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

Ovarian Cancer Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04729387
• Other study ID #: CBYL719K12301
• Secondary ID: 2019-004682-40
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 2, 2021
• Est. completion date: January 31, 2026

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 358
• Est. completion date: January 31, 2026
• Est. primary completion date: April 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Ovarian Cancer
• Ovarian Neoplasms

Intervention

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
• 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.
• 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
• 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

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Bs As	Buenos Aires
Australia	Novartis Investigative Site	Bedford Park	South Australia
Australia	Novartis Investigative Site	Randwick	New South Wales
Australia	Novartis Investigative Site	Shepparton	Victoria
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck	Tyrol
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Namur
Brazil	Novartis Investigative Site	Belo Horizonte	Minas Gerais
Brazil	Novartis Investigative Site	Sao Paulo	SP
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Chengdu	Sichuan
China	Novartis Investigative Site	Jinan
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Tianjin
Czechia	Novartis Investigative Site	Novy Jicin	Czech Republic
Czechia	Novartis Investigative Site	Ostrava Poruba
Czechia	Novartis Investigative Site	Praha 2
Denmark	Novartis Investigative Site	Herlev
Denmark	Novartis Investigative Site	Odense C
Finland	Novartis Investigative Site	Kuopio
Finland	Novartis Investigative Site	Tampere
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Besancon
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Pierre Benite
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Mannheim	Baden Wuerttemberg
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Vicenza	VI
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Malaysia	Novartis Investigative Site	Kota Kinabalu	Sabah
Malaysia	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan
Malaysia	Novartis Investigative Site	Kuala Lumpur
Malaysia	Novartis Investigative Site	Kuching	Sarawak
Mexico	Novartis Investigative Site	Ciudad de Mexico
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Netherlands	Novartis Investigative Site	Eindhoven
Portugal	Novartis Investigative Site	Loures
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Arkhangelsk
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Slovakia	Novartis Investigative Site	Bratislava
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United States	Texas Oncology P A Texas Oncology - South Austin	Bedford	Texas
United States	Dana Farber Cancer Institute .	Boston	Massachusetts
United States	Massachusetts General Hospital Massachusetts General Hospital	Boston	Massachusetts
United States	Oncology Hematology Care Inc	Cincinnati	Ohio
United States	University Of Cincinnati Dept of Oncology	Cincinnati	Ohio
United States	Texas Oncology Charles A. Sammons Cancer Ctr	Dallas	Texas
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Ctr .	New York	New York
United States	Arizona Oncology Associates SC	Phoenix	Arizona
United States	HonorHealth	Phoenix	Arizona
United States	Texas Oncology P A .	San Antonio	Texas
United States	Maryland Oncology Hematology P A .	Silver Spring	Maryland
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Texas Oncology Northeast Texas	Tyler	Texas
United States	Florida Cancer Specialists	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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