MC# 18-26 - A Phase I/II Study of MRTX849 in Patients with Advanced Solid Tumors with KRAS G12C Mutation

  • Agent(s): MRTX849
  • Disease Type(s): Solid Tumor
  • Phase(s): I, II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): HRAS, KRAS, NRAS

Mechanism of Action

MRTX849 is a potent, highly selective and orally available small molecule inhibitor of a form of KRAS that harbors an oncogenic substitution mutation (G12C)

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of MRTX849 can be given with an acceptable level of side effects
  • The effects of MRTX849 (good and bad)
  • How much of MRTX849 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from MRTX849
Inclusion Criteria
  • Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation
  • Unresectable or metastatic disease
  • Available and prior therapy:
    • No available treatment with curative intent,
    • No available standard-of-care treatment or patient is ineligible or declines treatment, except
    • In Phase II NSCLC cohorts, patients must have previously received treatment with at least a platinum-containing chemotherapy regimen and checkpoint inhibitor therapy
  • Presence of tumor lesions to be evaluated per RECIST 1.1:
    • In Phase I, Phase Ib cohorts that do not include a statistical evaluation of clinical activity, and cohort sub-studies, patients must have measurable or evaluable disease
    • In Phase Ib cohorts that include a statistical evaluation of clinical activity and Phase II, patients must have measurable disease
  • Age ≥ 18 years
  • Life expectancy of at least 3 months
  • Most recent prior systemic therapy (e.g., chemotherapy, immunotherapy or, investigational agent) and radiation therapy discontinued at least 2 weeks before first dose date
  • Recovery from the adverse effects of prior therapy at the time of enrollment to ≤ Grade 1 (excluding alopecia)
  • Eastern Cooperative Oncology Group (ECOG) performance status in 0 or 1
  • Laboratory values within the screening period:
    • Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 x 109/L)
    • Platelet count ≥ 100,000/mm3 (≥ 100 x 109/L)
    • Hemoglobin ≥ 9 g/dL, in the absence of transfusions for at least 2 weeks
    • Total bilirubin ≤1.5 x Upper Limit of Normal (ULN) (if associated with liver metastases or Gilbert’s disease, ≤3 x ULN)
    • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤3.0 x ULN (if associated with liver metastases, ≤5 x ULN)
    • Calculated creatinine clearance ≥ 60 mL/min by the Cockcroft-Gault equation
  • Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment
  • Completed informed consent process, including signing IRB/EC-approved informed consent form
  • Willing to comply with clinical trial instructions and requirements
Exclusion Criteria
  • Active brain metastases. Patients are eligible if brain metastases are adequately treated and patients are neurologically stable (except for residual signs or symptoms related to the central nervous system (CNS) treatment) for at least 2 weeks prior to enrollment without the use of corticosteroids or are on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent).
  • Patients with carcinomatous meningitis
  • History of significant hemoptysis or hemorrhage within 4 weeks of the first dose date
  • Undergone major surgery within 4 weeks of first dose date
  • History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications
  • Any of the following cardiac abnormalities within the last 6 months:
    • Unstable angina pectoris
    • Congestive heart failure ≥ NYHA Class 3
    • QTc > 480 milliseconds or family history of Long QT Syndrome
  • History of stroke or transient ischemic attack within the previous 6 months
  • Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to study entry
  • Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments
  • Known human immunodeficiency virus (HIV) seropositivity or active Hepatitis B or C.  Patients treated for hepatitis C with no detectable viral load are permitted.
  • Pregnancy.  WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior start of study drug.
  • Breast-feeding or planning to breast feed during the study or within 6 months after study treatment
  • Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient’s participation in the study, or with the interpretation of the results

Exclusion criterion specific to Phase II cohorts:

  • Prior treatment with a therapy targeting KRAS G12C mutation

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03785249

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Re: MC# 18-26