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Title A Randomised, Double-Blind, Parallel Group, Placebo-Controlled Multi-Centre Phase III Study to Assess the Efficacy and Safety of Olaparib Versus Placebo as Adjuvant Treatment in Patients with Germline BRCA1/2 Mutations and High Risk HER2 Negative Primary Breast Cancer Who Have Completed Definitive Local Treatment and Neoadjuvant or Adjuvant Chemotherapy

IRB NSABPB55

CC 16-602

Hospital Main Campus

Phase Phase 3

Disease Breast

Drug Olaparib

Description

Primary objective

• To assess the effect of adjuvant treatment with olaparib on Invasive Disease Free Survival (IDFS).

Secondary objectives

1. To assess the effect of adjuvant treatment with olaparib on overall survival (OS)
2. To assess the effect of adjuvant treatment with olaparib on Distant Disease Free Survival (DDFS)
3. To assess the effect of adjuvant treatment with olaparib on the incidence of new primary contralateral breast cancers (invasive and non-invasive), new primary ovarian cancer, new primary fallopian tube cancer and new primary peritoneal cancer
4. To assess the effect of olaparib on patient reported outcomes using the FACIT-Fatigue and EORTC QLQ-C30 QOL questionnaires
5. To assess the efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis)
6. To determine the exposure to olaparib (in plasma) in patients receiving olaparib as adjuvant therapy

Safety objective

• To assess the safety and tolerability of adjuvant treatment with olaparib

Exploratory objectives

1. To assess the consistency of treatment effects on efficacy endpoints across potential or expected prognostic factors, including the baseline stratification factors with special emphasis on hormone receptor status.
2. To explore methods for estimating overall survival (OS) adjusting for the impact of confounding by subsequent therapies, specifically the control arm receiving subsequent Polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerisation (PARP) inhibitors or platinum salts
3. To explore whether resistance mechanisms to olaparib can be identified through analysis of tumour and blood sample derivatives (cells, plasma and protein and nucleic acid derivatives) - archival tumour samples (mandatory), tumour biopsy at recurrence (optional), and blood samples at baseline, 30 days post olaparib treatment and on disease recurrence (mandatory). For adjuvant patients this refers to the surgical specimen; for neoadjuvant patients, both the pre-treatment biopsy and the surgical specimen with residual disease specimen are requested, but only one is mandatory. If the surgery tumour blocks are available, but cannot be submitted, sites may submit a portion of invasive tumour from the original block, either by taking at least one core of at least 3 mm in diameter, or by splitting the original block in two parts, and re-embedding one in a new block for central submission. If blocks containing pre-neoadjuvant treatment core biopsies are available but cannot be submitted, sections mounted on glass slides prepared from the block can be provided. If tumour sample can't be provided as requested above or if it's not available, approval by Study Team for patient's entry into the trial is required.
4. To determine the frequency of and describe the nature of BRCA mutation/s in tumour samples and to compare this with germline BRCA mutation status
5. Future exploratory research into factors that may influence development of cancer and/or response to treatment (where response is defined broadly to include efficacy, tolerability or safety) may be performed on the collected and stored tumour and blood samples
6. To collect and store DNA according to each country's local and ethical procedures for future exploratory research into genes/genetic variation that may influence response (i.e. distribution, safety, tolerability and efficacy) to study treatments and/or susceptibility to disease (optional)

Inclusion Criteria

1. Provision of informed consent prior to any study specific procedures
2. Female or male patients must be ≥18 years of age
3. For patients who underwent initial surgery and received adjuvant chemotherapy
   • TNBC patients must have been axillary node-positive (≥pN1, any tumour size) or axillary node negative (pN0) with invasive primary tumour pathological size > 2 cm (≥pT2).
   • ER and/or PgR positive/HER 2 negative patients must have had ≥ 4 pathologically confirmed positive lymph nodes.
   For patients who underwent neoadjuvant chemotherapy followed by surgery
   • TNBC patients must have residual invasive breast cancer in the breast and/or resected lymph nodes (non-pCR)
   • ER and/or PgR positive/HER2 negative patients must have residual invasive cancer in the breast and/or the resected lymph nodes (non-pCR) AND a CPS&EG score ≥3. Instructions on how to calculate the CPS&EG score (Mittendorf et al 2011; Jeruss et al 2008) are provided in Appendix J.
4. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the two following phenotypes:
   • TNBC defined as:
     • ER and PgR negative defined as IHC nuclear staining <1%. All ER and PgR assessments that are locally available must be negative. AND
     • HER2 negative (not eligible for anti-HER2 therapy) defined as:
       • IHC 0, 1+ without ISH OR
       • IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR
       • ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells (without IHC)
   • ER and/or PgR positive, HER2 negative breast cancer defined as:
     • ER and/or PgR positive defined as IHC nuclear staining ≥ 1%. Any tumour that has been locally assessed as ER and/or PgR positive in either the core biopsy or the surgical specimen is considered to be ER and/or PgR positive. AND
     • HER2 negative (not eligible for anti-HER2 therapy) defined as:
       • IHC 0, 1+ without ISH OR
       • IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR
       • ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells (without IHC)
   • Patients with multifocal or multicentric invasive disease are eligible as long as all the lesions for which HER2 characterization is available are HER2 negative.
   • Patients with synchronous bilateral invasive disease are eligible as long as all the lesions assessed for HER2 on both sides are negative.
   • In both cases, the lesion considered at highest risk for recurrence based on the investigator's discretion will be used for eligibility determination.
5. Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Local gBRCA testing results, if available, will be used for establishing eligibility. If local gBRCA testing results are not available, central testing will be provided for those patients who otherwise appear to be eligible (see Section 6.2.1).
6. Completed adequate breast surgery defined as:
   • The inked margins of breast conservation surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ with the exception of the posterior margin if this margin is the pectoralis major fascia or the anterior margin if this is the dermis. Patients with resection margins positive for lobular carcinoma in situ are eligible.
   • Patients with breast conservation must have adjuvant radiotherapy. Patients having mastectomy may have adjuvant radiotherapy according to local policy and/or international guidelines.
   Completed adequate axilla surgery defined as:
   • Adjuvant Chemotherapy Patients:
     • Sentinel lymph node biopsy alone if negative or if lymph node(s) only contain micrometastases (≤2.0 mm) OR
     • Positive sentinel lymph node biopsy followed by axillary nodal dissection or radiotherapy as per local guidelines OR
     • Axillary dissection
   • Neoadjuvant Chemotherapy Patients:
     • Sentinel lymph node biopsy performed before neoadjuvant chemotherapy:
       • If negative or if lymph node(s) only contain micrometastases (≤2.0 mm), additional axillary surgery is not required
       • If positive, axillary node dissection or axillary nodal radiotherapy should follow completion of neoadjuvant chemotherapy
   • Sentinel lymph node biopsy performed after neoadjuvant chemotherapy:
     • If negative, additional axillary surgery not mandated
     • If positive (micrometastases are regarded as positive), additional axillary surgery is required unless the patient is enrolled in an Executive Committee approved, Phase III multicentre clinical trials proposing radiotherapy as alternative treatment of the axilla
     • Axillary dissection
7. Completed at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or the combination of both. Prior platinum as potentially curative treatment for prior cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer is allowed. (For neoadjuvant patients all chemotherapy should be delivered prior to surgery. No further cycles of chemotherapy post-surgery are allowed.)
8. Patients must have adequate organ and bone marrow function measured within 28 days prior to randomisation with no blood transfusions (packed red blood cells and/or platelet transfusions) in the past 28 days prior to testing for organ and bone marrow function as defined below:
   • Haemoglobin ≥ 10.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
   • Platelet count ≥ 100 x 10⁹/L
   • Total Bilirubin ≤ ULN (institutional upper limit of normal) except elevated total bilirubin <1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin
   • AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN
   • ALP ≤ 2.5 x ULN
   To rule out metastatic breast cancer, patients with screening ALT/AST or ALP above institutional upper limit of normal should have liver ultrasound, CT or MRI at any time point between diagnosis of current breast cancer and randomisation. Screening bone scan is required if ALP and/or corrected calcium level are above the institutional upper limit. (Note PET/CT scan may be used as an alternative imaging techniques).
9. Serum or plasma creatinine ≤ 1.5 x ULN
10. ECOG performance status 0-1
11. Women who are not postmenopausal or have not undergone a hysterectomy must have documented negative pregnancy test within 28 days prior to randomisation.
    • Postmenopausal is defined as one or more of the following:
      • Age ≥ 60 yrs
      • Age < 60 and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment
      • Follicle stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range for women under 60
      • Radiation-induced oophorectomy with last menses >1 year ago
      • Bilateral oophorectomy
    Female patients of childbearing potential who are sexually active must agree, with their partners, to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for at least 1 month after the last dose of study drug, or they must totally/truly abstain from any form of sexual intercourse. Male patients must agree, with their partners who are sexually active and of childbearing potential, to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for 3 months after last dose of study drug, or they must totally/truly abstain from any form of sexual intercourse (For details please refer to Appendix F Acceptable Birth Control Methods).
12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
13. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumour, mandatory. NOTE: For adjuvant patients this refers to the surgical specimen; for neoadjuvant patients, both the pre-treatment biopsy and the surgical specimen with residual disease specimen are requested, but only one is mandatory. If the surgery tumour blocks are available, but cannot be submitted, sites may submit a portion of invasive tumour from the original block, either by taking at least one core of at least 3 mm in diameter, or by splitting the original block in two parts, and re-embedding one in a new block for central submission. If blocks containing pre-neoadjuvant treatment core biopsies are available but cannot be submitted, sections mounted on glass slides prepared from the block can be provided. If tumour sample can't be provided as requested above or if it's not available, approval by Study Team for patient's entry into the trial is required.
14. Patient should be randomised in the trial ideally within a maximum of 8 weeks of completion of their last treatment (surgery, chemotherapy or radiotherapy), but in no case longer than 12 weeks.

Exclusion Criteria

1. Involvement in the planning and/or conduct of the study.
2. Patients who do not have deleterious or suspected deleterious gBRCA1 and/or 2 mutations but only have BRCA1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favour polymorphism" or "benign polymorphism" etc.).
3. Previous randomisation in the present study.
4. Evidence of metastatic breast cancer. Patient considered at high risk of having disseminated disease (i.e. those with locally advanced disease, clinical N2-3 or pathological N1-3 with the exception of pN1a in adjuvant patients) should have a CT/MRI scan of the Thorax/Abdomen/Pelvis or any other area as clinically indicated the current breast cancer and randomisation to rule out metastatic breast cancer. (Note PET/CT scan may be used as an alternative imaging technique and precludes the need for bone scan). Patients with screening ALT/AST or ALP above institutional upper limit of normal should have liver ultrasound, CT or MRI at any time point between diagnosis of current breast cancer and randomisation. Screening bone scan is required if ALP and/or corrected calcium level are above the institutional upper limit. (Note PET CT scan may be used as an alternative imaging technique).
5. Exposure to an investigational product within 30 days or five half lives (whichever is the longer) prior to randomisation.
6. Any previous treatment with a PARP inhibitor, including olaparib and/or known hypersensitivity to any of the excipients of study treatment.
7. Patients with second primary malignancy, EXCEPTIONS:
   • adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma
   • other solid tumours and lymphomas (without bone marrow involvement) diagnosed ≥ 5 years prior to randomisation and treated with no evidence of disease recurrence and for whom no more than one line of chemotherapy was applied.
8. Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc ≤470 msec.
9. Patients receiving systemic chemotherapy within 3 weeks prior to randomisation.
10. Patients receiving adjuvant radiotherapy within 2 weeks prior to randomisation.
11. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. For further details and the minimum washout period prior to starting olaparib, refer to Appendix I.
12. Persistent toxicities (≥CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
13. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
14. Major surgery within 2 weeks prior to randomisation: patients must have recovered from any effects of any major surgery.
15. Patients considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, extensive bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that prohibits obtaining informed consent.
16. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
17. Pregnant or breastfeeding women.
18. Patients with known active Hepatitis B or C
19. Patients known to be HIV positive with one or more of the following:
    • Baseline CD4 count of < 250 cells/mm³
    • History of AIDS indicator conditions
    • Anti-retroviral therapy with any potent CYP3A4 inhibitor (see Section 5.6.2)
    • Previous allogeneic bone marrow transplant.
    • Whole blood transfusions in the last 120 days prior to entry to the study which may interfere with gBRCA testing (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no. 8)