Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors

Официальное название

A Platform Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors

Обзор

The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard(s) of Care (SOC) or with novel agents. The current subprotocols include the following: Subprotocol A: RMC-6236 + 5-fluorouracil-based regimens Subprotocol B: RMC-6236 + cetuximab with or without mFOLFOX6 Subprotocol C: RMC-6236 + gemcitabine + nab-paclitaxel Subprotocol D: RMC-9805 with or without RMC-6236 + 5-fluorouracil-based regimens Subprotocol E: RMC-9805 with or without RMC-6236 + cetuximab with or without mFOLFOX6 Subprotocol F: RMC-9805 with or without RMC-6236 + gemcitabine + nab-paclitaxel

Подробное описание

The platform study design allows combinations of RAS(ON) inhibitors with other anticancer agents to be evaluated in patients with RAS-mutated solid tumors with a focus on GI cancers.

This is an open-label platform study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard of Care (SOC) or with novel agents, and to define the Recommended Phase 2 Dose and Schedule (RP2DS). Enrollment of patients with RAS mutations will be specified in each subprotocol.

Subprotocol A is an open-label, multicenter study of RMC-6236 in combination with 5-fluorouracil-based regimens in patients with treatment-naïve unresectable or metastatic colorectal cancer or treatment-naïve metastatic pancreatic ductal adenocarcinoma. Subprotocol B is an open-label, multicenter study of RMC-6236 in combination with cetuximab with or without mFOLFOX6 in patients with unresectable or metastatic colorectal cancer or patients with previously treated or treatment-naïve metastatic pancreatic ductal adenocarcinoma. Subprotocol C is an open-label, multicenter study of RMC-6236 in combination with gemcitabine and nab-paclitaxel in patients with treatment-naïve metastatic pancreatic ductal adenocarcinoma. Subprotocol D is an open-label, multicenter study of RMC-9805 with or without RMC-6236 in combination with 5-fluorouracil-based regimens in patients with RAS G12D-mutant unresectable or metastatic colorectal cancer or metastatic pancreatic ductal adenocarcinoma. Subprotocol E is an open-label, multicenter study of RMC-9805 with or without RMC-6236 in combination with cetuximab-based therapies with or without mFOLFOX6 in patients with RAS G12D-mutant unresectable or metastatic colorectal cancer or metastatic pancreatic ductal adenocarcinoma. Subprotocol F is an open-label, multicenter study of RMC-9805 with or without RMC-6236 in combination with gemcitabine and nab-paclitaxel in patients with RAS G12D-mutant metastatic pancreatic ductal adenocarcinoma.

Each subprotocol consists of two parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.

Вмешательства

• Препарат RMC-6236
  Oral tablet
• Препарат mFOLFOX6 regimen
  IV infusion
• Препарат bevacizumab
  IV infusion
• Препарат mFOLFIRINOX regimen
  IV infusion
• Препарат cetuximab
  IV infusion
• Препарат gemcitabine
  IV infusion
• Препарат nab-paclitaxel
  IV infusion
• Препарат RMC-9805
  Oral Tablet

Первичные конечные точки

• Adverse events [Срок оценки: Up to 3 years]
• Dose limiting toxicities [Срок оценки: 28 days]

Вторичные конечные точки (7)

• Pharmacokinetics of RMC-6236 and RMC-9805 [Срок оценки: 21 weeks]
• ORR [Срок оценки: Up to 3 years]
• DOR [Срок оценки: Up to 3 years]
• DCR [Срок оценки: Up to 3 years]
• TTR [Срок оценки: Up to 3 years]
• PFS [Срок оценки: Up to 3 years]
• OS [Срок оценки: Up to 3 years]

Критерии участия

Критерии включения

All Patients (unless otherwise noted):

• ≥ 18 years of age
• ECOG PS is 0 to 1
• Adequate organ function as outlined by the study
• Pathologically or cytologically documented pancreatic carcinoma or poorly differentiated pancreatic carcinoma with metastatic disease or RAS-mutated, histologically or cytologically confirmed colorectal adenocarcinoma with documented unresectable or metastatic disease (Subprotocol A, B, and C)
• Presence of RAS G12D mutation (Subprotocol D, E, F)

Критерии исключения

All Patients:

• Primary central nervous system (CNS) tumors
• Impaired gastrointestinal (GI) function that may significantly alter the absorption of RMC drugs
• Major surgery within 28 days of first dose

Other inclusion/exclusion criteria may apply.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 32 центра

• Ironwood Cancer and Research Centers — Chandler
• Mayo Clinic Hospital — Phoenix
• HonorHealth Research Institute — Scottsdale
• UC San Diego Moores Cancer Center — La Jolla
• Cedars-Sinai Cancer at Cedars-Sinai Medical Center — Los Angeles
• UCLA Hematology/Oncology- Santa Monica — Los Angeles
• University of Colorado Hospital-Anschutz Cancer Pavilion — Aurora
• Yale-New Haven Hospital-Yale Cancer Center — New Haven
• … и ещё 24 центра

Публикации

• Cregg J, Edwards AV, Chang S, Lee BJ, Knox JE, Tomlinson ACA, Marquez A, Liu Y, Freilich R, Aay N, Wang Y, Jiang L, Jiang J, Wang Z, Flagella M, Wildes D, Smith JAM, Singh M, Wang Z, Gill AL, Koltun ES. Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers. J PMID 40056080

Идентификаторы

NCT: NCT06445062 · RMC-GI-102

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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