A Phase I, Open-label, Dose Escalation and Dose Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of 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 Pathway
Overview
- Phase
- Phase 1
- Intervention
- DAT-2645 tablet
- Conditions
- Solid Cancers
- Sponsor
- Danatlas Pharmaceuticals Co., Ltd
- Enrollment
- 112
- Locations
- 2
- Primary Endpoint
- 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
- Status
- Not yet recruiting
- Last Updated
- last year
Overview
Brief Summary
The primary objective of the study is to evaluate the safety, tolerability, PK, PD, and prilimary efficacy of 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.
Detailed Description
This study will include Part 1 dose escalation study and Part 2 dose expansion study. 24 eligible patients will be enrolled into Part 1 and 88 eligible patients will be enrolled into 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients have provided 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. DDR deficiency is defined as one of the following results:
- •Deleterious or suspected deleterious mutations in germline or tumor BRCA1/2 genes
- •HRD positive
- •The detection performed in local lab is acceptable. The sample to detect BRCA mutation include blood, saliva, and oral mucosal epithelium. The sample of HRD detection is tumor tissue preferentially. Prior result is acceptable. Patients harboring BRCA, HRD ,or co-occurring BRCA/HRD mutations can be enrolled.
- •Part 1: 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. The tumor types will include those defined in Part 2 and other types.
- •Part 2: Patients with advanced or metastatic solid tumor (as specified below), regardless of PARP inhibitors were used or not in previous treatment.
- •Cohort A: patients who have HER2 (-), BRCA1/2 loss of function alternations or other HRD breast cancer, regardless of ER/PR status, and have failed at least 1st line of prior threatment.
- •Cohort B: patients who have HRD prostate cancer or pancreas cancer, and have failed standard of care therapy, or are unable to tolerate standard of care therapy, or unable to obtain/unwilling to receive standard therapy.
Exclusion Criteria
- •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).
- •Any previous treatment with a PARG inhibitor.
- •Patients with active CNS metastases (patients with asymptomatic CNS metastases which are imaging stable and not require steroid treatment within 28 days prior to the first dose of study drug, and previous treated breast cancer brain metastasis, can only be enrolled in the Part 2 study).
- •Patients who have second primary malignant tumors within the past 3 years prior to screening, except for those who have been cured of basal cell carcinoma, cervical carcinoma in situ, or breast carcinoma in situ.
- •Patients with clinically significant cardiovascular or cerebrovascular diseases, including:
- •Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 110 mmHg) despite treatment;
- •History of myocardial infarction or unstable angina pectoris within 6 months prior to the first dose of study drug;
Arms & Interventions
Part 1, Dose escalation
Monotherapy, dose escalation to definite MTD or RDE.
Intervention: DAT-2645 tablet
Module 1 Part 2, Dose optimizing
Dose optimizing by 2 dose level after dose escalation to definite RP2D
Intervention: DAT-2645 tablet
Module 2 Part 2, Dose expansion
To evaluate safety and efficacy of DAT-2645 tablet in solid tumor under RP2D dosage
Intervention: DAT-2645 tablet
Outcomes
Primary Outcomes
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
Time Frame: 6 months
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
Time Frame: Approximately 2 years
Tumor response: Overall Response Rate(ORR) assessed by the investigators based on RECIST v1.1 criteria
Secondary Outcomes
- RP2D(Approximately 6 months)
- ORR(Average of 6 months)
- DCR(Average of 6 months)
- DoR(Approximately 1 years)
- PFS(Approximately 2 years)
- OS(Approximately 2 years)
- Area Under the Plasma Concentration Versus Time Curve (AUC) of DAT-2645(Approximately 1 years)
- Changes in lysate poly (ADP-ribose) (PAR) level(6 months)
- Correlations between patients' baseline characteristics and effecacy(Approximately 2 years)
- Time to Achieve Maximal Plasma Concentration (Tmax) of DAT-2645 in Part 1 and Part 2(Approximately 1 years)
- Maximal Plasma Concentration (Cmax) of DAT-2645 in Part 1 and Part 2(Approximately 1 years)