The primary objective of this study is to evaluate the safety and tolerability of TY-9591, with dose-escalation stage and dose-expansion stage.
Name: TY-9591(10mg,40mg) qd. po
Description: Incidence of Dose Limiting Toxicity (DLT)
Measure: Dose Limiting Toxicity (DLT) Time: First 29 days of dosingDescription: To determine the Maximum Tolerated Dose (MTD) of TY-9591 in subjects with NSCLC
Measure: Maximum Tolerated Dose (MTD) Time: 1yearDescription: Recommended Phase 2 dose (RP2D) of TY-9591 in subjects with NSCLC
Measure: Recommended Phase 2 dose (RP2D) Time: through study completion, an average of 2.5 yearsDescription: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Measure: Overall Response Rate (ORR) Time: At least 24 weeksDescription: Cmax of TY-9591 following single dose
Measure: Cmax Time: pharmacokinetics(PK) blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10,12, 24, 48, 72,96,120,144,168 and 192 hours post-dose.Description: Tmax of TY-9591 following single dose
Measure: Tmax Time: pharmacokinetics(PK) blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10,12, 24, 48, 72,96,120,144,168 and 192 hours post-dose.Description: AUC of TY-9591 following single dose
Measure: Area Under Curve(AUC) Time: pharmacokinetics(PK) blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10,12, 24, 48, 72,96,120,144,168 and 192 hours post-doseDescription: Cmax of TY-9591 following multiple dose
Measure: Cmax Time: The datas should be evaluated multiple times on Cycle 1 day1,8,15, 21 pre-dose; Cycle 2 day1 (at pre-dose, 0.5,1, 2, 3, 4, 6, 8, 10,12, 24 hours post-dose). Each cycle is 21 daysDescription: Cmin of TY-9591 following multiple dose
Measure: Cmin Time: The datas should be evaluated multiple times on Cycle 1 day1,8,15, 21 pre-dose; Cycle 2 day1 (at pre-dose, 0.5,1, 2, 3, 4, 6, 8, 10,12, 24 hours post-dose). Each cycle is 21 daysDescription: AUC of TY-9591 following multiple dose
Measure: AUC Time: The datas should be evaluated multiple times on Cycle 1 day1,8,15, 21 pre-dose; Cycle 2 day1 (at pre-dose, 0.5,1, 2, 3, 4, 6, 8, 10,12, 24 hours post-dose). Each cycle is 21 daysDescription: PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by by Investigator assessment in accordance to RECIST 1.1
Measure: Progression-free survival (PFS) Time: 10.1 monthsDescription: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
Measure: Duration of Response (DOR) Time: 9.7 monthsAllocation: N/A
Single Group Assignment
There is one SNP
5. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. 6. Documentation of disease progression while on previous continuous treatment with first-line EGFR TKI; patients must have confirmation of tumor EGFR activating mutations (exon 19 del, or exon 21 ) and T790M mutation status 7. Adequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a.Neutrophils (absolute value) ≥ 1.5×10^9/L; b.Hemoglobin ≥ 90 g/L; c.Platelet ≥ 80×10^9/L; d.Serum total bilirubin ≤ 1.5× ULN(for Patients with Gilbert Syndrome, total bilirubin ≤ 3×ULN and bilirubin ≤ 1.5×ULN should be permitted) f. --- T790M ---
Exclusion Criteria: 1. Treatment with any of the following: 1. Treatment with an EGFR TKI within 14 days or about 5x half-life, whichever is the longer, of the first dose of study drug; 2. Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 4 weeks of the first dose of study treatment; 3. Major surgery within 4 weeks of the first dose of study treatment; 4. Radiotherapy with a limited field of radiation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation that had to be completed within 4 weeks of the first dose of study treatment; 5. Previously treated by other third-generation epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) for T790M (for example Osimertinib). --- T790M ---