Brief Title: Sym021 in Combination With Either Sym022 or Sym023 in Patients With Advanced Solid Tumor Malignancies

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: To evaluate the preliminary efficacy of the combinations Sym021+Sym022

Primary Outcome 1 - Timeframe: Until disease progression or end of study

Primary Outcome 2 - Measure: Sym021+Sym023 and Sym021+Sym023+irinotecan in patients with BTC or ESCC by assessing overall response rates (ORRs) per Investigator assessment using RECISTv.1.1

Primary Outcome 2 - Timeframe: whichever comes first

Primary Outcome 3 - Measure: To evaluate the incidence

Primary Outcome 3 - Timeframe: assessed up to 24 months

Primary Outcome 4 - Measure: severity

Primary Outcome 4 - Timeframe: Through study completion up to 30 days after last dose of the three combinations

Primary Outcome 5 - Measure: and relationship of (S)AEs collected from administration of the first dose of study drug until 30 days after the last dose of the 3 combinations (Sym021+Sym022

Primary Outcome 5 - Timeframe: Through study completion up to a maximum of 24 months

Primary Outcome 6 - Measure: Sym021+Sym023 and Sym021+Sym023+irrinotecan)

Primary Outcome 6 - Timeframe: N/A

Primary Outcome 7 - Measure: To evaluate the AEs leading to dose interruption

Primary Outcome 7 - Timeframe: N/A

Primary Outcome 8 - Measure: dose delays

Primary Outcome 8 - Timeframe: N/A

Primary Outcome 9 - Measure: and permanent treatment stop of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023 +irinotecan)

Primary Outcome 9 - Timeframe: N/A

CONDITION

• Metastatic Cancer
• Solid Tumor

ELIGIBILITY

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
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

- * 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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Nehal Lakhani, MD

Role: Principal Investigator

Affiliation: START Midwest

Overall Contact

Name: N/A

Phone: N/A

Email: N/A

LOCATION