An Exploratory, Open-label, Multicenter Phase 1b Trial to Evaluate Safety and Efficacy of Sym021 (Anti-PD-1) in Combination with Either Sym022 (Anti-LAG-3) or Sym023 (Anti-TIM-3) or Sym023 and Irinotecan in Patients with Recurrent Advanced Biliary Tract Carcinomas
The study evaluates the preliminary efficacy of 3 combinations (Sym021+Sym022, Sym021+Sym023 and Sym021+Sym023+irinotecan) in patients with biliary tract carcinoma by assessing overall response rates (ORRs) per Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 The study will also evaluate the safety and tolerability profile of the 3 combinations
To evaluate the preliminary efficacy of the 2 combinations (Sym021+Sym022 and Sym021+Sym023) in each tumor type under study by assessing overall response rates (ORR) per Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
To evaluate the safety and tolerability profile of the 2 combinations (Sym021+Sym022 and Sym021+Sym023)
To characterize the pharmacokinetic (PK) profile of the 2 combinations (Sym021+Sym022 and Sym021+Sym023)
To confirm the recommended Phase 2 dose (RP2D) of each combination
To evaluate additional efficacy parameters to assess antitumor activity of each combination:
Duration of response, progression-free survival (PFS) and disease control rate according to RECIST v1.1 as assessed by the Investigator; ORR per Immunotherapeutics Response Evaluation Criteria in
Solid Tumors (iRECIST) and overall survival (OS) (note: the PFS rate at 6 months will additionally be evaluated in patients with small cell lung cancer [SCLC])
To evaluate the immunogenicity of each drug in the combinations: potential for anti-drug antibody (ADA) formation
Patients with locally advanced or metastatic biliary tract carcinoma including adenocarcinoma of the intra- and/or extra-hepatic bile ducts and gallbladder carcinoma.
Patients with ampullary cancers are excluded.
Patients must only have received and progressed on first-line gemcitabine and platinum-based chemotherapy in metastatic/advanced setting and should not have received prior anti-PD-(L)1 therapy. Patients with known fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement, or isocitrate dehydrogenase 1 (IDH1) mutation will be excluded.
Patients with measurable disease according to RECIST v1.1
Patients with an ECOG PS of 0 or 1, and anticipated life expectancy of at least 3 months
Patients must have adequate organ function as indicated by laboratory values
Patients with central nervous system (CNS) malignancy, untreated or unstable metastases
Patients with significant cardiovascular disease
Patients with (1) Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to the first study drug dose (2) Active uncontrolled bleeding or a known bleeding diathesis
Patients with a significant pulmonary disease or condition
Patients with a current or recent (within 6 months) significant gastrointestinal disease or condition
Patients with Gilbert's syndrome or patients with UGT1A1*28 homozygosity (also known as UGT1A1 7/7 genotype)
Patients with a significant ocular disease or condition
Patients with an active, known or suspected autoimmune disease
Patients with any other serious/active/uncontrolled infection
Patients with a history of organ transplantation
Patientswith human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active infection with hepatitis B virus or hepatitis C virus
Prior therapy with irinotecan or with anti-PD-(L)1, anti-LAG-3 or anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other IO therapies.
Patients must not be on warfarin, strong cytochrome P450 (CYP) 3A4 inducers, strong CYP3A4 inhibitors, or strong UGT1A1 inhibitors.
Patients with a history of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy
Patients with a known or suspected hypersensitivity to any of the excipients of formulated study drug
Patients with unresolved >Grade 1 toxicity associated with any prior antineoplastic therapy
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