DAT-2645 Monotherapy in Patients with Advanced/Metastatic Solid Tumors Harboring BRCA1/2 Loss of Function Alterations And/or Other Defects in the DDR Pathway

Phase 1

Not yet recruiting

• Conditions: Solid Cancers; BRCA Mutation; HRD Cancer; Breast Cancer; Prostate Cancer; Colorectal Cancer; Pancreatic Cancer; Endometrial Cancer; Gastric Cancer; Advanced Cancer
• Interventions: Drug: DAT-2645 tablet

• Registration Number: NCT06614751
• Lead Sponsor: Danatlas Pharmaceuticals Co., Ltd

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.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-18
• Study First Submitted QC: 2024-09-24
• Last Update Submitted: 2024-09-24
• Study First Posted: 2024-09-26
• Last Update Posted: 2024-09-26
• Study Start: 2024-11-01
• Primary Completion: 2026-11-01
• Study Completion: 2027-06-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 112

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:

  1. Deleterious or suspected deleterious mutations in germline or tumor BRCA1/2 genes
  2. 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.

• Cohort C: patients who have HRD colorectal cancer, gastric cancer, endometria cancer or other solid tumors, 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.

• At least one measurable lesion by RECIST v1.1 criteria.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0~2.

• Life expectancy of at least 3 months evaluated by the investigator.

• Adequate hematologic and non-hematologic function during the screening.

• Women of childbearing potential must have a negative result of serum pregnancy test at screening.

• Women of childbearing potential or male patients whose spouse have childbearing potential must agree to use a reliable and effective method of contraception during the study and for 3 months after the last dose of the study drug.

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:

  1. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 110 mmHg) despite treatment;
  2. History of myocardial infarction or unstable angina pectoris within 6 months prior to the first dose of study drug;
  3. History of cerebral hemorrhage, cerebral infarction or transient ischemic attack (TIA) within 6 months prior to the first dose of study drug;
  4. Congestive heart failure (left ventricular ejection fraction [LVEF] < 50%);
  5. Severe symptomatic arrhythmia requiring medication, except for asymptomatic atrial fibrillation that is controllable;
  6. The QT interval corrected for heart rate (QTcF) > 470 msec based on the mean value of triplicate ECG tests, or family history of congenital long QT syndrome.

• Active uncontrolled infections requiring intravenous antibiotics or hospitalization.

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of DAT-2645 and no history of bowel obstruction within 6 months prior to enrollment.

• Known pulmonary interstitial disease or pulmonary interstitial fibrosis.

• Patients known hypersensitivity to any component or excipient of DAT-2645.

• Any unresolved toxicities from any prior therapy with severity great than CTCAE Grade 1 prior to start of DAT-2645, except for alopecia and pigmentation and Grade 2 of peripheral sensory neuropathy.

• Participated in other clinical trials (except for screening failure) within 4 weeks prior to the first dose of the study drug in this study.

• Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (active HBV infection is defined as positive hepatitis B surface antigen [HbsAg], or HBV DNA exceeding the lower limit of detection; active HCV infection is defined as positive anti-HCV antibody, and HCV RNA exceeding the lower limit of detection).

• Known human immunodeficiency virus (HIV) infection (patients with adequate CD4+ T cell counts and without history of acquired immune deficiency syndrome [AIDS]-defining opportunistic infections could be enrolled after consultation with sponsor).

• Women who are pregnant or breastfeeding.

• Patients who have used moderate/strong inhibitors or inducers of CYP3A, P-gp inhibitors and substrates of P-gp, MATE1, MATE2-K with a narrow therapeutic indexes, within 14 days or 5 half-lives of this drug (depends on which is longer) prior to the first dose of DAT-2645.

• Patients who have used medication known to prolong the QT interval within 14 days prior to the first dose of DAT-2645.

• Patients who have used acid-suppressing drugs within 3 days or 5 half-lives of this drug (depends on which is longer) prior to the first dose of DAT-2645.

• History or evidence of any other clinically significant condition or disease (with the exception of those outlined above) that, in the opinion of the investigator, would be a risk to patient safety or interfere with the study evaluation, procedures or completion.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 1, Dose escalation	DAT-2645 tablet	Monotherapy, dose escalation to definite MTD or RDE.
Module 1 Part 2, Dose optimizing	DAT-2645 tablet	Dose optimizing by 2 dose level after dose escalation to definite RP2D
Module 2 Part 2, Dose expansion	DAT-2645 tablet	To evaluate safety and efficacy of DAT-2645 tablet in solid tumor under RP2D dosage

Primary Outcome Measures

Name	Time	Method
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	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	Approximately 2 years	Tumor response: Overall Response Rate(ORR) assessed by the investigators based on RECIST v1.1 criteria

Secondary Outcome Measures

Name	Time	Method
RP2D	Approximately 6 months	Recommended Phase 2 dose, will be definite by safety mornitoring committe(SMC).
ORR	Average of 6 months	Objective Response Rate (ORR) was calculated the rate of response of complete response (CR) or partial response (PR).
DoR	Approximately 1 years	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.
PFS	Approximately 2 years	Progression- free survival (PFS) by RECIST V1.1 criteria- from the beginning of treatment to the progression of disease or death.
OS	Approximately 2 years	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.
Area Under the Plasma Concentration Versus Time Curve (AUC) of DAT-2645	Approximately 1 years	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
Changes in lysate poly (ADP-ribose) (PAR) level	6 months	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.
Correlations between patients' baseline characteristics and effecacy	Approximately 2 years	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 to Achieve Maximal Plasma Concentration (Tmax) of DAT-2645 in Part 1 and Part 2	Approximately 1 years	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
Maximal Plasma Concentration (Cmax) of DAT-2645 in Part 1 and Part 2	Approximately 1 years	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
DCR	Average of 6 months	Defined as not meeting the criteria for progression and PR(partial response)

Trial Locations

Locations (2)

Peking University Cancer Hospital and Institute; 🇨🇳 Beijing, Beijing, China

Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; 🇨🇳 Beijjing, Beijing, China