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

Brief summary public domain (ClinicalTrials.gov)

This phase I trial tests the safety, side effects, best dose and effectiveness of AB801 in combination with chemotherapy and immunotherapy in treating patients with cholangiocarcinoma or pancreatic adenocarcinoma that may be removed by surgery (borderline resectable), that has spread to nearby tissue or lymph nodes (locally advanced), or that has spread from where it first started (primary site) to other places in the body (metastatic). AB801 is a drug designed to block a protein called AXL. AXL is found on the surface of certain cancer cells and plays an important role in helping tumors grow, spread to other parts of the body, and avoid the immune system. It is thought to contribute to resistance against common cancer treatments such as chemotherapy, radiation and immunotherapy. In many cancers, including cholangiocarcinoma and pancreatic adenocarcinoma, AXL is overactive and associated with worse outcomes. AB801 inhibits AXL which may make cancer cells more sensitive to chemotherapy and allow immune cells to better recognize and attack the tumor. Chemotherapy drugs, such as gemcitabine, cisplatin, oxaliplatin, irinotecan, leucovrin and fluorouracil, work in different ways to stop the growth of cancer cells either by killing the cells, by stopping them from dividing or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as durvalumab and zimberelimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving AB801 in combination with chemotherapy and immunotherapy may better treat patients with borderline resectable, locally advanced or metastatic cholangiocarcinoma or pancreatic adenocarcinoma.

Detailed description public domain (ClinicalTrials.gov)

PRIMARY OBJECTIVE: I. Assess safety and tolerability of ligritinib (AB801) in combination with chemotherapy and immunotherapy in patients with cholangiocarcinoma and pancreatic adenocarcinoma. SECONDARY OBJECTIVES: I. Objective response rate. II. Progression free survival. III. Duration of response. IV. Proportion of patients taken to curative intent surgery after neoadjuvant therapy. EXPLORATORY OBJECTIVES: I. To evaluate the effect on AXL expression by comparing pre-treatment core biopsies with post-therapy operative specimens or biopsies taken at time of progression. II. To evaluate the effects of study treatment on tumor microenvironment by comparing pre-treatment core biopsies with operative specimens or biopsies taken at time of progression via multiple modalities including immunohistochemistry (IHC), cytometry by time-of-flight (CyTOF), ribonucleic acid sequencing (RNA Seq)/spatial transcriptomics. III. To assess for changes in peripheral blood throughout treatment including but not limited to soluble AXL, immune cell populations and change in systemic cytokines. IV. To explore changes in gene alterations via whole exome sequencing. OUTLINE: This is a dose-escalation study of AB801 followed by a dose-expansion study. Patients are assigned to 1 of 2 cohorts. COHORT I: Patients with cholangiocarcinoma receive AB801 orally (PO) once daily (QD), gemcitabine and cisplatin intravenously (IV) over 30 minutes on days 1 and 8 and durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days for 24 weeks in the absence of disease progression or unacceptable toxicity. COHORT II: Patients with pancreatic cancer receive AB801 PO QD and zimberelimab IV over 60 minutes on day 1 of each cycle. Patients receive oxaliplatin IV over 120 minutes, leucovorin IV, and irinotecan IV on days 1 and 15 of each cycle and fluorouracil IV over 46 hours on days 1 and 15 of each cycle. Cycles repeat every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity. All patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial as well as tissue biopsy on trial. After completion of study treatment, patients are followed up at 30 and 90 days and then every 3 months.