
As of June 30, 2017, 29 patients have been accrued to
the MDS transformed to AML cohort. Three patients
went off treatment for reasons not specified in the
protocol: two were induction refractory and one went
on to receive transplant after achieving a complete
response. Among the 26 patients assessed for adverse
events, there were five deaths that were possibly
related to treatment: one due to respiratory failure
(reported as DLCO), one due to lung infection and
respiratory failure (coded as Lung Inf, Unk ANC:
lung), one due to hypoxia and respiratory failure
(reported as DLCO), one due to DLCO, and one due
to clostridium difficile (coded as GI Inf, Unk ANC:
sm bowel NOS) and infectious colitis. This last
patient also experienced Grade 4 multi-organ failure
(coded as Constitutional Symptoms-other). Three
additional patients reported treatment-related Grade 4
non-hematologic toxicities, including one instance of
Grade 4 respiratory failure (coded as Pulmonary-
other).
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 8
S0919/II
Registration by Institution
Initial Registration
Registrations ending June 30, 2017
Institutions
Total
Reg Institutions
Total
Reg
Stanford University 24 Loyola University 4
Cleveland Clinic OH 23 Birmingham, U of AL 3
Rochester, Univ of 15 PCRC NCORP 2
H Lee Moffitt CC 11 Tulane University 2
Colorado, U of 6 LSU-Shreveport/Gulf South MU-NCORP 1
Oregon Hlth Sci Univ 6 Mississippi, Univ of 1
Wichita NCORP 6 Tulane Univ MBCCOP 1
Baylor College 5 Total (16 Institutions) 115
New Mexico MU-NCORP 5
Registration, Eligibility, and Evaluability
Initial Registration
Registrations from April 1, 2013 through June 30, 2017; Data as of July 25, 2017
TOTAL
MDS
transformed to
AML
Refractory or
relapsed with
previous
remission < 6
months
NUMBER REGISTERED 79 29 50
INELIGIBLE 3 0 3
ELIGIBLE 76 29 47
Analyzable, Pend. Elig. 1 1 0
Not Analyzable 1 0 1
RESPONSE ASSESSMENT
Determinable 65 25 40
Not Determinable 9 3 6
Too Early 1 1 0
ADVERSE EVENT ASSESSMENT
Evaluable 75 29 46
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 9
S0919/II
Patient Characteristics
Initial Registration
Registrations from April 1, 2013 through June 30, 2017; Data as of July 25, 2017
MDS
transformed to
AML
(n=29)
Refractory or
relapsed with
previous
remission < 6
months
(n=46)
AGE
Median 64.9 57.3
Minimum 21.8 23.1
Maximum 77.1 75.0
SEX
Males 16 55% 24 52%
Females 13 45% 22 48%
HISPANIC
Yes 0 0% 4 9%
No 28 97% 38 83%
Unknown 1 3% 4 9%
RACE
White 28 97% 35 76%
Black 1 3% 2 4%
Asian 0 0% 6 13%
Multi-Racial 0 0% 3 7%
Treatment Summary
Induction
Registrations from April 1, 2013 through June 30, 2017; Data as of July 25, 2017
TOTAL
MDS
transformed to
AML
Refractory or
relapsed with
previous
remission < 6
months
NUMBER ON PROTOCOL TREATMENT 0 0 0
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
75 29 46
Treatment completed as planned 59 20 39
Adverse Event or side effects 2 1 1
Refusal unrelated to adverse event 1 0 1
Progression/relapse 0 0 0
Death 10 5 5
Other - not protocol specified 3 3 0
Reason under review 0 0 0
MAJOR PROTOCOL DEVIATIONS 1 0 1
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 10
S0919/II
Number of Patients with a Given Type and Grade of Adverse Event
Induction
Adverse Events Unlikely or Not Related to Treatment Excluded
Non-Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
Registrations from April 1, 2013 through June 30, 2017; Data as of July 25, 2017
MDS transformed to AML
(n=29)
Grade
Refractory or relapsed with
previous remission < 6
months
(n=46)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5
ALT 27 1 1 0 44 2 0 0
AST 26 2 1 0 45 1 0 0
Acidosis 28 1 0 0 46 0 0 0
Alkaline phosphatase 29 0 0 0 45 1 0 0
Alkalosis 28 1 0 0 46 0 0 0
Anorexia 28 1 0 0 46 0 0 0
Bilirubin 27 2 0 0 46 0 0 0
Cardiac ischemia/infarction 28 0 1 0 46 0 0 0
Colitis, infectious 28 0 0 1 45 1 0 0
Constitutional Symptoms-other 27 1 1 0 46 0 0 0
Creatinine 26 3 0 0 44 2 0 0
DLCO 25 0 1 3 45 0 0 1
Diarrhea 25 3 1 0 38 8 0 0
Distension 27 2 0 0 46 0 0 0
Dry mouth 28 1 0 0 46 0 0 0
Dyspnea 28 1 0 0 44 1 1 0
Edema-limb 27 2 0 0 46 0 0 0
Fatigue 27 2 0 0 44 2 0 0
Febrile neutropenia 11 18 0 0 14 27 5 0
GI Hemorrhage: duodenum 28 1 0 0 46 0 0 0
GI Inf, 3-4 ANC: stomach 29 0 0 0 45 1 0 0
GI Inf, Unk ANC: sm bowel NOS 28 0 0 1 46 0 0 0
GI Necrosis: small bowel 28 0 1 0 46 0 0 0
GI Obstruction: small bowel 28 1 0 0 46 0 0 0
GI Pain: abdomen 26 3 0 0 46 0 0 0
GI Pain: esophagus 29 0 0 0 45 1 0 0
GI Pain: oral cavity 29 0 0 0 43 3 0 0
GI Pain: peritoneum 28 0 1 0 46 0 0 0
GI Ulcer: duodenum 28 1 0 0 46 0 0 0
GU Inf, 3-4 ANC: kidney 29 0 0 0 45 1 0 0
Hyperglycemia 27 2 0 0 46 0 0 0
Hyperkalemia 27 1 1 0 46 0 0 0
Hypermagnesemia 28 1 0 0 46 0 0 0
Hypoalbuminemia 26 3 0 0 40 6 0 0
Hypocalcemia 24 5 0 0 43 2 1 0
Hypokalemia 26 3 0 0 43 3 0 0
Hyponatremia 29 0 0 0 45 1 0 0
Hypophosphatemia 25 4 0 0 44 2 0 0
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 11
S0919/II
MDS transformed to AML
(n=29)
Grade
Refractory or relapsed with
previous remission < 6
months
(n=46)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5
Hypotension 27 0 2 0 45 0 0 1
Hypoxia 27 0 1 1 43 3 0 0
Ileus 27 2 0 0 46 0 0 0
Inf, 3-4 ANC: blood 25 0 4 0 39 1 5 1
Inf, Unk ANC: blood 26 0 3 0 42 0 3 1
Infection-other 28 1 0 0 46 0 0 0
Lung Hemorrhage: bronchopulm. 29 0 0 0 45 0 1 0
Lung Hemorrhage: nose 29 0 0 0 45 1 0 0
Lung Inf, 3-4 ANC: bronchus 29 0 0 0 45 1 0 0
Lung Inf, 3-4 ANC: lung 27 1 1 0 40 5 1 0
Lung Inf, Unk ANC: lung 28 0 0 1 46 0 0 0
Lung Inf, Unk ANC: mucosa 29 0 0 0 45 1 0 0
Mucositis, clin: oral cavity 29 0 0 0 45 1 0 0
Mucositis, clin: pharynx 29 0 0 0 45 0 1 0
Mucositis, funct: oral cav. 29 0 0 0 45 1 0 0
Musculo. Pain: bone 29 0 0 0 45 1 0 0
Musculo. Pain: limb 29 0 0 0 45 1 0 0
Musculoskeletal-other 28 1 0 0 46 0 0 0
Nausea 28 1 0 0 43 3 0 0
Neuro Inf, 3-4 ANC: mening. 29 0 0 0 45 0 1 0
Opportunistic infection 29 0 0 0 44 2 0 0
Pleural effusion 28 1 0 0 46 0 0 0
Pulmonary-other 28 0 1 0 46 0 0 0
Rash 29 0 0 0 45 1 0 0
Renal failure 29 0 0 0 44 0 2 0
Renal-other 28 1 0 0 46 0 0 0
Skin Inf, 3-4 ANC: skin 28 1 0 0 46 0 0 0
Supra Arrhyth: Atrial Fib. 28 0 1 0 46 0 0 0
Typhlitis 29 0 0 0 45 1 0 0
Ulceration 29 0 0 0 45 1 0 0
Vomiting 27 2 0 0 46 0 0 0
Weight Loss 29 0 0 0 44 2 0 0
MAX. GRADE ANY ADVERSE
EVENT
4 17 3 5 3 28 11 4
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 12
S1204
S1204 Surveillance
A Sero-Epidemiologic Survey and Cost-Effectiveness Study of Screening for
Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and
Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients
Study Chairs:
S Ramsey, D Hershman
Statisticians:
J Unger, K Arnold
Data Coordinators:
H Dong, M Yee
Date Activated:
08/29/2013
Date Closed:
02/15/2017
Objectives Among newly diagnosed cancer patients presenting
to SWOG-affiliated community and academic
oncology clinics, estimate the prevalence of human
immunodeficiency virus (HIV), hepatitis B (HBV),
and hepatitis C (HCV) infection.
Evaluate known sociodemographic, clinical, and
behavioral factors that are significantly associated
with previously undiagnosed HIV, HBV, and/or
HCV infection in a population of people with newly
diagnosed cancer
Among patients who are identified as having HIV,
HBV, and/or HCV, evaluate the timing and type of
treatments received, both for the viral infections and
the cancers.
Evaluate type and rate of cancer treatment-related
adverse events in patients with HIV, HBV, and/or
HCV infection.
Determine the cost-effectiveness of (1) routine,
universal screening and (2) risk factor-directed
screening of newly diagnosed cancer patients for
HIV, HBV and/or HCV versus current care.
Patient Population Patients must be presenting for evaluation or
treatment for the first diagnosis of a new solid or
hematologic cancer malignancy. Confirmed diagnosis
date must be within 120 days prior to first clinic visit
as a newly diagnosed cancer patient at the registering
clinic. Patients presenting for "second opinions" of
confirmed malignancies are eligible, including those
who have started cancer treatment at other facilities.
Patients must be registered within 90 days after their
first clinic visit. Patients must not have been
diagnosed with a malignancy other than the current
malignancy within the past five years, with the
exception of basal cell or squamous cell skin cancer,
in situ cervical cancer, or in situ breast cancer.
Patients must have no evidence of disease for a prior
malignancy for at least five years prior to
randomization except as noted above.
Patients must be 18 years of age or older. Patients
must have had their blood drawn for viral status
testing for HIV, HBV and HCV or provide
acceptable viral status documentation prior to
registration, as defined in the protocol. Note that
patients must have blood drawn for testing prior to
registration for any of the three viruses not covered
by the documentation. Patients are allowed to
participate in other clinical trials.
Accrual Goals A total of 3,061 patients will be accrued to achieve
3,000 eligible patients.
Summary Statement For the current status of this study, please refer to the
Cancer Care Delivery chapter.
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 13
S1312/I
S1312 Phase I
A Phase I Study of Inotuzumab (NSC-772518) in Combination with CVP
(Cyclophosphamide, Vincristine, Prednisone) for Patients with
Relapsed/Refractory CD22-Positive Acute Leukemia (including B-ALL,
Mixed Phenotypic Leukemia, and Burkitt's Leukemia)
Study Chairs:
A Advani, M Liedtke
Statisticians:
M Othus, A Moseley
Data Coordinator:
L Highleyman
Date Activated:
04/01/2014
Objectives To assess the safety of inotuzumab in combination
with cyclophosphamide, vincristine and prednisone
(CVP) and to determine the maximum tolerated dose
(MTD) of inotuzumab in this regimen for patients
with relapsed or refractory CD22-positive acute
leukemia (B-ALL, mixed phenotype, and Burkitt's).
To estimate the preliminary activity [response rate:
complete remission (CR) + complete remission with
incomplete count recovery (CRi)] of this combination
in the expansion cohort.
To estimate the frequency and severity of toxicities
of this combination in this patient population.
Patient Population Patients must have a diagnosis of relapsed or
refractory CD22-positive acute leukemia including
B-ALL, mixed phenotype leukemia (bilineal and
biphenotypic), or Burkitt's leukemia based on WHO
classification. Patients with bilineal leukemia are
excluded. Patients must have evidence of acute
leukemia in their peripheral blood or bone marrow.
Patients must have ≥ 5% blasts in the peripheral
blood or bone marrow. At least ≥ 20% of those blasts
must be CD22-positive (surface) based on local
immunophenotyping and histopathology. Patients
must be refractory or have relapsed following prior
induction therapy.
Patients may have received prior allogeneic
transplant or autologous transplant. Patients with
prior allogeneic bone marrow transplant will be
eligible only if the conditions stated in the protocol
are met. Patients known to have Ph+ ALL must have
either failed treatment or been intolerant to treatment
with at least one second or third generation tyrosine
kinase inhibitor. Patients must not have received
prior treatment with inotuzumab. Previous treatment
with other anti-CD22 antibodies must have been
completed at least 90 days prior to registration.
Patients must not have received any chemotherapy,
investigational agents, or undergone major surgery
within 14 days prior to registration with the following
exceptions: (1) Monoclonal antibodies must not have
been received for one week prior to registration; (2)
Chimeric antigen receptor (CAR) T-cells must not
have been received for 28 days prior to registration;
(3) Steroids, hydroxyurea, vincristine, 6-
mercaptopurine, methotrexate, thioguanine and
intrathecal chemotherapy are permitted within any
time frame prior to registration. FDA-approved
tyrosine kinase inhibitors may also be administered
until one day prior to start of study therapy (C1, D1).
All drug-related toxicities must have resolved to ≤
Grade 2. Treatment with hydroxyurea and steroids is
permitted to bring down peripheral blast count.
Patients must be at least 18 years of age and have
Zubrod performance status of 0-2. Patients must not
have a systemic bacterial, fungal, or viral infection
that is not controlled. Patients must not have active
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 14
S1312/I
CNS involvement. Patients must have < Grade 2
neuropathy (sensory/motor). Patients must not have a
history of chronic or active hepatitis B or C infection.
Patients must not have evidence or history of veno-
occlusive disease or sinusoidal obstruction syndrome.
Patients who are known to be HIV+ are eligible
providing they meet all of the criteria in the protocol.
Patients with a history of a serious allergic or
anaphylactic reaction to humanized monoclonal
antibodies are not eligible. Patients must have
adequate hematologic, renal, hepatic and cardiac
function.
Accrual Goals Patient enrollment will follow the traditional "3+3"
algorithm until the MTD for inotuzumab is reached
or the highest dose tested is judged tolerable. This
study will accrue 3-30 eligible and evaluable patients
in the Phase I portion and six additional eligible
patients in the expansion cohort.
Summary Statement The study will evaluate up to five dose levels of
inotuzumab.
The initial dose level of 0.4 mg/m2 inotuzumab closed
on November 1, 2014 with five eligible patients
registered, three of whom were evaluable for dose
limiting toxicities (DLT). The second dose level of
inotuzumab at 0.6 mg/m2 on day 1 and 0.4 mg/m
2 on
day 15 closed on May 15, 2015 with five patients
registered, three of whom were evaluable for DLT.
One patient was ineligible due to inadequate liver
function, leaving four eligible patients in this dose
level. There were no DLTs in either the first or
second dose level.
The third dose level of inotuzumab at 0.8 mg/m2
on
day 1 and 0.4 mg/m2 on day 15 closed on April 15,
2016 with 11 patients registered. One patient was
ineligible due to inadequate liver function. Four
patients were not evaluable for DLT: two went off
treatment before their counts recovered and before
prolonged myelosuppression could be ruled out, one
died before receiving a full cycle of treatment, and
one continued to take tyrosine kinase inhibitor (TKI)
while on protocol and is coded as a major protocol
deviation. Six of the 10 eligible patients were
evaluable for DLT. One of the first three evaluable
patients experienced DLT (prolonged
myelosuppression), so three additional patients were
evaluated at this dose level. None of these additional
patients experienced a DLT. Among 10 patients
assessed for toxicity, one patient experienced Grade 4
hyperglycemia and another experienced Grade 4
hyperglycemia and oral mucositis.
The fourth dose level of inotuzumab at 0.8 mg/m2
on
day 1 and 0.4 mg/m2 on days 8 and 15 closed on
August 22, 2016 with five patients registered. Two
patients were not evaluable for DLT because they
went off treatment before their counts recovered and
before prolonged myelosuppression could be ruled
out. There were no DLTs and no Grade 4 or Grade 5
non-hematological toxicities related to treatment at
dose level 4.
The fifth dose level of inotuzumab at 0.8 mg/m2
on
day 1 and 0.5 mg/m2 on days 8 and 15 opened on
October 5, 2016 and as of June 30, 2017 had accrued
ten patients. Five patients went off treatment before
their counts recovered and before prolonged
myelosuppression could be ruled out and are
therefore not evaluable for DLT. One patient
experienced DLT: Grade 3 ascites, an event
considered clinically significant regardless of
duration. There have been no Grade 4 or Grade 5
non-hematological toxicities related to treatment at
dose level 5.
Twenty patients went off treatment for non-protocol
specified reasons, due to lack of treatment benefit,
physician decision, or transplant.
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 15
S1312/I
Registration by Institution
Initial Registration
Registrations ending June 30, 2017
Institutions Total Reg
City of Hope Med Ctr 13
Cleveland Clinic OH 10
Rochester, Univ of 7
Baylor College 4
Stanford University 2
Total (5 Institutions) 36
Registration, Eligibility, and Evaluability
Initial Registration
Registrations ending June 30, 2017; Data as of July 25, 2017
TOTAL
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
NUMBER REGISTERED 36 5 5 11 5 10
INELIGIBLE 2 0 1 1 0 0
ELIGIBLE 34 5 4 10 5 10
RESPONSE ASSESSMENT
Determinable 31 5 4 8 5 9
Not Determinable 2 0 0 2 0 0
Too Early 1 0 0 0 0 1
ADVERSE EVENT ASSESSMENT
Evaluable 34 5 4 10 5 10
DLT ASSESSMENT
Evaluable 20 3 3 6 3 5
Not Evaluable 14 2 1 4 2 5
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 16
S1312/I
Patient Characteristics
Initial Registration
Registrations ending June 30, 2017; Data as of July 25, 2017
CVP +
Inotuzumab
dose level 1
(n=5)
CVP +
Inotuzumab
dose level 2
(n=4)
CVP +
Inotuzumab
dose level 3
(n=10)
CVP +
Inotuzumab
dose level 4
(n=5)
CVP +
Inotuzumab
dose level 5
(n=10)
AGE
Median 48.9 42.3 42.8 49.6 39.4
Minimum 22.4 20.7 22.4 33.1 25.2
Maximum 73.7 56.4 75.4 50.2 58.7
SEX
Males 4 80% 0 0% 6 60% 3 60% 5 50%
Females 1 20% 4 100% 4 40% 2 40% 5 50%
HISPANIC
Yes 2 40% 2 50% 2 20% 4 80% 2 20%
No 3 60% 2 50% 7 70% 1 20% 6 60%
Unknown 0 0% 0 0% 1 10% 0 0% 2 20%
RACE
White 4 80% 3 75% 6 60% 5 100% 6 60%
Black 1 20% 1 25% 2 20% 0 0% 1 10%
Asian 0 0% 0 0% 0 0% 0 0% 1 10%
Unknown 0 0% 0 0% 2 20% 0 0% 2 20%
Treatment Summary
Registrations ending June 30, 2017; Data as of July 25, 2017
TOTAL
CVP +
Inotuzumab
dose level 1
CVP +
Inotuzumab
dose level 2
CVP +
Inotuzumab
dose level 3
CVP +
Inotuzumab
dose level 4
CVP +
Inotuzumab
dose level 5
NUMBER ON PROTOCOL TREATMENT 0 0 0 0 0 0
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
34 5 4 10 5 10
Treatment completed as planned 4 1 2 1 0 0
Adverse Event or side effects 3 0 0 2 0 1
Refusal unrelated to adverse event 0 0 0 0 0 0
Progression/relapse 6 1 1 4 0 0
Death 1 0 0 1 0 0
Other - not protocol specified 20 3 1 2 5 9
Reason under review 0 0 0 0 0 0
MAJOR PROTOCOL DEVIATIONS 1 0 0 1 0 0
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 17
S1312/I
Number of Patients with a Given Type and Grade of Adverse Event
Initial Registration
Adverse Events Unlikely or Not Related to Treatment Excluded
Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
Registrations ending June 30, 2017; Data as of July 25, 2017
CVP +
Inotuzumab
dose level 1
(n=5)
Grade
CVP +
Inotuzumab
dose level 2
(n=4)
Grade
CVP +
Inotuzumab
dose level 3
(n=10)
Grade
CVP +
Inotuzumab
dose level 4
(n=5)
Grade
CVP +
Inotuzumab
dose level 5
(n=10)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Anemia 3 1 1 0 2 1 1 0 3 7 0 0 2 3 0 0 5 5 0 0
Lymphocyte count decreased 3 0 2 0 3 1 0 0 7 2 1 0 2 1 2 0 5 2 3 0
Neutrophil count decreased 2 0 3 0 1 0 3 0 1 0 9 0 1 2 2 0 3 3 4 0
Platelet count decreased 3 0 2 0 2 0 2 0 3 1 6 0 1 1 3 0 5 1 4 0
White blood cell decreased 2 0 3 0 0 1 3 0 0 1 9 0 0 0 5 0 5 0 5 0
MAX. GRADE ANY ADVERSE
EVENT
2 0 3 0 0 0 4 0 0 0 10 0 0 0 5 0 1 2 7 0
Number of Patients with a Given Type and Grade of Adverse Event
Initial Registration
Adverse Events Unlikely or Not Related to Treatment Excluded
Non-Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
Registrations ending June 30, 2017; Data as of July 25, 2017
CVP +
Inotuzumab
dose level 1
(n=5)
Grade
CVP +
Inotuzumab
dose level 2
(n=4)
Grade
CVP +
Inotuzumab
dose level 3
(n=10)
Grade
CVP +
Inotuzumab
dose level 4
(n=5)
Grade
CVP +
Inotuzumab
dose level 5
(n=10)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Ascites 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 9 1 0 0
Dysphagia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0
Encephalopathy 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0
Enterocolitis 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 9 1 0 0
Fatigue 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0
Febrile neutropenia 5 0 0 0 2 2 0 0 8 2 0 0 2 3 0 0 9 1 0 0
Fever 4 1 0 0 3 1 0 0 9 1 0 0 5 0 0 0 10 0 0 0
GI disorders-Other, specify 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 10 0 0 0
Gastric hemorrhage 3 2 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 0 0 0
Headache 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 10 0 0 0
Hyperglycemia 5 0 0 0 4 0 0 0 6 2 2 0 1 4 0 0 8 2 0 0
Hypertension 5 0 0 0 4 0 0 0 9 1 0 0 4 1 0 0 10 0 0 0
Hypoalbuminemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0
Hypocalcemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 18
S1312/I
CVP +
Inotuzumab
dose level 1
(n=5)
Grade
CVP +
Inotuzumab
dose level 2
(n=4)
Grade
CVP +
Inotuzumab
dose level 3
(n=10)
Grade
CVP +
Inotuzumab
dose level 4
(n=5)
Grade
CVP +
Inotuzumab
dose level 5
(n=10)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5
Hypokalemia 5 0 0 0 4 0 0 0 10 0 0 0 4 1 0 0 10 0 0 0
Infections/infestations-Other 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 9 1 0 0
Intracranial hemorrhage 4 1 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 0 0 0
Lung infection 5 0 0 0 4 0 0 0 10 0 0 0 3 2 0 0 10 0 0 0
Mucositis oral 5 0 0 0 4 0 0 0 9 0 1 0 5 0 0 0 10 0 0 0
Skin infection 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 10 0 0 0
MAX. GRADE ANY ADVERSE
EVENT
1 4 0 0 2 2 0 0 3 5 2 0 0 5 0 0 7 3 0 0
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 19
S1318/II
S1318 Phase II
Coordinating Group: SWOG
A Phase II Study of Blinatumomab and POMP (Prednisone, Vincristine,
Methotrexate, 6-Mercaptopurine) for Elderly Patients (≥ 65 Years of Age)
with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)
Participants:
SWOG, CTSU (Supported by Alliance and ECOG-
ACRIN)
Study Chairs:
A Advani, K O'Dwyer, M Wiedewult (Alliance), J Park
(ECOG-ACRIN)
Statisticians:
M Othus, A Moseley
Data Coordinator:
T Maher
Date Activated:
01/12/2015
SCHEMA
REGISTRATION Step 1
D28 CR/CRi?
Dasatinib / Prednisone Induction
Continue Induction Cycle
YES
Blinatumomab
Re-induction 1
Ph-positive Patients:
NO
Until intolerance or progression for up to 10 years from registration, then
Protocol Therapy Complete
CR/CRi?
YES
NO
Off Protocol Therapy
REGISTRATION Step 2: Post-remission therapy
Blinatumomab/Dasatinib
REGISTRATION Step 3: Maintenance
Dasatinib/Prednisone
Ph-negative Patients:
Blinatumomab Induction
CR/CRi?
REGISTRATION Step 1
YES NO
REGISTRATION Step 2:
Post-remission therapy
Blinatumomab
Continued CR/Cri?
REGISTRATION Step 3:
Maintenance
POMP Chemotherapy
Protocol Therapy Complete
Blinatumomab
Re-induction
D56 CR/CRi?
YESNO
Continue Dasatinib
to Day 84
Continued CR/Cri?
YES
Blinatumomab
Re-induction 2
CR/CRi?
NO
YESYES
Continued CR/Cri?
NO
NO
CR/CRi?
YES NO
Off Protocol Therapy
YES NO
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 20
S1318/II
Objectives To evaluate the three-year survival rate in elderly
patients with newly diagnosed Philadelphia
chromosome (Ph) negative ALL treated with
blinatumomab followed by POMP maintenance.
To evaluate in a preliminary manner (feasibility
study) the safety of dasatinib-steroid based induction
followed by blinatumomab treatment in combination
with dasatinib followed by dasatinib-based
maintenance in elderly patients with newly diagnosed
Ph-positive ALL, relapsed/refractory Ph-positive
ALL, and Ph-like DSMKF ALL (newly-diagnosed
relapsed or refractory).
To evaluate toxicities in these patient populations
treated with these regimens.
To estimate the rates of complete response (CR),
complete response with incomplete count recovery
(CRi), and disease-free survival in Ph-negative
patients.
To estimate disease-free and overall survival in Ph-
positive ALL and Ph-like DSMKF ALL.
To estimate in each cohort the rate of minimal
residual disease (MRD) negativity, and the time to
achieve MRD negativity (exploratory analysis).
To determine whether anti-idiotype antibodies
directed against blinatumomab develop with
blinatumomab treatment in this study.
Patient Population Patients must have a new morphologic diagnosis of
precursor B cell acute lymphoblastic leukemia (ALL)
(non-T cell) based on WHO criteria as defined in
protocol. Patients with Burkitts (L3) are not eligible
for this study. Patients with Ph-positive or Ph-like
ALL with dasatinib-sensitive mutations or kinase
fusions (DSMKF) may have relapsed or refractory
diagnoses. Patients must have a diagnosis of Ph-
negative ALL or Ph-positive ALL by cytogenetics,
FISH or polymerase chain reaction (PCR). If not
already known, BCR-ABL status (p190 or p210)
must be evaluated in Ph-positive patients by PCR. To
be registered under the Ph-like DSMKF criterion, the
patient must have a known or presumed activating
Ph-like signature and dasatinib-sensitive mutation or
kinase fusion as defined in the protocol. Patients must
have evidence of ALL in their marrow or peripheral
blood with at least 20% lymphoblasts (at least 5% for
relapsed/refractory patients) within 14 days prior to
registration. At registration, relapsed/refractory
patients must submit pathology and cytogenetics
reports from time of original diagnosis.
Immunophenotyping of the blood or marrow
lymphoblasts must be performed to determine lineage
within 14 days prior to registration. Patients with
only extramedullary disease in the absence of bone
marrow or blood involvement are not eligible.
Patients must not have testicular involvement.
Patients must not have received any prior
chemotherapy, radiation therapy, or other therapy for
the treatment of ALL (other than those noted below)
and must not be receiving any immunosuppressive
therapy. Patients must not have received any prior
investigational therapy within 28 days prior to
registration. Patients may have received the following
within any time prior to registration: low dose
chemotherapy, TKI therapy, steroids, hydroxyurea,
leukapheresis, intrathecal chemotherapy, or
vincristine. Patients must not have received any
monoclonal antibody therapy within 42 days of
registration.
Patients must be at least 65 years of age and have a
Zubrod performance status of 0-2. Patients must have
adequate hepatic, cardiac and renal function. Patients
must not have a history or presence of clinically
relevant CNS pathology and must have a lumbar
puncture to determine CNS involvement of ALL
within 14 days prior to registration. Patients must not
have systemic fungal, bacterial, viral or other
infection that is not controlled. Patients must not have
Grade 2 or higher neuropathy (cranial, motor or
sensory) within 14 days prior to registration. Patients
known to be positive for HIV may be eligible,
providing they meet the criteria in the protocol.
Patients must not be candidates for allogeneic
hematopoietic stem cell transplant. Patients must not
have any known autoimmune disease. Ph-negative
patients must have PT/PTT/INR/fibrinogen and
neurologic assessment tests within 28 days prior to
registration. Ph-positive patients must not have active
pericardial effusion, ascites or pleural effusion of any
grade.
Stratification/Descriptive Factors Patients are stratified by Registration Cohort: Ph-
negative vs Ph-positive/Ph-like DSMKF.
Accrual Goals This study will accrue up to 26 eligible Ph-negative
patients. An interim analysis will be performed
among the first 11 patients. If at least five complete
remissions (CR or CRi) are observed, then the study
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 21
S1318/II
will continue to full accrual. The study will continue
accruing while the remission data is being reviewed.
This study will initially accrue six eligible and
evaluable Ph-positive/Ph-like DSMKF patients. If the
regimen is considered safe, then the study will accrue
nine additional eligible Ph-positive/Ph-like DSMKF
patients.
Summary Statement The study was activated on January 12, 2015. The
Ph-positive/Ph-like DSMKF cohort was temporarily
closed to Step 1 accrual on April 15, 2017 to assess
the safety profile of this cohort. The Ph-negative
cohort remains open to accrual.
As of June 30, 2017, 27 patients were enrolled to the
Ph-negative cohort and 16 were enrolled to the Ph-
positive/Ph-like DSMKF cohort. Two patients in the
Ph-negative cohort were ineligible: one due to
elevated alkaline phosphatase and another due to a
final diagnosis of follicular lymphoma.
Of the 32 patients evaluable for toxicities, one patient
in the Ph-negative cohort died of respiratory failure
related to treatment and this patient also experienced
treatment-related Grade 4 dyspnea. Another patient in
the Ph-negative cohort experienced treatment-related
Grade 4 lung infection. Two patients in the Ph-
positive/Ph-like DSMKF cohort experienced
treatment-related non-hematologic Grade 4 toxicities:
one had febrile neutropenia and the other had sepsis
and lung infection.
There have been no Grade 4 or higher treatment-
related non-hematologic toxicities reported on post-
remission or maintenance.
Registration by Institution
Initial Registration
Registrations ending June 30, 2017
Institutions
Total
Reg Institutions
Total
Reg
City of Hope Med Ctr 4 New Mexico MU-NCORP 1
Cleveland Clinic OH 4 Rochester, Univ of 1
Irvine, U of CA 3 San Diego, U of CA 1
So Calif, U of 3 UF Cancer Center/Arkansas, U of 1
Birmingham, U of AL 1 Wichita NCORP 1
Greenville NCORP 1 ALLIANCE 13
Heartland NCORP 1 ECOG-ACRIN 6
Loma Linda Univ 1 Total (16 Institutions) 43
Michigan, U of 1
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 22
S1318/II
Registration, Eligibility, and Evaluability
Initial Registration
Registrations ending June 30, 2017; Data as of July 25, 2017
TOTAL
Induction:
Ph-
Induction:
Ph+/Ph-like
NUMBER REGISTERED 43 27 16
INELIGIBLE 2 2 0
ELIGIBLE 41 25 16
Analyzable, Pend. Elig. 6 6 0
RESPONSE ASSESSMENT
Determinable 26 15 11
Not Determinable 2 1 1
Too Early 13 9 4
ADVERSE EVENT ASSESSMENT
Evaluable 32 20 12
Too Early 9 5 4
Patient Characteristics
Initial Registration
Registrations ending June 30, 2017; Data as of July 25, 2017
Induction:
Ph-
(n=25)
Induction:
Ph+/Ph-like
(n=16)
AGE
Median 75.6 73.3
Minimum 66.3 48.2
Maximum 84.0 87.3
SEX
Males 19 76% 3 19%
Females 6 24% 13 81%
HISPANIC
Yes 2 8% 3 19%
No 23 92% 12 75%
Unknown 0 0% 1 6%
RACE
White 24 96% 12 75%
Asian 1 4% 2 13%
Unknown 0 0% 2 13%
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 23
S1318/II
Treatment Summary
Induction
Registrations ending June 30, 2017; Data as of July 25, 2017
TOTAL
Induction:
Ph-
Induction:
Ph+/Ph-like
NUMBER ON PROTOCOL TREATMENT 14 10 4
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
27 15 12
Treatment completed as planned 19 11 8
Adverse Event or side effects 3 1 2
Refusal unrelated to adverse event 1 1 0
Progression/relapse 1 1 0
Death 3 1 2
Other - not protocol specified 0 0 0
Reason under review 0 0 0
MAJOR PROTOCOL DEVIATIONS 0 0 0
Number of Patients with a Given Type and Grade of Adverse Event
Induction
Adverse Events Unlikely or Not Related to Treatment Excluded
Non-Hematologic Adverse Events Only
Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed
Registrations ending June 30, 2017; Data as of July 25, 2017
Induction: Ph-
(n=20)
Grade
Induction: Ph+/Ph-like
(n=12)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5
ALT increased 19 1 0 0 12 0 0 0
Confusion 19 1 0 0 12 0 0 0
Cytokine release syndrome 19 1 0 0 12 0 0 0
Dehydration 20 0 0 0 11 1 0 0
Diarrhea 20 0 0 0 11 1 0 0
Dyspnea 18 1 1 0 11 1 0 0
Edema limbs 20 0 0 0 11 1 0 0
Febrile neutropenia 18 2 0 0 11 0 1 0
Generalized muscle weakness 20 0 0 0 11 1 0 0
Heart failure 20 0 0 0 11 1 0 0
Hematoma 20 0 0 0 11 1 0 0
Hyperglycemia 19 1 0 0 12 0 0 0
Hypertension 19 1 0 0 12 0 0 0
Hypocalcemia 19 1 0 0 12 0 0 0
Hypotension 19 1 0 0 12 0 0 0
Hypoxia 20 0 0 0 11 1 0 0
Infections/infestations-Other 19 1 0 0 11 1 0 0
Infusion related reaction 19 1 0 0 12 0 0 0
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 24
S1318/II
Induction: Ph-
(n=20)
Grade
Induction: Ph+/Ph-like
(n=12)
Grade
ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5
Lung infection 19 0 1 0 10 1 1 0
Nausea 20 0 0 0 11 1 0 0
Pneumonitis 19 1 0 0 12 0 0 0
Respiratory failure 19 0 0 1 12 0 0 0
Sepsis 20 0 0 0 11 0 1 0
TTP 19 1 0 0 12 0 0 0
Urinary tract infection 20 0 0 0 11 1 0 0
MAX. GRADE ANY ADVERSE
EVENT
10 8 1 1 7 3 2 0
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 25
S1612/II-III
S1612 Phase II-III
Coordinating Group: SWOG
A Randomized Phase II/III Trial of “Novel Therapeutics” Versus Azacitidine
in Newly Diagnosed Patients with Acute Myeloid Leukemia (AML) or High-
Risk Myelodysplastic Syndrome (MDS), Age 60 or Older LEAP: LEss-
Intense AML Platform Trial
Participants:
SWOG, CTSU (Supported by CCTG and ECOG-
ACRIN)
Study Chairs:
L Michaelis, R Walter, S Assouline (CCTG), A Im
(ECOG-ACRIN)
Statisticians:
M Othus, A Moseley
Data Coordinator:
T Maher
SCHEMA
Objectives Phase II Component: To select, based on overall
survival, any or all of the "Novel Therapeutic"
regimens for further testing against azacitidine in
patients age 60 and older with newly diagnosed acute
myeloid leukemia (AML) or myelodysplastic
syndrome with excessive blasts-2 (MDS-EB-2).
Phase III Component: To compare overall survival of
the "Novel Therapeutic" regimens selected in the
R
E
G
I
S
T
R
A
T
I
O
N
R
A
N
D
O
M
I
Z
A
T
I
O
N
Arm A (control):
Azacitidine
Arm B:
Azacitidine + Nivolumab
Arm C:
Azacitidine + Midostaurin
Arm D:
Decitabine/Cytarabine
*NOTE: Arm D will open to accrual when Arms B and C have met Phase II accrual and
are temporarily closed for Phase II analysis
FLT3 Testing
OCTOBER 11 - 14, 2017 SWOG LEUKEMIA 26
S1612/II-III
Phase II portion of the trial to azacitidine in these
patient populations.
To estimate the frequency and severity of toxicities
of the regimens in these patient populations.
To estimate response rates, event-free survival, and
relapse-free survival for these regimens in these
patient populations.
Patient Population Patients must have morphologically confirmed,
previously untreated AML or MDS-EB-2. Patients
with acute promyelocytic leukemia, biphenotypic
leukemia, blastic transformation of chronic
myelogenous leukemia are not eligible. Patients must
have disease present in the blood or bone marrow;
patients with only extramedullary disease are not
eligible. Patients must not be known to have AML in
the CNS. Patients must be deemed, in the judgment
of the treating physician, to be ineligible for intensive
induction therapy or must have refused intensive
induction therapy.
Patients who have received prior therapy with
midostaurin, any anti-PD-1 or anti-PD-L1 therapy,
any DNA-methyltransferase inhibitor, or prior 7+3
therapy for MDS are not eligible. Patients who are
transfusion-dependent and patients receiving growth
factor support are eligible; patients must discontinue
growth factor support prior to initiation of protocol
therapy. Prior malignancy is allowed providing
concurrent therapy is not required; active hormonal
therapy is allowed.
Patients must be at least 60 years old and must be
able to swallow oral medications. Clinical evaluation
at baseline including hematologic, hepatic, renal,
cardiac, and coagulation parameters must be
completed per protocol. Women and men must be
willing to use contraception as outlined in the
protocol. Patients must not have active infection
(systemic bacterial, fungal, or viral infection) that is
not controlled. Patients must be eligible for at least
one of the currently enrolling investigational
treatment arms. Refer to the protocol for arm-specific
eligibility criteria.
Patients must have specimens submitted for FLT3
testing as outlined in the protocol for randomization
stratification. Pretreatment cytogenetics must be
performed on all patients as outlined in the protocol.
Stratification/Descriptive Factors Patient randomization will be stratified by the
following factors: (1) Zubrod performance status: 0-1
vs 2-4; (2) FLT3-ITD status based on central
laboratory results: wild type FLT3 vs mutated FLT3-
ITD vs non-evaluable; and (3) baseline blast
percentage: MDS-EB-2 (< 20%) vs AML (20% or
higher).
Accrual Goals Up to 100 eligible patients will be enrolled to each
arm for Phase II analysis. Up to 200 additional
eligible patients will be enrolled to each arm for
Phase III analysis. If all three experimental arms
complete full Phase III accrual, this study will enroll
approximately 1500 eligible patients.
The Phase II interim analysis to evaluate for stopping
for futility will be performed when 52 events have
been observed. For arms carried forward for Phase III
testing, two additional interim analyses will be
performed when 50% and 75% of the expected
events have been observed (207 and 311 events,
respectively).
A041202 November 2016
Template Version Date: September 24, 2013
Alliance Study A041202 – A Randomized Phase III Study of Bendamustine Plus Rituximab Versus Ibrutinib Plus Rituximab Versus Ibrutinib Alone in Untreated Older Patients (>/= 65 Years of Age) with
Chronic Lymphocytic Leukemia (CLL)
Committee: Leukemia Study Statisticians: Sumithra Mandrekar, Ph.D. Study Chair: Jennifer Woyach, MD Amy S. Ruppert, M.A.S.
1.0 OBJECTIVES Primary
To determine whether progression free survival (PFS) is superior after therapy with bendamustine in combination with rituximab, ibrutinib alone, or ibrutinib in combination with rituximab in patients age 65 or older with previously untreated CLL
Secondary 1. To determine 2-year PFS in each of the three treatment arms 2. To determine which treatment arm produces superior overall survival (OS) 3. To determine the complete response (CR) rate, complete and nodular partial response
(CR/nPR) rate, and overall response (PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms
4. To determine the impact of MRD-negative disease at time of CR documentation and at 2 years on PFS and OS in each of the treatment arms
5. To determine duration of response after each of the three treatments and compare these treatment arms
6. To determine toxicity and tolerability of the three treatment regimens 7. To determine response and PFS of patients initially on the bendamustine in
combination with rituximab arm who cross over to ibrutinib 8. To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH
mutational status, or select DNA mutations predict outcomes or time to response in these three arms
9. To determine whether local FISH results for del(11q22.3) and del(17p13.1) are consistent with central analysis.
10. To determine whether baseline microRNA and gene expression markers are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years versus not), as well as to explore changes in microRNA expression from baseline to post-treatment time points, with a focus on those with persistent lymphocytosis and relapse
11. To determine whether eradication of MRD predicts longer duration of response with standard therapy and ibrutinib-based regimens
12. To describe the baseline functional status, comorbid medical conditions, and number of medications of older CLL patients who meet criteria for therapy
13. To determine how functional status changes with therapy using baseline to 3-month evaluation and end-of-study/2-year evaluation; to determine whether this change is different among the treatment groups
14. To determine whether geriatric assessment variables known to be associated with chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in the CLL population
15. To assess whether the FCGR3A polymorphism (rs396991) is correlated with depth of response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints CR rate, rapidity of response, and progression-free survival (PFS)
16. To assess whether C1QA polymorphism (rs172378) is correlated with MRD status, CR rate, rapidity of response, and PFS
A041202 November 2016
Template Version Date: September 24, 2013
2.0 CURRENT SCHEMA
3.0 ELIGIBILITY CRITERIA
• Diagnosis with CLL in accordance with IWCLL 2008 Criteria • Intermediate or high risk Rai Stage CLL • Criteria met for treatment as defined by IWCLL 2008 guidelines • No prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of
CLL with steroids or rituximab) • Age ≥ 65 • ECOG performance status 0-2 • No active hepatitis B • No active systemic anticoagulation with heparin or warfarin • No active intercurrent disease (see Section 4.8) • No history of Richter’s transformation or prolymphocytic leukemia • No prednisone over 20 mg daily or equivalent corticosteroid • No uncontrolled active system infection requiring intravenous antibiotics • No strong CYP3A4/5 inhibitors or inducers • No allergy to mannitol • No significant hypersensitivity to rituximab • No major surgery within 10 days or minor surgery within 7 days • ANC ≥ 1000/µL (unless due to bone marrow involvement) • AST and ALT ≤ 2.5 x ULN (except due to disease infiltration of the liver) • Total bilirubin ≤ 1.5 x ULN (unless due to liver involvement, hemolysis or Gilbert’s disease) • Creatinine Clearance ≥ 40 mL/min (calculated by Cockcroft-Gault formula) • Platelets ≥ 30,000/µL
A041202 November 2016
Template Version Date: September 24, 2013
4.0 TREATMENT SCHEDULE
The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report). 5.0 STUDY DESIGN
5.1 Study Phase/Type of Design/Stratification Factors For this phase III clinical trial, patients will be randomized using dynamic allocation procedures to three arms in a 1:1:1 manner: Arm 1: bendamustine + rituximab (BR) vs. Arm 2: ibrutinib (I) vs. Arm 3: ibrutinib + rituximab (IR). Randomization will be stratified on Rai stage (intermediate vs. high) and presence of high-risk FISH abnormalities (del(11q22.3) or del(17p13.1) vs. not). In addition, we will also stratify on ZAP-70 methylation status (methylated vs. not, using a 20% methylation cut point), which is hypothesized to be strongly associated with clinical outcomes in CLL.
5.2 Primary Endpoint
The primary endpoint of PFS will be compared in each of the 3 planned pairwise comparisons: Arm 1 vs Arm 2, Arm 2 vs Arm 3 and Arm 1 vs Arm 3. Each of these efficacy analyses will utilize an intent-to-treat approach, where patients will be analyzed in the arm to which they were randomized. Log-rank statistics will be used to compare the PFS distributions of the different treatment arms. The methods of Kaplan and Meier will be used to estimate PFS for the treatment arms. For each of the planned comparisons, we will assess the corresponding hazard ratios, 2-year PFS estimates, and PFS medians along with their 95% confidence intervals.
The overall Type I error rate for this trial will be constrained at 0.05 and with 90% power for each of the one-sided tests of the ibrutinib-based regimens versus bendamustine plus rituximab and for the one-sided comparison of the ibrutinib alone versus ibrutinib plus rituximab arms. Based on all of these considerations and constraints, this proposed study requires a total of 498 evaluable patients. This translates to 166 patients required for each treatment arm. We will plan to over-accrue by about 5% for a total accrual goal of 523 patients.
5.3 Target Accrual
The target accrual for this study is 523 patients using a 1:1:1 randomization. The target accrual rate is 15 patients per month.
6.0 CURRENT ACCRUAL
Study Activation Date 12/09/2013 Closure Date 5/16/2016 Target Accrual (n) 523 Final Accrual (n) 547
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7.0 CURRENT STUDY STATUS
This study opened on December 9, 2013. Registration for this trial closed on May 16, 2016. As of September 6, 2016, 547 patients have been randomized; 432 patients (79%) are alive and remain on active treatment. Twelve (12) patients have crossed over from Arm 1 (B+R) to Arm 2 (Ibrutinib alone).
8.0 PATIENT CHARACTERISTICS
All randomized participant are included in the table.
Table 8a. Demographics
Arm 1
(N=183) Arm 2
(N=182) Arm 3
(N=182) Total
(N=547) Age N 183 182 182 547 Mean (SD) 71.6 (5.1) 71.7 (5.0) 71.9 (4.6) 71.7 (4.9) Median 70.0 71.0 71.0 71.0 Q1, Q3 67.0, 76.0 68.0, 75.0 68.0, 75.0 68.0, 75.0 Range (65.0-86.0) (65.0-89.0) (65.0-86.0) (65.0-89.0)
0 313 12
1514
2022
1825
2919
1912
22
3120
2124
4626
17
36
3222
280 0 10
Expected Accrual 523 Patients
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Arm 1
(N=183) Arm 2
(N=182) Arm 3
(N=182) Total
(N=547) Race White 167 (91.3%) 169 (92.9%) 173 (95.1%) 509 (93.1%) Black or African American 9 (4.9%) 7 (3.8%) 7 (3.8%) 23 (4.2%) Asian 4 (2.2%) 2 (1.1%) 0 (0.0%) 6 (1.1%) American Indian or Alaska Native 1 (0.5%) 0 (0.0%) 1 (0.5%) 2 (0.4%) Not reported 1 (0.5%) 3 (1.6%) 1 (0.5%) 5 (0.9%) Unknown 1 (0.5%) 1 (0.5%) 0 (0.0%) 2 (0.4%) Gender Female 64 (35.0%) 59 (32.4%) 57 (31.3%) 180 (32.9%) Male 119 (65.0%) 123 (67.6%) 125 (68.7%) 367 (67.1%)
Table 8b. Stratification Factors
Arm 1
(N=183) Arm 2
(N=182) Arm 3
(N=182) Total
(N=547) Rai stage classification category Intermediate (Stage I/II) 84 (45.9%) 83 (45.6%) 84 (46.2%) 251 (45.9%) High (Stage III/IV) 99 (54.1%) 99 (54.4%) 98 (53.8%) 296 (54.1%) Presense of del(11q22) or del(17p13) Yes 51 (27.9%) 50 (27.5%) 50 (27.5%) 151 (27.6%) No 132 (72.1%) 132 (72.5%) 132 (72.5%) 396 (72.4%) Zap70 methlyation status of CpG3 Missing 1 0 0 1 <20% 95 (52.2%) 96 (52.7%) 96 (52.7%) 287 (52.6%) >= 20% 87 (47.8%) 86 (47.3%) 86 (47.3%) 259 (47.4%) (report generated on 06SEP2016)
9.0 ADVERSE EVENTS
9.1 Adverse Event Summary 525 (96%) patients are evaluable for adverse event (AE) analyses (Arm 1: 172, Arm 2: 175 and Arm 3: 178). Grade 3+ AE occurring in > 10% of patients include: Anemia (12% Arm 1, 10% Arm 2, 4% Arm 3), Leukocytosis (6% Arm 1, 10% Arm 2, 9% Arm 3), Lymphocyte count decreased (20% Arm 1, 2% Arm 2, 2% Arm 3), Lymphocyte count increased (7% Arm 1, 18% Arm 2, 13% Arm 3), Neutrophil count decreased (40% Arm 1, 12% Arm 2, 19% Arm 3), Platelet count decreased (16% Arm 1, 4% Arm 2, 3% Arm 3), White blood cell decreased (15% Arm 1, 2% Arm 2, 3% Arm 3), and hypertension (12% Arm 1, 20% Arm 2, 22% Arm 3). There have been 11 deaths reported on treatment:
• Sudden death NOS (unlikely) • Sudden death NOS (unlikely) • Neoplasms benign, malignant and unspecified: progressive disease (not related) • Heart failure (unlikely) • Death NOS (possible)
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• Death NOS (unlikely) • Respiratory failure, (not related) • Cardiac arrest (not related). • Leukoencephalopathy (definite) • Sudden death NOS (unlikely) • Hematoma (probable)
11 (92%) patients from Arm 1 who crossed over to Arm 2 are evaluable for AEs. The most common hematologic grade 3+ AEs reported in these patients after crossover were Neutrophil count decreased (Gr 3: 0 pts; Gr 4: 3 pts), Anemia (Gr 3: 4 pts, Gr 4: 0 pts), and lymphocyte count increased (Gr 3: 4 pts, Gr 4: 0 pts).One death on crossover treatment has been reported: Neoplasms benign, malignant and unspecified: brain metastases unknown primary (not related).
Initial Treatment Summary of Grade 3+ Adverse Events
Regardless of Attribution Number of Evaluable Patients:
Arm 1=172 Arm 2=175 Arm 3=178
Patients with a maximum: Arm n (%)
Total
Grade 3 Event 1 71 (41.3%)
2 85 (48.6%)
3 86 (48.3%)
Grade 4 Event 1 58 (33.7%)
2 15 (8.6%)
3 22 (12.4%)
Grade 5 Event 1 1 (0.6%)
2 4 (2.3%)
3 6 (3.4%)
Hematologic Adverse Events
Grade 3 Event 1 57 (33.1%)
2 53 (30.3%)
3 50 (28.1%)
Grade 4 Event 1 45 (26.2%)
2 9 (5.1%)
3 15 (8.4%)
Grade 5 Event 1 0 (0.0%)
2 0 (0.0%)
3 0 (0.0%)
Non-Hematologic Adverse Events
Grade 3 Event 1 70 (40.7%)
2 73 (41.7%)
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Initial Treatment Summary of Grade 3+ Adverse Events
Regardless of Attribution Number of Evaluable Patients:
Arm 1=172 Arm 2=175 Arm 3=178
Patients with a maximum: Arm n (%)
3 74 (41.6%)
Grade 4 Event 1 15 (8.7%)
2 6 (3.4%)
3 9 (5.1%)
Grade 5 Event 1 1 (0.6%)
2 4 (2.3%)
3 6 (3.4%)
Note: Summaries are based on available patient data
Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow
Anemia 1 20 ( 12%) 0 ( 0%) 0 ( 0%) 2 15 ( 9%) 1 ( 1%) 0 ( 0%) 3 8 ( 4%) 0 ( 0%) 0 ( 0%) Blood and lymphat sys disord - Oth spec
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Bone marrow hypocellular 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Leukocytosis 1 10 ( 6%) 0 ( 0%) 0 ( 0%) 2 18 ( 10%) 0 ( 0%) 0 ( 0%) 3 16 ( 9%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 1 21 ( 12%) 13 ( 8%) 0 ( 0%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 2 ( 1%) 1 ( 1%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Lymphocyte count increased 1 12 ( 7%) 0 ( 0%) 0 ( 0%) 2 31 ( 18%) 0 ( 0%) 0 ( 0%) 3 24 ( 13%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 1 38 ( 22%) 31 ( 18%) 0 ( 0%) 2 12 ( 7%) 8 ( 5%) 0 ( 0%) 3 20 ( 11%) 15 ( 8%) 0 ( 0%) Platelet count decreased 1 18 ( 10%) 10 ( 6%) 0 ( 0%) 2 6 ( 3%) 1 ( 1%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) White blood cell decreased 1 20 ( 12%) 5 ( 3%) 0 ( 0%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 5 ( 3%) 0 ( 0%) 0 ( 0%)
Non-Hematologic Adverse Events Blood and lymphatic sys disord
Febrile neutropenia 1 11 ( 6%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Thrombotic thrombocytopenic purpura
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Cardiac disorders Aortic valve disease 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Atrial fibrillation 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 9 ( 5%) 1 ( 1%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Atrial flutter 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Atrioventricular block complete 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Cardiac arrest 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Cardiac disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Chest pain - cardiac 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Heart failure 1 0 ( 0%) 2 ( 1%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 1 ( 1%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Myocardial infarction 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Pericardial effusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Sick sinus syndrome 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Ventricular tachycardia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Ear and labyrinth disorders Ear and labyrinth disorders - Oth spec
1 0 ( 0%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hearing impaired 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Eye disorders Conjunctivitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Retinopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%)
Gastrointestinal disorders Abdominal pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Ascites 1 3 ( 2%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Colitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Constipation 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Diarrhea 1 3 ( 2%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) Dysphagia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal disorders - Oth spec
1 2 ( 1%) 0 ( 0%) 0 ( 0%)
2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis oral 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Nausea 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Pancreatitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Small intestinal obstruction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Vomiting 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
Gen disord and admin site cond Death NOS 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 1 ( 1%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Edema face 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Edema limbs 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Fatigue 1 6 ( 3%) 0 ( 0%) 0 ( 0%) 2 6 ( 3%) 0 ( 0%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) Fever 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Infusion related reaction 1 11 ( 6%) 3 ( 2%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Multi-organ failure 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Non-cardiac chest pain 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Sudden death NOS 1 0 ( 0%) 0 ( 0%) 1 ( 1%) 2 0 ( 0%) 0 ( 0%) 1 ( 1%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%)
Hepatobiliary disorders Cholecystitis 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Immune system disorders Allergic reaction 1 3 ( 2%) 3 ( 2%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Anaphylaxis 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Immune system disorders - Other, specify
1 0 ( 0%) 1 ( 1%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
Infections and infestations Abdominal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Appendicitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Bladder infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Bone infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Gallbladder infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec
1 4 ( 2%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 1 ( 1%) 0 ( 0%) Joint infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 5 ( 3%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Meningitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Otitis media 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Papulopustular rash 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Scrotal infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Sepsis 1 0 ( 0%) 5 ( 3%) 0 ( 0%) 2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 2 ( 1%) 0 ( 0%) Skin infection 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%) 3 5 ( 3%) 0 ( 0%) 0 ( 0%) Upper respiratory infection 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Urinary tract infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Wound infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Inj, pois and proced complic Ankle fracture 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Fall 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Hip fracture 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Seroma 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Investigations Alanine aminotransferase increased
1 0 ( 0%) 1 ( 1%) 0 ( 0%)
2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Aspartate aminotransferase increased
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Blood bilirubin increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Cardiac troponin I increased 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Creatinine increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Ejection fraction decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Investigations - Other, specify 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Metabol and nutrition disord Anorexia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Dehydration 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Glucose intolerance 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypercalcemia 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperglycemia 1 4 ( 2%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 6 ( 3%) 0 ( 0%) 0 ( 0%) Hyperkalemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Hypernatremia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hyperuricemia 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Hypoalbuminemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hypocalcemia 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypokalemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypomagnesemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hyponatremia 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 3 ( 2%) 1 ( 1%) 0 ( 0%) 3 4 ( 2%) 0 ( 0%) 0 ( 0%) Hypophosphatemia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Tumor lysis syndrome 1 3 ( 2%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Musculosk and conn tiss disord Arthralgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Back pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Bone pain 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Generalized muscle weakness 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Joint effusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Muscle weakness right-sided 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Musculoskeletal, conn tissue - Oth spec
1 0 ( 0%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Myalgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Pain in extremity 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
Neoplsm benign, mal and unspec Neoplasms benign, mal, unspec - Oth spec
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 3 ( 2%) 0 ( 0%) 1 ( 1%) 3 4 ( 2%) 1 ( 1%) 0 ( 0%) Treatment related secondary malignancy
1 0 ( 0%) 0 ( 0%) 0 ( 0%)
2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Nervous system disorders Dizziness 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Encephalopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Headache 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 4 ( 2%) 0 ( 0%) 0 ( 0%)
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Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hydrocephalus 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Intracranial hemorrhage 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Leukoencephalopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Neuralgia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Stroke 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Syncope 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Tremor 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Psychiatric disorders Anxiety 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Confusion 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Depression 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Renal and urinary disorders Acute kidney injury 1 1 ( 1%) 0 ( 0%) 0 ( 0%)
A041202 November 2016
Template Version Date: September 24, 2013
Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Chronic kidney disease 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hematuria 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 2 ( 1%) 0 ( 0%) 0 ( 0%) Renal and urinary disorders - Oth spec
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal calculi 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Urinary retention 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%)
Respirat, thor, mediast disord Adult respiratory distress syndrome
1 0 ( 0%) 1 ( 1%) 0 ( 0%)
2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Aspiration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Chylothorax 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 1%) 0 ( 0%) Cough 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Dyspnea 1 1 ( 1%) 1 ( 1%) 0 ( 0%) 2 3 ( 2%) 1 ( 1%) 0 ( 0%)
A041202 November 2016
Template Version Date: September 24, 2013
Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) 3 4 ( 2%) 1 ( 1%) 0 ( 0%) Epistaxis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Hypoxia 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Pleural effusion 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Pneumonitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Pulmonary edema 1 0 ( 0%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Sore throat 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Skin and subcutan tiss disord Pruritus 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 1%) 0 ( 0%) 0 ( 0%) Rash maculo-papular 1 11 ( 6%) 0 ( 0%) 0 ( 0%) 2 3 ( 2%) 0 ( 0%) 0 ( 0%) 3 7 ( 4%) 0 ( 0%) 0 ( 0%) Skin and subcut tissue disord - Oth spec
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 3 ( 2%) 0 ( 0%) 0 ( 0%)
Surgical and medical proced
A041202 November 2016
Template Version Date: September 24, 2013
Initial Treatment Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 1=172 Arm 2=175 Arm 3=178
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Surgical and medical proced - Oth spec
1 1 ( 1%) 0 ( 0%) 0 ( 0%)
2 1 ( 1%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Vascular disorders Flushing 1 1 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Hematoma 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 1%) Hypertension 1 19 ( 11%) 1 ( 1%) 0 ( 0%) 2 35 ( 20%) 0 ( 0%) 0 ( 0%) 3 38 ( 21%) 1 ( 1%) 0 ( 0%) Hypotension 1 9 ( 5%) 1 ( 1%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 2 ( 1%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 1%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%)
Crossover Patients
Summary of Grade 3+ Adverse Events Regardless of Attribution
Number of Evaluable Patients: Arm 2 (Cross Over) =11
Patients with a maximum: Arm n (%)
Total
Grade 3 Event 2 (CO) 4 (36.4%)
Grade 4 Event 2 (CO) 3 (27.3%)
Grade 5 Event 2 (CO) 1 (9.1%)
Hematologic Adverse Events
Grade 3 Event 2 (CO) 4 (36.4%)
A041202 November 2016
Template Version Date: September 24, 2013
Crossover Patients Summary of Grade 3+ Adverse Events
Regardless of Attribution Number of Evaluable Patients:
Arm 2 (Cross Over) =11
Patients with a maximum: Arm n (%)
Grade 4 Event 2 (CO) 3 (27.3%)
Grade 5 Event 2 (CO) 0 (0.0%)
Non-Hematologic Adverse Events
Grade 3 Event 2 (CO) 3 (27.3%)
Grade 4 Event 2 (CO) 0 (0.0%)
Grade 5 Event 2 (CO) 1 (9.1%)
Note: Summaries are based on available patient data
Crossover Patients Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 2 (Cross over) =11
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow
Anemia 2 (CO) 4 ( 36%) 0 ( 0%) 0 ( 0%) Leukocytosis 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Lymphocyte count increased 2 (CO) 4 ( 36%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased 2 (CO) 0 ( 0%) 3 ( 27%) 0 ( 0%) Platelet count decreased 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%)
Non-Hematologic Adverse Events Blood and lymphatic sys disord
Febrile neutropenia 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Cardiac disorders
Atrial fibrillation 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Metabol and nutrition disord
Hypophosphatemia 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) Neoplsm benign, mal and unspec
Neoplasms benign, mal, unspec - Oth spec
2 (CO) 0 ( 0%) 0 ( 0%) 1 ( 9%)
A041202 November 2016
Template Version Date: September 24, 2013
Crossover Patients Listing of Grade 3+ Adverse Events
Max Grade Per Patient Per Event Regardless of Attribution
Number of Evaluable Patients: Arm 2 (Cross over) =11
Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal
n (%) n (%) n (%) Respirat, thor, mediast disord
Pleural effusion 2 (CO) 1 ( 9%) 0 ( 0%) 0 ( 0%) 10.0 IMBEDDED CORRELATIVES
A041202-LC1: Leukemia Correlative Studies in Alliance A041202 Participation to embedded correlative A041202-LC1 was mandatory for all patient registered to this study. As of September 6, 2016, there are 547 patients who consented. Bone marrow, peripheral blood and buccal cell samples are being collected. Within this correlative, ZAP 70 methylation testing is preformed centrally at pre-registration for stratification. In addition, samples are being banked for future analysis.
A041202-PP1: Evaluation of Candidate Pharmacogenetic Determinants of Ibrutinib or Ibrutinib/Rituximab Response
Participation to embedded correlative A041202-PP1 is optional for all patients registered to this study. As of September 6, 2016, there are 450 patients who consented and were randomized. Baseline peripheral blood samples are being banked for future analysis.
A041202-EL1: Geriatric Assessment in Alliance A041202
Participation to embedded correlative A041202-EL1 was optional for all patient registered to this study. As of September 6, 2016, there are 410 patients who consented and were randomized. Questionnaires are being completed by patients and health care professionals for future analysis.
CALGB 9665: The CALGB Leukemia Tissue Bank
Participation to stand alone correlative CALGB 9665 was optional for all patient registered to this study. This correlative study was closed to accrual as of March 1, 2014; 7 patients were randomized to A041202 and consented. For those who consented, samples are collected at baseline, remission and progression and are being banked for future analysis.
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 1
E1910 A PHASE III RANDOMIZED TRIAL OF BLINATUMOMAB FOR NEWLY
DIAGNOSED BCR-ABL NEGATIVE B ACUTE LYMPHOBLASTIC LEUKEMIA IN
ADULTS
Sponsor(s)
Coordinating Group ECOG-ACRIN
Chairperson(s) Dr. Mark Litzow
Statistician Dr. Zhuoxin Sun
Imaging Statistician Dr. Fenghai Duan
Data Specialist Henry Baptista
Phase of Study III
Type of Study Therapeutic
Committee Leukemia
Accrual Objective 360 Patients
Participating Groups ECOG-ACRIN, CTSU
DCP Treatment Credit 1.0
NSC# 740, 3590, 10023, 14575, 26271, 34521, 63878,
67574, 141540, 624239, 697732, 765986
Clinicaltrials.gov Study ID NCT02003222
Study Status Open to Accrual
Date Proposed June 26, 2012
Date Activated December 17, 2013
Schema
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 2
Schema Continued
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
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Schema Continued
Purpose of Study
1) To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to
chemotherapy alone in patients with BCR-ABL-negative B cell precursor ALL who are MRD positive after
induction and intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of
residual blasts. 2) If superiority of blinatumomab in the MRD positive group is shown, to compare the OS of
blinatumomab in conjunction with chemotherapy to chemotherapy alone in patients with
BCR-ABL-negative B cell precursor ALL who are MRD negative after induction and intensification
chemotherapy, based on MFC assessment of residual blasts. 3) If superiority of blinatumomab in the MRD
positive group is not shown, to compare the OS of blinatumomab in conjunction with chemotherapy to
chemotherapy alone in the overall population of patients with BCR-ABL-negative B cell precursor ALL. 4)
To determine if blinatumomab can convert patients who are MRD positive by MFC assessment of residual
blasts after induction and intensification chemotherapy to MRD negativity. 5) To assess the toxicities of
blinatumomab in this patient population. 6) To assess the toxicities of the modified E2993 chemotherapy
regimen in this patient population. 7) To describe the outcome of patients who proceed to allogeneic blood
or marrow transplant after treatment with or without blinatumomab. 8) To determine differences in MRD
kinetics among patients with the BCR/ABL1-like B-lineage ALL, and assess the efficacy of blinatumomab
in each molecular subgroup. 9) To evaluate the incidence of anti-blinatumomab antibody formation.
Study Population
Newly diagnosed, previously untreated BCR-ABL negative B cell precursor acute lymphoblastic leukemia
patients aged 30-70.
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 4
Summary of Study Design
The primary objectives of this phase III study are to compare the OS in patients who received blinatumomab
in conjunction with chemotherapy to that of patients who received chemotherapy alone in MRD+ subset,
MRD- subset, and the overall population. OS is defined as the time between randomization and death from
any cause. Patients last known to be alive at the time of an analysis will be censored. To control the overall
one-sided type I error at 0.025, the OS comparison in the MRD+ subset will be tested first at one-sided type
I error of 0.02. If it is significant, the OS comparison in MRD- subset will be tested at one-sided type I error
of 0.025. Otherwise, the OS comparison in overall population will be tested at one-sided type I error of
0.005. Based on the previous phase III ALL study E2993, we assume 88% of patients enrolled can achieve
CR after induction chemotherapy and 10% of patients will drop out between achievement of CR and
randomization to blinatumomab. Therefore, 285 patients will be randomized to receive either
blinatumomab or no blinatumomab. We assume that about 1/3 of randomized patients will be MRD+. We
assume the survival function of this ALL patient population can be described by a cure rate model. For
MRD+ patients, we assume a 20% long-term cure rate and 7.5-month median OS in the non-cured group in
the control arm. Adjusted for sequential monitoring, with 95 MRD+ patients, the study will have 80%
power to detect 54% reduction in hazard rate in the blinatumomab arm relative to the no blinatumomab arm,
using one-sided log rank test at the significance level of 0.02 and assuming 2 years of follow-up, which is
equivalent to detecting an improvement in the 3-year OS rate from 23% to 51%. The number of events
needed is 61. If the MRD+ subgroup is significant, the MRD- subgroup will be tested at one-sided type I
error of 0.025. For MRD- patients, we assume a 35% long-term cure rate and 13-month median OS in the
non-cured group in the control arm. Adjusted for sequential monitoring, with 190 MRD- patients (2/3 of all
patients), the study will have 80% power to detect 45% reduction in hazard rate in the blinatumomab arm
relative to the no blinatumomab arm, using one-sided log rank test at the significance level of 0.025 and
assuming 2 years of follow-up, which is equivalent to detecting an improvement in the 3-year OS rate from
45% to 64%. The number of events needed is 94. If the MRD+ subgroup is not significant, the overall
population will be tested at one-sided type I error of 0.005. For all patients, we assume a 30% long-term
cure rate and 11-month median OS in the non-cured group in the control arm. Adjusted for sequential
monitoring, with 285 patients, the study will have 80% power to detect 43% reduction in hazard rate in the
blinatumomab arm relative to the no blinatumomab arm, using one-sided log rank test at the significance
level of 0.005 and assuming 2 years of follow-up, which is equivalent to detecting an improvement in the
3-year OS rate from 37% to 57%. The number of events needed is 160. The projected accrual rate is 72
patients per year.
Progress to Date
This study was activated on December 17, 2013. As of March 2, 2017, 189 patients have been accrued.
Accrual status and accrual by group are summarized in Tables 1a, 1b and 1c. Expected and actual
cumulative accrual are shown in Figure 1. Patient status as of March 2, 2017 is summarized in Table 2.
Demographic data are shown in Tables 3a, 3b, 3c and 3d. Record status is shown in Table 4. The
distribution of the reasons for discontinuation of protocol treatment is given in Table 5 by step.
Treatment-related toxicity data are available on 145 patients and are summarized in Table 6 by step,
treatment arm and cycle. Table 7 summarizes lethal adverse events (regardless of treatment relation). Table
8 summarizes incidences of second primary cancer.
Outcome data are not included in this report, but will be presented to the Data Safety Monitoring Committee
when appropriate.
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 5
Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 0 Step 1 Step 2 Step 3 Step 4
Beth Israel Deaconess Medical Center 1 1 1 1 0
Cancer Research Consortium of West Michigan NCORP 1 1 1 1 0 Dayton NCORP 1 1 1 0 0
Froedtert and the Medical College of Wisconsin 13 12 9 7 3
Geisinger Cancer Institute NCORP 1 0 0 0 0 Georgia NCORP 7 5 0 0 0
Gulf South MU NCORP 1 1 0 0 0
Heartland Cancer Research NCORP 1 1 0 0 0 Johns Hopkins Univ/Sidney Kimmel Cancer Center 26 21 15 13 3
Loyola University Medical Center 2 1 1 1 0
Mayo Clinic 8 6 2 1 0 NorthShore Univ HealthSystem-Evanston Hospital 2 2 1 1 0
Northwestern University 9 6 3 2 0
Ochsner NCORP 4 1 1 1 1 Pacific Cancer Research Consortium NCORP 0 0 0 0 1
Penn State Milton S Hershey Medical Center 3 1 0 0 0
Rutgers Cancer Institute of New Jersey 3 1 0 0 0 Stanford Cancer Institute 1 1 0 0 0
University of Alabama at Birmingham Cancer Center 1 1 1 1 0
University of Pennsylvania/Abramson Cancer Center 18 13 7 5 2 University of Wisconsin Hospital and Clinics 3 3 1 1 0
VCU Massey Cancer Center MU NCORP 12 5 4 1 0
Washington University School of Medicine 5 3 0 0 0 Wichita NCORP 5 3 2 2 0
Total 128 90 50 38 10
Table 1b. Accrual by Group
Step 1 Step 2 Step 3 Step 4
ECOG-ACRIN 90 50 38 10
SWOG 50 31 25 14
ALLIANCE 46 26 19 5
NRG 3 3 2 1
Total 189 110 84 30
Table 1c. Projected Accrual
Step 1 Step 2 Step 3 Step 4
Accrual goal 360
Planned accrual rate 72/yr
Accrual to date 189 110 84 30
Annual accrual rate
Overall 59/yr 34/yr 26/yr 9/yr
Last 6 months 108/yr 50/yr 34/yr 18/yr
Projected date of closure September 2018
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 6
Table 2. Patient Status as of March 2, 2017
Step 1 Step 2 Step 3 Step 4
Cases Entered 189 110 84 30
Ineligible 5 6 4 0
Never Started Assigned Therapy 3 0 2 0
Reason for ineligibility Step 1:
Patient was BCR/ABL+ (19004, 19063, 19193, 19259). Bone Marrow pathology report was not done
(19155).
Reason for not starting assigned therapy Step 1:
Patient withdrawal/refusal (19066); patient ineligible (19155, 19193).
Reason for ineligibility Step 2:
CR/CRi not confirmed (19037, 19053, 19139, 19194, 19218); ECOG performance status as 3 and
neurological complications (19185).
Reason for ineligibility Step 3:
Baseline labs (bilirubin, creatinine, anc, blasts, platelets) not done before randomization (19040);
Serum Creatinine and Bilirubin were not obtained within 48 of step 3 registration in order to confirm
eligibility (19051, 19053); Overall Response reported as SD in Step 2 (19011).
Reason for not starting assigned therapy Step 3:
Patient withdrawal/refusal (19093); Disease progression (19044).
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 7
Table 3a. Demographics - Step 1
Variable Level
Arm A
(n=189)
Sex Male 98 (51.9)
Female 91 (48.1)
Race White 153 (91.1)
African-American 9 (5.4)
Asian 4 (2.4)
Native Hawaiian 1 (0.6)
Multirace 1 (0.6)
Unknown/Unreported 21
Ethnicity Hispanic 27 (15.3)
Non-Hispanic 149 (84.7)
Unknown/Missing 13
Age Median 52
Minimum 30
Maximum 69
Table 3b. Demographics - Step 2
Variable Level
Arm B
(n=110)
Sex Male 51 (46.4)
Female 59 (53.6)
Race White 90 (92.8)
African-American 4 (4.1)
Asian 2 (2.1)
Multirace 1 (1.0)
Unknown/Unreported 13
Ethnicity Hispanic 13 (12.6)
Non-Hispanic 90 (87.4)
Unknown/Missing 7
Age Median 53
Minimum 30
Maximum 69
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 8
Table 3c. Demographics - Step 3
Variable Level
Arm C
(n=44)
Arm D
(n=40)
Total
(n=84)
Sex Male 20 (45.5) 18 (45.0) 38 (45.2)
Female 24 (54.5) 22 (55.0) 46 (54.8)
Race White 37 (92.5) 32 (97.0) 69 (94.5)
African-American 3 (7.5) 1 (3.0) 4 (5.5)
Unknown/Unreported 4 7 11
Ethnicity Hispanic 6 (14.0) 7 (20.0) 13 (16.7)
Non-Hispanic 37 (86.0) 28 (80.0) 65 (83.3)
Unknown/Missing 1 5 6
Age Median 53 51 52
Minimum 31 30 30
Maximum 68 69 69
Table 3d. Demographics - Step 4
Variable Level
Arm E
(n=30)
Sex Male 13 (43.3)
Female 17 (56.7)
Race White 25 (96.2)
African-American 1 (3.8)
Unknown/Unreported 4
Ethnicity Hispanic 4 (14.3)
Non-Hispanic 24 (85.7)
Unknown/Missing 2
Age Median 54
Minimum 33
Maximum 68
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 9
Table 4. Record Status
Form Name
Forms
Due
Forms
Received %
Demography 181 181 100.0
Patient Characteristics 377 369 97.9
Treatment Agent: 6 Mercaptopurine 234 216 92.3
Treatment Agent: Blinatumomab 95 93 97.9
Treatment Agent: Cyclophosphamide (1d) 32 28 87.5
Treatment Agent: Cyclophosphamide (2d) 127 127 100.0
Treatment Agent: Cytarabine (16d) 127 127 100.0
Treatment Agent: Cytarabine (1d) 164 158 96.3
Treatment Agent: Cytarabine (5d) 113 110 97.3
Treatment Agent: Cytarabine (8d) 32 28 87.5
Treatment Agent: Daunorubicin (4d) 196 187 95.4
Treatment Agent: Dexamethasone 196 186 94.9
Treatment Agent: Etoposide (5d) 113 111 98.2
Treatment Agent: Leucovorin 96 92 95.8
Treatment Agent: Methotrexate (13d) 75 61 81.3
Treatment Agent: Methotrexate (1d) 309 297 96.1
Treatment Agent: Methotrexate (2d) 97 93 95.9
Treatment Agent: Methotrexate (4d) 128 128 100.0
Treatment Agent: Methotrexate IT (13d) 3 1 33.3
Treatment Agent: Pegaspargase 433 418 96.5
Treatment Agent: Prednisone 76 66 86.8
Treatment Agent: Vincristine (1d) 79 73 92.4
Treatment Agent: Vincristine (4d) 196 187 95.4
Adverse Event Form 711 646 90.9
Follow-Up Hematology/Chemistry 5972 5927 99.2
Late Adverse Event Form 3 3 100.0
Other Adverse Event Form 293 293 100.0
Disease Follow-up Status 855 823 96.3
Off Treatment 24 21 87.5
Off-Treatment with Intent to Reg Next Step 272 269 98.9
Table 5a. Reasons Off Treatment - Step 1
For Patients Not Registered To Subsequent Steps
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 2 4.7
Alternative therapy 3 7.0
Death on study 5 11.6
Disease progression- relapse during active treatment 8 18.6
Other 12 27.9
Patient withdrawal/refusal after beginning protocol therapy 6 14.0
Treatment completed per protocol criteria 7 16.3
Total off treatment 43 100.0
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 10
Table 5b. Reasons Off Treatment - Step 2
For Patients Not Registered To Subsequent Steps
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Disease progression- relapse during active treatment 6 37.5
Other 2 12.5
Patient withdrawal/refusal after beginning protocol therapy 1 6.3
Treatment completed per protocol criteria 7 43.8
Total off treatment 16 100.0
Table 5c. Reasons Off Treatment - Step 3
For Patients Not Registered To Subsequent Steps
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 3 9.1
Alternative therapy 2 6.1
Death on study 2 6.1
Disease progression- relapse during active treatment 3 9.1
Other 1 3.0
Patient withdrawal/refusal after beginning protocol therapy 2 6.1
Treatment completed per protocol criteria 19 57.6
Total off treatment 32 97.0
Table 5d. Reasons Off Treatment - Step 4
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Death on study 1 14.3
Disease progression- relapse during active treatment 1 14.3
Other 2 28.6
Patient withdrawal/refusal after beginning protocol therapy 2 28.6
Total off treatment 6 85.7
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 11
Table 6a. Toxicity Incidence- Step 1 (Arm A)
Toxicity Type
Treatment
Arm
A (n=145)
Grade
3 4 5
(n) (n) (n)
Anemia 66 14 -
Disseminated intravascular coagulation 1 - -
Febrile neutropenia 29 1 -
Chest pain - cardiac 1 - -
Sinus bradycardia 1 - -
Sinus tachycardia 1 - -
Fatigue 4 - -
General disorders and administration site conditions - Other, specify 1 - -
Pain 1 - -
Rash maculo-papular 1 - -
Abdominal pain 3 - -
Constipation 2 - -
Diarrhea 1 1 -
Gastrointestinal disorders - Other, specify 2 - -
Mucositis oral 1 - -
Nausea 10 - -
Pancreatitis 4 - -
Small intestinal obstruction - 1 -
Vomiting 9 - -
Hepatic failure - 1 -
Allergic reaction 1 - -
Anaphylaxis 1 - -
Catheter related infection 3 - -
Eye infection 1 - -
Infections and infestations - Other, specify 2 - -
Sepsis - 4 -
Sinusitis 1 - -
Skin infection 2 - -
Urinary tract infection 1 - -
Abdominal infection 1 - -
Bone infection 1 - -
Lung infection 1 - -
Alanine aminotransferase increased 12 2 -
Alkaline phosphatase increased 6 - -
Aspartate aminotransferase increased 9 1 -
Blood bilirubin increased 9 3 -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 12
Table 6a. Toxicity Incidence- Step 1 (Arm A)
Toxicity Type
Treatment
Arm
A (n=145)
Grade
3 4 5
(n) (n) (n)
Cholesterol high - 1 -
Fibrinogen decreased 2 - -
Lymphocyte count decreased 6 18 -
Neutrophil count decreased 4 111 -
Platelet count decreased 7 99 -
White blood cell decreased - 52 -
GGT increased 1 - -
Anorexia 2 - -
Dehydration 5 - -
Hyperglycemia 11 - -
Hyperkalemia 1 - -
Hypertriglyceridemia - 7 -
Hypoalbuminemia 2 - -
Hypocalcemia 1 - -
Hyponatremia 8 - -
Tumor lysis syndrome 12 - -
Glucose intolerance 3 - -
Arthralgia 1 - -
Back pain 1 - -
Generalized muscle weakness 1 - -
Cerebrospinal fluid leakage 1 - -
Cognitive disturbance 1 - -
Dizziness 2 - -
Encephalopathy 1 - -
Headache 7 - -
Syncope 3 - -
Vasovagal reaction 1 - -
Confusion 2 - -
Delirium 1 - -
Insomnia 1 - -
Personality change 1 - -
Dyspnea 2 - -
Epistaxis 1 - -
Pneumonitis 1 - -
Wheezing 1 - -
Acute kidney injury 1 - -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 13
Table 6a. Toxicity Incidence- Step 1 (Arm A)
Toxicity Type
Treatment
Arm
A (n=145)
Grade
3 4 5
(n) (n) (n)
Hypertension 6 - -
Hypotension 3 1 -
Thromboembolic event 3 2 -
WORST DEGREE (NON-HEMATOLOGIC) 61 23 -
Table 6b. Toxicity Incidence - Step 2 (Arm B)
Toxicity Type
Treatment
Arm
B (n=79)
Grade
3 4 5
(n) (n) (n)
Anemia 17 1 -
Febrile neutropenia 1 - -
Fatigue 1 - -
Hyperhidrosis 1 - -
Diarrhea 2 - -
Nausea 2 - -
Catheter related infection 2 - -
Sepsis - 1 -
Alanine aminotransferase increased 7 - -
Alkaline phosphatase increased 2 - -
Aspartate aminotransferase increased 6 - -
Blood bilirubin increased 2 1 -
Investigations - Other, specify 1 - -
Lipase increased - 1 -
Lymphocyte count decreased 6 4 -
Neutrophil count decreased 17 14 -
Platelet count decreased 2 9 -
White blood cell decreased 3 2 -
Alkalosis 1 - -
Dehydration 1 - -
Hyperglycemia 3 - -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 14
Toxicity Type
Treatment
Arm
B (n=79)
Grade
3 4 5
(n) (n) (n)
Hypertriglyceridemia - 1 -
Hypokalemia 1 - -
Hyponatremia 1 - -
Hypophosphatemia 1 - -
Tumor lysis syndrome 1 - -
Generalized muscle weakness 1 - -
Headache 1 - -
Hypertension 2 - -
Hypotension 1 - -
WORST DEGREE (NON-HEMATOLOGIC) 21 4 -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 15
Table 6c. Toxicity Incidence – Step3 (Arm C)
Toxicity Type
Treatment Arm
C (n=32)
Blinitumomab Consolidation
Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6
Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5
(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Anemia 2 - - - - - 2 - - 3 - - 7 - - 4 - - - - - 1 - - - - - 7 - -
Blood and lymphatic system disorders - Other,
specify - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - -
Febrile neutropenia - - - - - - - - - 2 1 - 1 - - 2 - - 1 - - 1 - - - - - 6 1 -
Chest pain - cardiac - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -
Fever - - - - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - -
General disorders and administration site
conditions - Other, specify - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -
Cytokine release syndrome 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - -
Appendicitis perforated - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - -
Catheter related infection 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Infections and infestations - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Sepsis - - - - - - - - - - 2 - - - - - - - - - - - - - - - - - 2 -
Urinary tract infection - - - 1 - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - -
Alanine aminotransferase increased - 1 - - - - - 1 - 1 - - 1 - - - - - - - - - - - - - - 1 - -
Aspartate aminotransferase increased - 1 - - - - - 1 - - - - 1 - - - - - - - - - - - - - - 1 - -
Lymphocyte count decreased - 2 - - - - - 2 - - - - - - - - - - - - - - - - - - - - - -
Neutrophil count decreased 3 2 - 1 - - 4 2 - - 13 - 1 9 - 1 10 - 2 1 - - 10 - 2 - - 1 15 -
Platelet count decreased - 2 - - - - - 2 - 3 6 - 1 7 - - 10 - 1 - - - 6 - - - - 2 14 -
White blood cell decreased - 1 - - - - - 1 - 2 2 - - - - - 1 - - - - - 1 - - - - 2 4 -
Dehydration 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 16
Toxicity Type
Treatment Arm
C (n=32)
Blinitumomab Consolidation
Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6
Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5
(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Hyperglycemia 1 - - - - - 1 - - - - - 1 - - 1 - - - - - - - - - - - 1 - -
Hyponatremia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Hypophosphatemia - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -
Cognitive disturbance 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Depressed level of consciousness 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Dysarthria - - - 1 - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Dysphasia 1 - - 1 - - 2 - - - - - - - - - - - - - - - - - - - - - - -
Encephalopathy 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - -
Headache - - - - - - - - - 1 - - 1 - - - - - - - - - - - - - - 2 - -
Intracranial hemorrhage - - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - -
Seizure 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - -
Tremor 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Epistaxis - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - -
Capillary leak syndrome 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - -
Hypertension - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - -
WORST DEGREE (NON-HEMATOLOGIC) 5 1 1 1 - - 6 1 1 4 2 - 4 - - 5 - - 1 - - 2 - - - - - 11 2 -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 17
Table 6d.Toxicity Incidence – Step 4 (Arm D)
Toxicity Type
Treatment Arm
D (n=29)
Cycle 1 Cycle 2 Cycle 3 Cycle 4
Cycles
1-4
Grade Grade Grade Grade Grade
3 4 5 3 4 5 3 4 5 3 4 5 3 4 5
(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)
Anemia 3 1 - 4 1 - 4 1 - 1 - - 9 2 -
Febrile neutropenia 3 - - 2 - - 1 - - - - - 5 - - Fatigue 1 - - - - - - - - - - - 1 - -
General disorders and administration site conditions -
Other, specify 1 - - - - - - - - - - - 1 - -
Vomiting 2 - - - - - - - - - - - 2 - -
Allergic reaction 1 - - - - - - - - - - - 1 - -
Catheter related infection 1 1 - - 1 - 1 - - - - - 2 1 -
Infections and infestations - Other, specify 1 - - - - - - - - - - - 1 - -
Sepsis - 2 - - 1 - - 1 - - - - - 3 -
Alanine aminotransferase increased 1 - - - - - - - - - - - 1 - -
Lymphocyte count decreased 2 - - - 1 - 1 2 - 2 - - 2 3 -
Neutrophil count decreased 4 16 - - 10 - 1 6 - 1 2 - 2 19 -
Platelet count decreased 5 9 - 1 5 - 2 3 - - 1 - 5 11 -
White blood cell decreased 1 6 - 2 1 - 2 2 - 1 2 - 1 7 -
Hyperglycemia - - - - - - 2 1 - - - - 2 1 -
Hypertriglyceridemia - 1 - - - - - - - - - - - 1 -
Hyponatremia 1 - - - - - - - - - - - 1 - -
Hypophosphatemia 1 - - - - - - - - - - - 1 - -
Headache 1 - - 2 - - 1 - - - - - 3 - -
Depression 1 - - - - - - - - - - - 1 - -
Hypertension 1 - - - - - - - - - - - 1 - -
WORST DEGREE (NON-HEMATOLOGIC) 7 3 - 3 1 - 2 2 - - - - 9 5 -
Table 6e. Toxicity Incidence – Step 3 Transplant
Toxicity Type
Treatment Arm
C (n=5) D (n=7)
Grade Grade
3 4 5 3 4 5
(n) (n) (n) (n) (n) (n)
Anemia 2 - - 2 - -
Febrile neutropenia 2 - - 2 - -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 18
Toxicity Type
Treatment Arm
C (n=5) D (n=7)
Grade Grade
3 4 5 3 4 5
(n) (n) (n) (n) (n) (n)
Atrial fibrillation 1 - - - - -
Anal mucositis - - - 1 - -
Colitis 1 - - - - -
Diarrhea 2 - - - - -
Mucositis oral - - - 1 - -
Nausea - - - 1 - -
Infections and infestations - Other, specify 1 - - - - -
Lung infection - - - 1 - -
Lymphocyte count decreased - - - - 2 -
Neutrophil count decreased - 3 - - 4 -
Platelet count decreased - 3 - - 3 -
White blood cell decreased - 2 - - 2 -
Anorexia - - - 1 - -
Dyspnea - - - 1 - -
Pulmonary edema - - - 1 - -
Respiratory failure - 1 - - - -
Acute kidney injury - 1 - - - -
WORST DEGREE (NON-HEMATOLOGIC) 2 1 - 2 - -
Table 6f. Toxicity Incidence – Step 4 Maintenance
Toxicity Type
Treatment Arm
C (n=12) D (n=10)
Grade Grade
3 4 5 3 4 5
(n) (n) (n) (n) (n) (n)
Anemia - - - 1 - -
Mucositis oral 2 - - - - - Nausea 1 - - - - -
Vomiting 1 - - - - -
Infections and infestations - Other, specify 1 - - - - -
Alanine aminotransferase increased 1 - - 2 - -
Aspartate aminotransferase increased 1 - - 2 - -
Blood bilirubin increased 1 - - 1 1 -
Lymphocyte count decreased - - - 2 - -
Neutrophil count decreased - 5 - 1 2 -
Platelet count decreased - 1 - - 1 -
White blood cell decreased 1 - - - 2 -
Dehydration 1 - - - - -
ECOG-ACRIN Cancer Research Group E1910
Study Progress and Safety Report Spring 2017
Page 19
Toxicity Type
Treatment Arm
C (n=12) D (n=10)
Grade Grade
3 4 5 3 4 5
(n) (n) (n) (n) (n) (n)
Hyperglycemia - - - 1 - -
Headache - - - 1 - -
Treatment related secondary malignancy - - 1 - - -
WORST DEGREE (NON-HEMATOLOGIC) 3 - 1 4 1 -
Table 7. Lethal Adverse Events
Case Arm Description of Event 19001 A Death NOS
19126 A Intracranial hemorrhage
19215 A Sudden death NOS
19220 A Febrile neutropenia
19243 A Sepsis
19119 C Intracranial hemorrhage
19088 D Cardiac arrest
Table 8. Second Primary Cancers
(By arm during which event was reported)
Site Arm A Arm E
Leukemia, Type Not Specified - 1
Non-Small Cell Lung 1 -
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 1
E1912 E1912: A RANDOMIZED PHASE III STUDY OF IBRUTINIB (PCI-32765)-BASED
THERAPY VS STANDARD FLUDARABINE, CYCLOPHOSPHAMIDE, AND
RITUXIMAB (FCR) CHEMOIMMUNOTHERAPY IN UNTREATED YOUNGER
PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Sponsor(s)
Coordinating Group ECOG-ACRIN
Chairperson(s) Dr. Tait Shanafelt
Statistician Dr. Xin Victoria Wang
Data Specialist Elene Assefa
Phase of Study III
Type of Study Therapeutic
Committee Leukemia
Accrual Objective 519 Patients
Participating Groups ECOG-ACRIN, SWOG, CTSU, ALLIANCE, NRG
DCP Treatment Credit 1.0
DCP Cancer Control Credit 0.4
NSC# 26271, 312887, 687451, 748645
Clinicaltrials.gov Study ID NCT02048813
Study Status Closed to Accrual
Date Proposed April 3, 2012
Date Activated January 31, 2014
Date Terminated June 9, 2016
Final Accrual 529 Patients
Schema
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 2
Purpose of Study
Primary Objective: To evaluate the ability of Ibrutinib-based induction therapy to prolong progression
free survival (PFS) compared to standard FCR chemoimmunotherapy for younger patients with CLL.
Secondary Objectives: (1) To evaluate overall survival (OS) of patients based on treatment arm. (2) To
monitor and assess toxicity of treatment with Ibrutinib-based induction relative to standard FCR
chemotherapy. (3) To monitor and assess quality of life (QOL) in CLL patients receiving Ibrutinib-based
induction therapy relative to standard FCR chemoimmunotherapy. (4) To determine the effect of
pretreatment clinical and biological characteristics (e.g. disease stage, IGHV mutation status, FISH) on
clinical outcomes (e.g. complete response, PFS) of the different arms. (5) To determine if the minimal
residual disease (MRD) status as assessed by flow cytometry at different time points during and after
treatment is an effective surrogate marker for prolonged PFS and overall survival. (6) To conduct
confirmatory validation genotyping of single nucleotide polymorphisms (SNPs) associated with the
efficacy and toxicity of fludarabine-based therapy as in a prior ECOG GWAS analysis in the E2997 trial.
(7) To explore the effects of FCR and Ibrutinib-based therapy on T-cell immune function. (8) To evaluate
the ability of prognostic model that incorporates clinical and biologic characters to predict response to
therapy and clinical outcome (PFS, OS). (9) To collect relapse samples to study mechanisms of resistance
to both FCR and Ibrutinib-based therapy.
Study Population
Patients </= 70 years old with untreated chronic lymphocytic leukemia (CLL). Age >/= 18 years and </=
70 years.
Summary of Study Design
Five hundred and nineteen (519) patients will be randomized 2:1 to the Ibrutinib-Rituximab arm (A) and
the FCR control arm (B). The primary objective is to definitively evaluate whether patients who receive
Ibrutinib have significantly longer PFS than those receiving FCR. With the planned sample size, we will
have 80% power to detect a true hazard ratio of 1.5 (FCR vs. Ibrutinib regimen; median PFS of 52 months
vs. 78 months) while controlling the one-sided type I error at 2.5%. Overall survival will be used as a
secondary endpoint. We expect the annual accrual rate to be approximately 180 patients per year. It will
take approximately 35 months to accrue the 519 patients for the study. Assuming median PFS for the
Ibrutinib and FCR arms to be 78 and 52 months, respectively, the study requires approximately 32 months
of follow-up to reach full information of 203 events.
Progress to Date
This study was activated on January 31, 2014 and terminated on June 9, 2016 with 529 patients accrued.
Accruals by ECOG-ACRIN institutions and by group are shown in Table 1a and 1b. Table 2 summarizes
patient status. Table 3 shows patient demographic information by treatment arm. Record status by form is
presented in Table 4. Table 5 summarizes off-treatment reasons. As of March 2, 2017, 14 patients have
refused to start protocol treatment. Treatment-related toxicity data are available for 358 patients and are
summarized in Table 6, with lethal toxicities briefly described in Table 7. Second primary cancers are
summarized in Table 8. A summary of the collection of quality of life data is presented in Table 9.
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 3
Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1
Aurora NCORP 15
Baystate Medical Center 2 Cancer Research Consortium of West Michigan NCORP 6
Cancer Research for the Ozarks NCORP 3
Carle Cancer Center NCORP 1 Case Western Reserve University 4
Catholic Health Initiatives NCORP 1
Colorado Cancer Research Program NCORP 5 Columbus NCORP 8
Dayton NCORP 3
Delaware/Christiana Care NCORP 5 Emory University/Winship Cancer Institute 7
Essentia Health NCORP 2
Fox Chase Cancer Center 1 Froedtert and the Medical College of Wisconsin 3
Geisinger Cancer Institute NCORP 5
Georgia NCORP 2 Heartland Cancer Research NCORP 10
Iowa-Wide Oncology Research Coalition NCORP 6
Main Line Health NCORP 5 Mayo Clinic 37
Metro Minnesota Community Oncology Res Consortium 17
Michigan Ca Res Consortium NCORP 12 Missouri Valley Cancer Consortium 1
Montana Cancer Consortium NCORP 1
Nevada Cancer Research Foundation NCORP 1 New Mexico MU NCORP 2
New York Oncology Hematology PC -Albany Med Center 4
NorthShore Univ HealthSystem-Evanston Hospital 6 Northwest NCORP 1
Northwestern University 8 Ochsner NCORP 4
Oncology Hematology West 1
Pacific Cancer Research Consortium NCORP 3 Penn State Milton S Hershey Medical Center 4
Sanford NCORP of the North Central Plains 5
Stanford Cancer Institute 6 Thomas Jefferson University Hospital 3
Toledo Community Hospital Oncology Program CCOP 1
Tufts Medical Center 1 UT Southwestern/Simmons Cancer Center-Dallas 1
University of Alabama at Birmingham Cancer Center 2
University of Massachusetts Medical School 5 University of Pennsylvania/Abramson Cancer Center 21
University of Pittsburgh Cancer Institute (UPCI) 10
University of Wisconsin Hospital and Clinics 10 VCU Massey Cancer Center MU NCORP 8
Washington University School of Medicine 6
Wichita NCORP 1 Wisconsin NCORP 10
Total 286
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 4
Table 1b. Accrual by Group
ECOG-ACRIN 286
SWOG 130
ALLIANCE 76
NRG 37
Total 529
Table 2. Patient Status as of March 2, 2017
Cases Entered 529
Ineligible 10
Never Started Assigned Therapy 19
Reason for ineligibility:
Violation of section 3.1.9 GFR, SGOT and total Billirubin test date is greater than 14 days prior to
registration: 19025, 19114 and 19146.
Violation of section 3.1.1 t(11;14) or negative stains for cyclin D1 was not performed prior to registration:
19034, 19135, 19139, 19163, 19246
Deletion 17p: 19414, 19510.
Reason for not starting assigned therapy:
Ineligible: 19205, 19414
Patient refusal: 19010, 19021, 19045, 19060, 19075, 19127, 19197, 19289, 19322, 19357, 19420, 19423,
19434, 19454
Not covered by insurance: 19052, 19487
Medical decision: 19088.
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 5
Table 3. Demographics
Variable Level
Arm A
(n=354)
Arm B
(n=175)
Total
(n=529)
Sex Male 236 (66.7) 120 (68.6) 356 (67.3)
Female 118 (33.3) 55 (31.4) 173 (32.7)
Race White 318 (91.9) 160 (93.6) 478 (92.5)
African-American 23 (6.6) 6 (3.5) 29 (5.6)
Asian 5 (1.4) 3 (1.8) 8 (1.5)
Native American 0 (0.0) 1 (0.6) 1 (0.2)
Multirace 0 (0.0) 1 (0.6) 1 (0.2)
Unknown/Unreported 8 4 12
Ethnicity Hispanic 7 (2.1) 3 (1.8) 10 (2.0)
Non-Hispanic 333 (97.9) 167 (98.2) 500 (98.0)
Unknown/Missing 14 5 19
Age Median 58 57 58
Minimum 31 28 28
Maximum 70 70 70
Table 4. Record Status
Form Name Forms Due Forms Received %
Demography 529 529 100.0
Patient Characteristics 529 528 99.8
Treatment Form 4673 4531 97.0
Adverse Event Form 5691 4703 82.6
Disease Follow-up Status 5742 4498 78.3
Off Treatment 225 219 97.3
Table 5. Reasons Off Treatment
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 59 29.5
Alternative therapy 1 0.5
Death on study 2 1.0
Disease progression- relapse during active treatment 6 3.0
Other 10 5.0
Patient off-treatment for other complicating disease 4 2.0
Patient withdrawal/refusal after beginning protocol therapy 14 7.0
Treatment completed per protocol criteria 104 52.0
Total off treatment 200 100.0
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 6
Table 6. Toxicity Incidence
Toxicity Type
Treatment Arm
A (n=352) B (n=156)
Grade Grade
3 4 5 3 4 5
(%) (%) (%) (%) (%) (%)
Ear pain <1 - - - - -
Anemia 1 - - 8 3 -
Blood and lymphatic system disorders - Other, specify - - - 1 - -
Febrile neutropenia 2 - - 12 3 -
Hemolysis - - - 2 - -
Leukocytosis 9 <1 - 1 - -
Atrial fibrillation 2 - - - - -
Atrial flutter 1 - - - - -
Chest pain - cardiac <1 - - - - -
Heart failure <1 - - - - -
Sinus bradycardia <1 - - - - -
Supraventricular tachycardia <1 - - - - -
Ventricular tachycardia <1 - - - - -
Chills <1 - - 1 - -
Fatigue 2 - - 3 - -
Fever <1 - - 1 - -
Pain <1 - - - - -
Infusion related reaction - <1 - 1 - -
Rash maculo-papular 2 - - 2 - -
Skin and subcutaneous tissue disorders - Other, specify <1 - - - - -
Colitis <1 - - - - -
Diarrhea 2 - - - - -
Mucositis oral <1 - - - - -
Nausea - - - 1 - -
Vomiting <1 - - - - -
Allergic reaction <1 - - - - -
Infections and infestations - Other, specify 1 - - 1 - -
Sepsis - <1 - - 3 1
Sinusitis - - - 1 - -
Skin infection - - - 1 - -
Upper respiratory infection <1 - - 2 - -
Urinary tract infection <1 - - - - -
Enterocolitis infectious - - - 1 - -
Lung infection 2 - - 3 - -
Scrotal infection <1 - - - - -
Soft tissue infection 1 <1 - - - -
Arterial injury <1 - - - - -
Alanine aminotransferase increased 1 - - - - -
Alkaline phosphatase increased <1 - - - - -
Aspartate aminotransferase increased 1 - - 1 - -
Blood bilirubin increased <1 - - - - -
Creatinine increased <1 - - - - -
Investigations - Other, specify <1 - - - - -
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 7
Toxicity Type
Treatment Arm
A (n=352) B (n=156)
Grade Grade
3 4 5 3 4 5
(%) (%) (%) (%) (%) (%)
Lymphocyte count decreased 1 - - 26 16 -
Lymphocyte count increased 11 - - 1 - -
Neutrophil count decreased 9 11 - 22 19 -
Platelet count decreased 2 1 - 10 4 -
White blood cell decreased 1 <1 - 21 14 -
Anorexia - - - 1 - -
Dehydration <1 - - - - -
Hypercalcemia - 1 - - - -
Hyperglycemia - - - 1 - -
Hyperkalemia 1 - - 1 - -
Hyperuricemia - <1 - - - -
Hypoalbuminemia - - - 1 - -
Hyponatremia <1 - - - - -
Tumor lysis syndrome 1 - - 1 - -
Arthralgia 4 - - 1 - -
Bone pain <1 - - - - -
Flank pain - - - 1 - -
Myalgia 1 - - - - -
Pain in extremity 1 - - - - -
Cognitive disturbance <1 - - - - -
Dizziness 1 - - - - -
Headache 1 - - 1 - -
Peripheral sensory neuropathy <1 - - 1 - -
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other,
specify <1 - - - - -
Treatment related secondary malignancy 1 - - - - -
Insomnia - - - 1 - -
Dyspnea <1 - - 1 - -
Hiccups <1 - - - - -
Pleural effusion <1 - - - - -
Pneumonitis <1 - - - - -
Respiratory failure - - - - 1 -
Renal hemorrhage <1 - - - - -
Surgical and medical procedures - Other, specify <1 - - - - -
Hematoma 1 - - 1 - -
Hypertension 3 - - 2 - -
Hypotension - - - 1 - -
Thromboembolic event - - - - 1 -
WORST DEGREE 38 12 - 34 35 1
ECOG-ACRIN Cancer Research Group E1912
Study Progress and Safety Report Spring 2017
Page 8
Table 7. Lethal Adverse Events
Case Arm Description of Event
19196 B Sepsis
19333 A Died at home unexpectedly after showing improvements from grade 2 and 3 events.
19229 A Respiratory failure
19306 A Respiratory failure
Table 8. Second Primary Cancers
Site Arm A Arm B
Basal Cell Carcinoma 3 1
Brain Tumor 1 -
Breast 2 -
Colon - 2
Gastric 1 -
Lung Cancer 1 -
Melanoma 3 1
Non-Small Cell Lung - 1
Other 1 1
Prostate - 1
Skin Cancer Not Melanoma 2 2
Table 9. QOL Table
QOL Timepoint
Patients
Reaching
Timepoint
% Forms
Completed
Baseline 510 99.4
Cycle 3 510 86.5
Cycle 6 502 81.5
At response evaluation 356 27.2
6 months post response evaluation 249 26.5
12 months post response evaluation 123 27.6
18 months post response evaluation 22 18.2
24 months post response evaluation 0
ECOG-ACRIN Cancer Research Group E2905
Study Progress and Safety Report Spring 2017
Page 1
E2905 RANDOMIZED PHASE III TRIAL COMPARING THE FREQUENCY OF MAJOR
ERYTHROID RESPONSE (MER) TO TREATMENT WITH LENALIDOMIDE
(REVLIMID) ALONE AND IN COMBINATION WITH EPOETIN ALFA (PROCRIT) IN
SUBJECTS WITH LOW- OR INTERMEDIATE-1 RISK MDS AND SYMPTOMATIC
ANEMIA
Sponsor(s)
Coordinating Group ECOG-ACRIN
Chairperson(s) Dr. Alan List
Statistician Dr. Zhuoxin Sun
Data Specialist Henry Baptista
Phase of Study III
Type of Study Therapeutic
Committee Leukemia
Accrual Objective 252 Patients
Participating Groups ECOG-ACRIN, RTOG, NCCTG, CALGB, SWOG,
NSABP, CTSU, ALLIANCE, NRG
DCP Treatment Credit 1.5
NSC# 628281, 703813
Clinicaltrials.gov Study ID NCT00843882
Study Status Closed to Accrual
Date Activated January 29, 2009
Date Suspended September 23, 2010
Date Reactivated February 4, 2011
Date Suspended December 31, 2012
Date Reactivated June 6, 2013
Date Terminated May 13, 2016
Final Accrual 248 Patients
Schema
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Purpose of Study
(1)To compare the rate of major erythroid response (MER) between lenalidomide monotherapy and
combined treatment of lenalidomide and epoetin alfa in erythropoietin non-responsive Low/Int-1 risk MDS
patients or erythropoietin-treatment naive patients with low probability of erythropoietin benefit. (2)To
compare the time to MER by treatment assignment. (3)To evaluate the duration of MER by treatment
assignment. (4)To estimate the frequency of MER to salvage combination therapy in patients who fail to
experience a MER with lenalidomide monotherapy. (5)To evaluate and compare the frequency of minor
erythroid response by treatment assignment. (6)To investigate the mechanism and target of lenalidomide
action in patients with chromosome 5q31.1 deletion. (7)To evaluate the frequency of cytogenetic response
and progression, and the relation between cytogenetic pattern and erythroid response. (8)To evaluate the
frequency of bone marrow response (CR+PR). (9) To evaluate the relationship between erythroid response
and laboratory correlates outlined below: (a) Pretreatment and onstudy endogenous erythropoietin level
(Arm A); (b)To evaluate the effect of CD45 isoform profile on lenalidomide enhancement of
erythropoietin-induced STAT5 phosphorylation in CD71Hi erythroid precursors and the relationship to
erythroid response. (c)To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q cells.
(d) To evaluate the frequency of cryptic chromosome 5q31 deletions in patients with non-del5q MDS by
array-based genomic scan, and to determine the relationship to hematologic response.
Study Population
Low-or intermediate-1 risk MDS and symptomatic anemia.
Summary of Study Design
This study requires 212 patients without 5q31.1 deletion for the primary endpoint comparison. Assuming
that 10% of patients in the MDS population as defined in this study have the 5q31.1 deletion, a total of 252
patients will be entered. The primary endpoint in this phase III study is major erythroid response (MER),
defined as sustained transfusion independence in transfusion-dependent patients or a rise in hemoglobin > 2
g/dL in transfusion-independent patients with anemia for a minimum of eight consecutive weeks. The
objective MER will be assessed 16 weeks after start of study treatment. We hypothesize that the MER rate
in Arm A (lenalidomide) will be 30% and anticipate that the MER rate in Arm B(lenalidomide + epoetin
alfa) will be at least 50%. Thus the study is designed to detect an improvement of 20% in the MER rate from
30% to 50%, comparing Arm A to Arm B. Using the statistical package EaSt (Cytel Software Corporation,
1993) to account for multiple interim looks in a sequential design for binomial distribution with continuity
correction, a sample size of 212 eligible cases will provide approximately 80% power to detect
improvement in MER rate with an overall one-sided type I error rate of 0.025.
Progress to Date
This study was activated on January 29, 2009. Due to an interruption in drug supply, the study was
suspended on September 23, 2010 and was reopened on February 4, 2011. The study was suspended again
on December 31, 2012 due to changes in the supply of Epoetin Alfa, and reopened on June 6, 2013, after an
amendment was approved to allow patients to receive Erythropoietin, recombinant human (Epoetin alfa,
Procrit-Ortho-Biotech) commercially. On May 13, 2016, the study was closed to accrual after
ECOG-ACRIN Data Safety Monitoring Committee reviewed the fifth planned interim analysis of major
erythroid response (MER) and the study met the protocol criteria for stopping for efficacy. 248 patients
have been accrued to the study. Accrual by ECOG-ACRIN institution and accrual by group are summarized
in Tables 1a and 1b. Patient status as of March 7, 2017 is summarized in Table 2. Demographic data are
shown in Tables 3a and 3b. Record status is shown in Table 4. The distribution of
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the reasons for discontinuation of protocol treatment is given in Tables 5a and 5b by step.
Treatment-related toxicity data are available for 240 patients and are summarized in Tables 6a and 6b. Table
7 summarizes lethal adverse events (regardless of treatment relation). Table 8 summarizes incidences of
second primary cancer.
Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1 Step 2
Aurora NCORP 1 0
Beaumont NCORP 1 0
Case Western Reserve University 1 0 Catholic Health Initiatives NCORP 2 0
Colorado Cancer Research Program NCORP 1 1
Delaware/Christiana Care NCORP 3 1 Essentia Health NCORP 1 1
Fox Chase Cancer Center 2 0
Froedtert and the Medical College of Wisconsin 3 1 Heartland Cancer Research NCORP 3 0
Indiana Univ/Melvin and Bren Simon Cancer Center 2 1 Iowa-Wide Oncology Research Coalition NCORP 3 2
Johns Hopkins Univ/Sidney Kimmel Cancer Center 5 1
Laura and Issac Perlmutter Ca Ctr at NYU Langone 5 2 Mayo Clinic 9 3
Memorial Hospital of South Bend 1 0
Metro Minnesota Community Oncology Res Consortium 9 2 Michigan Ca Res Consortium NCORP 6 0
Montefiore MU NCORP 11 1
Nevada Cancer Research Foundation NCORP 1 0 NorthShore Univ HealthSystem-Evanston Hospital 6 0
Northwestern University 8 0
Pacific Cancer Research Consortium NCORP 1 0 Penn State Milton S Hershey Medical Center 8 3
Rutgers Cancer Institute of New Jersey 1 0
Sanford NCORP of the North Central Plains 2 0
Toledo Community Hospital Oncology Program CCOP 1 0
University of Alabama at Birmingham Cancer Center 2 0
University of Miami Miller Schl Med-SylvesterCaCtr 1 1 University of Pennsylvania/Abramson Cancer Center 11 3
University of Pittsburgh Cancer Institute (UPCI) 2 0
University of Wisconsin Hospital and Clinics 11 2 Wichita NCORP 3 0
Wisconsin NCORP 7 2
Total 134 27
Table 1b. Accrual by Group
Step 1 Step 2
ECOG-ACRIN 134 27
RTOG 2 0
NCCTG 1 0
CALGB 12 1
SWOG 79 20
NSABP 3 0
ACOSOG 1 1
CTSU 1 0
ALLIANCE 8 2
NRG 7 0
Total 248 51
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Table 2. Patient Status as of March 7, 2017
Step 1 Step 2
Not Del 5q31.1 Del 5q31.1
Cases Entered 209 39 51
Ineligible 5 4 0
Never Started Assigned Therapy 0 2 0
Reason for ineligibility Step 1:
Baseline bone marrow was not done within 56 days (29003);
Baseline blood lab test was not done within the 21 days prior to randomization (29007, 29019, 29025);
History of thromboembolic events within 3 years prior to study randomization (29103).
No prior bone marrow documenting MDS lasting for more than 3 months (29055, 29090);
Serum erythropoietin level not documented before randomization and <= 56 days before day1 of study
treatment (29011, 29119).
Reason for not starting assigned therapy Step 1:
Patient refused treatment (29096); Medical decision (29142).
Table 3a. Demographics - Step 1
Variable Level
Arm A
(n=142)
Arm B
(n=106)
Total
(n=248)
Sex Male 82 (57.7) 78 (73.6) 160 (64.5)
Female 60 (42.3) 28 (26.4) 88 (35.5)
Race White 133 (97.8) 96 (94.1) 229 (96.2)
African-American 1 (0.7) 3 (2.9) 4 (1.7)
Asian 2 (1.5) 3 (2.9) 5 (2.1)
Unknown/Unreported 6 4 10
Ethnicity Hispanic 4 (3.0) 1 (1.0) 5 (2.1)
Non-Hispanic 131 (97.0) 97 (99.0) 228 (97.9)
Unknown/Missing 7 8 15
Age Median 74 73 74
Minimum 49 47 47
Maximum 89 92 92
Table 3b Demographics - Step 2
Variable Level
Arm B
(n=51)
Sex Male 35 (68.6)
Female 16 (31.4)
Race White 48 (94.1)
African-American 1 (2.0)
Asian 2 (3.9)
Ethnicity Non-Hispanic 49 (100.0)
Unknown/Missing 2
Age Median 73
Minimum 49
Maximum 90
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Table 4. Record Status
Form Type
Forms
Due
Forms
Received %
Baseline Step 1 Forms 489 465 95.1
Baseline Step 2 Forms 47 44 93.6
Treatment Forms 3126 2499 79.9
Disease Evaluation Forms 3366 2740 81.4
Adverse Event Forms 3211 2558 79.7
Hematology/Chemistry Forms 3890 3217 82.7
Off Treatment Forms 273 269 98.5
Follow-Up Forms 371 351 94.6
Table 5a. Reasons Off Treatment - Step 1
For Patients Not Registered To Subsequent Steps
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Treatment completed per protocol criteria 55 32.0
Disease progression, relapse during active treatment 29 16.9
Adverse events/side effects/complications 41 23.8
Death on study 6 3.5
Patient withdrawal/refusal after beginning protocol therapy 24 14.0
Alternative therapy 2 1.2
Patient off treatment for other complicating disease 7 4.1
Other 8 4.7
Total off treatment 172 100.0
Table 5b. Reasons Off Treatment - Step 2
(Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N %
Treatment completed per protocol criteria 20 42.6
Disease progression, relapse during active treatment 7 14.9
Adverse events/side effects/complications 4 8.5
Death on study 2 4.3
Patient withdrawal/refusal after beginning protocol therapy 6 12.8
Alternative therapy 1 2.1
Other 6 12.8
Unknown reason 1 2.1
Total off treatment 47 100.0
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Table 6a. Toxicity Incidence - Step 1
Toxicity Type
Treatment Arm
A (n=138) B (n=102)
Grade Grade
3 4 5 3 4 5
(%) (%) (%) (%) (%) (%)
Anemia 55 1 - 57 3 -
Febrile neutropenia 4 - - 3 1 -
Blood and lymphatic disorders - Other - 1 - - - -
Acute coronary syndrome - - - - 1 -
Atrial fibrillation 1 1 - - 1 -
Chest pain - cardiac - - - 1 - -
Heart failure 1 - - 1 - -
Left ventricular systolic dysfunction - - - 1 - -
Myocardial infarction - - - 1 - -
Cardiac disorders - Other, specify - - - 1 - -
Edema limbs 1 - - 1 - -
Fatigue 3 - - 8 - -
Fever - - - 1 1 -
Non-cardiac chest pain 1 - - - - -
Pruritus 1 - - - - -
Rash maculo-papular 5 - - 3 - -
Skin ulceration 1 - - - - -
Abdominal pain 1 - - 1 - -
Colitis 1 - - 1 - -
Colonic obstruction 1 - - - - -
Constipation - - - 1 - -
Diarrhea 2 - - 3 - -
Nausea - - - 1 - -
Vomiting 1 - - 1 - -
Anaphylaxis - - - 1 - -
Immune system disorders - Other, specify - - - 1 - -
Bronchial infection 1 - - - - -
Lung infection 1 - 1 1 1 -
Sepsis - 1 - - 1 -
Soft tissue infection 1 - - - - 1
Urinary tract infection - - - 1 - -
Blood bilirubin increased 1 - - 1 - -
Creatinine increased 1 1 - 3 1 -
Hemoglobin increased 1 - - - - -
Lymphocyte count decreased 3 - - 4 - -
Neutrophil count decreased 36 30 - 28 33 -
Platelet count decreased 17 14 - 17 9 -
Weight gain - - - 1 - -
White blood cell decreased 33 2 - 25 7 -
Anorexia - - - 1 - -
Dehydration 1 - - 1 - -
Hypocalcemia 1 - - - - -
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Toxicity Type
Treatment Arm
A (n=138) B (n=102)
Grade Grade
3 4 5 3 4 5
(%) (%) (%) (%) (%) (%)
Hypophosphatemia 1 - - - - -
Iron overload - - - 1 - -
Arthritis 1 - - - - -
Chest wall pain 1 - - - - -
Myalgia 1 - - - - -
Musculoskeletal and connective - Other - - - 1 - -
Ataxia - - - 1 - -
Dizziness - - - 1 - -
Peripheral motor neuropathy 1 - - - - -
Peripheral sensory neuropathy 1 - - - - -
Syncope 1 - - - - -
Treatment related secondary malignancy - - 1 - - -
Neoplasms - Other - - - 1 - -
Optic nerve disorder - - - 1 - -
Cough - - - 1 - -
Dyspnea 1 - - 3 - -
Respiratory thoracic mediastinal - Other - - - 1 - -
Renal and urinary disorders - Other - - - 1 - -
Thromboembolic event 1 - - - - -
WORST DEGREE (NON-HEMATOLOGIC) 27 3 1 26 4 1
Table 6b. Toxicity Incidence - Step 2
Toxicity Type
Treatment Arm
B (n=48)
Grade
3 4 5
(%) (%) (%)
Anemia 56 - -
Edema limbs 2 - -
Fatigue 4 - -
Multi-organ failure 2 - -
Pruritus 2 - -
Rash maculo-papular 2 - -
Constipation 2 - -
Wound infection 2 - -
Creatinine increased 2 - -
Lymphocyte count decreased 2 - -
Neutrophil count decreased 42 35 -
Platelet count decreased 10 8 -
White blood cell decreased 46 - -
Investigations - Other, specify - 2 -
Hyperglycemia - 2 -
Peripheral sensory neuropathy 2 - -
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Toxicity Type
Treatment Arm
B (n=48)
Grade
3 4 5
(%) (%) (%)
Acute kidney injury 2 - -
WORST DEGREE (NON-HEMATOLOGIC) 13 4 -
Table 7. Lethal Adverse Events via AdEERS (Regardless of
treatment relation)
Case # Arm Adverse Event Type
29009 A Infection Gr0-2 neut, lung
29052 A Death NOS
29084 A Acute coronary syndrome
29097 A Nervous system disorders - Other
29117 A Cardiac arrest
29123 A Intracranial hemorrhage
29129 A Neoplasms - Other
29141 A Treatment related secondary malignancy
29003 B cardiac-other
29004 B Soft tissue infection
29043 B Death NOS
29056 B Neoplasms - Other
29058 B Death NOS
29103 B Cardiac disorders
29112 B Sepsis
29159 B Death NOS
29244 B Neoplasms - Other
Table 8. Second Primary Cancers
(By arm during which event was reported)
Site Arm A Arm B
Acute Non-Lymphocytic Leukemia - ANLL, AML 1 4
Bladder, Urinary Tract - 1
Colon - 1
Endometrium, Uterine Corpus 1 -
Lung Cancer 1 1
Non-Hodgkins Lymphoma - 1
Squamous cell Carcinoma - 1
Skin Cancer Not Melanoma - 1