A Multi-center, Open-label, Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of AN9025 in Participants With Advanced or Metastatic Solid Tumors Harboring RAS Mutations
The goal of this clinical trial is to learn determine if AN9025 is safe and tolerable to treat solid cancer tumors with specific genetic mutations. It will help identify doses for use in future testing and establish the safety profile of the drug. The main questions it aims to answer are: Which dose(s) of AN9025 are safe and tolerable for use in evaluating anti-tumor activity in participants with Rat Sarcoma oncogene (RAS) mutated solid tumors? What medical problems do participants have when taking AN9025? Participants will: Take AN9025 by mouth every day until their disease progresses, they experience severe ill side effects from taking the drug, or withdraw from the study due to their own choice or as recommended by their physician. Visit the clinic 3-4 times during the first 21 days of treatment for study testing, blood draws and tumor tissue sample collection (if needed). The blood draws will be used to check drug levels in the participants blood for research purposes. Visit the clinic every 21 days for checkups and tests and monitoring of participant progress. Return to the clinic at 14 and 30 days after AN9025 treatment is stopped. Participants will be contacted every 3 months to check on the participants disease status and general well being. Participants may also partake in a food effect study, where the effect of eating is studied to see if there is any effect on AN9025 in the body.
• Aged ≥18 years old at the time of informed consent.
• Able to provide informed consent voluntarily before any study-related activities and according to local guidelines.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Have an estimated life expectancy ≥ 12 weeks, in the judgment of the Investigator.
• Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic with progression after treatment with available standard therapies.
• Documentation of KRAS/NRAS/HRAS mutation determined by validated local testing of tumor tissue or circulating free DNA (cfDNA) in a certified laboratory.
• Have consented to provide archival tumor tissue collected within 5 years or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Part 1 Dose-Escalation and Part 2 Food Effect Assessment: cancers including, but not limited to:
∙ Pancreatic ductal adenocarcinoma (PDAC)
‣ Colorectal cancer (CRC)
‣ Non-small cell lung cancer (NSCLC)
‣ Cutaneous melanoma
‣ Biliary tract cancer (BTC)
• Part 3 Dose-Expansion:
• Cohort 3A: RAS-mutated solid tumors (2L/3L)
‣ Histologically or cytologically confirmed advanced or metastatic disease
‣ Participants must not have tumors previously tested positive for targetable oncogenic driver mutations including Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK), B-Rapidly Accelerated Fibrosarcoma (BRAF), RET, and ROS1
‣ Participants must have received 1 or 2 prior lines of systemic therapy which include prior immune checkpoint inhibitor and platinum chemotherapy administered either concurrently or sequentially, and have not received docetaxel previously
‣ Participants must be refractory to anti-PD-1/PD-L1 therapy.
‣ Adjuvant therapy or multimodal therapy with curative intent is considered prior therapy if disease progression occurred or treatment completion was within 6 months of first dose of AN9025.
‣ Participants must not have tumors previously tested positive for Class I BRAF mutations i.e. V600X.
⁃ Have adequate organ functions prior to enrollment:
• ANC: \>= 1.5 x 10\^9/L
∙ Platelets: \>= 100x 10\^9/L
∙ Hemoglobin: \>= 9.0 g/dL
∙ AST and ALT: \<= 2.5 x Upper Limit of Normal (ULN) or ,+ x ULN if liver metastases are present
∙ Total bilirubin: \<= 1.5 x ULN
∙ Creatinine clearance (CrCl): CrCl \>= 50 ml/min as determined by Cockcroft-Gaulat formula
∙ International Normalized Ratio (INR) or prothrombin (PT) time or activated partial thromboplastin time (aPTT): PT or aPTT \<= 1.5 x ULN or INR \< 1.5
⁃ Have discontinued all previous treatments for cancer with resolution of any adverse events (AEs) to ≤ Grade 1 (except for alopecia, and endocrinopathies that are managed with replacement therapy), and all clinically significant toxicities from prior locoregional therapy, surgery, radiotherapy, or systemic anticancer therapy to ≤ Grade 1 prior to enrollment.
⁃ Corrected QT interval (QTc) ≤ 470 msec for females and ≤ 450 msec for males per the Fridericia's Formula (QTcF).
⁃ Able to swallow oral medication and comply with study requirements.
⁃ Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple gated acquisition (MUGA) scan.
⁃ Fertile men and women of childbearing potential must agree to use an effective method of birth control from providing signed consent and for 180 days after the last study treatment administration. Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test ≤ 14 days prior to the first dose of the study treatment.