Study of TU2218 in Combination With KEYTRUDA®(Pembrolizumab) in Patients With Advanced Solid Tumors

Inclusion Criteria:

1. Male and females ≥18 years of age

2. Life expectancy ≥12 weeks as judged by the Investigator

3. Measurable disease as defined by RECIST v1.1

4. ECOG 0 or 1

5. Able to swallow capsules

6. For Phase 1b and 2a: histologically or cytologically documented advancedunresectable solid tumor for which no effective standard therapy exists, or that hasprogressed on or not tolerated prior standard therapy. If previously treated with ananti-PD-1/L1 mAb administered either as monotherapy, or in combination with othercheckpoint inhibitors or other therapies, PD-1 treatment progression is defined bymeeting all of the following criteria:

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

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

9. Progressive disease has been documented within 16 weeks from the last dose ofanti-PD-1/L1 mAb

10. For HNSCC cohort in Phase 2a: anti-PD-(L)1 agent-naïve metastatic or withunresectable, recurrent head and neck squamous cell carcinoma (HNSCC) whose tumorsexpress programmed death ligand 1 (PD - L1) [combined positive score (CPS) ≥1] asdetermined by an FDA-approved test Or recurrent or metastatic head and neck squamouscell carcinoma (HNSCC) with disease progression on or after platinum-containingchemotherapy (as applicable).

11. For BTC cohort in Phase 2a: biliary tract cancer that has been locally advancedunresectable or metastatic or not tolerated prior standard first line chemotherapyand second line targeted therapy (as applicable).

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

13. 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 celltransfusion within the prior 2 weeks. Participants can be on stable dose oferythropoietin [≥ approximately 3 months])

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

11. Adequate hepatic and renal function

• Total bilirubin ≤1.5 × ULN

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

• Estimated creatinine clearance ≥60 mL/minute according to the Cockcroft Gaultformula.

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

13. QTcF interval ≤470 msec on screening ECG.

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

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

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

17. Completion of radiotherapy (palliative or curative) at least 14 days prior to thestart of treatment with resolution of any toxicity to maximum Grade 1. Participantsmust have recovered from all radiation-related toxicities and not requirecorticosteroids.

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

19. Not a woman of childbearing potential (WOCBP) defined as all female afterpuberty unless they are postmenopausal for at least 1 year or are surgicallysterile (hysterectomy or bilateral oophorectomy or tubal ligation).

20. A WOCBP who has a negative serum pregnancy test within 3 days of the firstadministration of study treatment and agrees to follow contraceptive guidanceduring the treatment period and for at least 30 days after the last dose ofTU2218 or until at least 120 days after the last administration ofpembrolizumab, whichever comes later.

Exclusion Criteria:

1. Myocardial infarction within 6 months prior to screening, or pericardial effusion

2. History of cardiac or aortic surgery within 12 months

3. Unstable angina pectoris, cerebrovascular accident, transient ischemic attack, orsymptomatic pulmonary embolism; deep venous thrombosis; arterial occlusive diseasein the past 12 months

4. Congestive heart failure of New York Heart Association class III/IV

5. Major arrhythmia or abnormalities identified by ECG per Investigator's judgement

6. Uncontrolled hypertension (as defined by systolic blood pressure ≥160 mmHg ordiastolic blood pressure ≥100 mmHg) during the Screening Period.

7. Elevated Troponin I levels (Grade 3) at screening

8. Metastatic disease to the brain or central nervous system, carcinomatous meningitis,massive uncontrolled effusions (pleural, pericardial, peritoneal), and pulmonarylymphangitis

9. Known history of difficulty swallowing, malabsorption or other conditions that mayreduce absorption of TU2218

10. Tumor that compresses or invades major blood vessels or tumor cavitation that in theopinion of the Investigator is likely to bleed

11. History of severe bleeding. Unable to stop anticoagulation therapy with heparin, lowmolecular weight heparin, vitamin K antagonists, anti-platelet agents, or factor Xainhibitors throughout the study and for at least 28 days post the last dose of studytreatment

12. Moderate or severe heart valve function defect including moderate or severe valvestenosis or regurgitation

13. Evidence or history of septal aneurysm, other heart aneurysm, or any aneurysm of themajor vessels

14. Female participants must not be pregnant or at risk of becoming pregnant during thestudy. Fertile male and female participants must agree to use a highly effectivemethod of birth control to avoid pregnancy (for female participants a double-barriermethod of contraception, for male participants a condom with spermicide) or totalabstinence from the time of providing informed consent until at least 30 days afterthe last dose of TU2218 or until at least 120 days after the last administration ofPembrolizumab, whichever comes later.

15. Female participants who are breastfeeding

16. For Phase 1b and BTC cohort in Phase 2a: discontinued prior therapy with ananti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to anotherstimulatory or co inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137), due to anirAE.

17. For CRC and HNSCC cohorts in Phase 2a: received prior therapy with an anti-PD-1,anti PD-L1, or anti PD-L2 agent or an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).

18. Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks (could consider shorter interval for kinase inhibitors or other shorthalf-life drugs) prior to treatment. Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy are eligible.Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormonereplacement are eligible. Note: If the participant had major surgery, the participant must have recoveredadequately from the procedure and/or any complications from the surgery prior tostarting study intervention.

19. Has received prior radiotherapy within 2 weeks of start of study treatment or havehad a history of radiation pneumonitis. Note: Participants must have recovered from all radiation-related toxicities and notrequire corticosteroids. A 1-week washout is permitted for palliative radiation (≤2weeks of radiotherapy) to non-central nervous system (CNS) disease.

20. Has received or planned to receive any live or live-attenuated vaccine (e.g.,measles, mumps, rubella or chickenpox) within 30 days prior to the first drugadministration and while participating the study. Note: Administration of killed vaccines are allowed. Receipt of mRNA vaccine,including Coronavirus disease-2019 (COVID-19) vaccine, within 7 days prior to drugadministration on Day 1 and during the first 2 cycles of study treatment will not beallowed

21. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study treatment Note: Participants who have entered the follow-up phase of aninvestigational study may participate as long as it has been 4 weeks after the lastdose of the previous investigational agent

22. Has had an allogeneic tissue/solid organ transplant

23. Received prior treatment targeting the signaling pathway of TGF-Beta

24. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior the first dose of study treatment

25. Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years Note: Participants with basal cell carcinoma ofthe skin, squamous cell carcinoma of the skin, or carcinoma in situ, excludingcarcinoma in situ of bladder, that have undergone potentially curative therapy arenot excluded

26. Has severe hypersensitivity (Grade ≥3) to Pembrolizumab and/or any of its excipients

27. Has an active autoimmune disease or history of autoimmune disease, except vitiligo,hypothyroidism or resolved childhood asthma/atopy, that has required systemictreatment in past 2 years (i.e., with use of disease modifying agents,corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine,insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment and is allowed

28. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease

29. Has an active infection requiring systemic antibiotic therapy

30. Active and clinically significant bacterial, fungal, or viral infection, includingknown history of hepatitis B virus (HBV), known hepatitis C virus (HCV), known humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related illness. Note: No testing for HBV, HCV, and HIV is required unless mandated by local healthyauthority

31. Unable or unwilling to stop use of strong inhibitors of cytochrome P450 (CYP)1A2, 2C8 and 3A4, and strong inhibitors of P-gP and breast cancer resistance protein (BCRP) at least 8 days prior to and during study treatment in all Phase 1b doseescalation cohorts

32. Unable or unwilling to stop use of gastric pH elevating agents including proton pumpinhibitors, H2-receptor antagonists and antacids at least 8 days prior to and duringstudy treatment in all Phase 1b dose escalation cohorts

33. Has a history or current evident of any condition, therapy, or laboratoryabnormality, or other circumstance that might confound the results of the study orinterfere with the participant's participation for the full duration of the study,such that it is not in the best interest of the participant to participate, in theopinion of the treating Investigator

34. Has a known psychiatric or substance abuse disorder that would interfere with theparticipant's ability to cooperate with the requirements of the study

35. Known history, or suspected hypersensitivity to any excipients of the clinical studytreatments

36. Any other serious medical condition which in the Investigator's opinion wouldpreclude safe participation in the study