Status and phase
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Study type
Funder types
Identifiers
About
This study consists of phase 1b and 2a to evaluate safety, Pharmacokinetics, and efficacy of TU2218 in combination with Pembrolizumab in patients with advanced solid tumors.
Full description
The primary objective of phase 1b is to determine the recommended phase 2 dose of the combination (RP2DC) of TU2218 given with pembrolizumab in advanced solid tumors.
The primary objective of phase 2a is to evaluate the efficacy of TU2218 administered in combination with pembrolizumab in selected advanced tumors.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
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:
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
Adequate hepatic and renal function
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:
Exclusion criteria
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
Primary purpose
Allocation
Interventional model
Masking
140 participants in 4 patient groups
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Central trial contact
TiumBio Global http://www.tiumbio.com/en/
Data sourced from clinicaltrials.gov
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