Colorectal Cancer Clinical Trials

• Male and females ≥18 years of age

• Life expectancy ≥12 weeks as judged by the Investigator

• Measurable disease as defined by RECIST v1.1

• ECOG 0 or 1

• Able to swallow capsules

• For Phase 1b and 2a: histologically or cytologically documented advanced unresectable solid tumor for which no effective standard therapy exists, or that has progressed on or not tolerated prior standard therapy. If previously treated with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies, PD-1 treatment progression is defined by meeting all of the following criteria:

∙ Has received at least 2 doses of an approved anti-PD-1/L1 mAb

‣ Has demonstrated clinical progression after anti-PD-1/L1 mAb therapy

‣ Progressive disease has been documented within 16 weeks from the last dose of anti-PD-1/L1 mAb

• For HNSCC cohort in Phase 2a: anti-PD-(L)1 agent-naïve metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) whose tumors express programmed death ligand 1 (PD - L1) \[combined positive score (CPS) ≥1\] as determined by an FDA-approved test Or recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy (as applicable).

• For BTC cohort in Phase 2a: biliary tract cancer that has been locally advanced unresectable or metastatic or not tolerated prior standard first line chemotherapy and second line targeted therapy (as applicable).

• For CRC cohort in Phase 2a: anti-PD-(L)1 agent-naïve colorectal adenocarcinoma of Proficient Mismatch Repair (pMMR)/Microsatellite Stable (MSS) subtype, as determined by an FDA-approved test, that has progressed on or not tolerated at least 2 lines of prior standard chemotherapy with biological agents where applicable. Patients with liver metastasis from primary CRC, as confirmed by RESIST v1.1, will be excluded from Phase 2a CRC cohort.

⁃ Adequate hematological function and coagulation defined by

∙ ANC ≥1,500 cells/μL

‣ Platelet count ≥100,000/μL

‣ Hemoglobin ≥9.0 g/dL (criteria must be met without packed red blood cell transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin \[≥ approximately 3 months\])

‣ International normalized ratio ≤1.5 upper limit of normal (ULN)

⁃ Adequate hepatic and renal function

∙ Total bilirubin ≤1.5 × ULN

‣ AST and alanine aminotransferase (ALT) ≤2.5 × ULN; if liver metastases are present, then ≤5 × ULN is allowed.

‣ Estimated creatinine clearance ≥60 mL/minute according to the Cockcroft Gault formula.

⁃ Able to understand and to comply with all protocol requirements, instructions, and restrictions. For Phase 2a, willing and able to provide archival tumor samples or undergo biopsy for biomarker testing during screening.

⁃ QTcF interval ≤470 msec on screening ECG.

⁃ Normal ejection fraction (within the reference range of the institution).

⁃ No concomitant anti-cancer treatments, including experimental agents for 5 half-lives for non-biological agents and a minimum of 4 weeks for any biologics prior to the start of treatment.

⁃ Resolution of any toxicity to maximum Grade 1 (except alopecia and Grade ≤2 neuropathy) prior to the start of treatment. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement are eligible.

⁃ Completion of radiotherapy (palliative or curative) at least 14 days prior to the start of treatment with resolution of any toxicity to maximum Grade 1. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.

⁃ A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) defined as all female after puberty unless they are postmenopausal for at least 1 year or are surgically sterile (hysterectomy or bilateral oophorectomy or tubal ligation).

∙ A WOCBP who has a negative serum pregnancy test within 3 days of the first administration of study treatment and agrees to follow contraceptive guidance during the treatment period and for at least 30 days after the last dose of TU2218 or until at least 120 days after the last administration of pembrolizumab, whichever comes later.