Sym021 in Combination With Either Sym022 or Sym023 or Sym023 and Irinotecan in Patients With Recurrent Advanced Selected Solid Tumor Malignancies

Inclusion Criteria:

For Sub-study 1 and 2:

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 or be intolerant of 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. Prior anti-PD-(L)1 therapy may be allowed during the trial if regulatory approval for such therapy is obtained while this trial is enrolling.

For Sub-study 3:

Patients with with locally advanced or metastatic esophageal squamous cell carcinoma
Patients must only have received and progressed on or be intolerant of first-line platinum-based chemotherapy in metastatic/advanced setting and should have received prior anti-PD-(L)1 therapy. Patients with mixed adenosquamous histology cancers are excluded.

For all Sub-studies :

Patients with measurable disease according to RECIST v1.1
Patients with an ECOG PS of 0 or 1, and anticipated life expectancy of ≥3 months
Patients must have adequate organ function as indicated by laboratory values
Adequate contraception required as appropriate

Exclusion Criteria:

Patients with central nervous system (CNS) malignancy, untreated or unstable metastases
Patients with significant cardiovascular disease

Patients with

Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to the first study drug dose
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
Patients with human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active infection with hepatitis B virus or hepatitis C virus
Prior therapy with irinotecan
For Sub-study 1 and Sub-study 2: 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 immuno-oncology (IO) therapies.
For Sub-study 3: Anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other IO therapies (other than anti-PD-(L)1 agents).
Patients must not be on warfarin, if they have a history of acute immune-related thrombocytopenia; patients must not be on strong cytochrome P450 (CYP) 3A4 inducers, strong CYP3A4 inhibitors, or strong UGT1A1 inhibitors.
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
Sub-study 1 and Sub-study 2: Patients with known FGFR2 fusion or rearrangement, or IDH1 mutation.
For Sub-study 3: Patients with a history of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy.