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

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors With HER2 Abnormalities; Advanced Solid Tumors With HER3 Abnormalities
• Intervention / Treatment: Drug: TAS0728

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 94800
    • Institut de Cancerologie Gustavo Roussy
• Spain
  • Barcelona, Spain, 8035
    • Hospital Vall d'Hebron
• United Kingdom
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute - UK
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute
  • New York
    • New York, New York, United States, 10029-6504
      • ICAHN School of Medicine at Mount Sinai
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - MD Anderson

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male or females with an age ≥ 18 years.

2. 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

   1. For Phase 1, only subjects HER2 or HER3 molecular/genetic alterations will be enrolled.
   2. 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).

3. At least 1 measurable lesion for solid tumor
4. Is able to take medications orally (e.g., no feeding tube).
5. Able to agree to and sign informed consent and to comply with the protocol
6. Has adequate organ function

Exclusion Criteria:

1. Has a serious illness or medical condition(s)
2. Has received treatment with any proscribed treatments within specified time frames prior to study drug administration
3. Impaired cardiac function or clinically significant cardiac disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TAS0728; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Publications and helpful links

General Publications

• Piha-Paul SA, Azaro A, Arkenau HT, Oh DY, Galsky MD, Pal SK, Hamada K, He Y, Yamamiya I, Benhadji KA, Hollebecque A. A first-in-human phase I study of TAS0728, an oral covalent binding inhibitor of HER2, in patients with advanced solid tumors with HER2 or HER3 aberrations. Invest New Drugs. 2021 Oct;39(5):1324-1334. doi: 10.1007/s10637-021-01104-7. Epub 2021 Mar 27.
• Irie H, Ito K, Fujioka Y, Oguchi K, Fujioka A, Hashimoto A, Ohsawa H, Tanaka K, Funabashi K, Araki H, Kawai Y, Shimamura T, Wadhwa R, Ohkubo S, Matsuo K. TAS0728, A Covalent-binding, HER2-selective Kinase Inhibitor Shows Potent Antitumor Activity in Preclinical Models. Mol Cancer Ther. 2019 Apr;18(4):733-742. doi: 10.1158/1535-7163.MCT-18-1085. Epub 2019 Feb 20.

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2018
• Primary Completion (Actual): June 9, 2022
• Study Completion (Actual): June 9, 2022

Study Registration Dates

• First Submitted: January 19, 2018
• First Submitted That Met QC Criteria: January 19, 2018
• First Posted (Actual): January 25, 2018

Study Record Updates

• Last Update Posted (Actual): September 5, 2024
• Last Update Submitted That Met QC Criteria: August 30, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: HER2; pharmacokinetics; Phase I; solid tumors; pharmacodynamics; MTD; TAS0728; 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
• Additional Relevant MeSH Terms: Neoplasms; Congenital Abnormalities
• Other Study ID Numbers: TO-TAS0728-101; 2017-004415-39 (EudraCT Number)

Drug and device information, study documents

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