Olaparib Treatment in Relapsed Germline Breast Cancer Susceptibility Gene (BRCA) Mutated Ovarian Cancer Patients Who Have Progressed at Least 6 Months After Last Platinum Treatment and Have Received at Least 2 Prior Platinum Treatments

Study Overview
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Brief Summary
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Comparison of olaparib vs. physician's choice of single agent standard of care non-platinum based chemotherapy in patients with germline Breast Cancer susceptibility gene (gBRCA) mutated ovarian cancer who have progressed at least 6 months after the last platinum based chemotherapy. Patient should have received at least 2 prior lines of platinum based chemotherapy. The aim of the study is to assess the efficacy and safety of olaparib tablets.

Detailed Description
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This open label, randomised, controlled, multi-centre study will assess the efficacy and safety of single agent olaparib vs. standard of care, based on physician's choice of single agent chemotherapy ( i.e paclitaxel, or topotecan, or pegylated liposomal doxorubicin, or gemcitabine) in platinum sensitive or partially platinum sensitive relapsed ovarian cancer patients who carry germline deleterious or suspected deleterious BRCA mutation and who have received at least 2 prior lines of platinum based chemotherapy. Patients are eligible to undergo BRCA testing even if they have not yet had recurrence or progression of disease >6 months (>/=183 days) after completion of their last platinum therapy.

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 Physician's Choice Single Agent Chemotherapy in the Treatment of Platinum Sensitive Relapsed Ovarian Cancer in Patients Carrying Germline BRCA1/2 Mutations.

Conditions
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Relapsed Ovarian Cancer, BRCA Mutation, Platinum Sensitivity

Intervention / Treatment
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* Drug: OLAPARIB
* Drug: Single agent chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be ≥ 18 years of age Patients with histologically diagnosed relapsed high grade serous ovarian cancer (including primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer. Patients are eligible to undergo BRCA testing even if they have not yet had recurrence or progression of disease >6 months (>/=183 days) after completion of their last platinum therapy. Documented germline mutation in Breast Cancer susceptibility genes: BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) At least one lesion that can be accurately assessed at baseline by CT/MRI and is suitable for repeated assessment. Patients must have received at least 2 prior platinum based lines of chemotherapy - Patients must be partially platinum sensitive or platinum sensitive Patients must be suitable to start treatment with single agent chemotherapy based on physician's choice Patients must have normal organ and bone marrow function measured within 28 days of randomisation, Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Patients must have a life expectancy ≥ 16 weeks Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing. Exclusion Criteria: BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental Exposure to any investigational product within 30 days or 5 half lives (whichever is longer) prior to randomisation Any previous treatment with a Polyadenosine 5'diphosphoribose polymerisation (PARP) inhibitor, including olaparib. Patients who have platinum resistant or refractory disease Patients receiving any systemic chemotherapy within 3 weeks prior to first dose of study treatment Previous single agent exposure to the selected chemotherapy regimen for randomisation. - Prior malignancy in the last 5 years, unless curatively treated and recurrence free (few exceptions apply).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/OLAPARIB<br>olaparib 300mg oral tablets; twice daily | Drug: OLAPARIB<br>* 300 mg olaparib tablets taken orally twice daily. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria.<br>|
| Active Comparator: 2/CHEMOTHERAPY<br>Physician's choice single agent chemotherapy | Drug: Single agent chemotherapy<br>* Treatment of relapsed disease with single agent chemotherapy based on physician's choice of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | To determine the efficacy of olaparib vs. physician's choice single agent chemotherapy by assessment of Objective Response Rate (ORR) using blinded independent central review (BICR) Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used by a Blinded Independent Central Review (BICR) to assess participant response to treatment ORR is the number of participants with Complete Response (CR) or Partial Response (PR) in the Measurable Disease Analysis Set (MDAS). Complete response is declared when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each. Partial response is declared when there is a decrease in sum of diameters of target lesions ≥ 30%. | RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by progression free survival (PFS) using BICR assessment according to RECIST 1.1 criteria PFS is defined as the time from randomization until the date of objective radiological disease progression according to RECIST 1.1 or death (by any cause in the absence of disease progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to disease progression (i.e., date of RECIST progression/death or censoring - date of randomization +1). | RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 
| Time From Randomisation to Second Progression (PFS2) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by second progression (PFS2). Time from randomization to PFS2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to first progression or death. The date of second progression was recorded by the investigator and defined according to local standard clinical practice, and could involve objective radiological, clinical, cancer antigen-125 (CA-125) progression or death. CA-125 progression was assessed per Gynecological Cancer Intergroup (GCIG) criteria. | Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Overall Survival (OS) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by overall survival (OS). Overall survival is defined as the time from the date of randomisation until death due to any cause. | Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Time To Earliest Progression By RECIST 1.1 Or Cancer Antigen (CA) -125 Or Death | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time to earliest progression by RECIST 1.1 or CA-125 or death. Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used to assess participant response to treatment. CA-125 progression was assessed per Gynecological Cancer Intergroup (GCIG). | RECIST and CA-125 follow-up assessments performed every 8 weeks (±1week), up to 48 weeks, then every 12 weeks (±1week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 
| Time From Randomization To First Subsequent Therapy Or Death (TFST) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time from randomisation to first subsequent therapy or death (TFST) TFST is defined as the time from the date of randomisation to the earlier of first subsequent chemotherapy start date or death. Anti-cancer treatments include chemotherapy and targeted agents. | Anti-cancer treatments initiated post discontinuation of study treatment and investigator's opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Time From Randomization To Second Subsequent Therapy Or Death (TSST) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time from randomisation to second subsequent therapy or death (TSST) TSST was defined as the time from the date of randomisation to the earlier of second subsequent chemotherapy start date or death. Anti-cancer treatments include chemotherapy and targeted agents. | Anti-cancer treatments initiated post discontinuation of study treatment and investigator's opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Time From Randomization To Study Treatment Discontinuation Or Death (TDT) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time to study treatment discontinuation or death (TDT) TDT was defined as the time from randomization to the earlier of the date of study treatment discontinuation or death. | Patients randomised to Olaparib administer their tablets orally at a dose of 300 mg twice daily and continue Olaparib until objective disease progression. Assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Duration of Response (DoR) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by duration of response (DoR) by BICR using RECIST 1.1 criteria for evaluable patients. Duration of response is the time from the first documentation of complete response (CR) or partial response (PR) until the date of progression or death, or the last evaluable RECIST assessment for participants that do not progress or progress after 2 missed assessments. Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used to assess participant response to treatment. | RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 
| Time to Response (TTR) | To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time to response (TTR) by BICR using RECIST 1.1 criteria for evaluable patients. TTR was defined as the time from randomization until the date of first documented response by Blinded independent central review (BICR) assessment. | RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 
| Mean Change From Baseline In Trial Outcome Index (TOI) Score | To compare the efficacy of single agent olaparib versus physician's choice single agent chemotherapy on the Health-related Quality of Life (HRQoL) as measured by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) The TOI score was derived from the sum of the scores of the 25 items included in the physical well-being (7 items), functional well-being (7 items), and additional concerns ovarian cancer subscale (11 items) of the FACT-O questionnaire Version 4. TOI score ranges from 0 to 100, a higher score indicates a higher HRQoL. A negative change in score from baseline indicated a worsening in symptoms. | Baseline (Day 1) to Week 48 (±1 week). DCO: 10Oct2018 | 
| Number of Participants Who Show an Improvement in TOI Score | To compare the efficacy of single agent olaparib versus physician's choice single agent chemotherapy on the Health-related Quality of Life (HRQoL) as measured by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) The TOI score was derived from the sum of the scores of the 25 items included in the physical well-being (7 items), functional well-being (7 items), and additional concerns ovarian cancer subscale (11 items) of the FACT-O questionnaire Version 4. TOI score ranges from 0 to 100, a higher score indicates a higher health-related quality of life (HRQoL). A change in at least 10 points was considered clinically relevant. | Baseline (Day 1) to Week 48 (±1 week). DCO: 10Oct2018 | 
| Objective Response Rate (ORR) in Breast Cancer Susceptibility (BRCA) Gene Population by Blinded Independent Central Review (BICR) | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). The number of participants with complete or partial response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Partial response is declared when there is a decrease in sum of target disease ≥ 30%. Complete response is declared when all lesions have disappeared or all lesions have disappeared and all nodal disease is < 10 mm each. | RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 
| Number of Participants Who Experienced Disease Progression or Death in BRCA Gene Population by Blinded Independent Central Review (BICR) | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). Progressive disease was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | RECIST follow-up assessments performed every 8 weeks (±1 week), up to 48 weeks, then every 12 weeks (±1 week) from randomisation, assessed from date of first patient randomised to data cut off: 10Oct2018 (approx. 3 years 8 months) | 
| Number of Participants Who Experienced Second Progression or Death (PFS2) in BRCA Gene Population | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). | Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Overall Survival (OS) in BRCA Gene Population | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). OS in BRCA gene population was measured by the number of participants who died due to any cause. | Visits to occur every 12 weeks from the date of first progression, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Number of Participants Who Discontinued Study Treatment or Died in BRCA Gene Population | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). | Patients randomised to Olaparib administer their tablets orally at a dose of 300 mg twice daily and continue Olaparib until objective disease progression. Assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Number of Participants Who Received Subsequent Chemotherapy or Died in BRCA Gene Population | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). Anti-cancer treatments include chemotherapy and targeted agents. | Anti-cancer treatments initiated post discontinuation of study treatment and investigator's opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Number of Participants Who Received Second Subsequent Chemotherapy or Died in BRCA Gene Population | BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis). Anti-cancer treatments include chemotherapy and targeted agents. | Anti-cancer treatments initiated post discontinuation of study treatment and investigator's opinion of response and date of progression recorded, assessed from date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 
| Geometric Mean Plasma Concentration of Olaparib | Summary of plasma concentrations (ug/mL) of olaparib | Day 1, 1 hour post-dose and Day 29 pre-dose. DCO: 10Oct2018 | 
| Number of Participants Who Experience at Least One Adverse Event (AE) | An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. | Safety Follow-up 30 days after last dose of IP, assessed from the date of first patient randomised to data cut off: 16Apr2021 (approx. 6 years 2 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA, ovarian, platinum, chemotherapy,