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)

Overview

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)

Interventions

• Drug avutometinib
  Avutometinib: administered orally
• Drug Defactinib
  Defactinib: administered orally
• Drug Pegylated liposomal doxorubicin
  administered intravenously
• Drug Paclitaxel
  administered intravenously
• Drug Letrozole
  administered orally
• Drug Anastrozole
  administered orally

Primary outcome measures

• Progression Free Survival (PFS) per blinded independent central review (BICR) [Time frame: Up to 24 months]

Secondary outcome measures (11)

• Overall Survival (OS) [Time frame: Up to 5 years]
• Progression Free Survival (PFS) per investigator assessment [Time frame: 24 months]
• Objective response rate (ORR) [Time frame: 12 months]
• Duration of Response (DOR) [Time frame: 12 months]
• Disease Control Rate (DCR) [Time frame: 6 months]
• Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) [Time frame: 25 months]
• Area under the plasma concentration-time curve (AUC) of avutometinib, defactinib and relative metabolites [Time frame: 5 months]
• Maximum plasma concentration (Cmax) of avutometinib, defactinib and relative metabolites [Time frame: 5 months]
• 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). [Time frame: 24 months]
• 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). [Time frame: 24 months]
• To assess the health-related quality of life and disease based on EuroQol-5 Dimension 5-level (EQ-5D-5L) [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

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.

Exclusion criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 38 centers

• HonorHealth — Phoenix
• University of Arkansas — Little Rock
• UCLA Health — Los Angeles
• UC Davis — Sacramento
• University of California, San Francisco — San Francisco
• Yale University — New Haven
• Florida Cancer Specialists - South — Fort Myers
• Mount Sinai — Miami Beach
• … and 30 more centers

Italy · 12 centers

• Centro di Riferimento Oncologico (CRO) — Aviano
• Spedali Civili — Brescia
• AO Cannizzaro — Catania
• San Raffaele Hospital — Milan
• Humanitas San Pio X — Milan
• European Institute of Oncology (IEO) — Milan
• Istituto Nazionale dei Tumori — Milan
• INT Napoli Hospital — Naples
• … and 4 more centers

United Kingdom · 8 centers

Center list to be confirmed — check the primary protocol.

Germany · 7 centers

• Agaplesion Markus Krankenhaus — Frankfurt am Main
• Charité - Universitätsmedizin Berlin — Berlin
• Universitätsklinikum Carl Gustav Carus — Dresden
• Kliniken Essen-Mitte — Essen
• UMC Hamburg-Eppendorf — Hamburg
• Universitätsklinikum Mannheim GmbH — Mannheim
• Universitätsfrauenkinik Ulm — Ulm

Spain · 7 centers

Center list to be confirmed — check the primary protocol.

Australia · 5 centers

• Prince of Wales Hospital — Randwick
• Icon Cancer Centre Wesley — Auchenflower
• Cancer Research South Australia — Adelaide
• Peter MacCallum Cancer Centre — Melbourne
• Sir Charles Gairdner Hospital — Nedlands

France · 5 centers

• Centre Hospitalier de Besançon — Besançon
• Site Georges François Leclerc — Dijon
• Centre Oscar Lambret — Lille
• Centre Léon Bérard — Lyon
• Institut Curie — Paris

Japan · 5 centers

• The Mie University Hospital — Tsu
• Aichi Cancer Center Hospital — Aichi
• Tohoku University Hospital — Miyagi
• Osaka Medical Center — Osaka
• The Jikei University Hospital — Tokyo

South Korea · 5 centers

Center list to be confirmed — check the primary protocol.

Canada · 4 centers

• Princess Margaret Cancer Center — Toronto
• Centre Hospitalier de l'Universite de Montreal (CHUM) — Montreal
• McGill University Health Centre — Montreal
• British of Columbia — Vancouver

Poland · 3 centers

Center list to be confirmed — check the primary protocol.

Belgium · 2 centers

• UZA — Edegem
• University Hospital Ghent — Ghent

Netherlands · 2 centers

Center list to be confirmed — check the primary protocol.

Denmark · 1 center

• Aalborg U.H — Aalborg

Ireland · 1 center

• St. James's Hospital — Dublin

New Zealand · 1 center

Center list to be confirmed — check the primary protocol.

Publications

• Banerjee SN, Van Nieuwenhuysen E, Aghajanian C, D'Hondt V, Monk BJ, Clamp A, Prendergast E, Oaknin A, Ring K, Colombo N, Holloway RW, Rodrigues M, Chon HS, Gourley C, Santin AD, Thaker PH, Gennigens C, Newman G, Salinas E, Youssoufian H, Moore KN, Lustgarten S, O'Malley DM, Van Gorp T, Grisham RN. The combination of avutometinib and defactinib in treating recurrent low-grade serous ovarian cancer: PMID 41384753
• Banerjee SN, Van Nieuwenhuysen E, Aghajanian C, D'Hondt V, Monk BJ, Clamp A, Prendergast E, Oaknin A, Ring K, Colombo N, Holloway RW, Rodrigues M, Chon HS, Gourley C, Santin AD, Thaker PH, Gennigens C, Newman G, Salinas E, Youssoufian H, Moore KN, Lustgarten S, O'Malley DM, Van Gorp T, Grisham RN. Efficacy and Safety of Avutometinib +/- Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Prim PMID 40644648
• Grisham R, Monk BJ, Van Nieuwenhuysen E, Moore KN, Fabbro M, O'Malley DM, Oaknin A, Thaker P, Oza AM, Colombo N, Gershenson D, Aghajanian CA, Choi CH, Lee YC, Mirza MR, Coleman RL, Cobb L, Harter P, Lustgarten S, Youssoufian H, Banerjee S. GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator's choice of treatment in pat PMID 39375168

Identifiers

NCT: NCT06072781 · VS-6766-301 · GOG-3097 · ENGOT-ov81

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗