A Phase 1/1b Trial of AB801 in Combination With Chemotherapy and PD-1/PD-L1 Blockade in Patients With Cholangiocarcinoma or Pancreatic Adenocarcinoma
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.
• Male or female ≥ 18 years of age and willing and able to provide informed consent
• Previously untreated cytologically or histologically confirmed, at least one measurable lesion via Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of cholangiocarcinoma or pancreatic adenocarcinoma meeting following criteria:
‣ Cholangiocarcinoma
• 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.
∙ Metastatic cholangiocarcinoma: Patients with metastatic cholangiocarcinoma patient who have not received prior systemic therapy
⁃ Pancreatic adenocarcinoma
• Borderline resectable pancreatic adenocarcinoma: There are multiple definitions of borderline resectable pancreatic ductal adenocarcinoma (PDAC). For the purposes of this study, borderline resectable disease will be identified per the National Comprehensive Cancer Network (NCCN) criteria. Per this definition, borderline resectable PDAC is defined as the presence of any one or more of the following on CT:
‣ An interface between the tumor and superior mesenteric artery (SMA) or celiac axis (CA) measuring \< 180º of the circumference of the vessel wall.
⁃ An interface between the tumor with the common hepatic artery without extension into the celiac axis or hepatic artery bifurcation allowing for safe and complete resection and reconstruction.
⁃ An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring ≥ 180° of the circumference of the vessel wall
⁃ Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
⁃ An interface between the primary tumor and the inferior vena cava (IVC)
∙ Locally advanced pancreatic adenocarcinoma: Multiple guidelines defining locally advanced PDAC have been developed. For the purposes of this study, locally advanced PDAC cases will be identified per the definition developed by the NCCN. Per this definition, locally advanced PDAC is defined as presence of any one or more of the following on CT:
‣ Interface between the tumor and SMA or CV measuring \> 180º of the circumference of the vessel wall or solid tumor contact with the CA and aortic involvement.
⁃ Occlusion of the SMV-PV that is not amenable to resection and venous reconstruction
⁃ Metastatic pancreatic adenocarcinoma: Patients with metastatic pancreatic adenocarcinoma who have not received prior systemic therapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Absolute neutrophil count (ANC) ≥ 1.5x10\^9/L
• Platelets ≥ 100x10\^9/L
• Hemoglobin ≥ 9 g/dL
• Creatinine clearance (Ccr) ≥ 50 mL/min (as calculated by Modified Cockcroft-Gault formula)
• Serum total bilirubin ≤ 2x upper limit of normal (ULN) or \< 3x ULN if Gilbert's syndrome
• 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
• 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
• 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
• 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
• 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
• 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
• Adequate baseline tumor tissue sample for correlative studies