Phase I Study of HSK41959 in Solid Tumors With MTAP Deletion

Official title

A Phase I, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic of HSK41959 in Patients With MTAP Deletion Locally Advanced or Metastatic Solid Tumors

Overview

This is a phase I, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and PD of HSK41959 when given orally in patients with MTAP Deletion locally advanced or metastatic Solid Tumors.

Detailed description

The study will contain two phases: Phase Ia is dose escalation phase and Phase Ib is dose expansion phase.

Phase Ia will contain two part: Dose Escalation Part (Part A) and Extension Part (Part B). Part A based on the "3+3" design for dose escalation and safety evaluation requirements. Patient cohorts at selected doses may be extended to further investigate the tolerability, PK and PD of HSK41959. The number of patients to be enrolled will be up to 10 subjects in each Part B cohort. Approximately 30-50 subjects will be enrolled in Phase Ia.

Phase Ib no less than 10-50 subjects will be enrolled in each expansion cohort.

Interventions

• Drug HSK41959
  Oral administration, QD

Primary outcome measures

• DLTs [Time frame: 24 days]
• MTD [Time frame: 24 days]
• AEs [Time frame: Up to approximately 3 years]
• RP2D [Time frame: Up to approximately 1 year]

Secondary outcome measures (9)

• Overall response rate (ORR) [Time frame: Up to approximately 3 years]
• Disease control rate (DCR) [Time frame: Up to approximately 3 years]
• Duration of response (DOR) [Time frame: Up to approximately 3 years]
• Progression free survival (PFS) [Time frame: Up to approximately 3 years]
• Overall survival (OS) [Time frame: Up to approximately 3 years]
• Area under the curve (AUC) of HSK41959 [Time frame: Up to approximately 6 months]
• maximum plasma concentration (Cmax) of HSK41959 [Time frame: Up to approximately 6 months]
• half-life (t1/2) of HSK41959 [Time frame: Up to approximately 6 months]
• Tmax(Time to maximum plasma concentration) of HSK41959 [Time frame: Up to approximately 6 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years，Male and female patients, at time of signing informed consent form (ICF).
• ECOG performance status 0-1.
• Life expectancy ≥ 3 months.
• Patients with locally advanced or metastatic solid tumors confirmed by histology or cytology, who have failed standard treatment (disease progression after treatment or intolerable treatment).
• Homozygous deletion of the MTAP gene detected in tumor tissue confirmed prior to the administration of HSK41959.
• Measurable disease by RECIST 1.1 criteria.
• Adequate hematologic, hepatic, and renal function.

Exclusion criteria

• Prior treatment with a PRMT5 or MAT2A inhibitor therapy.
• The presence of unstable, clinically symptomatic central nervous system metastases or leptomeningeal metastases.
• Malignant tumor within 2 years, with the exception of cutaneous squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, or other tumors with low malignancy.
• Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.

Treatment with any of the following:

• Prior treatment with anti-tumor drug within 4 weeks or approximately 5 × t1/2 prior to the first dose of HSK41959, whichever is shorter; Prior treatment with nitrosourea or mitomycin C within 6 weeks prior to the first dose of HSK41959; Prior treatment with palliative radiotherapy or anti-tumor herbs within 2 weeks prior to the first dose of HSK41959; Prior treatment with radiotherapy, electric field therapy, or other anti-tumor therapies within 4 weeks prior to the first dose of HSK41959.
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment, with the exception of alopecia, dermal toxicity, and other toxicity considering no safety risks by investigator.
• Any disease which would preclude drug absorption, metabolism or pharmacokinetics, e.g. active peptic ulcer or chronic gastroesophageal reflux disease.
• Patients who have clinically significant or uncontrolled cardiac disease, include: QTc interval ≥ 450(male)/470(female) msec; any clinically significant arrhythmia; left ventricular ejection fraction < 50%; myocardial infarction, unstable angina, or class III/IV cardiac failure by the NYHA that occurred within 6 months prior to the first dose of HSK41959.
• Any thromboembolic events within 6 months prior to the first dose of HSK41959; any familial or acquired thrombophilia.
• Uncontrolled hypertension (systolic pressure≥160mmHg, or diastolic pressure≥100mmHg), diabetes (fasting blood-glucose≥10mmol/L), seizures, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, pulmonary interstitial fibrosis, Parkinson's disease, active bleeding, or systemic active infection.
• Any unstable systemic disease, e.g. severe metabolic disease: liver cirrhosis, renal failure, or uremia.
• Patient with cognitive dysfunction, or history of mental illness, other uncontrolled comorbidities, alcohol dependence, hormone dependence or drug abuse.
• Other protocol-defined Inclusion/Exclusion criteria apply

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 3 centers

• The Affiliated Hospital of Guizhou Medical University — Guiyang
• Nanjing Drum Tower Hospital — Nanjing
• Shanghai East Hospital — Shanghai

Identifiers

NCT: NCT06968572 · HSK41959-101

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗