Clinical trial NCT04729387: Alpelisib Plus Olaparib in Platinum-resistant/Refractory, High-grade Serous Ovarian Cancer, With no Germline BRCA Mutation Detected
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 type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Ovarian Cancer
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-01-28
Enrollment: 358
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria
timeFrame: 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 outcomes:
measure: Overall survival
timeFrame: From randomization until death, assessed up to approximately 44 months
measure: Number of participants with dose interruptions and dose reductions
timeFrame: From randomization until end of treatment, assessed up to approximately 18 months
measure: Dose intensity
timeFrame: From randomization until end of treatment, assessed up to approximately 18 months
measure: Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS)
timeFrame: Up to approximately 18 months
measure: Overall Response Rate (ORR) with confirmed response based on BIRC assessment according to RECIST 1.1 criteria
timeFrame: Up to approximately 23 months
measure: Clinical benefit rate (CBR) with confirmed response based on BIRC assessment according to RECIST 1.1
timeFrame: Up to approximately 23 months
measure: Time to response (TTR) based on BIRC assessment and according to RECIST 1.1
timeFrame: From the date of randomization to the first documented response, assessed up to approximately 23 months
measure: Duration of response (DOR) with confirmed response based on BIRC assessment and according to RECIST 1.1
timeFrame: From first documented response to first documented progression or death, assessed up to approximately 23 months
measure: Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of alpelisib and olaparib
timeFrame: 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)
measure: Area under the curve from time zero to the last measurable concentration sampling time (AUClast)of alpelisib and olaparib
timeFrame: 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)
measure: Maximum Concentration (Cmax) of alpelisib and olaparib
timeFrame: 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)
measure: Time to reach maximum concentration (Tmax) of alpelisib and olaparib
timeFrame: 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)
measure: Change from baseline in Function Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI)
timeFrame: From baseline up to approximately 44 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Phoenix
country: United States
facility: HonorHealth
state: Arizona
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Silver Spring
country: United States
facility: Maryland Oncology Hematology P A
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Cincinnati
country: United States
facility: University Of Cincinnati
state: Ohio
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Bedford
country: United States
facility: Texas Oncology P A
state: Texas
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology P A
state: Texas
city: Tyler
country: United States
facility: Texas Oncology Northeast Texas
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: Bedford Park
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Shepparton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Sydney
country: Australia
facility: Novartis Investigative Site
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
state: Tyrol
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: Minas Gerais
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: London
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Chengdu
country: China
facility: Novartis Investigative Site
state: Sichuan
city: Beijing
country: China
facility: Novartis Investigative Site
city: Jinan
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Novy Jicin
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Ostrava
country: Czechia
facility: Novartis Investigative Site
state: Poruba
city: Praha
country: Czechia
facility: Novartis Investigative Site
city: Herlev
country: Denmark
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Kuopio
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Turku
country: Finland
facility: Novartis Investigative Site
city: Besancon Cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Vicenza
country: Italy
facility: Novartis Investigative Site
state: VI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kota Kinabalu
country: Malaysia
facility: Novartis Investigative Site
state: Sabah
city: Kuching
country: Malaysia
facility: Novartis Investigative Site
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
state: Wilayah Persekutuan
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Monterrey
country: Mexico
facility: Novartis Investigative Site
state: Nuevo Leon
city: Ciudad de Mexico
country: Mexico
facility: Novartis Investigative Site
city: Eindhoven
country: Netherlands
facility: Novartis Investigative Site
city: Loures
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
state: Slovak Republic
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Pamplona
country: Spain
facility: Novartis Investigative Site
state: Navarra
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.