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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Alpelisib; Drug: Olaparib; Drug: Paclitaxel; Drug: Pegylated liposomal doxorubicin (PLD)

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: Interventional
• Enrollment (Actual): 358
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1012AAR
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1056ABJ
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1125ABD
      • Novartis Investigative Site
    • Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1015ABO
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Novartis Investigative Site
  • South Australia
    • Bedford Park, South Australia, Australia, 5041
      • Novartis Investigative Site
  • Victoria
    • Shepparton, Victoria, Australia, 3630
      • Novartis Investigative Site
• Austria
  • Graz, Austria, 8036
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Namur, Belgium, 5000
    • Novartis Investigative Site
• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 04014-002
      • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
• China
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Jinan, China, 250012
    • Novartis Investigative Site
  • Shanghai, China, 200032
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
• Czechia
  • Ostrava Poruba, Czechia, 708 52
    • Novartis Investigative Site
  • Praha 2, Czechia, 128 51
    • Novartis Investigative Site
  • Czech Republic
    • Novy Jicin, Czech Republic, Czechia, 74101
      • Novartis Investigative Site
• Denmark
  • Herlev, Denmark, 2730
    • Novartis Investigative Site
  • Odense C, Denmark, DK 5000
    • Novartis Investigative Site
• Finland
  • Kuopio, Finland, FIN-70211
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33521
    • Novartis Investigative Site
  • Turku, Finland, FIN-20521
    • Novartis Investigative Site
• France
  • Besancon cedex, France, 25030
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Paris, France, 75012
    • Novartis Investigative Site
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Baden Wuerttemberg
    • Mannheim, Baden Wuerttemberg, Germany, 68305
      • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 8-00168
      • Novartis Investigative Site
  • VI
    • Vicenza, VI, Italy, 36100
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88996
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
  • Wilayah Persekutuan
    • Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50586
      • Novartis Investigative Site
• Mexico
  • Ciudad de Mexico, Mexico, 04700
    • Novartis Investigative Site
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Novartis Investigative Site
• Netherlands
  • Eindhoven, Netherlands, 5623 EJ
    • Novartis Investigative Site
• Portugal
  • Loures, Portugal, 2674514
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119228
    • Novartis Investigative Site
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 83310
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Andalucia
    • Cordoba, Andalucia, Spain, 14004
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site
• Taiwan
  • Taichung, Taiwan, 40705
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01160
    • Novartis Investigative Site
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
  • Ankara, Turkey, 06520
    • Novartis Investigative Site
  • Izmir, Turkey, 35575
    • Novartis Investigative Site
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • HonorHealth
    • Phoenix, Arizona, United States, 85016
      • Arizona Oncology Associates SC
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists
  • Maryland
    • Silver Spring, Maryland, United States, 20904
      • Maryland Oncology Hematology P A .
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute .
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr .
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Dept of Oncology
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57106
      • Avera Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Bedford, Texas, United States, 76022
      • Texas Oncology P A Texas Oncology - South Austin
    • Dallas, Texas, United States, 75246
      • Texas Oncology Charles A. Sammons Cancer Ctr
    • San Antonio, Texas, United States, 78217
      • Texas Oncology P A .
    • Tyler, Texas, United States, 75702
      • Texas Oncology Northeast Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alpelisib+olaparib; Alpelisib 200 mg orally once daily and olaparib 200 mg orally twice daily on a continuous dosing schedule.	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 Names: 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.
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.	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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General 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 Oct;18(31):3481-3492. doi: 10.2217/fon-2022-0666. Epub 2022 Sep 6.

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2021
• Primary Completion (Estimated): December 27, 2024
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: January 25, 2021
• First Posted (Actual): January 28, 2021

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: olaparib; paclitaxel; pegylated liposomal doxorubicin; Alpelisib; 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
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Antibiotics, Antineoplastic; Paclitaxel; Olaparib; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: CBYL719K12301; 2019-004682-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No