A Phase 1 Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PAS-004, a MEK (1/2) Inhibitor, in Patients With MAPK Pathway-driven Advanced Solid Tumors With a Documented RAS, NF1, or RAF Mutation or Patients Who Have Failed BRAF/MEK Inhibition
The main purpose of this clinical trial is to test PAS-004 in people with advanced solid tumors with rat sarcoma virus (RAS), neurofibromatosis type I (NF1), or rapidly accelerated fibrosarcoma (RAF) mutations. The main questions it aims to answer are: * How well participants are able tolerate different doses of PAS-004, and * What side effects PAS-004 might have. Study participants will have regular visits to the study doctor and be asked to have tests and exams done to check on their health and safety. Everyone participating in the study will take PAS-004 by mouth as a single dose, followed by one week observation, then once a day during the study, in 28-day cycles. Participants will continue on daily PAS-004 for up to 2 years, or until: * They decide to withdraw from the study, or * They experience unacceptable side effects, or * Their disease progresses, or another illness interferes with taking the study drug, or * The sponsors stops the study.
• Capable of giving signed informed consent which includes compliance with the requirements, prohibitions and restrictions listed in the informed consent form (ICF).
• Patient has been informed both verbally and in writing about the objectives of the clinical study, the methods, the anticipated benefits, the potential risks, and the discomfort to which they may be exposed and has given written consent to participation in the study prior to study start and any study-related procedure.
• Patient must be at least 18 years of age at the time of signing the ICF.
• Patient must be able to swallow oral medication.
• Patient with histologically or cytologically diagnosed mitogen-activated protein kinase (MAPK) pathway driven advanced solid tumors with all of the following characteristics:
∙ Tumor cannot be surgically resected
‣ Patient has failed or is ineligible for standard of care therapy
‣ Patient has no available treatment options with known clinical benefit
‣ Documented evidence of rat sarcoma virus (RAS), neurofibromatosis type I (NF1), and/or rapidly accelerated fibrosarcoma (RAF) mutations. Patients with RAF mutations must have previously failed v-Raf murine sarcoma viral oncogene homolog B (BRAF) / MEK inhibition.
• Prior to enrollment, patients without an existing prior genetic test result or adequate tumor tissue sample must agree to provide tumor tissue via biopsy (paraffin section or fresh tissue specimens) that will be sent for analysis to confirm eligibility.
• Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix B).
• Patient must have an estimated life expectancy of at least 12 weeks in the opinion of the Investigator at the time of informed consent.
• Patient must have adequate organ function at screening as indicated by the following laboratory value ranges:
∙ Serum total bilirubin ≤ 1.5 × upper limit normal (ULN) (Serum total bilirubin can be ≤ 3.0 × ULN if patients have hemolysis or congenital hemolytic diseases)
‣ Aspartate aminotransferase (AST) ≤ 2.5 × ULN or 5 × ULN for patient with liver metastases
‣ Alanine aminotransferase (ALT) ≤ 2.5 × ULN or 5 × ULN for patient with liver metastases
‣ Albumin ≥2 mg/dL
‣ Creatinine clearance ≥ 45 mL/min (as calculated per Cockcroft-Gault)
‣ Absolute neutrophil count (ANC) ≥ 1.5×109/L
‣ Platelets ≥ 100×109/L
‣ Hemoglobin ≥ 90 g/L (Note: Criteria must be met without a transfusion within 2 weeks of obtaining the sample)
⁃ Patient must agree to maintain abstinence (no heterosexual intercourse) or use a highly effective form of contraception during study treatment and for at least 90 days after the last dose of IP. Male patients must agree not to donate sperm while receiving IP and for at least 90 days after the last dose of IP.