Updated Results From a Phase 2 Study of Pracinostat in Combination With Azacitidine in Elderly Patients With Acute Myeloid LeukemiaGuillermo Garcia-Manero, MD1; Ehab Atallah, MD2; Samer K. Khaled, MD3; Martha Arellano, MD4; Mrinal Patnaik, MD5; Vanessa Esquibel6; Katie Wood6; Bruno Medeiros, MD7 1Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI; 3Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, CA; 4Winship Cancer Institute, Emory University, Atlanta, GA; 5Mayo Clinic, Rochester, MN; 6MEI Pharma, Inc., San Diego, CA; 7Division of Hematology/Oncology, Stanford Cancer Center, Stanford University, Stanford, CA.

BACKGROUND• Elderly patients with acute myeloid leukemia (AML), deemed unsuitable for

intensive therapy, have limited treatment options.

• A phase 1 study of single-agent pracinostat demonstrated clinical activity in patients with AML.

• We previously reported a high initial response rate in the first stage of this phase 2 study of pracinostat plus azacitadine in this population (ASH 2014; Abstract 947). Presented here are updated results, which include additional patients.

METHODS

Treatment Regimen• Pracinostat 60 mg is administered orally 3 days a week (days 1, 3, and

5 of each week) for 21 days of each 28-day cycle.

• Azacitidine is administered subcutaneously or intravenously on days 1–7 or days 1–5 and 8–9 (per site preference) of each 28-day cycle.

• Dose modifications

§ Reductions

– Begin with azacitidine, which may be reduced to 75% of the starting dose

– Subsequent reduction to 45 mg of pracinostat is allowed

§ Delays (between or within cycles)

– Indicated for treatment-related grade ≥3 hematologic toxicity in the absence of disease

– Indicated for treatment-related grade ≥3 nonhematologic toxicity following maximal medical treatment

Eligibility Criteria• Key inclusion

§ Age ≥65 years

§ Newly diagnosed de novo, secondary, or treatment-related AML with intermediate or unfavorable-risk cytogenetics based on the Southwest Oncology Group classifications2

§ ≥20% bone marrow blasts

§ Adequate renal, cardiac, and liver function

§ QTcF ≤450 ms for males or ≤470 ms for females

• Key exclusion

§ Acute promyelocytic leukemia (FAB M3); t(15;17), t(8;21), t(16;16), del(16q), or inv(16) karyotype

§ Candidate for intensive chemotherapy (induction chemotherapy, bone marrow or stem cell transplant) within the next 4 months

§ Active central nervous system disease

Study Evaluations• Primary endpoint: complete response (CR) + complete response with

incomplete blood count recovery (CRi) + morphologic leukemia-free state (MLFS)

• Secondary endpoints

§ Overall response rate (CR + CRi + partial response [PR] + PR with incomplete blood count recovery [PRi] + MLFS)

§ Complete cytogenetic response + molecular complete remission

§ Duration of response

§ Event-free survival

§ Overall survival (OS)

§ Tolerability and adverse event (AE) profile

• Response assessments were conducted at end of cycle 1 or 2, and then every other cycle until CR is achieved or as clinically indicated

RESULTS• 50 patients have been enrolled at 15 centers.

• First patient in: December 25, 2013; last patient in: November 24, 2014.

Table 1. Patient Disposition

N=50

Number of patients active, n (%) 25 (50.0)

Number of patients discontinued, n (%) 25 (50.0)

Reasons for discontinuation, n (%)

Death 2 (8.0)

Progressive disease 9 (36.0)

Adverse event 8 (32.0)

Othera 6 (24.0)aOther includes patient or physician decision.

Table 2. Baseline Characteristics

N=50

Age, years

Median 75

Range 66-84

Gender, n (%)

Male 29 (58.0)

Female 21 (42.0)

AML disease status, n (%)

Newly diagnosed de novo 33 (66.0)

Secondary (AHD and treatment related) 17 (34.0)

ECOG performance status, n (%)

0-1 43 (86.0)

2 7 (14.0)

Bone Marrow Blasts at Baseline

Median % (range) 40 (20-89)

20-29% range, n (%) 14 (28.0)

30-49% range, n (%) 21 (42.0)

≥50% range, n (%) 15 (30.0)

Cytogenetic risk category, n (%)

Intermediate 27 (54.0)

High 21 (42.0)

Not evaluable 2 (4.0)

AHD, antecedent hematologic disorder; AML, acute myeloid leukemia; ECOG, Eastern Cooperative Oncology Group.

Table 3. Response

Response Assessment

Cytogenetic riska

All, n (%)N=50

Intermediate, n (%)n=27

High, n (%)n=21

CR/CRi/MLFS (primary endpoint) 27 (54.0) 17 (63.0) 10 (48.0)

CR 16 (32.0) 10 (37.0) 6 (28.0)

CRi 7 (14.0) 5 (19.0) 2 (10.0)

MLFS 4 (8.0) 2 (7.0) 2 (10.0)

PR/PRi 3 (6.0) 2 (7.0) 0a2 patients not evaluable for cytogenetic risk assessment. CR, complete response; CRi, complete response with incomplete blood count recovery; MLFS, morphologic leukemia-free state; PR, partial response; PRi, partial response with incomplete blood count recovery.

Figure 1. Duration on Study and Best Response

1st

-Lin

e Eld

erly

AM

L Pat

ients

(N

=50)

151398

Months on Study

540 1410 11 126 7321

CR

Response Based on Clinical Review of Ef�cacy Data

CRi

MLFS

PR/PRi

Stable Disease

Progressive Disease

No On-StudyAssessmentTime to 1st Bone Marrow Assessmentfor RespondersOngoing

Data as of 5 May 2015

AML, acute myeloid leukemia; CR, complete response; CRi, complete response with incomplete blood count recovery; MLFS, morphologic leukemia-free state; PR, partial response; PRi, partial response with incomplete blood count recovery.

Figure 2. Overall Survival (OS) by Risk GroupPro

port

ion o

f Pat

ients

Aliv

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time (months)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1615

Intermediate Risk

Intermediate (CNSR)

High Risk

High Risk (CNSR)

Overall

Overall (CNSR)

Patients are censored as of the date of last contact to determine survival status on or after 15 May 2015. CNSR, censored.

Table 4. Treatment-Emergent Adverse Events in ≥20% of Patients (All Causality)

All Grades, n (%) N=50

Grades 3/4, n (%) N=50

Hematologic

Febrile neutropenia 20 (40.0) 16 (32.0)

Thrombocytopenia 16 (32.0) 16 (32.0)

Anemia 13 (26.0) 7 (14.0)

Neutropenia 12 (24.0) 11 (22.0)

Nonhematologic

Nausea 33 (66.0) 2 (4.0)

Constipation 29 (58.0) 0

Fatigue 24 (48.0) 8 (16.0)

Diarrhea 15 (30.0) 1 (2.0)

Vomiting 14 (28.0) 1 (2.0)

Decreased appetite 14 (28.0) 2 (4.0)

Hypokalemia 13 (26.0) 0

Pyrexia 12 (24.0) 0

Dizziness 12 (24.0) 0

Dyspnea 12 (24.0) 0

Rash 10 (20.0) 0

Table 5. Treatment-Emergent Adverse Events Leading to Drug Discontinuation (n=8)

AE Term GradeDiscontinuation

(Cycle/Day) Outcome

Peripheral motor neuropathy 3 3/35 Resolved

Parainfluenza 3 3/9 Resolved with sequelae

Prolonged QTc/AF 3 2/4 Resolved

Failure to thrive 2 2/39 Not recovered

Mucositis 3 3/9 Not recovered

Sepsis 5 1/6 Fatal

Sepsis 5 1/17 Fatal

Fatigue 2 4/28 Not recoveredAE, adverse event; AF, atrial fibrillation; QTc, corrected QT interval.

CONCLUSIONS• Pracinostat in combination with azacitidine demonstrates significant

clinical activity in elderly patients with newly diagnosed AML. § To date, 27 of 50 patients (54%) achieved the primary endpoint of

CR + CRi + MLFS. § The CR rate was 32% (16/50 patients). § Most clinical responses occur within the first 2 cycles and continue to

improve with ongoing therapy. § Median overall survival has not been reached in the study population.

The 60-day mortality rate is 10% (5/50 patients). § Survival of patients with intermediate-risk cytogenetic abnormalities

appears greater than that for patients with high-risk cytogenetics.• Pracinostat in combination with azacitidine was well tolerated in this

population of elderly AML patients. § The most common treatment-emergent AEs included febrile

neutropenia, thrombocytopenia, nausea, and fatigue. § AEs resulting in dose reductions were uncommon and frequently due

to the disease under study. § Five patients to date have received the study drug beyond 1 year,

reflecting long-term tolerability.• The response rate for the combination of pracinostat + azacitidine

compares favorably with previous studies of azacitidine alone in elderly AML patients (Dombret H et al. Blood. 2015).

• While overall survival is encouraging, longer follow-up is necessary to get an accurate survival estimate of the combination.

DisclosuresG. Garcia-Manero receives consultancy fees from MEI Pharma; E. Atallah reports nothing to disclose; S.K. Khaled reports nothing to disclose; M. Arellano reports nothing to disclose; M. Patnaik reports nothing to disclose; V. Esquibel is an employee of MEI Pharma; K. Wood is an employee of MEI Pharma; B. Medeiros receives research funding from MEI Pharma.

Presented at the 20th Congress of the European Hematology Association, June 11–14, 2015, Vienna, Austria

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