The primary objective of the study is to evaluate the safety, tolerability, PK, PD, and prilimary efficacy of a PARG inhibitor DAT-2645 in patients with advanced/metastatic solid tumors harboring BRCA1/2 loss of function alterations and/or other defects in the DNA damage repair (DDR) pathway.
Signed informed consent prior to initiation of any procedures in this study.
At least 18 years of age (inclusive).
Evidence of an DDR deficiency status in tumor tissue determined by validated testing method.
Patients with advanced or metastatic solid tumor who have failed standard of care therapy, or are unable to tolerate standard of care therapy, or unable to obtain/unwilling to receive standard therapy. Regardless of PARP inhibitors were used or not in previous treatment.
Patients who received systemic chemotherapy, small-molecule targeted drugs within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
Patients who received biological anti-tumor drugs (including immunotherapy, target therapy, antibody-drug conjugate [ADC]) within 4 weeks prior to the first dose of the study drug.
Patients who have undergone major surgery within 4 weeks prior to the first dose of study drug.
Patients who have received radiotherapy within 4 weeks prior to the first dose of study drug (palliative radiotherapy for non-target lesions could be acceptable if it was performed before 14 days prior to the first dose of study drug).
Sequential
DAT-2645 tablet
DrugThe patient will be randomized into 2 groups and take DAT-2645 tablet daily. dosage is optimal dose-1 or optimal dose-2, 21day/ Cycle. The subject of this part is to optimize dosage and definite RP2D.
DAT-2645 tablet
DrugThe study set 6 dose level cohorts in dose escalation part.On C0D1, patient take DAT-2645 one time (Single use), The dosage is same as his enrolled cohort dose level. if no DLT, 7 days later(C1D1), patients will continue taking DAT-2645 tablet daily, dasage is same as before, 21days/cycle.
Part 1, Dose esclalation study:To characterize the safety and tolerability of DAT-2645 monotherapy by evaluating the number of participants with dose limiting toxicities, adverse events, and laboratory abnormalities as graded by NCI CTCAE version 5.0
The incidence of dose limiting toxicites Incidence of treatment-emergent Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing
Part 2, Dose expansion study: To evaluate preliminary preliminary anti-tumor activity of DAT-2645 tablet monotherapy in participants by measuring tumor Overall Response Rate using RECIST criteria v1.1
Tumor response: Overall Response Rate(ORR) assessed by the investigators based on RECIST v1.1 criteria
RP2D
Recommended Phase 2 dose, will be definite by safety mornitoring committe(SMC).
ORR
Objective Response Rate (ORR) was calculated the rate of response of complete response (CR) or partial response (PR).
DCR
Defined as not meeting the criteria for progression and PR(partial response)
DoR
DoR(duration of response) per RECIST v1.1(Response Evaluation Criteria in Solid Tumours). Measured in CT/MRI image from the time when measurement criteria for complete/ partial response are met till time when progression of the disease is documented.
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