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

Prior treatment

• 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
• 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 with unresolved \>Grade 1 toxicity associated with any prior antineoplastic therapy
• 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.

Other illness

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

Other

• Sub-study 1 and Sub-study 2: Patients with known FGFR2 fusion or rearrangement, or IDH1 mutation.

• 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