A Study of Avutometinib (VS-6766) + Defactinib (VS-6063) in Recurrent Low-Grade Serous Ovarian Cancer

Официальное название

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)

Обзор

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.

Подробное описание

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)

Вмешательства

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

Первичные конечные точки

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

Вторичные конечные точки (11)

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

Критерии участия

Критерии включения

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.

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 38 центров

• 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
• … и ещё 30 центров

Италия · 12 центров

• 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
• … и ещё 4 центра

Великобритания · 8 центров

Список центров уточняется — проверьте первичный протокол.

Германия · 7 центров

• 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

Испания · 7 центров

Список центров уточняется — проверьте первичный протокол.

Австралия · 5 центров

• 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

Франция · 5 центров

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

Япония · 5 центров

• 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 центров

Список центров уточняется — проверьте первичный протокол.

Канада · 4 центра

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

Польша · 3 центра

Список центров уточняется — проверьте первичный протокол.

Бельгия · 2 центра

• UZA — Edegem
• University Hospital Ghent — Ghent

Нидерланды · 2 центра

Список центров уточняется — проверьте первичный протокол.

Дания · 1 центр

• Aalborg U.H — Aalborg

Ирландия · 1 центр

• St. James's Hospital — Dublin

Новая Зеландия · 1 центр

Список центров уточняется — проверьте первичный протокол.

Публикации

• 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

Идентификаторы

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

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗