Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of DAT-1604 in Advanced Solid Tumor

Danatlas Pharmaceuticals Co., Ltd

Status and phase: Begins enrollment in 1 month; Phase 1

Conditions: Advanced Solid Tumors

Treatments: Drug: DAT-1604 tablet

Study type: Interventional

Funder types: Industry

Identifiers

NCT06998173

Danatlas Pharmaceuticals

Details and patient eligibility

About

The primary objective of the study is to evaluate the safety, tolerability, PK, and preliminary efficacy of a Polθ Inhibitor DAT-1604 in patients with advanced/metastatic solid tumors, which is refractory to standard therapies, or for which no standard therapies exist.

Full description

In Part 1, 6 dose cohorts will be set and defined maximum tolerated dose(MTD)/recommended dose for expansion (RDE). In Part 2, Food effects on pharmacokinetic of DAT-1604 will be assessed at RDE, and dose optimization will be conducted to definite recommended phase 2 dose (RP2D). Then , The RP2D expansion will be conducted in another 3 cohorts to evaluate the efficacy.

Enrollment: 228 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Signed informed consent.

2. Male or female aged ≥18 years.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

4. Advanced or metastatic solid tumor, which is refractory to standard therapies, or for which no standard therapies exist.

5. Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis.

6. Discontinued all previous treatments for cancer for at least 21 days or 5 half-lives, whichever is shorter, and recovered from the acute effects of therapy. Palliative radiotherapy must have completed 1 week prior to start of study treatment.

7. At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation by RECIST v1.1 for subjects.

8. Acceptable hematologic, renal, hepatic, and coagulation functions independent of transfusions and granulocyte colony-stimulating factor indicated by the following laboratory values:

   • Hemoglobin (Hgb) greater than or equal to 10 g/dL;
   • Leukocytes greater than or equal to 3,000/mcL;
   • Absolute neutrophil count greater than or equal to 1,500/mcL;
   • Platelets greater than or equal to 100,000/mcL;
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2 × upper limit of normal (ULN); if liver metastases, then ≤ 3 × ULN;
   • Bilirubin ≤ 1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert's syndrome;
   • Serum albumin ≥ 30 g/L (3.0 g/dL);
   • Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault Equation).

9. Willingness to abide by protocol defined contraceptive requirements for the duration of the study.

10. Estimated life expectancy of ≥12 weeks.

Exclusion criteria

1. Subjects who are pregnant.

2. Subjects with Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) or with features suggestive of MDS/AML.

3. Have ongoing interstitial lung disease or pneumonitis.

4. Have any major gastrointestinal issues that could impact absorption of DAT-1604.

5. Subjects with brain metastases (subjects with treated brain metastases could be eligible if follow-up brain imaging after central nervous system-directed therapy shows no evidence of progression at least more than 4 weeks without neuropsychiatric symptom).

6. Have received a live vaccine within 30 days before the first dose of study treatment.

7. Recent major surgery within 4 weeks prior to entry into the study.

8. Have a history of allergy or hypersensitivity to study drug components.

9. Persistent toxicities ([CTCAE] Grade > 1) from prior anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.

10. Any of the following ECG findings at Screening, Admission and/or pre dose on Day 1:

    • Any out of range ECG parameter(s) or abnormal finding(s) considered clinically significant by the Investigator;
    • Any ECG finding that, in the opinion of the Investigator, may compromise interpretation of ECG for cardiac safety assessments and/or complicate interpretation of events that may occur post dose (e.g., QT not accurately measurable, conduction abnormalities);
    • QTcF > 470 ms;
    • Any of the following: History or current evidence of congenital long QT syndrome; history of Torsades de Pointes, concomitant medications known to prolong QT interval or history of medication-related QT prolongation;
    • Resting HR <50 bpm or >90 bpm when vital signs are measured at Screening or Admission.

11. COVID-19 positive for active disease.

12. Myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease or congestive heart failure) resulting in heart failure by New York Heart Association (NYHA) Criteria (Class III or IV staging).

13. Current treatment with drugs known as sensitive substrates or substrates having a narrow therapeutic index of CYP2B6, CYP3A4, and transporters including OAT1 and OAT3.

14. Have received inhibitors or inducers of P-gp within 2 weeks prior to receiving the first dose of study drug.

15. Current treatment with drugs which can prolong QTc in adverse reaction.

16. Current treatment with highly competitive protein binding medications, such as warfarin, phenytoin, chlorpromazine, doxorubicin, gentamicin, indomethacin, metoprolol, meclezine.

17. Known hypersensitivity to study drug(s) or any of its constituents.

18. Unwilling or unable to follow study restrictions and requirements

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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228 participants in 4 patient groups

Part 1, Dose escalation

Experimental group

Description:

The part 1 is the dose escalation study, and set 6 dose level cohorts.On day 1 of cycle 1(C0D1), The patient takes DAT-1645 orally one time (single use) at the dose level in his or her enrollment cohort . Since C1D1(C0D4)，the DAT-1604 tablet is administered orally once daily at same dose level for 21 days per treatment cycle. Treatment continues until disease progression, or toxicity intolerance, or withdrawal from the study, or loss to follow-up, or initiation of new antitumor therapy, whichever occurs first.

Treatment:

Drug: DAT-1604 tablet

Module 1 Part 2, dose expansion study to assess the food effects on pharmacokinetics（PK）.

Experimental group

Description:

On day 1 of cycle 0 (C0D1), a single recommended oral dose of DAT-1604 is administered in the fasted state, withing a drug-free washout period of day 2 and day 3, and a single same dose of DAT-1604 is administered in the postprandial state on C0D4, with elution of the drug by C0D5, C0D6. Since C1D1(C0D7) , the DAT-1604 is administered orally once daily at the same dosage level, for 21 days as 1 treatment cycle , administered until disease progression, or toxicity intolerance, or withdrawal from the study, or loss to follow-up, or initiation of new antitumor therapy, or trial closure/termination, whichever occurs first.

Treatment:

Drug: DAT-1604 tablet

Module 2 Part 2, optimized dose expansion

Experimental group

Description:

The study sets two recommended dose levels. The patient will receive one of the dose levels, and be administered orally once daily at the same dosage level, for 21 days as 1 treatment cycle , administered until disease progression, or toxicity intolerance, or withdrawal from the study, or loss to follow-up, or initiation of new antitumor therapy, or trial closure/termination, whichever occurs first.

Treatment:

Drug: DAT-1604 tablet

Module 3 Part 2, RP2D expansion

Experimental group

Description:

The patient will be administered DAT-1604 with recommended phase 2 dose (RP2D) level, orally once daily , for 21 days as 1 treatment cycle , and administered until disease progression, or toxicity intolerance, or withdrawal from the study, or loss to follow-up, or initiation of new antitumor therapy, or trial closure/termination, whichever occurs first.

Treatment:

Drug: DAT-1604 tablet