View Cancer Clinical Trials

Details

Title A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to assess the efficacy and safety of Olaparib Monotherapy versus Physician’s Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients with germline BRCA1/2 Mutations

IRB ZNCA1114

CC 14-656

Hospital Main Campus

Phase Phase 3

Disease Breast

Drug Olaparib

Description

Primary objective

1. To determine the efficacy of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by progression-free survival (PFS) using blinded independent central review (BICR) data assessed by Response Evaluation Criteria in Solid Tumours (RECIST 1.1).

Secondary objectives

1. To compare the efficacy of single agent olaparib versus physician's choice chemotherapy (capecitabine, vinorelbine or eribulin) by assessment of overall survival, time to second progression or death (PFS2) and objective response rate (ORR) using BICR data assessed by RECIST 1.1.
2. To assess the effect of olaparib on the Health-related Quality of Life (HRQoL) as measured by EORTC QLQ-C30 global QoL scale.
3. To assess 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).
4. To determine the exposure to olaparib in patients receiving olaparib monotherapy

Safety objective

1. To assess the safety and tolerability of single agent olaparib vs physician's choice chemotherapy (capecitabine, vinorelbine or eribulin)

Exploratory objectives

1. To explore the impact of olaparib on symptoms and HRQoL as measured by the EORTC QLQ-C30 disease related multi-item symptom and functional scales.
2. To explore patients' treatment satisfaction (as measured by the Satisfaction with Therapy scale of the CTSQ and the other sub-scales and items of the CTSQ) on Olaparib, compared to physician's choice chemotherapy.
3. To investigate the health economic impact of treatment and the disease on hospital related resource use.
4. To explore methods of estimating overall survival (OS) adjusting for the impact of the control arm receiving subsequent Polyadenosine 5'diphosphoribose [poly (ADP ribose)] polymerise (PARP) inhibitors or imbalances between the treatment arms for other potentially active agents.
5. To explore whether resistance mechanisms to olaparib can be identified through analysis of tumour and blood samples - archival tumour (mandatory if available), blood samples at baseline and on disease progression (mandated) and serial biopsies at baseline and disease progression (optional).
6. 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.
7. 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 archival tumour samples (mandatory if available), blood samples at baseline and on disease progression (mandated) and serial biopsies at baseline and disease progression (optional).
8. 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. Patients must be male or female ≥18 years of age
3. Histologically or cytologically confirmed breast cancer with evidence of metastatic disease
4. Documented 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) (See Section 3.1)
5. Patients must have received treatment with an anthracycline (e.g. doxorubicin, epirubicin) unless contraindicated and a taxane (e.g. paclitaxel, docetaxel) in either a neo-adjuvant / adjuvant or metastatic setting.
6. Patients who have received platinum (cisplatin or carboplatin, either as monotherapy or in combination) for advanced breast cancer are eligible to enter the study provided there has been no evidence of disease progression during the platinum chemotherapy
7. Patients who have received prior platinum based chemotherapy are eligible if platinum was given either as potentially curative treatment for a prior non-breast cancer (eg ovarian cancer) with no evidence of disease for ≥ 5 years prior to study entry or as adjuvant/neoadjuvant treatment for breast cancer provided at least 12 months have elapsed between the last dose of platinum-based treatment and randomization
8. Patients with estrogen and/or progesterone receptor-positive disease must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy
9. At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT (MRI where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
10. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
    • Haemoglobin ≥ 10.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
    • Platelet count ≥ 100 x 10⁹/L
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal
    • AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN
    • Serum or plasma creatinine ≤ 1.5 x institutional upper limit of normal (ULN)
11. ECOG performance status 0-1 within 21 days of randomization
12. Postmenopausal or hysterectomized; women of childbearing potential are eligible with a negative urine or serum pregnancy test documenting evidence of nonchildbearing status.Postmenopausal is defined as any of the following:
    • Age > 60 years
    • Age < 60 years and amenorrheic for 1 year or more in the absence of chemotherapy and/or hormonal treatment
    • luteinising hormone (LH), follicle stimulating hormone (FSH) and plasma oestradiol levels in the postmenopausal range for women under 60 years of age
    • radiation-induced oophorectomy with last menses >1 year ago
    • or surgical sterilisation (bilateral oophorectomy)
13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
14. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary tumour if available for inclusion in
    • the optional exploratory genetic research and/or
    • the optional tumour biopsy research, patients must fulfil the following criteria:
      • Provision of informed consent for genetic research
      • Provision of informed consent for tumour biopsy research

If a patient declines to participate in the optional exploratory genetic research or the optional tumour biopsy research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.

Exclusion Criteria

1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff/BCA staff and/or staff at the study site).
2. 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. Cytotoxic chemotherapy or non-hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Endocrine therapy must have been discontinued 7 or more days before Cycle 1 Day 1. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment.
4. Patients with HER2-positive disease (3+ by IHC or ISH amplified ≥ 2.0).
5. Previous randomisation in the present study.
6. Exposure to an investigational product within 30 days or 5 half lives (whichever is longer) prior to randomization
7. Any previous treatment with a PARP inhibitor, including olaparib.
8. Patients with second primary cancer, EXCEPTIONS: adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 years prior to study entry.
9. 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.
10. Patients cannot have received more than 2 prior lines of cytotoxic chemotherapy for metastatic disease. Prior treatments with hormonal therapy and non-hormonal targeted therapy are allowed and not counted as a prior line of cytotoxic chemotherapy. For the purposes of this protocol, the combination of an aromatase inhibitor and everolimus is not considered cytotoxic chemotherapy.
11. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. For further detail 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/treatment related acute myeloid leukaemia.
14. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
15. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
16. Patients considered a 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, unstable spinal cord compression, superior vena cava syndrome, extensive bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that would limit ability to comply with study procedures, and any other medical condition that, in the opinion of the investigator, places the patient at unacceptable risk of toxicity.
17. Patients with a history of treated CNS metastases are eligible, provided they meet all of the following criteria: Disease outside the CNS is present. No clinical evidence of progression since completion of CNS-directed therapy. Minimum of 2 weeks between completion of radiotherapy and Cycle 1 Day 1 and recovery from significant (Grade ≥3) acute toxicity with no ongoing requirement for > 10mg of prednisone per day or an equivalent dose of other corticosteroid.
18. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
19. Pregnant or breast feeding women.
20. Previous allogeneic bone marrow transplant.
21. Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
22. Whole blood transfusions in the last 120 days prior to enrolment 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.10)