MC# 22-17 - Phase I/Ib Multicenter Open-Label Study of RMC-6236 in Subjects with Advanced Solid Tumors Harboring Specific Mutations in KRAS
Disease Type(s): Colorectal, Pancreatic, Solid Tumor, Lung-NSCLC
Drug Classification(s): Small Molecule, Targeted Therapy
Molecular Target(s): KRAS G12A, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V
Mechanism of Action
RMC-6236 inhibits the RAS(ON) state of multiple RAS variants both mutant and wild-type proteins.
In this study, the sponsor and investigators want to learn:
- How much of RMC-6236 can be given with an acceptable level of side effects
- The effects of RMC-6236 (good and bad)
- How much of RMC-6236 is absorbed into the blood and how fast it is removed
- Subject must be ≥18 years of age and capable of giving signed informed consent as described in the protocol (which includes compliance with the requirements and restrictions listed in the ICF and in the protocol) at the time of signing the ICF
- Pathologically documented, locally advanced or metastatic malignancy with KRASG12A, KRASG12D, KRASG12R, KRASG12S, or KRASG12V mutations identified through deoxyribonucleic acid (DNA) sequencing of an archival biopsy or ctDNA obtained within 3 years of C1D1 or fresh tumor biopsy (Note, per Exclusion Criteria 1, subjects with tumors harboring KRASG12C are excluded)
- Subject must have received prior standard therapy appropriate for tumor type and stage (disease specific criteria identified below [bullets a-c])
- Subjects with histologically documented NSCLC–specific inclusion:
- Part 1 (Dose Escalation) – prior anticancer treatment with at least one prior line of therapy with platinum-based combination therapy and/or targeted therapies (e.g., epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], or reactive oxygen species [ROS] [ROS1 (ROS proto-oncogene 1)] inhibitors or immune checkpoint inhibitors) are required prior to receiving RMC-6236
- Part 2 (Dose Expansion) – one to 3 prior lines of prior systemic therapy. Subjects must have received platinum-based combination chemotherapy AND targeted therapy (if indicated) and/or checkpoint inhibitor immunotherapy.
- Subjects with histologically documented CRC–specific inclusion:
- Part 1 (Dose Escalation) – subjects with metastatic CRC must have at least two prior systemic regimen. Microsatellite unstable subjects must have been treated with nivolumab or pembrolizumab for one regimen if they were clinically able to receive checkpoint inhibitors.
- Part 2 (Dose Expansion) – Must have progressed or had intolerable toxicity per the investigator’s judgement after fluoropyrimidine, oxaliplatin, and irinotecan. Microsatellite unstable subjects must have been treated with nivolumab or pembrolizumab for one regimen if they were clinically able to receive checkpoint inhibitors.
- Subjects with histologically documented other-cancer specific inclusion (including PDAC):
- Must have failed at least one prior systemic therapy
- Subjects with histologically documented NSCLC–specific inclusion:
- Subjects must provide archival tumor samples collected within 3 years or be willing to undergo pretreatment tumor biopsy. Fresh pretreatment tumor biopsies are not required forenrollment, but subjects are encouraged to undergo pretreatment tumor biopsies when possible.
- Measurable disease per Response Evaluation Criteria in Solid Tumors (version 1.1) (RECIST v1.1) is required. Subjects with nonmeasurable, but evaluable disease (nontarget lesions only per RECIST v1.1) may be eligible for the Dose-Escalation Phase pending Sponsor Medical Monitor approval.
- The subject’s ECOG PS of 0 to 1 with no deterioration in PS within 2 weeks prior to C1D1 (C1D -3 for food effect cohorts). Rescreening is required if PS is >1 for any reason prior to C1D1 (C1D -3 for food effect cohorts).
- Female subjects of childbearing potential and male subjects with female partners of childbearing potential must agree to always use highly effective forms of contraception during the course of the study and for at least 1 month after completion of study intervention. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- Female subjects of childbearing potential must have a negative blood pregnancy test within 14 days of commencement of study intervention
- Male subjects must agree to refrain from donating sperm during the course of the study and for at least 3 months after completion of study treatment
- Food effect Assessment – Additional Specific Inclusion Criteria
- Subjects must be able to consume a standardized meal within 30 minutes
- Subjects must be able to fast for ≥12 hours
- Subject with tumors harboring KRASG12C mutations are not eligible
- Subjects with primary central nervous system (CNS) brain tumors
- Subject has known or suspected leptomeningeal or brain metastases or spinal cord compression. However, a subject who was previously treated for these conditions with stable CNS disease (no evidence of clinical or radiographic disease progression and asymptomatic in the absence of corticosteroids or anticonvulsant therapy) are eligible to participate in the study in consultation with the Sponsor medical monitor, as long as stable disease is documented by a brain magnetic resonance imaging (MRI) performed within 28-days of C1D1.
- Subjects with seizure disorder requiring antiepileptics.
- Subjects with a prior history of (<5 years ago) or concurrent malignancy are excluded. Exceptions may include prior malignancies considered to be clinically insignificant and for which no systemic anticancer treatment is required (e.g., basal cell or squamous cell carcinoma of the skin post–curative surgical resection; carcinoma in situ of the cervix post-curative surgical resection). Approval from the Sponsor Medical Monitor is required for exceptions.
- Subjects with known or suspected impairment of GI function including any conditions which might hinder drug absorption, the ability to take PO medication, other malabsorption, or uncontrolled inflammatory GI disease such as Crohn’s disease or ulcerative colitis
- Subjects receiving specific oncologic therapies:
- Subjects who have had prior therapy with any direct RAS inhibitor
- Treatment with chemotherapy or tyrosine kinase inhibitor (TKI) within 14 days or 5 half-lives (for nitrosourea and mitomycin C within 6 weeks) of C1D1, whichever is shorter
- Subject has had treatment with chemotherapy or biologics/monoclonal antibodies (non-immunotherapy) <21 days or 5 half-lives (whichever is shorter) before C1D1
- Treatment with radiation therapy within 14 days of C1D1
- Treatment with immunotherapy (e.g., checkpoint inhibitors) within 28 days of C1D1
- Treatment with any other anticancer treatment not included in “1” through “5” above within 28 days of C1D1
- Dallas, TX - Mary Crowley Cancer Research - Medical City