A Study of TAS0728 in Patients With Solid Tumors With HER2 or HER3 Abnormalities

Study Overview
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Brief Summary
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This is a First-in-Human (FIH), 2-part, Phase 1/2, open-label, multicenter study design to evaluate the safety, tolerability, PK, pharmacodynamics, PGx, and efficacy of TAS0728. This study consists of Phase 1 and Phase 2 components in subjects with advanced solid tumors with HER2 or HER3 overexpression, amplification, or mutation who have progressed despite standard therapy or for which no standard therapy exists, particularly urothelial cancer, biliary tract cancer, metastatic breast cancer, non-small cell lung cancer and colorectal cancer.

Official Title
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A Phase 1/2, Open Label, Multicenter Study to Investigate the Safety, Pharmacokinetics, and Efficacy of TAS0728, an Oral Covalent Binding Inhibitor of HER2, in Subjects With Advanced Solid Tumors With HER2 or HER3 Abnormalities

Conditions
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Advanced Solid Tumors With HER2 Abnormalities, Advanced Solid Tumors With HER3 Abnormalities

Intervention / Treatment
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* Drug: TAS0728


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or females with an age ≥ 18 years. Subjects with histological- or cytological-confirmed, advanced cancer, who have progressed on (or not been able to tolerate) standard therapy or for whom no standard anticancer therapy exists For Phase 1, only subjects HER2 or HER3 molecular/genetic alterations will be enrolled. For Phase 2a, subjects with one of the following tumor types will be enrolled: i. Urothelial cancer with HER2 or HER3 mutation ii. Biliary tract cancer with HER2 or HER3 mutation iii. Breast cancer with HER2 or HER3 mutation iv. Breast cancer with HER2 amplification or overexpression v. NSCLC with HER2 or HER3 mutation vi. CRC with HER2 mutation or amplification vii. Other tumors with HER2 mutation/amplification/overexpression or HER3 mutation (gastric/GEJ, endometrial). At least 1 measurable lesion for solid tumor Is able to take medications orally (e.g., no feeding tube). Able to agree to and sign informed consent and to comply with the protocol Has adequate organ function Exclusion Criteria: Has a serious illness or medical condition(s) Has received treatment with any proscribed treatments within specified time frames prior to study drug administration Impaired cardiac function or clinically significant cardiac disease

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: In Phase 1, TAS0728 will be evaluated for safety and tolerability, and in phase 2 will be evaluated preliminary efficacy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAS0728<br>Group 1: Urothelial cancer with HER2 or HER3 mutation Group 2: Biliary tract cancer with HER2 or HER3 mutation Group 3: Breast cancer with HER2 or HER3 mutation Group 4: Breast cancer with HER2 amplification or overexpression as per American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) 2013 guidelines Group 5: Non-small cell lung cancer (NSCLC) with HER2 or HER3 mutation Group 6: Colorectal cancer (CRC) with HER2 mutation or amplification Group 7: Other tumors with HER2 or HER3 mutation, amplification, or overexpression (eg, gastric or gastroesophageal junction (GEJ), endometrial) | Drug: TAS0728<br>* TAS0728 is an oral HER2 covalent inhibitor investigated in patients with advanced solid tumor harboring HER2 or HER3 abnormalities. It will be administered orally at a starting dose of 50 mg BID each morning and evening and escalated to the DLT. The MTD will be used for the phase 2 arms of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients experiencing Dose Limiting Toxicity graded according to CTCAE Version 4.03, observed in the Cycle 1 in order to meet the objective of assessment of the MTD of TAS0728. |  | 21-day cycles | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] (Phase 1 and 2) |  | Safety monitoring will begin at the informed consent obtained and continue up to 30 days after the last dose of TAS0728 or until new antitumor therapy, whichever is earlier. | 
| Objective Response Rate using Response Evaluation Criteria in Solid Tumors 1.1 (RECIST) (Phase2) |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) after administration of TAS0728 (Phase 1) |  | 21 days in Cycle 1 | 
| Area under the plasma drug concentration-time curve (AUC) after administration of TAS0728 (Phase 1) |  | 21 days in Cycle 1 | 
| Disease Control Rate using RECIST 1.1 (phase 1 and 2) |  | 3 years | 
| Progression free survival (phase 1 and 2) |  | 3 years | 
| Duration of response (phase 1 and 2) |  | 3 years | 
| Overall survival (phase 1 and 2) |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, solid tumors, pharmacokinetics, pharmacodynamics, MTD, TAS0728, HER2, HER3 mutation, amplification or overexpression, Urothelial cancer with HER2 or HER3 mutation, Biliary tract cancer with HER2 or HER3 mutation, MBC with HER2 amplification or overexpression or HER3 mutation, NSCLC with HER2 or HER3 mutation, CRC with HER2 or HER3 mutation, amplification