Clinical Trial 23090

• Overview

  Study Title:

  Phase 1b/2, Multicenter, Open-label, Dose Escalation and Dose Expansion Study of Elironrasib and Daraxonrasib as Monotherapies and in Combination Therapy in Patients with Advanced KRAS G12C-Mutated Solid Tumors

  Objective:

  Primary * To evaluate the safety and tolerability of RMC-6291 in combination with RMC-6236 in participants with KRASG12C-mutated solid tumors * To estimate the MTD and/or RP2DS for RMC-6291 in combination with RMC-6236 in participants with KRASG12C-mutated solid tumors Secondary * To characterize the plasma PK of RMC-6291 and blood PK of RMC-6236 following administration as combination therapy * To evaluate preliminary antitumor effects of RMC-6291 in combination with RMC-6236 in KRASG12C-mutated solid tumors

• Treatments

  Therapies:

  Therapy (NOS)

  Medications:

  Daraxonrasib (); Elironrasib (); RMC-6236 (Daraxonrasib); RMC-6291 (Elironrasib)

• Inclusion Criteria

  Key Inclusion Criteria:
  • At least 18 years of age, able and willing at the time of signing the informed consent form (ICF).
  • Histology: pathologically documented, KRASG12C-mutated, advanced or metastatic solid tumors not amendable to curative therapy: Part 1. Dose Escalation: solid tumors, previously treated. Part 2. Dose Expansion: NSCLC, previously treated with immunotherapy, chemotherapy, and KRASG12C (OFF) inhibitors. NSCLC, previously treated with immunotherapy and chemotherapy, naïve to KRASG12C (OFF) inhibitors. NSCLC, previously treated with immunotherapy, chemotherapy, with untreated, asymptomatic central nervous system (CNS) metastases > Measurable disease per RECIST 1.1.
  • Participant must have a life expectancy of at least 3 months, in the opinion of the Investigator.
  • Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 1 at screening and enrollment.
  • Able to take oral (PO) medications.
  • Adequate organ function as defined by the protocol.
  • A female participant is eligible to participate if she meets the following criteria: Is not a woman of childbearing potential (WOCBP), OR. Is a WOCBP and using a contraceptive method that is highly effective (ie, with a failure rate of > A male participant is eligible to participate if he agrees to the following during the Treatment Period and for at least 3 months after the last dose of study treatment: Refrains from donating sperm (any donation of sperm should be conducted prior to study start), PLUS, either: Abstain from intercourse as his preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent, OR Must agree to use a male condom AND should also be advised of the benefit for a nonpregnant female partner to use a highly effective method of contraception as a condom may break or leak.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Primary CNS tumor(s).
  • Untreated brain or leptomeningeal metastases. Treated CNS metastases are allowed if ALL of the following conditions are met: Radiation therapy ending at least 2 weeks prior to C1D1. Asymptomatic and on a stable dose of steroids and/or anticonvulsant therapy for (if applicable) at least 14 days prior to C1D1. No evidence of clinical or radiographic progression by a CNS imaging performed within 28 days of C1D1.
  • History of (> Impaired cardiovascular function as defined by the protocol.
  • History of interstitial lung disease (ILD) requiring treatment with glucocorticoids, history of noninfectious pneumonitis requiring glucocorticoids, or any active ILD or pneumonitis.
  • History of cerebrovascular accident or transient ischemic attack within 6 months prior to C1D1.
  • Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • Active, untreated human immunodeficiency virus (HIV) infection (CD4+ T cell counts less than or equal to 350 cells/microL and presence of acquired immunodeficiency syndrome [AIDS]-defining opportunistic infections in the past 12 months).
  • Active/chronic hepatitis B (positive for hepatitis B surface antigen with detected hepatitis B virus) or C (positive for hepatitis C ribonucleic acid [RNA]).
  • Impaired gastrointestinal (GI) function that may significantly alter the absorption of RMC-6291 or RMC-6236 (eg, uncontrolled nausea and vomiting, diarrhea, malabsorption syndrome, inflammatory bowel disease, gastrectomy, or small bowel resection).
  • History of severe allergic reactions to any of the study treatment components.
  • Major surgical procedure(s) within 28 days or non-study-related minor procedure(s) within 7 days prior to C1D1; in all cases, the participant must be sufficiently recovered and stable before study treatment administration.
  • Symptomatic pulmonary embolism or a pulmonary embolism not being treated with a stable dose of anticoagulants.
  • Ongoing adverse events (AEs) from prior cancer therapy that have not recovered to Grade 1, normal, or baseline.
  • Other unstable or clinically significant concurrent medical condition (including, but not limited to substance abuse, uncontrolled intercurrent illness such as active infection requiring systemic therapy within 72 hours of C1D1, or arterial thrombosis) that would, in the opinion of the Investigator or Sponsor Medical Monitor, jeopardize the safety of a participant, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol.
  • Has had prior exposure to an inhibitor (eg, small molecule, molecular glue, or degrader) that binds to the guanosine-5'-triphosphate (GTP)-bound state of KRAS, HRAS), or NRAS protein (eg, a RAS(ON) inhibitor).
  • Requires treatment with other investigational agents that do not fit in the above categories
  • Requires treatment with systemic cyclosporine A or derivative.
  • Requires treatment with proton pump inhibitors or H2 receptor antagonists (H2 blockers) within 3 days of C1D1 or during study participation (refer to Appendix 2 for prohibited medications). Antacid or other acid reducing agent may be used (See Appendix 2).
  • Other exclusion criteria may apply.

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