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

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ClinicalTrials.gov Identifier: NCT04729387
Recruitment Status : Recruiting
First Posted : January 28, 2021
Last Update Posted : May 24, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE January 25, 2021
First Posted Date  ICMJE January 28, 2021
Last Update Posted Date May 24, 2022
Actual Study Start Date  ICMJE July 2, 2021
Estimated Primary Completion Date June 2, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 25, 2021)
Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria [ Time Frame: 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 ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 25, 2021)
  • Overall survival [ Time Frame: From randomization until death, assessed up to approximately 44 months ]
    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
  • Number of participants with dose interruptions and dose reductions [ Time Frame: From randomization until end of treatment, assessed up to approximately 18 months ]
    Tolerability measured by the number of participants who have dose interruptions and dose reductions
  • Dose intensity [ Time Frame: From randomization until end of treatment, assessed up to approximately 18 months ]
    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.
  • Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS) [ Time Frame: Up to approximately 18 months ]
    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.
  • Overall Response Rate (ORR) with confirmed response based on BIRC assessment according to RECIST 1.1 criteria [ Time Frame: Up to approximately 23 months ]
    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
  • Clinical benefit rate (CBR) with confirmed response based on BIRC assessment according to RECIST 1.1 [ Time Frame: Up to approximately 23 months ]
    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
  • Time to response (TTR) based on BIRC assessment and according to RECIST 1.1 [ Time Frame: From the date of randomization to the first documented response, assessed up to approximately 23 months ]
    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
  • Duration of response (DOR) with confirmed response based on BIRC assessment and according to RECIST 1.1 [ Time Frame: From first documented response to first documented progression or death, assessed up to approximately 23 months ]
    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
  • Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of alpelisib and olaparib [ Time Frame: 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) ]
    The AUCtau will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
  • Area under the curve from time zero to the last measurable concentration sampling time (AUClast)of alpelisib and olaparib [ Time Frame: 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) ]
    The AUClast will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
  • Maximum Concentration (Cmax) of alpelisib and olaparib [ Time Frame: 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) ]
    The Cmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
  • Time to reach maximum concentration (Tmax) of alpelisib and olaparib [ Time Frame: 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) ]
    The Tmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
  • Change from baseline in Function Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI) [ Time Frame: From baseline up to approximately 44 months ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alpelisib Plus Olaparib in Platinum-resistant/Refractory, High-grade Serous Ovarian Cancer, With no Germline BRCA Mutation Detected
Official Title  ICMJE 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
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Ovarian Cancer
Intervention  ICMJE
  • Drug: Alpelisib
    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
    Other Name: BYL719
  • Drug: Olaparib
    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.
  • Drug: Paclitaxel
    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
  • Drug: Pegylated liposomal doxorubicin (PLD)
    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
Study Arms  ICMJE
  • Experimental: Alpelisib+olaparib
    Alpelisib 200 mg orally once daily and olaparib 200 mg orally twice daily on a continuous dosing schedule.
    Interventions:
    • Drug: Alpelisib
    • Drug: Olaparib
  • Active Comparator: Paclitaxel or PLD
    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.
    Interventions:
    • Drug: Paclitaxel
    • Drug: Pegylated liposomal doxorubicin (PLD)
Publications * Konstantinopoulos PA, Gonzalez-Martin A, Cruz FM, Friedlander M, Glasspool R, Lorusso D, Marth C, Monk BJ, Kim JW, Hinson P, Ajipa O, Pretre V, Han Y, Matulonis UA. EPIK-O/ENGOT-OV61: Alpelisib plus olaparib vs cytotoxic chemotherapy in high-grade serous ovarian cancer (phase III study). Future Oncol. 2022 Sep 6. doi: 10.2217/fon-2022-0666. [Epub ahead of print] Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 21, 2021)
358
Original Estimated Enrollment  ICMJE
 (submitted: January 25, 2021)
326
Estimated Study Completion Date  ICMJE January 31, 2025
Estimated Primary Completion Date June 2, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Gender Based Eligibility: Yes
Gender Eligibility Description: adult women,
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   China,   Czechia,   Denmark,   Finland,   France,   Germany,   Italy,   Korea, Republic of,   Malaysia,   Mexico,   Netherlands,   Portugal,   Russian Federation,   Singapore,   Slovakia,   Spain,   Taiwan,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04729387
Other Study ID Numbers  ICMJE CBYL719K12301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Current Responsible Party Novartis ( Novartis Pharmaceuticals )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Novartis Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date May 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP