This phase II/III trial studies how well the addition of ivonescimab to standard chemotherapy (gemcitabine and cisplatin) works when compared to usual chemotherapy and immunotherapy (durvalumab or pembrolizumab) in treating patients with biliary tract cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Gemcitabine is a chemotherapy drug that blocks the cells from making deoxyribonucleic acid (DNA) and may kill tumor cells. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Immunotherapy with monoclonal antibodies, such as durvalumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ivonescimab is a bispecific antibody that is directed against both the programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF) protein. By targeting PD-1, ivonescimab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. By targeting VEGF, ivonescimab may help stop the formation of blood vessels that bring oxygen and nutrients to tumor. Adding ivonescimab to standard chemotherapy may work better than usual chemotherapy and immunotherapy in lowering the chance of advanced biliary tract cancer growing or spreading.
PRIMARY OBJECTIVE: I. To compare overall survival (OS) of ivonescimab plus chemotherapy (with gemcitabine and cisplatin) versus standard of care durvalumab or pembrolizumab plus chemotherapy (with gemcitabine and cisplatin) in all randomized patients. SECONDARY OBJECTIVES: I. To compare progression free survival (PFS) of ivonescimab plus chemotherapy (with gemcitabine and cisplatin) versus standard of care therapy durvalumab or pembrolizumab plus chemotherapy (with gemcitabine and cisplatin) in all randomized patients. II. To assess additional measures of clinical activity in all randomized patients including objective response rate (ORR), duration of response, and disease control rate. III. To assess the safety and tolerability of ivonescimab in combination with gemcitabine and cisplatin. IV. To assess the pharmacokinetic (PK) profile of ivonescimab in combination with gemcitabine and cisplatin (GemCis). V. To assess the immunogenicity profile of ivonescimab in combination with GemCis. CORRELATIVE OBJECTIVE: I. To perform correlative analyses on tissue and blood biospecimens collected within this trial. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive gemcitabine intravenously (IV) over 30-60 minutes and cisplatin IV on days 1 and 8 of each cycle, as well as durvalumab IV over 60 minutes or pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. After cycle 8, patients receive durvalumab IV over 60 minutes or pembrolizumab IV over 30 minutes on day 1 of each cycle with or without gemcitabine IV over 30-60 minutes on days 1 and 8 of each cycle per the investigator's discretion. Cycles repeat every 21 days for up to 2 years from study treatment initiation in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood and urine samples throughout the study. ARM B: Patients receive gemcitabine IV over 30-60 minutes and cisplatin IV on days 1 and 8 of each cycle, as well as ivonescimab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. After cycle 8, patients receive ivonescimab IV over 60 minutes on day 1 of each cycle with or without gemcitabine IV over 30-60 minutes on days 1 and 8 of each cycle per the investigator's discretion. Cycles repeat every 21 days for up to 2 years from study treatment initiation in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and collection of blood and urine samples throughout the study. After completion of study treatment, patients are followed every 3 months for years 0-2 from randomization and then every 6 months for years 2-3 from randomization.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
336
Undergo blood and urine sample collection
Given IV
Undergo CT
Given IV
Given IV
Given IV
Undergo MRI
Given IV
Overall survival (OS)
Time frame: From date of randomization until the date of death from any cause, assessed up to 3 years
Progression-free survival
Will be measured per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 as assessed by the investigator.
Time frame: From the date of randomization until disease progression or death from any cause, whichever comes first, assessed up to 3 years
Objective response rate
Will be defined as the proportion of patients who have achieved best overall response of confirmed complete response (CR) or partial response (PR) to study therapy as assessed by the investigator according to RECIST v1.1.
Time frame: Up to 3 years
Duration of response
Will be measured per RECIST v1.1 as assessed by the investigator.
Time frame: From the first objective response (CR or PR) until the date of first documented disease progression or death, whichever comes first, assessed up to 3 years
Disease control rate
Will be defined as the proportion of patients who have achieved CR, PR, or stable disease for ≥ 9 weeks from date of randomization as assessed by the investigator according to RECIST v1.1.
Time frame: From 9 weeks from date of randomization up to 3 years
Incidence and severity of adverse events and serious adverse events
Will be graded per Common Terminology Criteria for Adverse Events. Will evaluate any clinically meaningful trends in safety parameters.
Time frame: Up to 24 months
Pharmacokinetic profile (Arm B)
Will evaluate serum drug concentrations of ivonescimab in patients at different time points after ivonescimab administration.
Time frame: Before and end of infusion on cycle 1, day 1 and cycle 6, day 1; Before infusion on cycle 2, day 1, cycle 13, day 1, and at end of treatment (up to 24 months of treatment) 1 Cycle = 21 Days
Number and percentage of patients with detectable anti-ivonescimab antibody (Arm B)
Will evaluate serum drug concentrations of ivonescimab in patients at different time points after ivonescimab administration.
Time frame: Up to 24 months
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