SYNOPSIS OF STUDY PROTOCOL VERSION 1.0 FROM 14-NOV-2019 99-GeparTREIZE_Protocol... · SYNOPSIS OF STUDY PROTOCOL VERSION 1.0 FROM 14-NOV-2019 Study Title A Phase III, Randomized,

GBG 99 – GeparTreize Protocol Synopsis (Version 1.0 – 14-NOV-2018) EudraCT-Nr. 2018-001155-13 1

SYNOPSIS OF STUDY PROTOCOL VERSION 1.0 FROM 14-NOV-2019

Study Title A Phase III, Randomized, Open-Label Study Investigating the Addition of

Durvalumab to an Anthracycline-Taxane based Chemotherapy in Early-Stage

Triple-Negative Breast Cancer (GeparTreize)

Study Code GBG 99

EudraCT Number 2018-001155-13

Sponsor GBG Forschungs GmbH, Neu-Isenburg

Phase Phase III

Rationale To date no targeted agents are available to treat early-stage triple-negative

breast cancer (TNBC). Currently, chemotherapy is the only available systemic

treatment option. TNBC often has a high amount of tumour infiltrating

lymphocytes (TILs) correlating with improved outcome; further stimulating the

immune response by adding an immune-checkpoint modulator to standard

neoadjuvant chemotherapy might therefore offer the chance to increase the

pCR rate which is highly correlated with long-term outcome in aggressive breast

cancer subtypes such as TNBC.

Preliminary reports from early TNBC have demonstrated an increased pCR rate

by adding a checkpoint inhibitor to chemotherapy. The I-SPY-2 study suggested

an increase in pCR by adding pembrolizumab from 20% with paclitaxel-EC alone

to 60%. The KEYNote-173 study demonstrated a pCR rate with the addition of

pembrolizumab of 60% and 80%, respectively, depending on the addition of

carboplatin. The GeparNUEVO study demonstrated a numerically but not

statistically significant higher pCR rate by adding durvalumab, a fully human

monoclonal antibody targeting programmed cell death ligand-1 (PD-L1), to an

anthracycline/taxane based chemotherapy. Patients who received durvalumab

prior to the start of chemotherapy derived a significantly higher benefit from

adding durvalumab. The pCR rate increased from 38% to 60%. The Phase III

study Impassion 130 in metastatic TNBC demonstrated an increase in PFS with

the addition of the PD-L1 antibody atezolizumab. PFS increased by 38%

(stratified HR = 0.62; (95% CI: 0.49, 0.78); P < 0.0001) in the PD-L1 positive

cohort.

Based upon these data, this phase III trial will evaluate efficacy (pCR and EFS)

and safety of durvalumab in addition to standard neoadjuvant chemotherapy

after a priming dose of durvalumab followed by adjuvant therapy with

durvalumab in TNBC patients.

Study Overview This is a prospective, randomized, open-label, parallel-group, phase III study to

evaluate the potential incremental efficacy and safety of neoadjuvant and

adjuvant administration of durvalumab in early-stage TNBC. Patients will be

randomized to receive neoadjuvant either a sequential regimen of weekly

paclitaxel (with or without carboplatin weekly or once every three weeks, at the

discretion of the investigator) followed by Epirubicin/Cyclophosphamid (EC) or

Doxorubicin/Cyclophosphamid (AC) administered once every two or three

weeks with durvalumab (IMP arm) or alone (non-IMP arm).

Patients will then undergo surgery 3-6 weeks after the last chemotherapy

application. Following recovery from surgery, patients will continue for another

12 months adjuvant therapy with durvalumab vs. no treatment. Radiotherapy

will be administered based upon local standards; if applied, durvalumab will be


administered concurrently (Lewy A et al. Eur J Cancer 2016; 68:156-162). In

addition, postneoadjuvant chemotherapy at the discretion of the investigator

(e.g. capecitabine) is allowed but not recommended. Information regarding

postneoadjuvant treatment will be captured. Core biopsies of breast primary at

baseline are a study requirement for all patients. Additional tissue samples will

be collected after 4 weeks of chemotherapy (optional) and at surgery. Target

accrual for this study will be 1528 randomized patients. It will take about 24

months to accrue 1528 patients. A total study duration of 66 months is planned

and patients will be followed until the final overall survival analysis has been

conducted.

Investigational

Product and

Formulation

Non-

investigational

Products and

Formulations

Durvalumab:

Durvalumab 1.500 mg i.v. every 4 weeks.

The first dose is given alone followed by another full dose of 1500mg i.v. 2

weeks later (priming)

The protocol will provide procedures for specific adverse events requesting

dose modifications or delays of durvalumab.

No specific supportive treatment is required for durvalumab.

Chemotherapy:

Paclitaxel 80 mg/m² every week for 12 weeks (total of 4 cycles).

Carboplatin AUC 5 i.v. every 3 weeks for 4 cycles or AUC 2 every week for 12

weeks (administration of carboplatin is at the discretion of the investigator,

decision must be taken prior to randomization).

Epirubicin 90 mg/m² i.v. every 2 or 3 weeks for 4 cycles in combination with

cyclophosphamide 600 mg/m² i.v. every 2 or 3 weeks (EC) OR doxorubicin

60 mg/m² i.v. every 2 or 3 weeks for 4 cycles in combination with

cyclophosphamide 600 mg/m² i.v. every 2 or 3 weeks (AC).

Supportive treatments are recommended according to AGO, ESMO, or ASCO

guidelines.

Chemotherapy will be used according to marketed formulation via normal

procedures at each site and applied according to recommendations of the

manufacturers.

Primary Objectives

and Endpoints

1. Pathologic complete response in the breast and axillary lymph nodes

(ypT0/ypN0):

To compare pathological complete response (pCR=ypT0/ypN0) rates

between TNBC patients treated with durvalumab concurrently given to

chemotherapy (weekly paclitaxel +/- carboplatin followed by EC or AC) vs.

chemotherapy alone.

Endpoint: Pathological complete response (ypT0/ypN0) is defined as no

microscopic evidence of residual invasive and no non-invasive viable tumor

cells in all resected specimens of the breast and axilla.

2. Event-Free Survival (EFS):

To compare EFS rates between TNBC patients treated with durvalumab

concurrently given to chemotherapy (weekly paclitaxel +/- carboplatin

followed by EC or AC) followed by adjuvant treatment with durvalumab vs.

no study treatment (observation).

Endpoint: EFS is defined as time from randomization until first EFS event,

which are progression on protocol therapy resulting in administration of


non-protocol therapy or inoperability, local invasive recurrence following

mastectomy, local invasive recurrence in the ipsilateral breast following

lumpectomy, regional recurrence, distant recurrence, contralateral invasive

breast cancer, second non-breast primary cancer (excluding squamous or

basal cell carcinoma of the skin), or death from any cause prior to

recurrence or second primary cancer.

Key Secondary

Objective and

Endpoint

Overall Survival (OS):

To determine and compare overall survival (OS) in both treatment groups.

Endpoint: OS is defined as time from randomization until death from any

cause.

Secondary

Objectives and

Endpoints

Association of PD-L1 status with pathologic complete response in the breast

and lymph nodes (ypT0/ypN0):

To evaluate the predictive role of PD-L1 expression at baseline.

Association of PD-L1 status with EFS:

To evaluate the prognostic and predictive role of PD-L1 expression at

baseline.

Pathologic complete response in the breast (ypT0/Tis/ypN0/+):

To determine and compare the pCR rates in the breast in both treatment

groups.

Endpoint: ypT0/Tis/ypN0/+ is defined as no microscopic evidence of residual

invasive viable tumor cells in all resected specimens of the breast,

irrespective of lymph node status.

Pathologic complete response in the breast (ypT0/ypN0/+):

To determine and compare the pCR rates in the breast in both treatment

groups.

Endpoint: ypT0/ypN0/+ is defined as no microscopic evidence of residual

invasive and no non-invasive viable tumor cells in all resected specimens of

the breast, irrespective of lymph node status.

Pathologic complete response in the breast and lymph nodes (ypT0/Tis/ypN0):

To determine and compare the pCR rates in the breast and lymph nodes

evaluated histologically in both treatment groups.

Endpoint: ypT0/Tis/ypN0 is defined as no microscopic evidence of residual

invasive viable tumor cells in all resected specimens of the breast and axilla.

Breast conservation rate:

To determine and compare the rates of breast conserving surgery in both

treatment groups.

Endpoint: Percentage of patients undergoing breast conserving surgery

(defined as tumorectomy, segmentectomy or quadrantectomy as a most

radical surgery) following neoadjuvant therapy.

Positive nodal status conversion rate:

To determine and compare the conversion rate from node-positive to node-

negative in both treatment groups.

Endpoint: Percentage of patients node-positive by palpation or ultrasound

that convert to pathologically node-negative following completion of

neoadjuvant chemotherapy.


Disease free survival (DFS):

To determine and compare DFS in both treatment groups.

Endpoint: DFS is defined as time from randomization until first DFS event:

local invasive and non-invasive recurrence following mastectomy, local

invasive and non-invasive recurrence in the ipsilateral breast following

lumpectomy, regional recurrence, distant recurrence, contralateral invasive

breast cancer, second non-breast primary malignancies (excluding

squamous or basal cell carcinoma of the skin), or death from any cause prior

to recurrence or second primary cancer.

Locoregional recurrence-free interval (LRRFI):

To determine and compare LRRFI in both treatment groups.

Endpoint: LRRFI is defined as time from randomization until any loco-

regional (ipsilateral breast (invasive), chest wall, local/regional lymph nodes)

recurrence of disease or any invasive contralateral breast cancer whichever

occurs first. Progression under therapy is not considered as an event for

LRRFI. Distant recurrence, secondary malignancy and death are considered

competing events.

Distant disease-free survival (DDFS):

To determine and compare DDFS in both treatment groups.

Endpoint: DDFS is defined as time from randomization until distant

recurrence of disease, second primary invasive cancer (non-breast), and

death due to any cause.

Brain metastases free survival (BMFS):

To determine and compare BMFS in both treatment groups.

Endpoint: BMFS is defined as time from randomization until brain metastasis

with or without prior locoregional or distant recurrence outside of the

central nervous system or death from any cause.

Quality-of-Life (QoL):

To assess and compare the impact of study treatment on QoL in both

treatment groups.

Endpoints: Patient reported breast cancer specific quality of life as

measured by FACT-B. Patient reported global quality of life will be assessed

by EQ-5D-5L.

Compliance:

To assess and compare the compliance with study therapy in both treatment

groups.

Endpoints: Dose-density, dose reductions, dose delays, treatment

interruptions and treatment discontinuation rates.

Toxicity:

To assess and compare toxicity associated with study therapy in both

treatment groups.

Endpoints: Frequency and severity of adverse events graded according to

the NCI Common Terminology Criteria for Adverse Events (CTCAE) version

5.0.


Translational

Research

Objectives

Association of percentage of TILs at baseline with pCR in the breast and lymph

nodes (ypT0/ypN0):

To evaluate baseline percentage of TILs as predictor for pCR of breast and

nodes and predict durvalumab effect following neoadjuvant administration

of durvalumab with chemotherapy.

Association of percentage of TILs at baseline and surgery with EFS:

To evaluate the predictive and prognostic role of percentage of TILs at

baseline and surgery.

pCR in the breast and lymph nodes (ypT0/ypN0) in patients with deleterious

germline/somatic BRCA (g/sBRCA) or other pathogenic (e.g. PALB2; CHECK2,…)

mutations:

To determine and compare pCR in the breast and post-therapy lymph nodes

evaluated histologically in patients with deleterious g/sBRCA or other

pathogenic mutations in both treatment groups.

EFS in patients with deleterious g/sBRCA mutation or other pathogenic (e.g.

PALB2, CHECK2,…) mutations:

To determine and compare EFS in patients with deleterious g/sBRCA

mutation status or other pathogenic mutations in both treatment groups.

Association of immune signatures (mRNA) and immune markers (e.g. CD3,

CD8, CD20, FOXP3) with pCR and EFS

To evaluate the predictive and prognostic role of immune signatures and

immune markers.

Association of the mutational burden as measured by whole genome/exome

sequencing with pCR and EFS

To evaluate the predictive and prognostic role of mutational burden.

Association of tumor antigens with pCR and EFS

To evaluate the predictive and prognostic role of tumor antigens.

Association of microbiome with pCR and EFS

To evaluate the predictive and prognostic role of microbiome.

Association of ctDNA with pCR and EFS

To evaluate the predictive and prognostic role of ctDNA.

Immune monitoring and association of immune markers to response

To evaluate the predictive role of other immune markers (e.g. HLA-G,

granulocyte-to-dendritic cell-ratio).

Analysis of further novel biomarkers of response and resistance to checkpoint

inhibitors

To use baseline and on therapy specimens to explore potential new

biomarkers of responses and resistance to neoadjuvant administration of

durvalumab with chemotherapy followed by adjuvant administration of

durvalumab.


Inclusion Criteria Patients will be eligible for study participation only if they comply with the

following criteria:

1. Written informed consent for all study procedures according to local

regulatory requirements prior to beginning specific protocol procedures.

2. Unilateral or bilateral primary carcinoma of the breast, confirmed

histologically by core biopsy. Fine-needle aspiration alone is not sufficient.

Incisional biopsy or lumpectomy prior to randomisation is not allowed. In

case of bilateral cancer, the investigator has to decide prospectively which

side will be evaluated for the primary endpoint pCR. In case of bilateral

breast cancer, all lesions have to be histologically proven TNBC (local

assessment).

3. Tumor lesion in the breast or the nodes must be measurable in two

dimensions, preferably by sonography. In case of inflammatory disease, the

extent of inflammation can be used as measurable lesion.

4. Patients must be in the following stages of disease:

IIA: T2 N0 M0, T1 N1 M0

IIB: T2 N1 M0, T3 N0 M0

IIIA: T0–2 N2 M0, T3 N1–2 M0

IIIB: T4 N0–2 M0

IIIC: T1-4 N3 M0

In patients with multifocal or multicentric breast cancer, the largest lesion

should be measured.

5. Triple negative disease with centrally confirmed ER negative/PR

negative/HER2 negative, and centrally confirmed Ki-67 value (target lesion).

ER negative is defined as <10%, PR negative is defined as <10% stained cells

and HER2-negative is defined as either IHC 0/1+ or IHC 2+ and in-situ

hybridisation (ISH) of either ratio <2.0 or less than 6 copies of HER2 per

tumor cell.

6. Stromal TILs will be centrally evaluated in three groups: low immune

infiltrate (0-10% stromal TILs), intermediate immune infiltrate (11-59%

stromal TILs) and lymphocyte-predominant breast cancer (60-100% stromal

TILs).

7. PD-L1 status will be evaluated centrally by IHC.

8. Age 18 years. Age must be 20 for patients enrolled in Japan.

9. Male and female.

10. ECOG Performance status 0-1.

11. Normal cardiac function must be confirmed by ECG and cardiac ultrasound

(LVEF or shortening fraction) within 3 months prior to randomization.

Results for LVEF must be above the normal limit of the institution.

12. Laboratory requirements:

Hematology

- Absolute neutrophil count (ANC) 1,5 x 109 / L

- Platelets 100 x 109 / L

- Hemoglobin 10 g/dL (6.2 mmol/L)

Hepatic function

- Total bilirubin <1.5x UNL

- AST and ALT 1.5x UNL

- Alkaline phosphatase 2.5x UNL.

Renal Function

- <1.25x ULN creatinine


Thyroid function

- Serum TSH within normal limits prior to randomisation.

- In case of abnormal serum TSH additional fT3 and fT4 must be

performed. Initiation or adjustment of thyroid medication is allowed

to improve TSH value to meet entry criteria.

13. Negative pregnancy test (urine or serum) within 14 days prior to

randomization for all women of childbearing potential. A woman is

considered to be of childbearing potential if she is not postmenopausal.

Postmenopausal is defined as:

Age 60 years.

Age <60 years and 12 continuous months of amenorrhea with no

identified cause other than menopause.

Surgical sterilization (bilateral oophorectomy and/or hysterectomy).

14. For women of childbearing potential and males with partners of childbearing

potential: agreement to remain abstinent (refrain from heterosexual

intercourse) or use contraceptive methods that result in a failure rate of

1% per year during the treatment period and for at least 3 months after

the last dose of durvalumab and/or 6 months after the last dose of

chemotherapy. Examples of non hormonal contraceptive methods with a

failure rate of 1% per year include: bilateral tubal ligation; male partner

sterilization; intrauterine devices.

15. Complete staging work-up within 3 months prior to randomization:

Breast imaging by breast ultrasound plus either bilateral mammography

or breast MRI (one of those 21 day),

Chest X-ray (PA and lateral),

Abdominal ultrasound or CT scan or MRI,

Bone scan may be performed additionally according to local guidelines.

In case of positive bone scan, bone X-ray is mandatory.

16. Patient must be willing and able to comply with scheduled visits, treatment

plans, laboratory tests, and other study procedures.

Exclusion Criteria 1. Known hypersensitivity reaction to one of the compounds or substances

used in this protocol.

2. Sentinel node biopsy or axillary dissection prior to start of neoadjuvant

therapy.

3. Patients with definitive clinical or radiologic evidence of Stage IV cancer

(metastatic disease) are not eligible.

4. Patients with a history of any malignancy are ineligible with the following

exeptions:

Patient has been disease-free for at least 5 years and is at low risk for

recurrence of that malignancy (at the investigator’s discretion).

CIS of the cervix, basal cell and squamous cell carcinomas of the skin.

5. All previous chemotherapies for any malignancy.

6. Treatment (including radiation therapy, chemotherapy or targeted therapy)

for the currently diagnosed breast cancer prior to randomization.

7. Sex hormones prior treatment must be stopped before study entry.

Concurrent treatment with GnRH-analogues allowed.

8. Any previous treatment with a PD1 or PD-L1 inhibitor, including but not

limited to durvalumab.

9. Participation in another clinical trial with any investigational, not marketed

drug within 30 days prior to study entry.


10. Female patients: pregnancy or lactation at the time of randomization or

intention to become pregnant during the study and up to 3 months after

treatment with durvalumab and/or up to 6 months after chemotherapy.

11. Inadequate general condition (not fit for anthracycline-taxane-based

chemotherapy).

12. Body weight ≤30kg.

13. Major surgery within 28 days of initiation of study treatment.

14. Known or suspected congestive heart failure (>NYHA I) and/or coronary

heart disease, angina pectoris requiring antianginal medication, previous

history of myocardial infarction, evidence of prior infarction on ECG,

uncontrolled or poorly controlled arterial hypertension (i.e. BP >150 / 90

mm Hg under treatment with at maximum three antihypertensive drugs),

rhythm abnormalities requiring permanent treatment (excluding chronic

artrial fibrillation not requiring a pacemaker), clinically significant valvular

heart disease, supraventricular and nodal arrhythmias requiring a

pacemaker or not controlled with medication; conduction abnormality

requiring a pacemaker.

15. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.,

bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis,

or evidence of active pneumonitis on screening chest CT scan.

16. Active or prior documented inflammatory bowel disease (e.g., Crohn’s

disease, ulcerative colitis).

17. History of primary immunodeficiency.

18. History of allogeneic organ transplant.

19. Uncontrolled intercurrent illness including, but not limited to serious chronic

gastrointestinal conditions associated with diarrhea, active peptic ulcer

disease or gastritis, active bleeding diatheses, or active interstitial lung

disease.

20. Receipt of live attenuated vaccination within 30 days prior to study entry or

within 30 days of receiving durvalumab.

21. Active or history of autoimmune disease or immune deficiency, including

but not limited to myasthenia gravis, myositis, autoimmune hepatitis,

systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel

disease (patients with a history of diverticulosis might be eligible)

antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome,

Guillain-Barré syndrome, sarcoidosis syndrome, or multiple sclerosis (see

section 24.8) with the following exceptions:

a. Patients with a history of autoimmune-related hypothyroidism on a

stable dose of thyroid replacement hormone may be eligible for this

study.

b. Patients with controlled Type 1 diabetes mellitus on a stable dose of

insulin regimen may be eligible for this study.

c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo

with dermatologic manifestations only (e.g., patients with psoriatic

arthritis are excluded) are permitted provided all of following

conditions are met:

- Rash must cover < 10% of body surface area.

- Disease is well controlled at baseline and requires only low-potency

topical corticosteroids.

- No occurrence of acute exacerbations of the underlying condition


requiring psoralen plus ultraviolet A radiation, methotrexate,

retinoids, biologic agents, oral calcineurin inhibitors, or high-potency

or oral corticosteroids within the previous 12 months.

22. History of significant neurological or psychiatric disorders including

psychotic disorders, dementia or seizures that would prohibit the

understanding and giving of informed consent.

23. Any condition that, in the opinion of the investigator, would interfere with

evaluation of study treatment or interpretation of patient safety or study

results.

24. Pre-existing motor or sensory neuropathy of a severity ≥ grade 2 by NCI-

CTCAE criteria v5.0.

25. Known currently active infection including tuberculosis (clinical evaluation

that includes clinical history, physical examination and radiographic

findings, and tuberculosis testing in line with local practice), hepatitis B

(known positive HBV surface antigen (HBsAg) result), hepatitis C, or human

immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or

resolved HBV infection (defined as the presence of hepatitis B core antibody

[anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis

C (HCV) antibody are eligible only if polymerase chain reaction is negative

for HCV RNA.

26. Incomplete wound healing or unhealed bone fracture.

27. Contraindications for the use of corticosteroids.

28. Concurrent treatment with:

chronic corticosteroids prior to study entry with the exceptions of

intranasal and inhaled corticosteroids or systemic corticosteroids at

physiological doses, which are not to exceed 10 mg/day of prednisone,

or equivalent corticosteroid.

other immunosuppressive medication (e.g. low dose MTX, anti-TNFα

antibodies).

Randomisation Patients will be assigned to treatment arms using randomization in stratified

permuted blocks. Eligible triple-negative breast cancer patients will be

randomized in a 1:1 ratio to receive either

• Durvalumab followed by

• paclitaxel +/- carboplatin / durvalumab followed by

• doxorubicin / cyclophosphamide / durvalumab or

• epirubicin / cyclophosphamide / durvalumab followed by

• adjuvant durvalumab after surgery followed by

• follow-up

OR

• paclitaxel +/- carboplatin followed by

• doxorubicin / cyclophosphamide or

• epirubicin / cyclophosphamide followed by

• observation after surgery followed by

• follow-up

Stratification

Factors

The stratification factors for the study are:

1. PD-L1 Status (<1% (negative) vs ≥1% (positive))

2. Intended carboplatin use (yes; no)

3. Clinical size of the primary tumor (≤3.0 cm; >3.0 cm, cT4)


Statistical

Methods

Analyses sets

The 'intent-to-treat' (ITT) set includes all patients who are randomized

(including those who have not started treatment). Patients will be analysed

according to the group they were randomized to.

The 'per-protocol' analysis set is a subset of the ITT set and excludes patients in

whom pre-defined major protocol deviation occurred; the detailed definition of

major protocol violations is provided in protocol section Fehler! Verweisquelle

konnte nicht gefunden werden..

The safety set includes all patients who receive at least one dose of study

therapy and will be used for the toxicity endpoints. Patients will be analysed

according to treatment actually received, thus any patient receiving at least one

dose of durvalumab will comprise the experimental group.

Analyses of primary endpoints

The main analysis of the primary endpoints will be performed in the ITT set. The

overall significance level of alpha=0.05 will be non-equally split between two

primary endpoints.

pCR rate in breast and nodes (ypT0/ypN0)

Pathological response will be assessed considering all removed breast and

lymphatic tissues from all surgeries.

Patients with no axillary surgery at all will be counted as no pCR. Patients

who have not received breast surgery will be counted as no pCR. Analysis of

pCR will be performed after all patients have had surgery and after

information from all pathology reports are captured on the corresponding

CRF.

The rate of pCR will be summarized per treatment arm and overall, two-

sided 95% confidence intervals will be calculated according to Pearson and

Clopper.

The difference in the rates of pathological complete remission rates will be

evaluated as odds ratio and will be tested with a two-sided Cochran-Mantel-

Haenszel test using an alpha level of 0.001.

Event free survival (EFS)

The two treatment arms will be compared regarding EFS in the ITT

population using a 2-sided stratified log-rank test at the overall significance

level 0.049. The factors used in the stratified log-rank test will be:

- PD-L1 Status (<1% (negative) vs ≥1% (positive))

- Intended carboplatin use (yes vs no),

- Tumor size (≤ 3cm vs. >3cm and T4).

The nominal significance level for the final analysis of EFS is 0.043 because of

the two planned efficacy interim analyses.

For subjects with no EFS event, EFS time will be censored at the date of last

disease assessment or cut-off date, whichever comes first. Patients alive

who do not have post baseline disease assessment will have their EFS times

censored at Day 1.

EFS curves will be estimated in each treatment arm using the Kaplan-Meier

method. Cox regression model stratified by the factors used in the stratified

log-rank test will be used to estimate the treatment hazard ratio. The EFS

rates at 3 years will also be estimated for each arm. The final analysis will

take place when 390 EFS events are observed which is estimated to occur


approximately 66 months after first patient randomized.

In case that new data will emerge that the subgroup of PD-L1 positive

patients benefit more from treatment with Durvalumab, testing of

differences between treatment arms in co-primary endpoint EFS will be

included in hierarchical testing.

Analyses of secondary endpoints

Time to event curves for the secondary time to event endpoints will be

estimated in each treatment arm using the Kaplan-Meier method and stratified

log-rank tests will be used. Cox regression models stratified by PD-L1- Status

(<1% (negative) vs ≥1% (positive), intended carboplatin use (yes vs no), and

Tumor size (<= 3cm vs. >3cm and T4) will be used to estimate the treatment

hazard ratio.

Subgroup analysis for the primary endpoints will be performed in the groups

defined by the stratification factors using the same methods as for the analysis

of the primary endpoints.

OS will be analysed using a hierarchical test procedure (for details see section

Fehler! Verweisquelle konnte nicht gefunden werden.).

For all other secondary time to event endpoints no adjustments for multiple

comparisons will be made and the significance level for those tests is set to a

significance level of 0.05.

Pathological complete response of other definitions as well as breast

conservation, and positive nodal status conversion will be summarized as

rates in each treatment group. Two-sided 95% confidence intervals will be

calculated according to Pearson and Clopper, and the Cochran-Mantel-

Haenszel test will be performed to evaluate the difference of rates in

treatment arms; these tests are considered explorative.

Safety, tolerability, and treatment compliance: the number and percentage

of patients whose treatment had to be reduced, delayed or permanently

stopped will be summarized for each treatment arm, reasons for dose

modification, delay and premature termination will be categorized according

to the main reason and will be presented in frequency tables. Treatment

arms will be compared regarding the occurrence of any adverse events (AE)

(grade 1-5), low grade AE (grade 1-2), and high grade AE (grade 3-5) using

Fisher’s exact test. Those tests are descriptive in nature and no adjustments

for multiple comparisons will be made.

PRO analyses

For each treatment group and at each time point, the number and

percentage of patients who completed the instrument will be

summarized, as well as the reasons for non-completion of these

questionnaires. An instrument is considered completed if at least one

item was answered by the patient.

For each of the FACT-B scales and for the EQ-5D-5L instrument, the

results will be summarized using descriptive statistics for each treatment

group at each time point. Results based on the observed values as well as

changes from baseline (including both within group and between group

differences) will be displayed. For each of the scales, statistical

comparison between the two treatment groups will be based on a

longitudinal repeated measures analysis using a mixed effects model. No


adjustments for multiple comparisons will be made.

Sample Size

Determination

Sample size was determined to test the primary endpoint event free survival

(EFS). Hazard rates of EFS (based on data of the GeparSixto und GeparSepto

trials) are not constant over time and thus hazard rates per year were used

(year 1: 0.007, year 2: 0.011, year 3: 0.006, year 4 and all subsequent

years: 0.004).

A total of 390 events are required to achieve 80% power to detect a hazard ratio

(HR) of 0.75 in favor of durvalumab plus chemotherapy using a two-sided,

stratified log-rank test at a significance level of 0.049. This corresponds to an

approximate improvement in 3-years EFS rates from 75% to 81%.

The sample size estimation includes two interim analyses planned at 50% and

75% of total EFS events, given a 1:1 randomization. O’Brien–Fleming type

stopping boundaries based on the Lan-DeMets spending function will be used.

Assuming a 5% drop-out rate on either treatment arm and a non-uniform

enrolment rate with 111 patients per month at the peak, it was estimated that

1528 patients will need to be randomized (764 patients per arm).

The final EFS analysis will take place when approximately 390 EFS events are

observed which is estimated to occur approximately 66 months after first

patient randomized.

For the co-primary endpoint pCR a power calculation based on the sample size

of 1528 patients (calculated for the primary endpoint EFS) was performed. For

the control arm (without Durvalumab) a pCR rate of 55% was assumed. The

available sample size of 1528 patients will provide at least 82% power to detect

an improvement in pCR rate of 11% or an even higher power if the

improvement is greater.

Overall survival (OS) is defined as key secondary endpoint. For the analysis of OS

a hierarchical test procedure will be applied (for details section Fehler!

Verweisquelle konnte nicht gefunden werden.).

For the timing of the final OS analysis a risk reduction of 20% was considered

clinically relevant (HR=0.8). Hazard rates per year were used: year 1 = 0.002,

year 2 = 0.006, year 3 = 0.005, year 4 = 0.004, all further years: 0.001. Assuming

an OS rate of 81% at 5 years in the control arm, on a significance level of 0.049,

47% power will be achieved if the analysis will be performed at a fixed time of

4.5 yrs (54 mo) after final analysis (equivalent to 10 yrs after first patient

randomized). It is estimated that approximately 293 OS events will have been

documented at this time. An interim analysis of OS will be conducted at the

time of final EFS analysis (approximately 66 months after first patient

randomized), when 240 OS events will have been documented.


Interim Analyses

for Efficacy

Two efficacy interim analyses (EIA) of EFS will be performed in the study, both

with the objective to allow for early stopping of the trial due to overwhelming

efficacy. O’Brien-Fleming type stopping boundaries based on the Lan-DeMets

spending function will be applied.

The first EIA will take place after the first 195 events (50% of the total events)

have occurred, which is estimated approximately 35 months after first patient

randomized. The second EIA will take place after the first 293 events (75% of the

total events) have occurred, which is estimated approximately 46 months after

first patient randomized.

The final EFS analysis will take place when approximately 390 EFS events are

observed which is estimated to occur approximately 66 months after first

patient randomized. At that time an interim analysis of OS will be conducted

when approximately 240 OS events will have been documented.

The following table summarizes the parameter of both interim analyses and of

the final analysis of EFS. The actual nominal alpha levels for the interim analyses

and for the final analysis will depend on the fraction of total events occurred at

the time of interim analysis, in order to control the overall type I error for the

endpoint of EFS.

Analysis Events

(IF)

Time HR Cum.

alpha

Cum.

Power

Objective

1. EIA 195

(50%)

35

mo

0.65 0.003 17% Safety

overwhelming

efficacy

2. EIA 293(75%) 46

mo

0.76 0.019 54% Safety

overwhelming

efficacy

Final

EFS

390

(100%)

66

mo

0.82 0.049 80% final EFS

analysis

interim OS

analysis

* IF=information fraction

Enrollment period It would take about 24 months to accrue 1528 patients. (Q-II 2019 – Q-II 2021).

Follow-up A total follow-up period of about 96 months is planned after the last patient is

randomized. The final EFS analysis will take place when 390 EFS events are

observed which is estimated to occur approximately 42 months after last

patient randomized.

The final OS analysis will take place approximately 96 months after last patient

randomized (when approximately 293 OS events will have been observed).

Number of sites It is planned to conduct the study within approximately 250 sites globally.


Timelines: FPI QII 2019

LPI QII 2021

LP EOT QIV 2022

pCR Analysis QI 2022

1st Interim Analysis QII 2022

2nd Interim Analysis QI 2023

Final EFS QIV 2024

Final OS Analysis QII 2029

Figure 1

GBG 99-GeparTREIZE Study Design

Figure Legends:

* Paclitaxel 80 mg/m2 IV weekly x 12 doses

** Carboplatin AUC5 IV day 1 every 3 weeks for 4 cycles or carboplatin AUC2 IV weekly x 12 doses

† Durvalumab 1500 mg IV will be given as monotherapy 2 weeks prior to start of chemotherapy

(priming) followed by Durvalumab 1500 mg IV day 1 every 4 weeks until surgery. Following

recovery from surgery, patients will reinitiate Durvalumab 1500 mg IV day 1 every 4 for another

12 months

†† Epirubicin (E) 90 mg/m2 IV + cyclophosphamide (C) 600 mg/m2 IV Day 1 every 2 or 3 weeks for 4

cycles or doxorubicin (A) 60 mg/m2 IV + cyclophosphamide (C) 600 mg/m2 IV Day 1 every 2 or 3

weeks for 4 cycles

Collection of biomaterials (tissue and blood samples; refer to 11.3 and 13.0)

Documents

SYNOPSIS OF STUDY PROTOCOL VERSION 1.0 FROM 14-NOV-2019 99-GeparTREIZE_Protocol... · SYNOPSIS OF STUDY PROTOCOL VERSION 1.0 FROM 14-NOV-2019 Study Title A Phase III, Randomized,