A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer
- Conditions
- Low Grade Serous Ovarian Cancer
- Interventions
- Registration Number
- NCT06072781
- Lead Sponsor
- Verastem, Inc.
- Brief Summary
This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with defactinib versus Investigator's choice of treatments (ICT) in subjects with recurrent LGSOC who have progressed on a prior platinum-based therapy.
- Detailed Description
This international, randomized, open-label, Phase 3 study will compare the investigational combination of avutometinib plus defactinib versus Investigator's Choice of Treatments (ICT) in patients with recurrent LGSOC who have progressed on a prior platinum-based therapy. Avutometinib and defactinib are both types of drugs called kinase inhibitors. Kinase inhibitors block cancer cell growth. The study will compare the progression-free survival (PFS) of the combination of avutometinib plus defactinib versus ICT. The study will also evaluate the effect of the combination on safety, overall survival, other efficacy endpoints, and health-related quality of life and disease related symptoms. The study is being conducted by gynecological cancer specialists. Patients who are eligible and agree to participate in this study will be treated with either a combination of avutometinib with defactinib, or with one of four standard of care NCCN and ESMO treatment recommendations for recurrent LGSOC, and then with subsequent follow up appointments. Patients who originally received one of the standards of care treatments who are determined to have progressive disease may be eligible to crossover to receive the investigational combination avutometinib plus defactinib.Avutometinib and defactinib are investigational drugs that have not been approved by the U.S. Food and Drug Administration (FDA)
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Female
- Target Recruitment
- 270
Patients may be eligible for inclusion in the study if they meet the following criteria:
- Histologically proven LGSOC (ovarian, fallopian, peritoneal)
- Documented mutational status of KRAS by a validated tumor-tissue based diagnostic test.
- Suitable for treatment with at least one of the Investigator's Choice of Treatments:pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole.
- Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease.
- Measurable disease according to RECIST v1.1.
- An Eastern Cooperative Group (ECOG) performance status ≤ 1.
- Adequate organ function.
- Adequate recovery from toxicities related to prior treatments.
- For patients with reproductive potential, a negative pregnancy test must be confirmed and agreement to use highly effective method of contraceptive.
- Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
Patients will be excluded from the study if they meet any of the following criteria:
- Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
- Co-existing high-grade serous ovarian cancer or mixed histology.
- Prior treatment with avutometinib, defactinib, or other FAK inhibitors.
- History of prior malignancy with recurrence <3 years from the time of enrollment.
- Major surgery within 4 weeks, minor surgery within 1 week, or palliative radiotherapy within 1 week of the first dose of study intervention.
- Symptomatic brain metastases requiring steroids or other interventions, known leptomeningeal metastases, or spinal cord compression.
- An active skin disorder that has required systemic therapy within one year of the first dose of study intervention.
- History of medically significant rhabdomyolysis.
- For subjects with prior MEK or RAF exposure, Grade 4 toxicity is deemed related to the MEK inhibitor.
- Symptomatic bowel obstruction within 3 months of the first dose of study intervention
- Concurrent ocular disorders.
- Concurrent heart disease or severe obstructive pulmonary disease.
- Active or past medical history of interstitial lung disease/pneumonitis, including drug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS).
- Subjects with the inability to swallow oral medications.
- History of hypersensitivity to any of the active agents or ingredients of study intervention: peanut, soya, polyoxyl castor oil, etcetc.). Prior hypersensitivity to anthracyclines or anthracenediones if the use of pegylated liposomal doxorubicin (PLD) is planned.
- Pregnant or breastfeeding.
- Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description avutometinib + defactinib avutometinib Avutometinib 3.2 mg, PO, twice weekly for 21 days on, 7 days off in a 28-day (4 weeks) cycle in combination with defactinib 200 mg, PO, twice daily for 21 days on, 7 days off in a 28-day(4 week) cycle. avutometinib + defactinib Defactinib Avutometinib 3.2 mg, PO, twice weekly for 21 days on, 7 days off in a 28-day (4 weeks) cycle in combination with defactinib 200 mg, PO, twice daily for 21 days on, 7 days off in a 28-day(4 week) cycle. Investigator Choice of Treatment (ICT) Pegylated liposomal doxorubicin Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle. Investigator Choice of Treatment (ICT) Paclitaxel Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle. Investigator Choice of Treatment (ICT) Letrozole Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle. Investigator Choice of Treatment (ICT) Anastrozole Patients will receive one of the following therapies as determined by the Investigator: * Pegylated liposomal doxorubicin: 40 mg/m2 IV on Day 1 of each 28-day (4 week) cycle. * Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of each 28-day (4 week) cycle. * Anastrozole: 1 mg, PO, once daily of each 28-day (4 week) cycle. * Letrozole: 2.5 mg, PO, once daily of each 28-day (4 week) cycle.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) per blinded independent central review (BICR) Up to 24 months Confirmed overall response rate per RECIST 1.1 per blinded independent central review (BICR)
- Secondary Outcome Measures
Name Time Method Overall Survival (OS) Up to 5 years From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause
Progression Free Survival (PFS) per investigator assessment 24 months From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause
Objective response rate (ORR) 12 months From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause
Duration of Response (DOR) 12 months From the time of first dose of study intervention to PD as assessed per RECIST 1.1 by Investigator or death from any cause
Disease Control Rate (DCR) 6 months CR+PR+Stable disease
Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) 25 months Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale
Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites 5 months Area under plasma Concentration (AUC) 0 to t
Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites 5 months maximum plasma concentration
To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire Core module C30 (QLQ-C30). 24 months The EORTC QLQ-C30 is a validated questionnaire to assess the quality of life of ovarian cancer patients.
To assess the health-related quality of life and disease based on European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire Ovarian Cancer module OV28 (QLQ-OV28). 24 months The EORTC QLQ-OV28 is a validated questionnaire to assess the quality of life of ovarian cancer patients.
To assess the health-related quality of life and disease based on EuroQol-5 Dimension 5-level (EQ-5D-5L) 24 months The EuroQol-5 Dimension 5-level (EQ-5D-5L) is a validated questionnaire used to measure a patient's overall health.
Trial Locations
- Locations (91)
HonorHealth
🇺🇸Phoenix, Arizona, United States
University of Arkansas
🇺🇸Little Rock, Arkansas, United States
UCLA Health
🇺🇸Los Angeles, California, United States
UC Davis
🇺🇸Sacramento, California, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Yale University
🇺🇸New Haven, Connecticut, United States
Florida Cancer Specialists - South
🇺🇸Fort Myers, Florida, United States
Mount Sinai
🇺🇸Miami Beach, Florida, United States
AdventHealth
🇺🇸Orlando, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Florida Cancer Specialists Research East
🇺🇸West Palm Beach, Florida, United States
Winship Cancer Institute at Emory University
🇺🇸Atlanta, Georgia, United States
NorthShore University HealthSystem
🇺🇸Evanston, Illinois, United States
Louisiana State University
🇺🇸New Orleans, Louisiana, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Karmanos Cancer Center
🇺🇸Detroit, Michigan, United States
Minnesota Oncology Hematology
🇺🇸Minneapolis, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Atrium Health
🇺🇸Charlotte, North Carolina, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Ohio State
🇺🇸Hilliard, Ohio, United States
University of Oklahoma Medical Center
🇺🇸Oklahoma City, Oklahoma, United States
Willamette Valley Cancer Institute
🇺🇸Eugene, Oregon, United States
Northwest Cancer Specialists
🇺🇸Portland, Oregon, United States
Asplundh Cancer Pavilion | Jefferson Health
🇺🇸Philadelphia, Pennsylvania, United States
Allegheny Health Network
🇺🇸Pittsburgh, Pennsylvania, United States
Texas Oncology Central
🇺🇸Austin, Texas, United States
Texas Oncology-Fort Worth Cancer Center
🇺🇸Fort Worth, Texas, United States
Houston Methodist
🇺🇸Houston, Texas, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Texas Oncology
🇺🇸Tyler, Texas, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Virginia Cancer Specialists, PC
🇺🇸Gainesville, Virginia, United States
Prince of Wales Hospital
🇦🇺Randwick, New South Wales, Australia
Icon Cancer Centre Wesley
🇦🇺Auchenflower, Queensland, Australia
Cancer Research South Australia
🇦🇺Adelaide, South Australia, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
UZA
🇧🇪Edegem, Belgium
University Hospital Ghent
🇧🇪Ghent, Belgium
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
McGill University Health Centre
🇨🇦Montreal, Quebec, Canada
Centre Hospitalier de l'Universite de Montreal (CHUM)
🇨🇦Montréal, Quebec, Canada
British of Columbia
🇨🇦Vancouver, Canada
Centre Hospitalier de Besançon
🇫🇷Besançon, France
Site Georges François Leclerc
🇫🇷Dijon, France
Centre Oscar Lambret
🇫🇷Lille, France
Centre Léon Bérard
🇫🇷Lyon, France
Institut Curie
🇫🇷Paris, France
Agaplesion Markus Krankenhaus
🇩🇪Frankfurt, Hessen, Germany
Charité - Universitätsmedizin Berlin
🇩🇪Berlin, Germany
Universitätsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
Kliniken Essen-Mitte
🇩🇪Essen, Germany
UMC Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitätsklinikum Mannheim GmbH
🇩🇪Mannheim, Germany
Universitätsfrauenkinik Ulm
🇩🇪Ulm, Germany
St. James's Hospital
🇮🇪Dublin, Ireland
Centro di Riferimento Oncologico (CRO)
🇮🇹Aviano, Italy
Spedali Civili
🇮🇹Brescia, Italy
AO Cannizzaro
🇮🇹Catania, Italy
Istituto Nazionale dei Tumori
🇮🇹Milano, Italy
San Raffaele Hospital
🇮🇹Milan, Italy
Humanitas San Pio X
🇮🇹Milan, Italy
European Institute of Oncology (IEO)
🇮🇹Milan, Italy
Istituto Oncologico Veneto (IOV)
🇮🇹Padova, Italy
IRCCS Gemelli
🇮🇹Roma, Italy
Istituti Fisioterapici Ospitalieri
🇮🇹Rome, Italy
S.C.D.U. Oncologia
🇮🇹Torino, Italy
Seoul National University Bundang Hospital
🇰🇷Seongnam, Korea, Republic of
Yonsei University Severance Hospital
🇰🇷Seoul, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Gangnam Severance Hospital
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Netherlands Cancer Insitute
🇳🇱Amsterdam, Netherlands
Radboud UMC
🇳🇱Nijmegen, Netherlands
Auckland City Hospital
🇳🇿Auckland, New Zealand
Clínico Virgen de La Arrixaca
🇪🇸El Palmar, Murcia, Spain
H. Vall d´ Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Reina Sofía
🇪🇸Córdoba, Spain
H.U. Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Clínico Universitario de Santiago
🇪🇸Santiago de Compostela, Spain
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Spain
Greater Glasgow and Clyde (GGC)
🇬🇧Glasgow, Scotland, United Kingdom
University of Edinburgh Cancer Research Centre
🇬🇧Edinburgh, United Kingdom
Hope Cancer Trials Centre
🇬🇧Leicester, United Kingdom
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
The Christie NHS Foundation Trust
🇬🇧Manchester, United Kingdom