A Phase I, Dose-escalation/Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Tumor Activity of SY-5933 Tablets in Patients With Advanced KRAS p.G12C Mutant Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- SY-5933
- Conditions
- Advanced Solid Tumor
- Sponsor
- Shouyao Holdings (Beijing) Co. LTD
- Enrollment
- 50
- Locations
- 1
- Primary Endpoint
- Incidence of Dose-limiting toxicities (DLTs)
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a single-arm, open-label, phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of SY-5933 in patients with KRAS p.G12C mutant advanced solid tumors.
Detailed Description
The study will be conducted in 2 parts: Part 1 - Dose Escalation and Part 2 - Dose Expansion. Part 1 is aimed at evaluating the safety, tolerability, PK and pharmacodynamics of SY-5933 and determining the recommended phase II dose (RP2D) of repeat daily (QD) dosing schedule in subjects with advanced KRAS p.G12C mutant solid tumors using accelerated titration and 3+3 design. The dose escalation part of the study will consist of 7-13 subjects and the dose expansion part will consist of 30-60 additional subjects, comprising 2 cohorts. Cohort A includes patients with non-small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations and Cohort B includes patients with other advanced solid tumors (colorectal, pancreatic cancers, etc.). Patients in dose expansion study will receive SY-5933 tablets QD, oral administration, 28 days as a dosing cycle, to further evaluate the safety, PK profile, and efficacy of SY-5933, and to further define RP2D. Administration of SY-5933 may continue until evidence of disease progression, intolerance to SY-5933, or withdrawal of consent.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Men or women ≥ 18 years old
- •Eastern Collaboration Oncology Group (ECOG) performance status (PS) scored of 0-
- •Estimated life expectancy \>12 weeks.
- •Patients must have at least one assessable lesion in the dose-escalation part and one measurable lesion in the dose-expansion part per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
- •In the dose-escalation part, patients must have histologically or cytologically confirmed advanced solid tumors harboring the KRAS p.G12C mutation and have progressed after standard therapy, or standard therapy is inappropriate or unavailable.
- •In the dose-expansion part, patients must have histologically or cytologically confirmed advanced KRAS p.G12C mutant NSCLCs (cohort A) and CRCs, PDACs, and other solid tumors (Cohort B) and have progressed after standard therapy, or standard therapy is inappropriate or unavailable.
- •Adequate organ function as defined in the below:
- •Hepatic function Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times upper limit of normal (ULN), or ≤ 5 times ULN in the presence of liver metastases. Total serum bilirubin (TBIL) ≤ 1.5 times ULN; TBIL≤3×ULN and direct bilirubin（DBIL）≤1.5×ULN in the presence of liver metastases or with Gilbert's syndrome.
- •Bone marrow function No blood transfusion or hematopoietic stimulator treatment within 7 days; absolute neutrophil count (ANC) ≥1.5×10\^9/L; platelets (PLT) count ≥75×10\^9/L; hemoglobin (Hb) ≥ 90 g/L.
- •Renal function Creatinine clearance ≥ 50 mL/min. Coagulation function International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times ULN.
Exclusion Criteria
- •Dose-escalation phase: patients with known driver alterations other than KRAS p.G12C, e.g., EGFR, ALK, ROS1, RET, TRK, etc. (Enrollment of patients with co-mutations may be discussed with the investigator).
- •Dose-expansion phase: prior use of selective KRAS inhibitors.
- •Patients who received chemotherapy, radiotherapy, biological therapy, endocrine therapy, immunotherapy, and other anti-tumor treatment within 3 weeks before the first administration, except for the following: Nitrosourea or mitomycin C was received within 6 weeks before the first administration; Oral fluoropyrimidines and small molecule targeted drugs within 2 weeks or 5 half-lives of the drug (whichever is longer) prior to the first administration; Chinese proprietary medicines with anti-tumor indications were received within 2 weeks before the first administration.
- •Received other unapproved investigational drugs or treatments within 4 weeks prior to the first administration.
- •Have undergone major organ surgery (excluding needle biopsy) or had significant trauma within 4 weeks prior to the first administration.
- •Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade ≤ 1(exceptions for toxicities judged by the investigator to be of no safety concern, e.g. alopecia, grade 2 peripheral neurotoxicity, etc.).
- •Presence of spinal cord compression, meningeal metastases, clinically symptomatic brain metastases, or need for increased steroid doses to control central nervous system (CNS) disease; patients with symptomatic CNS metastases that are already under control may be eligible for this study.
- •Patients with active infection who need systematic anti-infective therapy within 2 weeks prior to the first administration.
- •Active hepatitis (Hepatitis B: Hepatitis B virus surface antigen \[HBsAg\] positive with HBV DNA ≥2000 IU/mL; Hepatitis C: Hepatitis C virus antibody positive with HCV RNA ≥1000 IU/mL), HIV antibody positive, active syphilis (double positive for syphilis non-specific and syphilis specific antibodies) that is uncontrolled by treatment and inappropriate for enrollment as determined by the investigator.
- •Presence of other lung diseases requiring systemic treatment or severe lung diseases such as active tuberculosis, interstitial lung disease, etc., which in the opinion of the investigator may affect the interpretation of the study results or place the patient at high risk;
Arms & Interventions
Dose-escalation and Dose-expansion
In dose-escalation phase, SY-5933 tablets will be administrated orally, repeat daily, 28 days as a dosing cycle, in ascending doses. In dose-expansion phase, RP2D of SY-5933 determined in dose-escalation phase will be administrated orally, repeat daily, 28 days as a dosing cycle.
Intervention: SY-5933
Outcomes
Primary Outcomes
Incidence of Dose-limiting toxicities (DLTs)
Time Frame: 31 days after the first dose (single dose for 3 days and dose-escalation cycle 1 for 28 days)
Number of participants with DLTs
Number of participants with adverse events
Time Frame: Up to 18 months
Patients will be assessed for incidence and severity of adverse events (AEs) according to NCI-CTCAE v5.0 criteria
Secondary Outcomes
- Pharmacokinetics (Cmax) for SY-5933(Protocol-defined time points during 3 days after the first dose and cycle 1 (each cycle is 28 days))
- Pharmacokinetics (Tmax) for SY-5933(Protocol-defined time points during 3 days after the first dose and cycle 1 (each cycle is 28 days))
- Overall Response Rate (ORR) as assessed by RECIST 1.1 criteria(Up to 24 months)
- Duration of response (DOR)(Up to 24 months)
- Pharmacokinetics (AUC0-t) for SY-5933(Protocol-defined time points during 3 days after the first dose and cycle 1 (each cycle is 28 days))
- Disease control rate (DCR) as assessed by RECIST 1.1 criteria(Up to 24 months)
- Pharmacokinetics (t½) for SY-5933(Protocol-defined time points during 3 days after the first dose and cycle 1 (each cycle is 28 days))