A PARG Inhibitor 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

Official title

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

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.

Detailed description

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.

Interventions

• Drug DAT-2645 tablet
  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.
• Drug DAT-2645 tablet
  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.

Primary outcome measures

• 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]
• 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]

Secondary outcome measures (11)

• RP2D [Time frame: Approximately 6 months]
• ORR [Time frame: Average of 6 months]
• DCR [Time frame: Average of 6 months]
• DoR [Time frame: Approximately 1 years]
• PFS [Time frame: Approximately 2 years]
• OS [Time frame: Approximately 2 years]
• Area Under the Plasma Concentration Versus Time Curve (AUC) of DAT-2645 [Time frame: Approximately 1 years]
• Changes in lysate poly (ADP-ribose) (PAR) level [Time frame: 6 months]
• Correlations between patients' baseline characteristics and effecacy [Time frame: Approximately 2 years]
• Time to Achieve Maximal Plasma Concentration (Tmax) of DAT-2645 in Part 1 and Part 2 [Time frame: Approximately 1 years]
• Maximal Plasma Concentration (Cmax) of DAT-2645 in Part 1 and Part 2 [Time frame: Approximately 1 years]

Eligibility criteria

Inclusion criteria

• 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.
• At least one measurable lesion by RECIST v1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0\~2.
• Life expectancy at least 3 months.
• 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 6 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.
• 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.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Peking University Cancer Hospital and Institute — Beijing
• Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College — Beijjing

Identifiers

NCT: NCT06614751 · Danatlas Pharmaceuticals Co.

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗