Clinical Trial 24394

• Overview

  Study Title:

  A Multi-center, Open-label, Phase I Study Evaluating the Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AN9025 in Participants with Advanced or Metastatic Solid Tumors Harboring RAS Mutations

  Summary:

  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 or once a week 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.

  Objective:

  Part 1 Dose Escalation: Primary Objectives: * To evaluate the safety and tolerability of multiple dosing schedules of AN9025 in advanced or metastatic solid tumors with RAS mutations * To determine the MTD and/or RDE of multiple dosing schedules of AN9025 in advanced or metastatic solid tumors with RAS mutations Secondary Objectives: * To characterize the PK profile of multiple dosing schedules of AN9025 following administration as an oral capsule formulation * To assess the preliminary anti-tumor activity of multiple dosing schedules of AN9025 as monotherapy in advanced or metastatic solid tumors with RAS mutations Part 2 Food Effect Assessment: Primary Objectives: * To evaluate the preliminary effect of food on the PK of AN9025 Secondary Objectives: * To evaluate the safety and tolerability of AN9025 in advanced or metastatic solid tumors with RAS mutations * To assess the preliminary anti-tumor activity of AN9025 as monotherapy in advanced or metastatic solid tumors with RAS mutations Part 3 Dose- Expansion: Primary Objectives: * To evaluate the safety and tolerability of AN9025 at the RDE in selected RAS-mutated solid tumors Secondary Objectives: * To characterize the PK profile of AN9025 at the RDE * To evaluate the preliminary antitumor activity of AN9025 in selected RAS-mutated solid tumors

• Treatments

  Therapies:

  Orally bioavailable small-molecule pan-RAS (ON) inhibitor

  Medications:

  AN9025 ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • 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. Note: Participants with melanoma who have documented loss-of-function NF1 mutation and wild type KRAS/NRAS/HRAS/BRAF are also eligible for the backfill of Part 1 cohorts QD, QW.
  • 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.
  • 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.
  • Additional criteria will apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Are currently enrolled in a clinical study involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
  • Have tumors previously tested positive for Class I BRAF mutations i.e. V600X.
  • Prior treatment with a pan-RAS(ON) inhibitor, ) except for participants enrolled in the backfill cohorts who have experienced radiological or clinical disease progression on prior pan-RAS(ON) inhibitor therapy.
  • Gastrointestinal conditions that may interfere with drug absorption (e.g., malabsorption syndrome, chronic nausea/vomiting, active inflammatory bowel disease).
  • Have a serious concomitant systemic disorder that, in the judgment of the Investigator, would compromise the participant's ability to adhere to the protocol.
  • The participant has a serious pre-existing medical condition(s) that, in the judgment of the Investigator, would preclude participation in this study, including interstitial lung disease (ILD), severe dyspnea at rest, or requiring oxygen therapy.
  • Prior or second concurrent primary malignancies that, in the judgment of the Investigator, may affect the interpretation of results. Participants with carcinoma in situ of any origin and participants with prior malignancies who are in remission and whose likelihood of recurrence is very low (such as basal cell carcinoma), as judged by the Investigator, or malignancies that don't need treatment (i.e., small renal cell carcinoma [RCC] and localized prostate cancer) are eligible for this study.
  • Moderate or severe cardiovascular disease.
  • Have symptomatic central nervous system (CNS) malignancy or metastasis.
  • Are pregnant or planning to become pregnant during the study or within 6 months following the last dose of AN9025. Plan to be breastfeeding from the initial dose of study treatment or within 6 months following the last dose of AN9025.
  • Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
  • Use of other herbal supplements, traditional medicines, or prescription medications that are known or suspected to interact with the investigational product or effect disease treatment/side effect management, as determined by the study Investigator.
  • Known allergic reaction against any of the components of the study treatments.
  • Current use of drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications.
  • Current use of drugs known to be of P-glycoprotein (P-gp) inhibitors.
  • Participants who are unable to discontinue proton pump inhibitors (PPIs) for at least 5 days prior to the first dose of AN9025, or unable to abstain from PPI use throughout the study treatment period.
  • Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participant and Investigator's knowledge.
  • Additional criteria will apply.

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