Oral AN9025 for advanced solid tumors with RAS mutations

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

This trial tests whether the oral drug AN9025 is safe and tolerable for adults with advanced solid tumors that have RAS mutations.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 91 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Adlai Nortye Biopharma Co., Ltd. (industry)
• Drugs / interventions: chemotherapy
• Locations: 2 sites (Orlando, Florida and 1 other locations)
• Trial ID: NCT07252479 on ClinicalTrials.gov

What this trial studies

This first-in-human, open-label, multicenter Phase 1 study gives adults with advanced or metastatic RAS-mutant solid tumors daily oral AN9025 to define safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity. Part 1 uses a multiple-ascending dose escalation with dose-limiting toxicity monitoring to identify the maximum tolerated dose or recommended dose for expansion, including single-dose lead-ins and back-fill cohorts. Part 2 uses a single-sequence crossover to evaluate the effect of food on AN9025 pharmacokinetics, and Part 3 expands selected dose cohorts to explore activity in specific tumor types. The study includes frequent early clinic visits for blood draws, PK sampling, and tumor biopsy and is being conducted at sites in the United States and China.

Who should consider this trial

Good fit: Adults (≥18 years) with advanced or metastatic solid tumors and documented KRAS/NRAS/HRAS mutations who have progressed on available standard therapies, with ECOG performance status 0–1 and estimated life expectancy ≥12 weeks.

Not a fit: Patients without confirmed RAS mutations, with poor performance status (ECOG ≥2), very limited life expectancy, or who cannot attend frequent clinic visits are unlikely to gain benefit from this study.

Why it matters

Potential benefit: If successful, AN9025 could provide a new oral targeted treatment option that slows tumor growth in patients with RAS-mutant cancers.

How similar studies have performed: KRAS G12C-specific inhibitors have shown clinical benefit, but broadly acting oral pan‑RAS inhibitors like AN9025 are largely novel and have limited prior clinical data.

Eligibility criteria

Inclusion Criteria:

1. Aged ≥18 years old at the time of informed consent.
2. Able to provide informed consent voluntarily before any study-related activities and according to local guidelines.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. Have an estimated life expectancy ≥ 12 weeks, in the judgment of the Investigator.
5. Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic with progression after treatment with available standard therapies.
6. Documentation of KRAS/NRAS/HRAS mutation determined by validated local testing of tumor tissue or circulating free DNA (cfDNA) in a certified laboratory.
7. 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.
8. Part 1 Dose-Escalation and Part 2 Food Effect Assessment: cancers including, but not limited to:

   1. Pancreatic ductal adenocarcinoma (PDAC)
   2. Colorectal cancer (CRC)
   3. Non-small cell lung cancer (NSCLC)
   4. Cutaneous melanoma
   5. Biliary tract cancer (BTC)
9. Part 3 Dose-Expansion:

   Cohort 3A: RAS-mutated solid tumors (2L/3L)
   1. Histologically or cytologically confirmed advanced or metastatic disease
   2. 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
   3. 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
   4. Participants must be refractory to anti-PD-1/PD-L1 therapy.
   5. 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.
   6. Participants must not have tumors previously tested positive for Class I BRAF mutations i.e. V600X.
10. Have adequate organ functions prior to enrollment:

    1. ANC: \>= 1.5 x 10\^9/L
    2. Platelets: \>= 100x 10\^9/L
    3. Hemoglobin: \>= 9.0 g/dL
    4. AST and ALT: \<= 2.5 x Upper Limit of Normal (ULN) or ,+ x ULN if liver metastases are present
    5. Total bilirubin: \<= 1.5 x ULN
    6. Creatinine clearance (CrCl): CrCl \>= 50 ml/min as determined by Cockcroft-Gaulat formula
    7. 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
11. 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.
12. Corrected QT interval (QTc) ≤ 470 msec for females and ≤ 450 msec for males per the Fridericia's Formula (QTcF).
13. Able to swallow oral medication and comply with study requirements.
14. Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple gated acquisition (MUGA) scan.
15. 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.

Exclusion Criteria:

Participants meeting any of the following criteria will not be eligible for participation in the study.

1. 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.
2. Have tumors previously tested positive for Class I BRAF mutations i.e. V600X.
3. Prior treatment with a pan-RAS(ON) inhibitor.
4. Gastrointestinal conditions that may interfere with drug absorption (e.g., malabsorption syndrome, chronic nausea/vomiting, active inflammatory bowel disease).
5. Have a serious concomitant systemic disorder that, in the judgment of the Investigator, would compromise the participant's ability to adhere to the protocol, such as the following:

   1. Known human immunodeficiency virus (HIV) infection per HIV 1 and/or 2 antibodies.
   2. Participants with evidence of active Hepatitis B or Hepatitis C infections (positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody)
   3. Active tuberculosis, fungal infection
   4. Active infection requiring intravenous antibiotic therapy. Use of oral antibiotics for minor infections (e.g., uncomplicated UTI or URI) is permitted if clinically stable, at the Investigator's discretion
6. 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.
7. 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.
8. Moderate or severe cardiovascular disease, such as the following:

   1. congestive heart failure
   2. New York Heart Association Class III/IV heart disease
   3. unstable angina pectoris
   4. myocardial infarction or cardiovascular event within the last 6 months before enrollment
   5. valvulopathy that is severe, moderate, or deemed clinically significant
   6. arrhythmias that are symptomatic or require treatment (not including Participants with rate-controlled supraventricular tachycardia)
   7. a history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT syndrome)
   8. require the use of concomitant medications that prolong the QT/QTc interval
9. Have symptomatic central nervous system (CNS) malignancy or metastasis.
10. 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.
11. 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.
12. 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.
13. Known allergic reaction against any of the components of the study treatments.
14. Current use of drugs known to be strong or moderate inhibitors or inducers of isoenzyme cytochrome P450 3A4 (CYP3A4) including herbal medications.
15. Current use of drugs known to be of P-glycoprotein (P-gp) inhibitors.
16. 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.
17. 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.

Where this trial is running

Orlando, Florida and 1 other locations

• Sarah Cannon Research Institute at Florida Cancer Specialists — Orlando, Florida, United States (RECRUITING)
• University of Texas MD Anderson Cancer Center — Houston, Texas, United States (NOT_YET_RECRUITING)

Study contacts

• Study coordinator: Clinical Trial Manager

Conditions: Solid Tumors, RAS Mutation, RAS, RAS Solid Tumor, KRAS G12X, KRAS G13D, NRAS Q61X, Oral Pan RAS medication