Study 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.

Condition or Disease	Intervention/Treatment
Ovarian Cancer	Drug: Alpelisib Drug: Olaparib Drug: Paclitaxel Drug: Pegylated liposomal doxorubicin (PLD)

Study Design

Study Type	Interventional
Actual Enrollment	358 participants
Design Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	None (Open Label)
Primary Purpose	Treatment
Official Title	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
Study Start Date	July 2, 2021
Actual Primary Completion Date	April 21, 2023
Anticipated Study Completion Date	January 31, 2026

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
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 Drug: Olaparib
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 Drug: Pegylated liposomal doxorubicin (PLD)

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria [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

Secondary Outcome Measures

1. Overall survival [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
2. Number of participants with dose interruptions and dose reductions [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
3. Dose intensity [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.
4. Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS) [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.
5. Overall Response Rate (ORR) with confirmed response based on BIRC assessment according to RECIST 1.1 criteria [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
6. Clinical benefit rate (CBR) with confirmed response based on BIRC assessment according to RECIST 1.1 [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
7. Time to response (TTR) based on BIRC assessment and according to RECIST 1.1 [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
8. Duration of response (DOR) with confirmed response based on BIRC assessment and according to RECIST 1.1 [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
9. Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of alpelisib and 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)]
   The AUCtau will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
10. Area under the curve from time zero to the last measurable concentration sampling time (AUClast)of alpelisib and 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)]
    The AUClast will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
11. Maximum Concentration (Cmax) of alpelisib and 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)]
    The Cmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
12. Time to reach maximum concentration (Tmax) of alpelisib and 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)]
    The Tmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib
13. Change from baseline in Function Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI) [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.

Eligibility Criteria

Ages Eligible for Study	18 Years and Older (Adult, Older Adult)
Sexes Eligible for Study	All
Accepts Healthy Volunteers	No
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

Contacts and Locations

Sponsors and Collaborators

Novartis Pharmaceuticals

Locations

Arizona Oncology Associates SC | Phoenix, Arizona, United States, 85016 HonorHealth | Phoenix, Arizona, United States, 85016 Florida Cancer Specialists | Fort Myers, Florida, United States, 33901 Florida Cancer Specialists | West Palm Beach, Florida, United States, 33401 Maryland Oncology Hematology P A . | Silver Spring, Maryland, United States, 20904 Massachusetts General Hospital Massachusetts General Hospital | Boston, Massachusetts, United States, 02114 Dana Farber Cancer Institute . | Boston, Massachusetts, United States, 02115 Memorial Sloan Kettering Cancer Ctr . | New York, New York, United States, 10065 Oncology Hematology Care Inc | Cincinnati, Ohio, United States, 45242 University Of Cincinnati Dept of Oncology | Cincinnati, Ohio, United States, 45267 Avera Cancer Institute | Sioux Falls, South Dakota, United States, 57106 Sarah Cannon Research Institute | Nashville, Tennessee, United States, 37203 Texas Oncology P A Texas Oncology - South Austin | Bedford, Texas, United States, 76022 Texas Oncology Charles A. Sammons Cancer Ctr | Dallas, Texas, United States, 75246 Texas Oncology P A . | San Antonio, Texas, United States, 78217 Texas Oncology Northeast Texas | Tyler, Texas, United States, 75702 Novartis Investigative Site | Caba, Buenos Aires, Argentina, C1125ABD Novartis Investigative Site | Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1015ABO Novartis Investigative Site | Buenos Aires, Argentina, C1012AAR Novartis Investigative Site | Randwick, New South Wales, Australia, 2031 Novartis Investigative Site | Bedford Park, South Australia, Australia, 5041 Novartis Investigative Site | Shepparton, Victoria, Australia, 3630 Novartis Investigative Site | Sydney, Australia, 2031 Novartis Investigative Site | Innsbruck, Tyrol, Austria, 6020 Novartis Investigative Site | Graz, Austria, 8036 Novartis Investigative Site | Bruxelles, Belgium, 1000 Novartis Investigative Site | Leuven, Belgium, 3000 Novartis Investigative Site | Namur, Belgium, 5000 Novartis Investigative Site | Belo Horizonte, Minas Gerais, Brazil, 30130-100 Novartis Investigative Site | Sao Paulo, SP, Brazil, 04014-002 Novartis Investigative Site | Calgary, Alberta, Canada, T2N 4N2 Novartis Investigative Site | Vancouver, British Columbia, Canada, V5Z 4E6 Novartis Investigative Site | London, Ontario, Canada, N6A 5W9 Novartis Investigative Site | Toronto, Ontario, Canada, M4N 3M5 Novartis Investigative Site | Chengdu, Sichuan, China, 610041 Novartis Investigative Site | Beijing, China, 100036 Novartis Investigative Site | Jinan, China, 250012 Novartis Investigative Site | Shanghai, China, 200032 Novartis Investigative Site | Tianjin, China, 300480 Novartis Investigative Site | Novy Jicin, Czech Republic, Czechia, 74101 Novartis Investigative Site | Ostrava, Poruba, Czechia, 708 52 Novartis Investigative Site | Ostrava Poruba, Czechia, 708 52 Novartis Investigative Site | Praha 2, Czechia, 128 51 Novartis Investigative Site | Praha, Czechia, 12808 Novartis Investigative Site | Herlev, Denmark, 2730 Novartis Investigative Site | Odense C, Denmark, DK 5000 Novartis Investigative Site | Kuopio, Finland, FIN-70211 Novartis Investigative Site | Tampere, Finland, FIN-33521 Novartis Investigative Site | Turku, Finland, FIN 20521 Novartis Investigative Site | Besancon Cedex, France, 25030 Novartis Investigative Site | Besancon, 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 | Mannheim, Baden Wuerttemberg, Germany, 68305 Novartis Investigative Site | Berlin, Germany, 13353 Novartis Investigative Site | Dresden, Germany, 01307 Novartis Investigative Site | Essen, Germany, 45136 Novartis Investigative Site | Bologna, BO, Italy, 40138 Novartis Investigative Site | Firenze, FI, Italy, 50134 Novartis Investigative Site | Milano, MI, Italy, 20133 Novartis Investigative Site | Milano, MI, Italy, 20141 Novartis Investigative Site | Roma, RM, Italy, 00168 Novartis Investigative Site | Roma, RM, Italy, 8-00168 Novartis Investigative Site | Vicenza, VI, Italy, 36100 Novartis Investigative Site | Napoli, Italy, 80131 Novartis Investigative Site | Seoul, Korea, Republic of, 03080 Novartis Investigative Site | Seoul, Korea, Republic of, 03722 Novartis Investigative Site | Kota Kinabalu, Sabah, Malaysia, 88996 Novartis Investigative Site | Kuching, Sarawak, Malaysia, 93586 Novartis Investigative Site | Kuala Lumpur, Wilayah Persekutuan, Malaysia, 50586 Novartis Investigative Site | Kuala Lumpur, Malaysia, 59100 Novartis Investigative Site | Monterrey, Nuevo Leon, Mexico, 64460 Novartis Investigative Site | Ciudad de Mexico, Mexico, 04700 Novartis Investigative Site | Eindhoven, Netherlands, 5623 EJ Novartis Investigative Site | Loures, Portugal, 2674514 Novartis Investigative Site | Porto, Portugal, 4200-072 Novartis Investigative Site | Arkhangelsk, Russian Federation, 163045 Novartis Investigative Site | Singapore, Singapore, 119074 Novartis Investigative Site | Singapore, Singapore, 119228 Novartis Investigative Site | Singapore, Singapore, 168583 Novartis Investigative Site | Bratislava, Slovak Republic, Slovakia, 83310 Novartis Investigative Site | Bratislava, Slovakia, 83310 Novartis Investigative Site | Cordoba, Andalucia, Spain, 14004 Novartis Investigative Site | Barcelona, Catalunya, Spain, 08035 Novartis Investigative Site | Barcelona, Catalunya, Spain, 08036 Novartis Investigative Site | Valencia, Comunidad Valenciana, Spain, 46010 Novartis Investigative Site | Pamplona, Navarra, Spain, 31008 Novartis Investigative Site | Madrid, Spain, 28034 Novartis Investigative Site | Taichung, Taiwan, 40705 Novartis Investigative Site | Taichung, Taiwan, 407219 Novartis Investigative Site | Taipei, Taiwan, 10002 Novartis Investigative Site | Taipei, Taiwan, 11217 Novartis Investigative Site | Adana, Turkey, 01160 Novartis Investigative Site | Ankara, Turkey, 06100 Novartis Investigative Site | Ankara, Turkey, 06230 Novartis Investigative Site | Ankara, Turkey, 06520 Novartis Investigative Site | Izmir, Turkey, 35575 Novartis Investigative Site | Glasgow, United Kingdom, G12 0YN Novartis Investigative Site | London, United Kingdom, SE1 9RT Novartis Investigative Site | Manchester, United Kingdom, M20 2BX Novartis Investigative Site | Manchester, United Kingdom, M20 4BX

More Information

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.

Additional Relevant MeSH Terms

• Ovarian Neoplasms
• Carcinoma, Ovarian Epithelial
• Endocrine Gland Neoplasms
• Neoplasms by Site
• Neoplasms
• Ovarian Diseases
• Adnexal Diseases
• Genital Diseases, Female
• Female Urogenital Diseases
• Female Urogenital Diseases and Pregnancy Complications
• Urogenital Diseases
• Genital Neoplasms, Female
• Urogenital Neoplasms
• Genital Diseases
• Endocrine System Diseases
• Gonadal Disorders
• Carcinoma
• Neoplasms, Glandular and Epithelial
• Neoplasms by Histologic Type