Clinical trial NCT06072781: A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer
Official title: A Phase 3, Randomized, Open-Label Study of Combination Therapy With Avutometinib Plus Defactinib Versus Investigator's Choice of Treatment in Patients With Recurrent Low-Grade Serous Ovarian Cancer (LGSOC) (RAMP 301)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Low Grade Serous Ovarian Cancer
Keywords: Low Grade Serous Ovarian Cancer
KRAS
KRAS wt
KRAS mt
Lead sponsor: Verastem, Inc.
Sponsor class: INDUSTRY
Collaborators: name: GOG Foundation
name: European Network of Gynaecological Oncological Trial Groups (ENGOT)
name: Australia New Zealand Gynaecological Oncology Group
name: Korean Gynecologic Oncology Group
First posted: 2023-10-10
Enrollment: 270
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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)

Eligibility criteria: Inclusion Criteria:

Patients may be eligible for inclusion in the study if they meet the following criteria:

1. Histologically proven LGSOC (ovarian, fallopian, peritoneal)
2. Documented mutational status of KRAS by a validated tumor-tissue based diagnostic test.
3. Suitable for treatment with at least one of the Investigator's Choice of Treatments:pegylated liposomal doxorubicin, paclitaxel, letrozole, anastrozole.
4. Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease.
5. Measurable disease according to RECIST v1.1.
6. An Eastern Cooperative Group (ECOG) performance status ≤ 1.
7. Adequate organ function.
8. Adequate recovery from toxicities related to prior treatments.
9. For patients with reproductive potential, a negative pregnancy test must be confirmed and agreement to use highly effective method of contraceptive.
10. Willingness to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy.
2. Co-existing high-grade serous ovarian cancer or mixed histology.
3. Prior treatment with avutometinib, defactinib, or other FAK inhibitors.
4. History of prior malignancy with recurrence \<3 years from the time of enrollment.
5. Major surgery within 4 weeks, minor surgery within 1 week, or palliative radiotherapy within 1 week of the first dose of study intervention.
6. Symptomatic brain metastases requiring steroids or other interventions, known leptomeningeal metastases, or spinal cord compression.
7. An active skin disorder that has required systemic therapy within one year of the first dose of study intervention.
8. History of medically significant rhabdomyolysis.
9. For subjects with prior MEK or RAF exposure, Grade 4 toxicity is deemed related to the MEK inhibitor.
10. Symptomatic bowel obstruction within 3 months of the first dose of study intervention
11. Concurrent ocular disorders.
12. Concurrent heart disease or severe obstructive pulmonary disease.
13. Active or past medical history of interstitial lung disease/pneumonitis, including drug-induced or radiation pneumonitis, pulmonary fibrosis, or adult respiratory distress syndrome (ARDS).
14. Subjects with the inability to swallow oral medications.
15. 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.
16. Pregnant or breastfeeding.
17. Active, uncontrolled infection (bacterial, viral, or fungal) requiring systemic therapy.

Primary outcomes:
measure: Progression Free Survival (PFS) per blinded independent central review (BICR)
timeFrame: Up to 24 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to 5 years
measure: Progression Free Survival (PFS) per investigator assessment
timeFrame: 24 months
measure: Objective response rate (ORR)
timeFrame: 12 months
measure: Duration of Response (DOR)
timeFrame: 12 months
measure: Disease Control Rate (DCR)
timeFrame: 6 months
measure: Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs)
timeFrame: 25 months
measure: Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites
timeFrame: 5 months
measure: Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites
timeFrame: 5 months
measure: 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).
timeFrame: 24 months
measure: 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).
timeFrame: 24 months
measure: To assess the health-related quality of life and disease based on EuroQol-5 Dimension 5-level (EQ-5D-5L)
timeFrame: 24 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: HonorHealth
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas
state: Arkansas
city: Los Angeles
country: United States
facility: UCLA Health
state: California
city: Sacramento
country: United States
facility: UC Davis
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - South
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai
state: Florida
city: Orlando
country: United States
facility: AdventHealth
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists Research East
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute at Emory University
state: Georgia
city: Evanston
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: New Orleans
country: United States
facility: Louisiana State University
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Oncology Hematology
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Atrium Health
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Hilliard
country: United States
facility: Ohio State
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Medical Center
state: Oklahoma
city: Eugene
country: United States
facility: Willamette Valley Cancer Institute
state: Oregon
city: Portland
country: United States
facility: Northwest Cancer Specialists
state: Oregon
city: Philadelphia
country: United States
facility: Asplundh Cancer Pavilion | Jefferson Health
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Health Network
state: Pennsylvania
city: Austin
country: United States
facility: Texas Oncology Central
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology-Fort Worth Cancer Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology
state: Texas
city: The Woodlands
country: United States
facility: Texas Oncology
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Gainesville
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: Icon Cancer Centre Wesley
state: Queensland
city: Adelaide
country: Australia
facility: Cancer Research South Australia
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Edegem
country: Belgium
facility: UZA
city: Ghent
country: Belgium
facility: University Hospital Ghent
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal (CHUM)
state: Quebec
city: Vancouver
country: Canada
facility: British of Columbia
city: Besançon
country: France
facility: Centre Hospitalier de Besançon
city: Dijon
country: France
facility: Site Georges François Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Paris
country: France
facility: Institut Curie
city: Frankfurt
country: Germany
facility: Agaplesion Markus Krankenhaus
state: Hessen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Essen
country: Germany
facility: Kliniken Essen-Mitte
city: Hamburg
country: Germany
facility: UMC Hamburg-Eppendorf
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim GmbH
city: Ulm
country: Germany
facility: Universitätsfrauenkinik Ulm
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico (CRO)
city: Brescia
country: Italy
facility: Spedali Civili
city: Catania
country: Italy
facility: AO Cannizzaro
city: Milano
country: Italy
facility: Istituto Nazionale dei Tumori
city: Milan
country: Italy
facility: San Raffaele Hospital
city: Milan
country: Italy
facility: Humanitas San Pio X
city: Milan
country: Italy
facility: European Institute of Oncology (IEO)
city: Napoli
country: Italy
facility: INT Napoli Hospital
city: Padova
country: Italy
facility: Istituto Oncologico Veneto (IOV)
city: Roma
country: Italy
facility: IRCCS Gemelli
city: Rome
country: Italy
facility: Istituti Fisioterapici Ospitalieri
city: Torino
country: Italy
facility: S.C.D.U. Oncologia
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Insitute
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Gdańsk
country: Poland
facility: Gdański Uniwersytet Medyczny
city: El Palmar
country: Spain
facility: Clínico Virgen de La Arrixaca
state: Murcia
city: Barcelona
country: Spain
facility: H. Vall d´ Hebron
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
city: Madrid
country: Spain
facility: H.U. Ramón y Cajal
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Glasgow
country: United Kingdom
facility: Greater Glasgow and Clyde (GGC)
state: Scotland
city: Edinburgh
country: United Kingdom
facility: University of Edinburgh Cancer Research Centre
city: Leicester
country: United Kingdom
facility: Hope Cancer Trials Centre
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
Study officials:
affiliation: GOG Foundation
name: Rachel Grisham, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: European Network of Gynecological Oncological Trial Groups (ENGOT)
name: Susana Banerjee, MBBS, MA, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: RAMP301@verastem.com
name: Melina Arazy, MD Verastem Medical Monitor
role: STUDY_DIRECTOR
References: