A First-in-human Study of RLY-8161 in Advanced NRAS-Mutant Solid Tumors

Официальное название

A First-in-human Study of RLY-8161 for Treatment of Advanced NRAS-Mutant Melanoma and Other Solid Tumors

Обзор

This is a Phase 1 first-in-human, open-label multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of RLY-8161, an NRAS-selective inhibitor, in participants with advanced NRAS-mutant melanoma and other solid tumors.

Подробное описание

This is a Phase 1 first-in-human, open-label multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of RLY-8161, an NRAS-selective inhibitor, in participants with advanced NRAS-mutant melanoma and other solid tumors. This study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2).

Part 1, dose escalation will explore multiple ascending doses of RLY-8161 in participants with any advanced NRAS-mutant solid tumor until maximum tolerated dose is reached or one or more recommended Phase 2 dose (RP2D) is identified.

Part 2, dose expansion will be at the RP2D(s) identified in Part 1 in NRAS-mutant solid tumors.

Вмешательства

• Препарат RLY-8161
  RLY-8161 is an NRAS-selective inhibitor

Первичные конечные точки

• Part 1: Maximum Tolerated Dose (MTD) and/or RP2D of RLY-8161 [Срок оценки: Cycle 1 (28-day cycle) of treatment for MTD and at the end of every cycle (28-day cycle) for RP2D until treatment discontinuation, approximately 12 months]
• Part 1: Number of participants with Adverse Events (AEs) or Serious Adverse Events (SAEs), with changes in vital signs, electrocardiograms (ECGs), and laboratory tests [Срок оценки: Cycle 1 (28-day cycle) of treatment and at the end of every cycle (28-day cycle) until 30 days after treatment discontinuation, approximately 13 months]
• Part 2: Objective Response Rate (ORR) of RLY-8161 as assessed by RECIST v1.1 [Срок оценки: Approximately every 8 weeks on treatment and every 12 weeks after last dose in the absence of progressive disease, approximately 18 months]

Вторичные конечные точки (8)

• Part 1 and Part 2: Changes in NRAS mutant allele fraction in ctDNA [Срок оценки: Approximately every 2 weeks in Cycle 1 (28-day cycle), at the beginning of Cycle 2 (28-day cycle), and at the beginning of every odd cycle (28-day cycle) until End of Treatment (EOT), approximately 12 months]
• Part 1 and Part 2: Plasma concentration and PK parameters of RLY-8161 [Срок оценки: Approximately every 2 weeks in Cycle 1 (28-day cycle) and at Day 1 of every cycle (28-day cycle) through Cycle 4]
• Part 1: ORR of RLY-8161 as assessed by RECIST v1.1 [Срок оценки: Approximately every 8 weeks on treatment and every 12 weeks after last dose in the absence of progressive disease, approximately 18 months]
• Part 1 and 2: Duration of Response (DOR) of RLY-8161 as assessed by RECIST v1.1 [Срок оценки: Approximately every 8 weeks on treatment and every 12 weeks after last dose in the absence of progressive disease, approximately 18 months]
• Part 1 and 2: Disease Control Rate (DCR) of RLY-8161 as assessed by RECIST v1.1 [Срок оценки: Approximately every 8 weeks on treatment and every 12 weeks after last dose in the absence of progressive disease, approximately 18 months]
• Part 2: Progression-free survival (PFS) as assessed by RECIST v1.1 [Срок оценки: Approximately every 8 weeks on treatment and every 12 weeks after last dose in the absence of progressive disease, approximately 18 months]
• Part 2: Overall Survival [Срок оценки: Cycle 1 (28-day cycles) until study completion, approximately 30 months]
• Part 2: Number of participants with AEs or SAEs, with changes in vital signs, ECGs, and laboratory tests [Срок оценки: Cycle 1 (28-day cycle) of treatment and at the end of every cycle (28-day cycle) until 30 days after treatment discontinuation, approximately 13 months]

Критерии участия

Критерии включения

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Histologically confirmed diagnosis of unresectable Stage III or IV melanoma or other solid tumor.
• Disease is refractory to standard therapy (including targeted therapy), participant is intolerant of standard therapy, or participant has declined standard therapy.
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• One or more documented primary oncogenic NRAS mutation(s).

Критерии исключения

• Known activating KRAS, HRAS, or BRAF mutation or known alterations in other driver oncogenes.
• Prior treatment with ERK, MEK, RAF, or RAS targeting agents or any agent whose mechanism of action is to inhibit the RAS-MAPK pathway.
• For participants with melanoma: lactate dehydrogenase (LDH) >2×ULN.
• Central nervous system (CNS) metastases that are associated with progressive neurologic symptoms or require ongoing corticosteroids to control the CNS disease.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 9 центров

• University of California, Los Angeles — Los Angeles
• University of California, San Francisco — San Francisco
• University of Colorado Hospital — Aurora
• Massachusetts General Hospital — Boston
• Dana Farber Cancer Institute — Boston
• START Midwest, LLC — Grand Rapids
• Memorial Sloan Kettering Cancer Center — New York
• Sarah Cannon Research Institute Oncology Partners — Nashville
• … и ещё 1 центр

Идентификаторы

NCT: NCT07584226 · RLY-8161-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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