Alpelisib Plus Olaparib in Platinum-resistant/Refractory, High-grade Serous Ovarian Cancer, With no Germline BRCA Mutation Detected

Study Overview
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Brief Summary
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The objective of this study is to assess the efficacy and safety of the combination of alpelisib and olaparib compared with single agent cytotoxic chemotherapy in patients with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected.

Detailed Description
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This study will include adult women with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected. Participants will be randomized in a 1:1 ratio to either alpelisib plus olaparib or single agent cytotoxic chemotherapy (paclitaxel or PLD) in this open-label, active controlled study. Participants will continue to receive study treatment until disease progression, unacceptable toxicity that precludes further treatment, or until discontinuation of study treatment due to any other reason. After treatment discontinuation, all participants will enter in the post-treatment follow-up period, which consists of a safety follow-up visit and a 9-week post-progression visit. Once they complete the post-treatment follow-up, participants will then enter the survival follow-up period.

Official Title
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EPIK-O: A Phase III, Multi-center, Randomized (1:1), Open-label, Active-controlled, Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Olaparib as Compared to Single Agent Cytotoxic Chemotherapy, in Participants With no Germline BRCA Mutation Detected, Platinum-resistant or Refractory, High-grade Serous Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Alpelisib
* Drug: Olaparib
* Drug: Paclitaxel
* Drug: Pegylated liposomal doxorubicin (PLD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation) If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125 Participant has no germline BRCA1/2 mutation as determined by an FDA approved assay. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions. The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry. Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment. Participant has adequate bone marrow and organ function Exclusion Criteria: Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor. Participant is concurrently using other anti-cancer therapy Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease Participant has had surgery within 14 days prior to starting study drug or has not recovered from major side effects Participant has not recovered from all toxicities 5 related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade ≤1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study. Participants with liver impairment and Child Pugh score B or C Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related side effects of such therapy (with the exception of alopecia). Participant has a known hypersensitivity to any of the study drugs or excipients Other inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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: Alpelisib+olaparib<br>Alpelisib 200 mg orally once daily and olaparib 200 mg orally twice daily on a continuous dosing schedule. | Drug: Alpelisib<br>* Alpelisib will be administered at 200 mg orally once daily following food on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle<br>* Other names: BYL719;Drug: Olaparib<br>* Olaparib will be administered at 200 mg orally twice daily irrespective of meals on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle.<br>|
| Active Comparator: Paclitaxel or PLD<br>Investigator's choice of one of 2 single agent cytotoxic chemotherapies: Paclitaxel 80 mg/m2 intravenously weekly or Pegylated liposomal Doxorubicin (PLD) 40-50 mg/m2 (physician discretion) intravenously every 28 days. | Drug: Paclitaxel<br>* Paclitaxel will be administered at 80 mg/m2 as an intravenous infusion weekly during a 28-day treatment cycle, starting on Cycle 1 Day 1, and on Day 8, Day 15 and Day 22 of every cycle thereafter<br>Drug: Pegylated liposomal doxorubicin (PLD)<br>* PLD will be administered at 40-50 mg/m2 (physician discretion) as an intravenous infusion once every 28-days in a 28 day treatment cycle, starting on Cycle 1 Day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria | PFS is defined as the time from the date of randomization to the date of the first documented progression (based on RECIST 1.1 criteria) or death due to any cause. If a participant has not had an event, PFS will be censored at the date of the last adequate tumor assessment | From randomization until the date of the first documented progression or death due to any cause, whichever comes first, assessed up to approximately 23 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive | From randomization until death, assessed up to approximately 44 months | 
| Number of participants with dose interruptions and dose reductions | Tolerability measured by the number of participants who have dose interruptions and dose reductions | From randomization until end of treatment, assessed up to approximately 18 months | 
| Dose intensity | Tolerability measured by the dose intensity of study drug. Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure. | From randomization until end of treatment, assessed up to approximately 18 months | 
| Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS) | PS will be assessed using ECOG scale. The scale consists of 6 grades (from 0 to 5) where 0 implies fully active and 5 implies dead. Time to definitive deterioration in ECOG PS is defined as the time from the date of randomization to the date when ECOG PS has definitively deteriorated by at least one category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG PS back to the baseline category or above. | Up to approximately 18 months | 
| Overall Response Rate (ORR) with confirmed response based on BIRC assessment according to RECIST 1.1 criteria | ORR with confirmed response is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), as per BIRC assessment according to RECIST 1.1 | Up to approximately 23 months | 
| Clinical benefit rate (CBR) with confirmed response based on BIRC assessment according to RECIST 1.1 | Clinical benefit rate (CBR) with confirmed response is defined as the proportion of participants with a best overall response of confirmed CR or PR, or stable disease (SD) lasting for a duration of at least 24 weeks. CR, PR and SD are defined as per BIRC assessment according to RECIST 1.1 | Up to approximately 23 months | 
| Time to response (TTR) based on BIRC assessment and according to RECIST 1.1 | TTR is defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR) based on tumor response data as per BIRC assessment and according to RECIST 1.1 | From the date of randomization to the first documented response, assessed up to approximately 23 months | 
| Duration of response (DOR) with confirmed response based on BIRC assessment and according to RECIST 1.1 | DOR with confirmed response only applies to participants whose best overall response is confirmed CR or confirmed PR according to RECIST 1.1 based on tumor response data per BIRC assessment. The start date is the date of first documented response of CR or PR and the end date is defined as the date of the first documented progression or death due to underlying cancer | From first documented response to first documented progression or death, assessed up to approximately 23 months | 
| Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of alpelisib and olaparib | The AUCtau will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | 
| Area under the curve from time zero to the last measurable concentration sampling time (AUClast)of alpelisib and olaparib | The AUClast will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | 
| Maximum Concentration (Cmax) of alpelisib and olaparib | The Cmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | 
| Time to reach maximum concentration (Tmax) of alpelisib and olaparib | The Tmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib | Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose) | 
| Change from baseline in Function Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI) | Health-related quality of life will be assessed by the Trial Outcome Index (TOI) of the Function Assessment of Cancer Therapy - Ovarian (FACT-O). The TOI is an index driven from FACT-O summarizing patients' physical and functional well-being as well as ovarian cancer-specific symptoms driven from FACT-O. The FACT-O TOI score ranges from 0 to 100 with higher scores indicating better quality of life. | From baseline up to approximately 44 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alpelisib, olaparib, paclitaxel, pegylated liposomal doxorubicin, high grade, serous ovarian, fallopian or peritoneal cancer, no germline BRCA mutation, BRCA wild type, platinum-resistant or refractory, prior PARP inhibitor exposure, EPIK-O