This is a 2-part, phase I/II, open-label, multicenter study designed to evaluate the safety, PK, PD and preliminary efficacy of TCC1727 tablets administered orally QD.
Male or female subjects who have provided voluntary informed consent for participation in the study and to follow the protocol requirements
Male or female subjects 18-70 years of age
Subjects with histologically or cytologically confirmed malignant advanced solid tumors who have progressed on (or have not been able to tolerate) standard therapy or for whom no suitable effective standard therapy exists
For Phase I, all tumor types will be enrolled
Imaging examination suggests intracranial metastasis, which requires local treatment (in case of asymptomatic or symptomatic brain metastasis requiring no local treatment based on the investigator's judgement, the subject can still be included), or currently taking steroid hormone prior to inclusion, such as >10 mg prednisone (or equivalent) for intracerebral edema from brain metastases; subjects with meningeal carcinomatosis will be excluded regardless of their clinical stability
History of previously received major surgery or surgical therapy for any cause within 4 weeks of the first dose; radiotherapy, chemotherapy, other clinical trial drugs or other anti-tumor treatment, within 5 half-lives or 3 weeks (whichever is shorter), prior administering the first dose of study drug on Day 1
History of previous treatment with ATR inhibitors or other DDR related inhibitors (except poly ADP ribose polymerase enzyme (PARP) inhibitors)
carcinomas in situ, (e.g., breast, cervix, and prostate)
Single group
TCC1727 tablet（1）
DrugTCC1727 tablet will be administered orally once a day (QD) every morning for 3 days followed by discontinuation for 4 days, and 21 days/cycle on an empty stomach.
TCC1727 tablet（2）
DrugDrug: TCC1727 tablet TCC1727 tablet will be administered orally twice a day (BID) every morning , and 21 days/cycle on an empty stomach.
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Treatment groupsSee each treatment group below.
Phase I: To determine dose-limiting toxicity (DLT) at each dose level and identify MTD and RP2D.
Phase I: Dose Escalation To observe the tolerability and safety of TCC1727 tablets and determine the maximum-tolerated dose (MTD) and the recommended phase II dose (RP2D) of TCC1727 tablets when administered orally once a day (QD) in 21-day cycle in patients with advanced solid tumors.
Phase II: To evaluate the preliminary efficacy of TCC1727 tablets as measured by ORR in patients with advanced solid tumors with DNA damage response (DDR) defects
Phase II: Cohort Expansion ORR according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1, 2009) for each tumor type. The overall response rate is defined as proportion of subjects who had the best overall response (BOR) of complete response (CR) or partial response (PR).
Phase I: Dose Escalation To observe the preliminary efficacy of TCC1727 tablets as measured by overall response rate (ORR) in patients with advanced solid tumors.
To evaluate the preliminary efficacy by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression free survival (PFS) and overall survival (OS).
Phase I: To evaluate the pharmacokinetic (PK) of TCC1727 tablets in patients with advanced solid tumors
Phase I: Dose Escalation Pharmacokinetic parameters: Tmax
Phase I:
Phase I: Dose Escalation Pharmacokinetic parameters: Cmax
Phase I:
Phase I: Dose Escalation Pharmacokinetic parameters: t1/2
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