The study is divided into 2 cohorts, Cohort 1 is patients with KRASG12C mutated non-small cell lung cancer who have failed standard therapy or no standard therapy and have been treated with KRASG12C inhibitor; Cohort 2 is patients with KRASG12C mutated solid tumors (except non-small cell lung cancer) who have failed standard therapy or have no standard therapy and have been treated with KRASG12C inhibitor. Each cohort consists of two stages, and 10 subjects are planned to be enrolled in the first stage of each cohort. According to the preliminary efficacy and safety data, each party will discuss and decide whether to continue the second stage. Twenty to fifty subjects were planned to be enrolled in Stage II of each cohort. A total of 20-120 subjects were enrolled.
Screened eligible subjects received GH21 in combination with D-1553 in 21-day cycles until the investigator considered the subject no longer benefiting, or the subject developed intolerable toxicity, or the subject withdrew consent, or the subject died, or was lost to follow-up, or received a new anticancer treatment, whichever came first.
1)Patients or their legal representatives can understand and voluntarily sign a written informed consent form (before starting this study and any study procedures); 2)Age ≥ 18 years, male or female; 3)Cohort 1: Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer with KRASG12C mutation who have failed standard therapy or no standard therapy and have been treated with KRASG12C inhibitors; Cohort 2: Histologically or cytologically confirmed locally advanced or metastatic solid tumors (except non-small cell lung cancer) with KRASG12C mutation who have failed standard therapy or have no standard therapy and have been treated with KRASG12C inhibitors.
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L without granulocyte colony-stimulating factor support within 14 days;
Platelets≥100×109/L without thrombopoietin (TPO) and interleukin-11 (IL-11) transfusion within 14 days;
Hemoglobin ≥ 90 g/L without transfusion within 14 days and without erythropoietin (EPO); Renal
nitrosourea or mitomycin C within 6 weeks before the first use of study drugs;
oral fluorouracil, small molecule targeted drugs and Chinese herbal medicine or Chinese patent medicine with anti-tumor indications within 5 half-lives or 2 weeks before the first use of study drugs (whichever is shorter);
Local palliative radiotherapy within 2 weeks before the first use of study drugs; 2)Receiving other unmarketed investigational drugs or treatments within 5 half-lives or 4 weeks (whichever is shorter) before the first dose; 3)Patients who underwent major organ surgery (excluding needle biopsy) or had significant trauma within 4 weeks before the first dose, or required elective surgery during the trial; 4)Use of strong inhibitors or strong inducers of CYP3A4 or P-gp within 2 weeks or 5 half-lives before the first dose; 5)Previous treatment with other SHP2 inhibitors. 6)Evidence of the following cardiac diseases: acute myocardial infarction, unstable angina pectoris, coronary artery bypass grafting, cerebrovascular accident or transient ischemic attack within 6 months prior to the first dose;
Grade III-IV heart failure according to New York Heart Association functional classification at screening;
Single group
GH21，D-1553
Drug* D-1553 tablet, BID, orally. Each cycle lasts 3 weeks. * GH21 Capsule: QD, oral, Each treatment cycle lasts 3 weeks.
Objective response rate (ORR) based on RECIST 1.1 criteria
ORR is defined as the proportion of participants with complete response or partial response (CR+PR)
Safety and tolerability
All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs , etc
Duration of response (DOR) based on RECIST 1.1 criteria
DOR is defined as the time from the participant's initial objective response (CR or PR) to study drug therapy, to disease progression or death due to any cause, whichever occurs first.
Disease Control Rate (DCR) based on RECIST 1.1 criteria
DCR is defined as proportion of participants with complete response, partial response, stable disease(CR+PR+SD).
Progression-free survival (PFS) based on RECIST 1.1 criteria
PFS is defined as the interval of time between the date of first treatment to the earliest date of disease progression or death which occurs first.
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