A Phase I, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic of HSK40118 in Patients With EGFR Mutation Locally Advanced or Metastatic NSCLC
Overview
- Phase
- Phase 1
- Intervention
- HSK40118
- Conditions
- NSCLC
- Sponsor
- Haisco Pharmaceutical Group Co., Ltd.
- Enrollment
- 220
- Locations
- 12
- Primary Endpoint
- MTD
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a phase I, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and PD of HSK40118 when given orally in patients with active EGFR mutation locally advanced or metastatic non-small cell lung cancer (NSCLC).
The study will contain two phase: Phase Ia is dose escalation phase and Phase Ib is dose expansion phase.
Detailed Description
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 HSK40118. The number of patients to be enrolled will be up to 10 subjects in each Part B cohort. Approximately 30-70 subjects will be enrolled in Phase Ia. Phase Ib no less than 130 subjects will be enrolled in each expansion cohort, cohort A will be enrolled 30-50 subjects, cohort B will be enrolled no less than 100 subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years, Male and female patients, at time of signing informed consent form (ICF).
- •ECOG=0-1, with no deterioration in 2 weeks before first dose of HSK
- •Histological or cytological confirmed diagnosis of unresectable locally advanced or metastatic NSCLC.
- •Patients will provide blood or tumor sample according to their own willingness.
- •Patients in Phase Ia and Ib will fulfill the different criteria of the following:
- •Phase Ia(Part A): Previous treatment with at least one EGFR-TKI, including 1st, 2nd and 3rd-generation EGFR-TKI; Phase Ia(Part B)/Phase Ib: Previous treatment with 3rd-generation EGFR-TKI.
- •tumour lesions/lymph nodes: Phase Ia(Part A): Patients should have at least one assessable tumour lesions/malignant lymph nodes; Phase Ia(Part B) /Phase Ib: Patients should have at least one measurable tumour lesions/malignant lymph nodes.
- •Life expectancy ≥ 3 months.
- •Adequate hematologic and organ function per protocol.
- •Women of childbearing potential (WOCBP) and fertile males with WOCBP partners must use highly effective contraception per protocol throughout and after 90 days of the last dose of the study.
Exclusion Criteria
- •malignant tumor within 5 years, with the exception of cutaneous squamous cell carcinoma, cervical carcinoma in situ, papillary thyroid carcinoma, or other tumors with low malignancy.
- •Unstable spinal cord compression or brain metastases per protocol.
- •Uncontrollable pleural effusion, ascites, or pericardial effusion per protocol.
- •Prior treatment with 4th-generation EGFR-TKIs(TKI for 3th-generation resistance).
- •Treatment with any of the following:
- •Prior treatment with an EGFR-TKI or other small-molecule anti-tumor drug within 7 days or approximately 5 × t1/2 prior to the first dose of HSK40118, whichever is shorter; Prior treatment with chemotherapy, palliative radiotherapy, or Herbal therapy within 2 weeks or approximately 5 × t1/2 prior to the first dose of HSK40118, whichever is shorter; Prior treatment with radiotherapy, immunotherapy/biotherapy therapy, or other pharmaceutical clinical trial within 4 weeks or approximately 5 × t1/2 prior to the first dose of HSK40118, whichever is shorter.
- •Treatment with inhibitors for P-glycoprotein (P-gp) within 7 days prior to the first dose of HSK
- •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 cause chronic diarrhea, eg. Crohn's disease, or irritable bowel syndrome.
- •Any disease which would preclude drug absorption, metabolism or pharmacokinetics, eg. active peptic ulcer or chronic gastroesophageal reflux disease.
Arms & Interventions
Phase Ia(Part A): HSK40118 as monotherapy
Phase 1a(Part A): dose escalation of HSK40118 as monotherapy at various dose levels
Intervention: HSK40118
Phase Ia(Part B): HSK40118 as monotherapy
Phase 1a(Part B): dose extention of HSK40118 as monotherapy at certain dose levels
Intervention: HSK40118
Phase Ib: HSK40118 as monotherapy
Phase 1b: dose expansion for HSK40118 as monotherapy at a dose determined during Phase 1 in patients with previous treatment with 3rd-generation EGFR-TKI
Intervention: HSK40118
Outcomes
Primary Outcomes
MTD
Time Frame: Up to approximately 52 months
MTD determination: dose limiting toxicity (DLT) rate
Eastern Cooperative Oncology Group Performance Status Scale(ECOG PS)
Time Frame: Up to approximately 52 months
Change of the grade as a part of HSK40118 safety data. The functional status of patients will be assessed by the ECOG PS, which is described as a scale including grade 0(fully active) to grade 5(dead).
DLTs
Time Frame: Up to approximately 52 months
Incidence of dose-limiting toxicities (DLTs) at Cycle 0 and Cycle1
AEs
Time Frame: Up to approximately 52 months
Rate and severity of adverse events of HSK40118 as monotherapy
Secondary Outcomes
- Overall response rate(ORR)(Up to approximately 52 months)
- Disease control rate (DCR)(Up to approximately 52 months)
- Overall survival (OS)(Up to approximately 52 months)
- AUC of HSK40118(Blood samples will be collected on 6 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3, cycle 1 day 1, cycle 1 day 8 and cycle 1 day 15.)
- Cmin of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 1 day 1, cycle 1 day 8 and cycle 1 day 15.)
- Tmax of HSK40118(Blood samples will be collected on 6 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3, cycle 1 day 1, cycle 1 day 8 and cycle 1 day 15.)
- Terminal half life(t1/2) after single dosing of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3.)
- Vd/F of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3.)
- λz of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3.)
- Cav,ss(average concentration at steady state) of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 1 day 1, cycle 1 day 8 and cycle 1 day 15.)
- Duration of response (DOR)(Up to approximately 52 months)
- Progression free survival (PFS)(Up to approximately 52 months)
- Cmax of HSK40118(Blood samples will be collected on 6 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3, cycle 1 day 1, cycle 1 day 8 and cycle 1 day 15.)
- CL/F of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3.)
- MRT(Mean residence time) of HSK40118(Blood samples will be collected on 3 occasions for each patient throughout study: cycle 0 day 1, cycle 0 day 2, cycle 0 day 3.)