This is a Phase Ib/II clinical study. The Phase Ib dose-escalation study aims to evaluate and determine the recommended Phase II dose (RP2D) of TCC1727 in combination with benmelstobart /olaparib /topotecanfor patients with advanced solid tumors.
The Phase II expansion study will assess the efficacy and safety of TCC1727 combined with benmelstobart /olaparib/topotecanin selected advanced solid tumor indications.
The study pre-specifies three treatment combinations, with Combination 1 (TCC1727 + benmelstobart) being prioritized for initial evaluation. The decision to proceed with Combination 2 and Combination 3will be based on clinical data from Combination 1.
-Voluntarily participate in this study and sign the informed consent form.
At the time of signing the informed consent, subjects must be ≥18 years of age (inclusive).
Phase Ib :Subjects with advanced, recurrent, or refractory solid tumors, which may include (but are not limited to) the specific tumor types in Phase II.
At least one measurable lesion (per RECIST v1.1; lesions previously treated with local therapy may be considered target lesions if they show clear progression per RECIST v1.1).
Known primary central nervous system (CNS) tumors (including meningeal tumors); symptomatic brain metastases, spinal cord compression, carcinomatous meningitis, or uncontrolled CNS metastases. Exceptions: Subjects with completely resected and/or irradiated CNS metastases that are stable or improved for ≥4 weeks before screening (no evidence of brain edema and no need for corticosteroids or anticonvulsants). Asymptomatic brain metastases <1 cm in diameter without surrounding edema are also allowed.
Major surgery, radiotherapy, chemotherapy, or other investigational anti-tumor therapy completed <4 weeks before the first dose (exceptions: small-molecule anti-tumor therapy completed >5 half-lives or >10 days before the first dose, whichever is longer; palliative radiotherapy completed >2 weeks before the first dose).
Use of strong CYP3A4 inhibitors or inducers within 14 days before the first dose (e.g., rifampin, rifapentine, St. John's wort, carbamazepine, phenytoin, barbiturates, ketoconazole, itraconazole, clarithromycin, voriconazole, atazanavir, ritonavir, saquinavir, grapefruit juice).
Any unresolved ≥Grade 2 toxicity (per CTCAE v5.0) from prior anti-tumor therapy (except alopecia, pigmentation, or laboratory abnormalities meeting inclusion criteria).
Sequential
TCC1727 tablet 90mg
DrugTCC1727 tablets 90 mg, orally, twice daily (bid), continuous dosing in 21-day cycles until disease progression
TCC1727 tablet 120mg
DrugTCC1727 tablets 120 mg, orally, twice daily (bid), continuous dosing in 21-day cycles until disease progression
TCC1727 tablet 160mg
DrugTCC1727 tablets 160 mg, orally, twice daily (bid), continuous dosing in 21-day cycles until disease progression
benmelstobart Injection
Combination productAdminister 1200 mg per dose via intravenous infusion on Day 1 of every 3-week cycle until disease progression.
Phase Ib：To determine dose-limiting toxicity (DLT) at each dose level
Dose Escalation To observe the tolerability and safety of TCC1727 combination therapy.
MTD
The maximum tolerated dose (MTD) of TCC1727 in combination with benmelstobart/olaparib/topotecan will be determined based on safety, tolerability, kinetics, preliminary efficacy, and other available data
RP2D
The recommended Phase II dose (RP2D) of TCC1727 in combination with benmelstobart/olaparib/topotecan will be determined based on safety, tolerability, kinetics, preliminary efficacy, and other available data
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Adverse events (AEs) were assessed according to NCI-CTCAE v5.0, including severity grading of abnormal findings in laboratory tests, vital signs, physical examinations, and electrocardiograms (ECGs) from signing of informed consent through the end of the safety follow-up period or prior to the start of a new anticancer therapy
Assess objective response rate (ORR: complete response + partial response), based on RECIST 1.1
Efficacy evaluation was performed every 6 weeks (± 7 days), extended to 9 weeks (± 7 days) after 8 cycles for efficacy evaluation, and patients were assessed for tumor by the investigator according to RECIST v1.1
PK parameters of TCC1727
Blood samples were collected before and after administration of C1, C2 to evaluate the kinetic (PK) parameters of TCC1727: Cmax
PK parameters of TCC1727
Blood samples were collected before and after administration of C1, C2 to evaluate the kinetic (PK) parameters of TCC1727: Tmax
PK parameters of TCC1727
Blood samples were collected before and after administration of C1, C2 to evaluate the kinetic (PK) parameters of TCC1727: Trough concentration (minimum concentration at steady state)-Ctrough
Baseline tumor tissue predictive biomarkers
including but not limited to the correlation between PD-L1 expression, tumor mutational burden (TMB)-related gene mutation status, and the efficacy of TCC1727 combined with benmelstobart in subjects with advanced solid tumors
Correlation between mutation status of DDR-related genes in baseline tumor tissues and efficacy of TCC1727 combination therapy
Mutation status of DDR-related genes in baseline tumor tissue including but not limited to correlation of ATM mutations with efficacy of TCC1727 in combination with Benmelstobart/olaparib/topotecan in subjects with advanced solid tumors
Before and after treatment, the distribution changes of blood immune cells . (only applicable to the combination with Benmelstobart)
The changes in the distribution of blood immune cells at screening period and Cycle1D8, Cycle1D15 and Cycle2D1 . (only applicable to the combination with Benmelstobart)
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