A Study of TY-9591 in Advanced Non-small Cell Lung Cancer(NSCLC) Patients With EGFR Positive Mutation

Phase I, Open-label, Single-arm Study to Evaluate the Safety, Tolerance, Pharmacokinetics and Preliminary Efficacy of TY-9591 Tablets in Advanced NSCLC Patients With Epidermal Growth Factor Receptor( EGFR) Positive Mutation

The primary objective of this study is to evaluate the safety and tolerability of TY-9591, with dose-escalation stage and dose-expansion stage.

Study Overview

• Status: Completed
• Conditions: NSCLC
• Intervention / Treatment: Drug: TY-9591(10mg,40mg) qd. po

Detailed Description

• To define the maximum tolerated dose(MTD) and the recommended phase 2 dose (RP2D)
• To investigate the pharmacokinetic profile of TY-9591 and its metabolites after single then multiple doses of TY-9591 administered orally once daily
• To evaluate the anti-cancer activity of TY-9591 in NSCLC patients with EGFR mutation(ORR、PFS、DoR、DCR、and CBR)

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 201203
    • Shanghai Chest Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-75years old, male or female.
2. Histological or cytological confirmation diagnosis of NSCLC
3. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
4. Life expectancy of at least 3 months.
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. Aspartate aminotransferase(AST)、alanine aminotransferase(ALT) ≤ 2.5×ULN; for patients with hepatic metastases, AST、ALT ≤ 5×ULN; g. International standardized ratio (INR) < 1.5, and activated partial prothrombin time (APTT) < 1.5×ULN;

8. Female subjects have a negative urine or serum pregnancy.
9. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.

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).
   6. Patients currently receiving (or at least within 1 week prior to receiving the first dose )medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 isoenzyme (CYP)3A4.
2. 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 and grade 2, prior platinum-therapy related neuropathy.
3. Spinal cord compression or brain metastases unless asymptomatic.
4. Dysphagia, or active digestive system diseases or previous significant bowel resection or medical conditions potentially affect TY-9591 absorption.

5. Cardiac function and disease are consistent with the following:

   1. Corrected QT interval(QTc)> 470 milliseconds from 3 electrocardiograms (ECGs);
   2. Any clinically important abnormalities in rhythm;
   3. Any factors that increase the risk of QTc prolongation;
   4. Left ventricular ejection fraction (LVEF) <50%;
6. Active human immunodeficiency virus (HIV), syphilis, hepatitis c virus (HCV) or hepatitis b virus (HBV) infection, with the exception of asymptomatic chronic hepatitis b or hepatitis c carriers.

7 .Previous history of interstitial lung disease(ILD)、drug-induced ILD or radiation pneumonitis require steroid treatment, or any evidence of clinically active ILD diseases.

8. Previous allogeneic bone marrow transplant. 9. Hypersensitivity to TY-9591 or similar compounds or excipients. 10.Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TY-9591; Find maximum tolerated dose of TY-9591 given orally. Escalating doses of TY-9591 starting at 20mg daily.	Drug: TY-9591(10mg,40mg) qd. po; Increased dose cohorts from low dose to MTD(20mg Cohort1, 40mg Cohort2, 80mg Cohort3,120mg Cohort4, 160mg Cohort5, 200mg Cohort6); Other Names: TY-9591

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT)	Incidence of Dose Limiting Toxicity (DLT)	First 29 days of dosing
Maximum Tolerated Dose (MTD)	To determine the Maximum Tolerated Dose (MTD) of TY-9591 in subjects with NSCLC	1year
Recommended Phase 2 dose (RP2D)	Recommended Phase 2 dose (RP2D) of TY-9591 in subjects with NSCLC	through study completion, an average of 2.5 years
Overall Response Rate (ORR)	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)	At least 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	Cmax of TY-9591 following single dose	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.
Tmax	Tmax of TY-9591 following single dose	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.
Area Under Curve(AUC)	AUC of TY-9591 following single dose	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
Cmax	Cmax of TY-9591 following multiple dose	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 days
Cmin	Cmin of TY-9591 following multiple dose	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 days
AUC	AUC of TY-9591 following multiple dose	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 days
Progression-free survival (PFS)	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	10.1 months
Duration of Response (DOR)	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	9.7 months

Collaborators and Investigators

• Sponsor: TYK Medicines, Inc
• Investigators: Principal Investigator: Baohui Han, MD, Shanghai Chest Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2020
• Primary Completion (Actual): March 3, 2023
• Study Completion (Actual): May 18, 2023

Study Registration Dates

• First Submitted: December 12, 2019
• First Submitted That Met QC Criteria: December 16, 2019
• First Posted (Actual): December 19, 2019

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: TYKM1601101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No