Clinical trial NCT06968572: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumors
Lead sponsor: Haisco Pharmaceutical Group Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2025-05-13
Enrollment: 245
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years，Male and female patients, at time of signing informed consent form (ICF).
2. ECOG performance status 0-1.
3. Life expectancy ≥ 3 months.
4. 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).
5. Homozygous deletion of the MTAP gene detected in tumor tissue confirmed prior to the administration of HSK41959.
6. Measurable disease by RECIST 1.1 criteria.
7. Adequate hematologic, hepatic, and renal function.

Exclusion Criteria:

1. Prior treatment with a PRMT5 or MAT2A inhibitor therapy.
2. The presence of unstable, clinically symptomatic central nervous system metastases or leptomeningeal metastases.
3. 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.
4. Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.

   Treatment with any of the following:
5. 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.
6. 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.
7. Any disease which would preclude drug absorption, metabolism or pharmacokinetics, e.g. active peptic ulcer or chronic gastroesophageal reflux disease.
8. 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.
9. Any thromboembolic events within 6 months prior to the first dose of HSK41959; any familial or acquired thrombophilia.
10. 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.
11. Any unstable systemic disease, e.g. severe metabolic disease: liver cirrhosis, renal failure, or uremia.
12. Patient with cognitive dysfunction, or history of mental illness, other uncontrolled comorbidities, alcohol dependence, hormone dependence or drug abuse.
13. Other protocol-defined Inclusion/Exclusion criteria apply

Primary outcomes:
measure: DLTs
timeFrame: 24 days
measure: MTD
timeFrame: 24 days
measure: AEs
timeFrame: Up to approximately 3 years
measure: RP2D
timeFrame: Up to approximately 1 year
Secondary outcomes:
measure: Overall response rate (ORR)
timeFrame: Up to approximately 3 years
measure: Disease control rate (DCR)
timeFrame: Up to approximately 3 years
measure: Duration of response (DOR)
timeFrame: Up to approximately 3 years
measure: Progression free survival (PFS)
timeFrame: Up to approximately 3 years
measure: Overall survival (OS)
timeFrame: Up to approximately 3 years
measure: Area under the curve (AUC) of HSK41959
timeFrame: Up to approximately 6 months
measure: maximum plasma concentration (Cmax) of HSK41959
timeFrame: Up to approximately 6 months
measure: half-life (t1/2) of HSK41959
timeFrame: Up to approximately 6 months
measure: Tmax(Time to maximum plasma concentration) of HSK41959
timeFrame: Up to approximately 6 months
Other outcomes:
measure: Changes in SDMA concentration
timeFrame: Up to approximately 6 months
Locations:
city: GuiYang
country: China
facility: The Affiliated Hospital of Guizhou Medical University
state: Guizhou
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital
state: Jiangsu
city: Shanghai
country: China
facility: Shanghai East Hospital
state: Shanghai
Study officials:
References: