Advanced Solid Tumors
Conditions
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.
Interventions
DRUGHSK41959
Oral administration, QD
Sponsors
Haisco Pharmaceutical Group Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| RP2D | Up to approximately 1 year | RP2D determination: DLT, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary safety and anticancer activity data |
| DLTs | 24 days | Incidence of dose-limiting toxicities (DLTs) at Cycle 0 and Cycle1 |
| MTD | 24 days | MTD determination: dose limiting toxicity (DLT) rate |
| AEs | Up to approximately 3 years | Rate and severity of adverse events of HSK41959 as monotherapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) | Up to approximately 3 years | PFS, defined as the time frocease or death due to any cause, whichever occurs first |
| Overall survival (OS) | Up to approximately 3 years | OS, defined as the time from the first dose of HSK41959 until the date of death due to any cause |
| Area under the curve (AUC) of HSK41959 | Up to approximately 6 months | — |
| half-life (t1/2) of HSK41959 | Up to approximately 6 months | — |
| Tmax(Time to maximum plasma concentration) of HSK41959 | Up to approximately 6 months | — |
| maximum plasma concentration (Cmax) of HSK41959 | Up to approximately 6 months | — |
| Overall response rate (ORR) | Up to approximately 3 years | ORR, defined as the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1 |
| Disease control rate (DCR) | Up to approximately 3 years | DCR, defined as the proportion of patients who experience a best response of CR, PR, or stable disease (SD) according to RECIST 1.1 |
| Duration of response (DOR) | Up to approximately 3 years | DOR, defined as the time from first documented response of complete response (CR) or partial response (PR) to the date of first documented progressive disease or death due to any cause, whichever occurs first |
Other
| Measure | Time frame |
|---|---|
| Changes in SDMA concentration | Up to approximately 6 months |
Countries
China
Outcome results
None listed