Official title: an open-label, single-arm, and multicenter phase I study to evaluate the safety, tolerance, pharmacokinetics, and preliminary efficacy of TY-9591 tablet for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC)

 

Primary purpose: evaluate the safety, tolerance, MTD, and DLT of TY-9591 tablet in EGFR-mutant positive, who have failed the previous standard treatment advanced NSCLC patient, and to determine the RP2D.

 

Secondary purpose: 1) evaluate the PK characteristic of TY-9591 tablet in single and repeated drug administration to advanced NSCLC patients; 2) preliminary evaluation of the anti-tumor effect of TY-9591 tablet (ORR, DoR, DCR, CBR, and PFS); 3) the PD characteristics of TY-9591 tablet.

 

Study design

Trial category	Other
Trial phase	Phase I
Design category	Single arm
Allocation	Non-randomization
Masking	None (open label)
Trial geography	China

 

Inclusion criteria

1. Histological or cytological confirmation of locally advanced or metastatic, non-squamous cell lung carcinoma (NSCLC) in patients according to the AJCC Tumor-nodes-metastasis (TNM) Version 8.
2. Patients must have EGFR sensitive mutation (including exon 19, exon 21, L858R mutation or G719X, L861Q, etc) and disease progression after first-line standard therapy (radiographic evidence, as judged by a central lab). The number of previous treatment lines can exceed the first line.
3. Tissue samples and/or peripheral blood samples were obtained prior to enrollment, and sent to a central laboratory for testing to confirm T790M mutations positive
4. Patients should have adequate bone marrow reserve or no liver and kidney coagulopathy, and laboratory values must meet the following conditions:

1. Absolute neutrophil count ＞ 5 × 109/L and white blood cell count > 3 × 109/L
2. Platelet count >80 × 109/L
3. Haemoglobin> 90g/L
4. Serum creatinine ＜ 5 × upper limit of normal (ULN) and the creatinine clearance calculated by the Cockroft-Gault formula ＞ 50 mL/min
5. AST and ALT <5 × ULN (no confirmed liver metastases); AST and ALT <5 × ULN (confirmed liver metastases)
6. Total bilirubin < 1.5 × ULN (no confirmed liver metastases); Total bilirubin <3 × ULN (confirmed liver metastases or patients with Gilbert syndrome (hyper indirect bilirubinemia))
7. International Normalized Ratio (INR) <5 and activated partial thromboplastin time (APTT) <1.5 × ULN

5.At least one measurable disease according to RECIST 6.All relevant toxicities associated with previous treatment (except hair loss and grade 2 neurotoxicity associated with previous platinum-based chemotherapy) have been restored (reverted to grade ≤1) prior to the first administration of the study drug

7.Patients do not have brain metastases (except for asymptomatic brain metastases, who have been stable for more than 4 weeks after local treatment)

8.Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1

9.Life expectancy of at least 3 months

10.Provision of signed and dated, written informed consent prior to any study specific procedures, sampling, and analyses.

 

Exclusion criteria

1. Known or suspected hypersensitivity to the substance of the study drug or its analogues
2. Patients with the following treatments:

1. Time from treatment with reversible EGFR-TKI (e.g., Gefitinib, Eerlotinib, and Erlotinib) to the first dose in this study did not exceed 8 days or 5 half-lives (whichever is longer); Irreversible EGFR-TKIs (e.g., Afatinib, Daclatinib, Lenatinib, etc.) have not been treated for more than 14 days or 5 half-lives (whichever is longer)
2. Received chemotherapy, biologic/targeted drug (excluding EGFR-TKI) therapy, immunotherapy, or other antitumor therapy within 4 weeks prior to the first dose of the study drug
3. Major surgery within 4 weeks prior to the first administration of the study drug
4. Previous treatment with Osimertinib or other third-generation EGFR TKIs
5. Those who have participated in other clinical trials (except non-interventional drug clinical trials) within 4 weeks prior to the first administration of the study drug
6. Patients who underwent topical radiotherapy within 1 week prior to the first dose of the study drug, except those who had completed > 30% of bone marrow radiotherapy or extensive radiotherapy within 4 weeks prior to the first dose of the study drug
7. Currently receiving or receiving treatment with a strong inducer or strong inhibitor of CYP3A4 (including Chinese herbal therapy) at least 1 week prior to the first administration of the study drug

3.The patient has spinal cord compression

4.Serious gastrointestinal dysfunction, or disease that may affect the intake, transport, or absorption of investigational product

5.Any of the following cardiac criteria:

1. Average resting QTc > 470ms (corrected QT interval [corrected by Fridericia formula]), average of 3 ECG QTc, QT interval measurements should be from the beginning of the QRS complex wave to the end of the T wave)
2. Rhythmic, conduction, or morphological abnormalities of any clinically important resting ECG, such as complete left bundle branch block, 2^ndand 3^rd degree heart block, PR interval> 250 ms, etc
3. Any factors that increase the risk of QTc prolongation or arrhythmias, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or sudden unexplained death in first-degree relatives under 40 years of age, or any combination of medications known to prolong the QT interval
4. Left ventricular ejection fraction (LVEF) < 50%
5. Patients with a history of decreased myocardial contractility and symptoms within 6 months prior to study administration, such as chronic congestive heart failure, pulmonary edema, or decreased cardiac ejection fraction
6. Previous history of acute or chronic cardiovascular disease with relevant symptoms within 6 months prior to study dosing: e.g., myocardial infarction, severe or unstable angina, cerebral infarction, cerebral hemorrhage, or transient ischemic attack

6.Combined with other viral infections (anti-HCV, anti-HIV positive, HBsAg positive) or combined with syphilis infection

7.Previous allogeneic bone marrow transplantation

8.Prior history of clearly diagnosed interstitial lung disease or interstitial pneumonia (ILD), or drug-induced ILD, or radiation pneumonia requiring hormone therapy

9.People with other malignant tumors or a history of other malignant tumors

10.For women of childbearing age (postmenopausal women must have been menopausal for at least 12 months to be considered infertile) who have a positive serum pregnancy test result within 7 days prior to the first dose of the study drug; or who, in the judgment of the investigator, intend to become pregnant, breastfeed, or are unwilling to use effective contraception during the study period and within 3 months of the last dose of the study drug (including male subjects and their female spouses of childbearing age)

11.The patient has any instability or any other disease or medical condition that may affect his or her safety or compliance with the study

12.The investigator believes that the subjects are not eligible to participate in this trial.