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.
This the the FIH trial of PARG inhibitor DAT-2645.This study will include Part 1 dose escalation study and Part 2 dose expansion study. Eligible patients will be enrolled into Part 1 and Part 2. In Part 1, 6 dose cohorts will be set and definte MTD/RDE. In Part 2, Dose optimization will be conducted firstly to definite RP2D. dose expansion will be conducted in another 2 cohorts to evaluate the efficacy.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
112
The 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.
The 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.
Peking University Cancer Hospital and Institute
Beijing, Beijing Municipality, China
Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Beijjing, Beijing Municipality, China
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
Time frame: 6 months
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
Time frame: Approximately 2 years
RP2D
Recommended Phase 2 dose, will be definite by safety mornitoring committe(SMC).
Time frame: Approximately 6 months
ORR
Objective Response Rate (ORR) was calculated the rate of response of complete response (CR) or partial response (PR).
Time frame: Average of 6 months
DCR
Defined as not meeting the criteria for progression and PR(partial response)
Time frame: Average of 6 months
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.
Time frame: Approximately 1 years
PFS
Progression- free survival (PFS) by RECIST V1.1 criteria- from the beginning of treatment to the progression of disease or death.
Time frame: Approximately 2 years
OS
Overall Survival (OS) was defined as the time interval between a patient randomized and death from any cause or the end of the last follow-up date.
Time frame: Approximately 2 years
Area Under the Plasma Concentration Versus Time Curve (AUC) of DAT-2645
PK parameters of DAT-2645 and metabolite over time at Cycle 0 Day 1 and at steady state (Cycle 1 Day 21) to model Area Under the the Plasma Concentration Versus Time Curve (AUC) with trough levels at the beginning of every Cycle thereafter
Time frame: Approximately 1 years
Changes in lysate poly (ADP-ribose) (PAR) level
As a PD parameter, detect the PAR level in peripheral blood mononuclear cell (PBMC) before and after administration of DAT-2645. Explore the correlation between DAT-2645 exposure and PD parameter, safety events.
Time frame: 6 months
Correlations between patients' baseline characteristics and effecacy
Correlations between patients' baseline characteristics (e.g., DDR deficiency type, tumor type) and objective response rate (ORR), to explore the best biomarker for tumor selection.
Time frame: Approximately 2 years
Time to Achieve Maximal Plasma Concentration (Tmax) of DAT-2645 in Part 1 and Part 2
PK parameters of DAT-2645 and metabolite over time at Cycle 0 Day 1 and at steady state (Cycle 1 Day 21) to model time to maximum concentration (Tmax) with trough levels at the beginning of every Cycle thereafter
Time frame: Approximately 1 years
Maximal Plasma Concentration (Cmax) of DAT-2645 in Part 1 and Part 2
PK parameters ofDAT-2645 and metabolite over time at Cycle 0 Day 1-Cycle 0 Day 6 and at steady state (Cycle 1 Day 21) to model maximum concentration (Cmax) with trough levels at the beginning of every Cycle thereafter
Time frame: Approximately 1 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.