Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

Study Overview
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Brief Summary
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This open label, randomised, controlled, multi-centre phase III study will assess the efficacy and safety of single agent olaparib vs standard of care based on physician's choice of capecitabine, vinorelbine or eribulin in metastatic breast cancer patients with gBRCA 1/2 mutations.

Official Title
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A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to Assess the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

Conditions
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Breast Cancer Metastatic, BRCA 1 Gene Mutation, BRCA 2 Gene Mutation

Intervention / Treatment
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* Drug: Olaparib
* Drug: Physician's choice chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious. Histologically or cytologically confirmed breast cancer with evidence of metastatic disease. Prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting. Prior platinum allowed as long as no breast cancer progression occurred on treatment or if given in adjuvant/neoadjuvant setting at least 12 months from last dose to study entry elapsed. ER/PR breast cancer positive patients 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. ECOG performance status 0-1. Adequate bone marrow, kidney and liver function. Exclusion Criteria: Prior treatment with PARP inhibitor. Patients with HER2 positive disease. More than 2 prior lines of chemotherapy for metastatic breast cancer. Untreated and/or uncontrolled brain metastases. Prior malignancy unless curatively treated and disease-free for > 5 years prior to study entry. Prior adequately treated non-melanoma skin cancer, in situ cancer of the cervix, DCIS or stage I grade 1 endometrial cancer allowed. Known HIV (Human Immunodeficiency Virus) infection. Pregnant or breast-feeding women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olaparib<br>Olaparib tablet 300mg bd po | Drug: Olaparib<br>* Patients will be administered olaparib orally twice daily (bid) at 300 mg. Two (2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 mL of water.<br>|
| Active Comparator: Physician's choice chemotherapy<br>Capecitabine 2500 mg/m2 d1-14 q 21, or Vinorelbine 30 mg/m2 d1,8 q 21, or Eribulin 1.4 mg/m2 d1,8 q 21 | Drug: Physician's choice chemotherapy<br>* Investigators will declare one of the following regimens: Capecitabine 2500 mg/m2 po daily (divided in 2 doses) x 14 days, repeat every 21 days Vinorelbine 30 mg/m2 IV Day 1 and Day 8, repeat every 21 days Eribulin 1.4 mg/m2 IV Day 1 and Day 8, repeat every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) | Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Radiological scans performed at baseline then every  6 weeks up to 24 weeks, then every   12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Second Progression or Death (PFS2) | Time from randomisation to the earliest of the progression event subsequent to the first objective radiological progression, or death. Second progression may involve any of; objective radiological or symptomatic progression or death. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Symptomatic progression is assessed by investigators based on clinical examination. | Second progression status reviewed every 8 weeks following the first objective radiological progression as per investigator assessment. Assessed up to a maximum of 30 months. | 
| Overall Survival (OS) | Time from randomisation until death due to any cause. | Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 30 months. | 
| Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) | Number of responders according to blinded independent central review (BICR) assessment. Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) for target lesions assessed by CT or MRI: Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as >=30% decrease in the sum of the longest diameter of target lesions; Overall Response = CR + PR. | Radiological scans performed at baseline then every  6 weeks up to 24 weeks, then every   12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months. | 
| Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30) | Change from baseline in global health status/quality of life (QoL) score assessed using a mixed model for repeated measures (MMRM) analysis, including all post-baseline global health status/QoL scores up to the latest scheduled visit where at least 20 patients on each treatment arm have a score. Global health status/QoL score is on a scale from 0 to 100. A higher score represents an improved health status/QoL. | EORTC QLQ-C30 assessments performed at baseline then every  6 weeks until objective radiological disease progression. Assessed up to a maximum of 30 months. | 
| Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm | Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Assessed in patients with 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). | Radiological scans performed at baseline then every  6 weeks up to 24 weeks, then every   12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months. | 
| Overall Survival (OS) at Final OS | Time from randomisation until death due to any cause. | Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 40 months. | 
| Overall Survival (OS) at Extended OS | Time from randomisation until death due to any cause. | Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Metastatic, Olaparib, BRCA, PARP inhibitor, HER2, chemotherapy