AB801 in Combination With Chemotherapy and Immunotherapy for the Treatment of Patients With Borderline Resectable, Locally Advanced or Metastatic Cholangiocarcinoma or Pancreatic Cancer

ClinicalTrials.gov Identifier

NCT07619313

Institution Name

UCLA

Full Institution Address

2020 Santa Monica Blvd Suite 600 Santa Monica, CA 90404-2023 United States

Institution Phone

310-829-5471

Principal Investigator

Dr. Lee Rosen

Principal Investigator Phone

310-829-5471

Principal Investigator Email

[email protected]

Additional Principal Investigators

Dr. Jonathan Boiarsky, 310-829-5471, [email protected]

Study Coordinator

Chris Lim

Study Coordinator Phone

310-829-5471

Study Coordinator Email

[email protected]

Study Overview

Cholangiocarcinoma (bile duct cancer) remains a highly lethal disease with poor outcomes even with current treatments. The majority of patients present with disease that cannot be surgically removed, and survival remains limited with standard chemotherapy and immunotherapy alone. While gemcitabine, cisplatin, and durvalumab represent the current standard of care, most patients ultimately progress, highlighting the urgent need for better treatment strategies. AXL, a protein overexpressed in cholangiocarcinoma, drives tumor growth, spread, and resistance to chemotherapy and immunotherapy. Preclinical data from our group at UCLA demonstrate that blocking AXL restores chemosensitivity and enhances immune recognition of tumor cells. This trial will evaluate adding AB801, a novel AXL inhibitor, to standard gemcitabine/cisplatin/durvalumab in patients with borderline resectable, locally advanced, or metastatic cholangiocarcinoma.

Enrollment Information

23

Study Start Date

20260601

Study End Date

20280630

Study Purpose

The purpose of this study is to evaluate the safety and tolerability of adding AB801, a novel AXL inhibitor, to standard chemotherapy and immunotherapy (gemcitabine, cisplatin, and durvalumab) in patients with cholangiocarcinoma that is borderline resectable, locally advanced, or metastatic. The study will determine the safest and most effective dose of AB801 to carry forward into future studies. Additional objectives include measuring tumor response rates, how long patients remain free of disease progression, and the proportion of patients whose tumors shrink enough to become eligible for curative surgery. A key component of the study is a translational research program that will analyze tumor tissue and blood samples collected throughout treatment to better understand how AB801 affects the tumor and immune system, with the goal of identifying biomarkers that predict response.

Inclusion Criteria

1. Male or female ≥ 18 years of age and willing and able to provide informed consent 2. Previously untreated cytologically or histologically confirmed, at least one measurable lesion via Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of cholangiocarcinoma meeting following criteria: a. Borderline resectable/locally advanced cholangiocarcinoma: to be defined as unresectable disease on evaluation by a hepatobiliary multi-disciplinary tumor board/surgeon based on tumor size/location, vascular involvement, and absence of extrahepatic metastasis. b. Metastatic cholangiocarcinoma: Patients with metastatic cholangiocarcinoma patient who have not received prior systemic therapy 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 4. Absolute neutrophil count (ANC) ≥ 1.5x10^9/L 5. Platelets ≥ 100x10^9/L 6. Hemoglobin ≥ 9 g/dL 7. Creatinine clearance (Ccr) ≥ 50 mL/min (as calculated by Modified Cockcroft-Gault formula) 8. Serum total bilirubin ≤ 2x upper limit of normal (ULN) or < 3x ULN if Gilbert's syndrome 9. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) ≤ 2.5 X ULN; < 5x ULN in patients with liver metastases 10. Women with no childbearing potential because of surgery or who are at least 1 year postmenopausal (ie, 12 months post last menstrual period) or with menopause confirmed by follicle-stimulating hormone testing, OR Women of childbearing potential (defined as any female who has experienced menarche and is not permanently sterile or post-menopausal) must use an effective nonhormonal method of contraception (intrauterine device or intrauterine system; condom or occlusive cap [diaphragm or cervical or vault caps] with spermicidal foam or gel or film or cream or suppository; or vasectomized male partner if he is the sole partner of that participant) or practice true abstinence for the duration of the study and for up to 14 months after the last systemic treatment 11. Male participants must use an effective method of contraception (condom or occlusive cap [diaphragm or cervical or vault caps] with spermicidal foam or gel or film or cream or suppository; or vasectomy) or practice true abstinence as defined throughout the study and for up to 11 months after the systemic treatment 12. Immunosuppressive doses of systemic medications, such as corticosteroids or absorbed topical corticosteroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks (14 days) before study treatment administration. Physiologic doses of corticosteroids (≤ 10 mg/day of prednisone or its equivalent) or short pulses of corticosteroids (≤ 3 days) may be permitted 13. Products with known potential to prolong the corrected QT (QTc) interval should be avoided when possible. When able will replace non-prolonging QTc acting drug when available and if medically necessary 14. Major surgery as defined by the Investigator must be completed at least 4 weeks before study treatment administration. Participants should have recovered from the surgical procedure prior to the first dose being administered 15. Adequate baseline tumor tissue sample for correlative studies

Exclusion Criteria

1. Previous treatment with any of planned study drugs in cholangiocarcinoma, though patients with one cycle of gemcitabine/cisplatin/durvalumab will be considered eligible 2. Peripheral neuropathy > grade 2 3. Known status of HIV which is not well-controlled (CD4 < 300) at the time of study eligibility. Patients with controlled and treated HIV/hepatitis C virus (HCV) and an undetectable viral load are allowed 4. Untreated hepatitis B infection; Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection (testing is not mandatory, unless known active or known history of infection or required by local regulation): 5. Participants with resolved or treated HCV (ie, HCV antibody positive but undetectable HCV ribonucleic acid [RNA]) will not be excluded from this study Underlying medical conditions that, in the Investigator's opinion, will make the administration of investigational product (IP)(s) hazardous, including but not limited to: Interstitial lung disease, including history of interstitial lung disease or non-infectious pneumonitis, Active viral, bacterial, or fungal infections requiring parenteral treatment within 14 days of the initiation of the IP, Active infection or antibiotics within 48 hours prior to study screening; A condition or unresolved adverse event (AE) from a prior investigational drug that may obscure the interpretation of toxicity determination or AEs, History of prior solid-organ transplantation 6. Any history of malignancy less than 5 years prior to the time of study eligibility (Patients with history of skin cancers excluding melanoma and cancers with a very low risk of recurrence i.e., low grade prostate cancer, thyroid cancer and low risk cervical cancer will be eligible for participation) 7. Serious medical comorbidities such as New York Heart Association Class III/IV cardiac disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12 months 8. Known family history or personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least grade 3 (QTc > 500 ms) 9. Screening 12-lead electrocardiogram (ECG), in triplicate, with a measurable QTc interval of > 450ms 10. Known, existing uncontrolled coagulopathy. Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation are eligible IF: they are appropriately anticoagulated and have not had a grade 2 or greater bleeding episode in the 3 weeks before day 1 11. Known pregnancy, nursing women or positive pregnancy test. Requirement for women of childbearing potential (WOCBP): Negative serum pregnancy test at screening and serum or urine prior to dosing on cycle 1 day 1, within 24 hours prior to the start of treatment (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]). WOCBP must also have a negative serum or urine pregnancy test every 3 weeks, within 24 hours prior to the start of treatment 12. Any condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the investigator 13. History of trauma or major surgery within 28 days prior to the first dose 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial 15. Any active or documented history of autoimmune disease, including but not limited to inflammatory bowel disease, celiac disease, Wegner syndrome, Hashimoto syndrome, systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 3 years of the first dose of study treatment, except for the following: Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, or alopecia not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger. Endocrinopathies where the participant is stable on hormone replacement therapy History of Hashimoto syndrome within 3 years of the first of study treatment that resolved to hypothyroidism alone

Required Tests Prior to Study

Blood tests, EKGs and imaging must be done and be within the study criteria within 28 days of study enrollment. If there is no tissue available from a prior biopsy, a repeat biopsy will be performed.

Potential Side Effects

This trial combines three drugs — AB801, gemcitabine/cisplatin, and durvalumab — each of which can cause side effects. The degree of side effects depends on the individual patient and how they respond to treatment. Gemcitabine and cisplatin are standard chemotherapy drugs with a well-established side effect profile in cholangiocarcinoma. Common side effects include nausea, vomiting, fatigue, loss of appetite, and low blood counts, which can increase the risk of infection, bleeding, or anemia. Cisplatin can also cause numbness or tingling in the hands and feet and kidney stress, which is managed with extra IV fluids during each infusion. Durvalumab is an immunotherapy drug that activates the immune system to fight cancer. It can occasionally cause the immune system to attack healthy organs, leading to inflammation in the lungs, liver, thyroid, or intestines. These immune-related side effects are usually manageable when identified and treated early. AB801 is an investigational drug still being studied in people, and the full side effect profile is not yet known. Based on data from approximately 50 patients treated to date, the following side effects were observed in more than 1 in 10 patients: Fatigue; Nausea; Shortness of breath Diarrhea; Abdominal bloating Cough; Fluid around the lungs Abnormal liver tests; Low red blood cell counts Itching; Headache See NCT07619313 (https://clinicaltrials.gov/study/NCT07619313) for additional information.

Financial Assistance Available

No

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