A Study of TY-302 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of TY-302 single and the combination with Tamoxifen in dose-escalation and dose-expansion study.The drugs involved in this study are: TY-302 Tamoxifen

Detailed Description
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This is an open-label, single-arm, phase I trial. The purpose of this study is to : Test a safe and tolerable dose of TY-302 single and the combination with Tamoxifen Determine the response rate of the combination Further evaluate the safety and side effect profile for the combination of TY-302 and Tamoxifen.

Official Title
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A Phase I Study to Evaluate the Safety, Tolerability and Pharmacokinetic Characteristics of TY-302 Capsules in Patients With Advanced Solid Tumors in China

Conditions
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Breast Cancer, Solid Tumor

Intervention / Treatment
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* Drug: TY-302: capsule, 25mg/50mg ; Tamoxifen: tablet,10mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-70years old, male or female with solid tumors, female with breast cancer Histological or cytological confirmation diagnosis of advanced solid tumors (except small cell lung cancer and eye cancer) in TY-302 alone study; and advanced breast cancer in the combination study. Biopsy proven diagnosis of ER and/or PR positive, HER2 negative. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. Life expectancy of at least 3 month. Adequate organ function as defined by the following criteria: Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to underlying malignancy; total serum bilirubin ≤1.5 x ULN; Absolute neutrophil count (ANC) ≥1.5×109/L; platelets(PLT)≥75×109/L ; Hemoglobin(Hb) ≥ 90g/L; Serum creatinine ≤1.5 x ULN; Left ejection fraction (LVEF)≥50%; QTc≤470 msec (based on the mean value of the triplicate ECGs). Female subjects have a negative urine or serum pregnancy. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses. Exclusion Criteria: Subjects presenting with any of the following were not to be included in the study: Previously treated by other CDK4/6 inhibitor. Hypersensitivity to TY-302(or Tamoxifen in the combination study) or to any of its excipients. Ocular fundus diseases in the combination study. Uncontrolled intercurrent illness including active infection, human immunodeficiency virus infection, active hepatitis or other severe acute or chronic medical or psychiatric condition. Current alcohol/drug abuse or dependence. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE grade≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure of NCI CTCAE grade≥2, cerebrovascular accident. Presence of a condition that would interfere with enteric absorption of TY-302 and/or Tamoxifen. Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 4 weeks of the first dose. Spinal cord compression or brain metastases unless asymptomatic. Major surgery within 8 weeks of first study treatment. Current use or anticipated need for drugs that are known strong CYP3A4 inhibitors, strong CYP3A4 inducers, Narrow therapeutic index for CYP3A sensitive substrates, CYP2D6 inhibitors, CYP2D6 inducers. Patients on chronic anticoagulation. The subject inappropriate for entry into this study in the judgment of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TY-302 ; TY-302 combine with Tamoxifen<br>TY-302 Find the maximum tolerated dose(MTD) and the recommended phase 2 dose (RP2D) of TY-302, given orally. Increased dose cohorts from low dose to MTD, starting at 25mg daily. TY-302 combine withTamoxifen in dose-escalation stage TY-302: RP2D-1to RP2D daily for 28 days of each 28 day cycle. Tamoxifen: 20mg twice daily for 28 days of each 28 day cycle. TY-302 combine withTamoxifen in dose-expansion stage TY-302: RP2D daily for 28 days of each 28 day cycle. Tamoxifen: 20mg twice daily for 28 days of each 28 day cycle. | Drug: TY-302: capsule, 25mg/50mg ; Tamoxifen: tablet,10mg<br>* TY-302 is taken orally. Tamoxifen is taken orally.<br>* Other names: Tamoxifen Citrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TY-302 | To determine the MTD and RP2D of TY-302 in subjects with solid tumors | 1 year | 
| Dose Limiting Toxicity (DLT) of TY-302 | Incidence of Dose Limiting Toxicity (DLT) of TY-302 | First 35 days of dosing | 
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TY-302 combine with Tamoxifen | To determine the MTD and RP2D of TY-302 and Tamoxifen on the combination in subjects with breast cancer | 1 year | 
| Dose Limiting Toxicity (DLT) of TY-302 combine with Tamoxifen | Incidence of Dose Limiting Toxicity (DLT) of TY-302 and Tamoxifen on the combination | First 28 days of dosing | 
| Overall Response Rate (ORR) of TY-302 combine with Tamoxifen | To assess the effect of TY-302 combine with Tamoxifen on ORR( 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) ) in the treatment of ER+/HER2- advanced breast cancer. | 6 months | 
| Disease Control Rate(DCR) of TY-302 combine with Tamoxifen | To assess the effect of TY-302 combine with Tamoxifen on DCR(the proportion of patients with CR, PR, or stable disease(SD) assessment in accordance to RECIST 1.1) in the treatment of ER+/HER2- advanced breast cancer. | 9 months | 
| Duration of Response (DOR) of TY-302 combine with Tamoxifen | To assess the effect of TY-302 combine with Tamoxifen on DOR( 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) in the treatment of ER+/HER2- advanced breast cancer. | 9 months | 
| Progression-free Survival (PFS) of TY-302 combine with Tamoxifen | To assess the effect of TY-302 combine with Tamoxifen on PFS(time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1) in the treatment of ER+/HER2- advanced breast cancer. | 12 months |