Advanced NRAS-Mutant Melanoma, Advanced NRAS-Mutant Solid Tumors, NRAS G12D, NRAS G12V, NRAS G13D, NRAS G13R, NRAS Mutation, NRAS Q61H, NRAS Q61K, NRAS Q61L, NRAS Q61R
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGRLY-8161
RLY-8161 is an NRAS-selective inhibitor
Sponsors
Relay Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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).
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: Maximum Tolerated Dose (MTD) and/or RP2D of RLY-8161 | 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 | 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 | Approximately every 8 weeks on treatment and every 12 weeks after last dose in the absence of progressive disease, approximately 18 months |
Secondary
| Measure | Time frame |
|---|---|
| Part 1 and Part 2: Changes in NRAS mutant allele fraction in ctDNA | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 |
Countries
United States
Contacts
CONTACTRelay Therapeutics, Inc
Outcome results
None listed