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

Exclusion Criteria41

• Myocardial infarction within 6 months prior to screening, or pericardial effusion
• History of cardiac or aortic surgery within 12 months
• Unstable angina pectoris, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism; deep venous thrombosis; arterial occlusive disease in the past 12 months
• Congestive heart failure of New York Heart Association class III/IV
• Major arrhythmia or abnormalities identified by ECG per Investigator's judgement
• Uncontrolled hypertension (as defined by systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) during the Screening Period.
• Elevated Troponin I levels (Grade 3) at screening
• Metastatic disease to the brain or central nervous system, carcinomatous meningitis, massive uncontrolled effusions (pleural, pericardial, peritoneal), and pulmonary lymphangitis
• Known history of difficulty swallowing, malabsorption or other conditions that may reduce absorption of TU2218
• Tumor that compresses or invades major blood vessels or tumor cavitation that in the opinion of the Investigator is likely to bleed
• History of severe bleeding. Unable to stop anticoagulation therapy with heparin, low molecular weight heparin, vitamin K antagonists, anti-platelet agents, or factor Xa inhibitors throughout the study and for at least 28 days post the last dose of study treatment
• Moderate or severe heart valve function defect including moderate or severe valve stenosis or regurgitation
• Evidence or history of septal aneurysm, other heart aneurysm, or any aneurysm of the major vessels
• Female participants must not be pregnant or at risk of becoming pregnant during the study. Fertile male and female participants must agree to use a highly effective method of birth control to avoid pregnancy (for female participants a double-barrier method of contraception, for male participants a condom with spermicide) or total abstinence from the time of providing informed consent until 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.
• Female participants who are breastfeeding
• For Phase 1b and BTC cohort in Phase 2a: discontinued prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137), due to an irAE.
• 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 co inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-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 hormone replacement are eligible.
• Note: If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
• Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis.
• Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
• 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 drug administration 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 drug administration on Day 1 and during the first 2 cycles of study treatment will not be allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has had an allogeneic tissue/solid organ transplant
• Received prior treatment targeting the signaling pathway of TGF-Beta
• 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 of immunosuppressive therapy within 7 days prior the first dose of study treatment
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, that have undergone potentially curative therapy are not excluded
• Has severe hypersensitivity (Grade ≥3) to Pembrolizumab and/or any of its excipients
• Has an active autoimmune disease or history of autoimmune disease, except vitiligo, hypothyroidism or resolved childhood asthma/atopy, that has required systemic treatment 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 pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic antibiotic therapy
• Active and clinically significant bacterial, fungal, or viral infection, including known history of hepatitis B virus (HBV), known hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome-related illness.
• Note: No testing for HBV, HCV, and HIV is required unless mandated by local healthy authority
• 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 dose escalation cohorts
• Unable or unwilling to stop use of gastric pH elevating agents including proton pump inhibitors, H2-receptor antagonists and antacids at least 8 days prior to and during study treatment in all Phase 1b dose escalation cohorts
• Has a history or current evident of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere 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 the opinion of the treating Investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
• Known history, or suspected hypersensitivity to any excipients of the clinical study treatments
• Any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study