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

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.

Inclusion criteria

• Signed informed consent.
• Male or female aged ≥18 years.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
• Advanced or metastatic solid tumor, which is refractory to standard therapies, or for which no standard therapies exist.
• Non-irradiated tumor tissue sample (archival or newly obtained core biopsy of a tumor lesion) available for submission for analysis.
• 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.
• 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.
• 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).
• Willingness to abide by protocol defined contraceptive requirements for the duration of the study.
• Estimated life expectancy of ≥12 weeks.

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Exclusion criteria

• Subjects who are pregnant.
• Subjects with Myelodysplastic syndrome (MDS)/Acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
• Have ongoing interstitial lung disease or pneumonitis.
• Have any major gastrointestinal issues that could impact absorption of DAT-1604.
• 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).
• Have received a live vaccine within 30 days before the first dose of study treatment.
• Recent major surgery within 4 weeks prior to entry into the study.
• Have a history of allergy or hypersensitivity to study drug components.
• Persistent toxicities ([CTCAE] Grade > 1) from prior anticancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy.
• 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.
• COVID-19 positive for active disease.
• 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).
• Current treatment with drugs known as sensitive substrates or substrates having a narrow therapeutic index of CYP2B6, CYP3A4, and transporters including OAT1 and OAT3.
• Have received inhibitors or inducers of P-gp within 2 weeks prior to receiving the first dose of study drug.
• Current treatment with drugs which can prolong QTc in adverse reaction.
• Current treatment with highly competitive protein binding medications, such as warfarin, phenytoin, chlorpromazine, doxorubicin, gentamicin, indomethacin, metoprolol, meclezine.
• Known hypersensitivity to study drug(s) or any of its constituents.
• Unwilling or unable to follow study restrictions and requirements