Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities (MARGARET)

Phase I/II Study of the Selective RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities

Phase 1 and 2 trial to study the safety, pharmacokinetics, and efficacy of TAS0953/HM06 in patients with advanced solid tumors with RET gene abnormalities. Phase 1 aims to determine the Maximum Tolerated Dose (MTD) and identify the Recommended Phase 2 Dose (RP2D) to be used in phase 2.

Study Overview

• Status: Recruiting
• Conditions: RET-altered Solid Tumors; RET-altered Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: TAS0953/HM06; Drug: TAS0953/HM06

• Study Type: Interventional
• Enrollment (Estimated): 244
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Kazuo Koba; Phone Number: +08 8010113399; Email: k-koba@taiho.co.jp

Study Locations

• Japan
  • Fukuoka, Japan
    • Recruiting
    • National Hospital Organization Kyushu Cancer Center
    • Contact: Masafumi Yamaguchi, MD; Phone Number: +81-92-541-3231; Email: k-koba@taiho.co.jp
  • Kanagawa, Japan
    • Recruiting
    • Kanagawa Cancer Center
    • Contact: Shuji Murakami, MD; Phone Number: +81-45-520-2222; Email: murakami.0260j@kanagawa-pho.jp
  • Okayama, Japan
    • Recruiting
    • Kurashiki Central Hospital
    • Contact: Toshihide Yokoyama, MD; Phone Number: +81-86-422-0210; Email: ty14401@kchnet.or.jp
  • Chiba
    • Kashiwa-shi, Chiba, Japan
      • Recruiting
      • National Cancer Center Hospital East
      • Contact: Kiyotaka Yoh, MD; Phone Number: +81-4-7133-1111; Email: kyoh@east.ncc.go.jp
  • Miyagi
    • Sendai, Miyagi, Japan
      • Recruiting
      • Tohoku University Hospital
      • Contact: Eisaku Miyauchi, MD; Phone Number: +81-22-717-8539; Email: eisaku.miyauchi.b5@tohoku.ac.jp
  • Okayama-ken
    • Okayama, Okayama-ken, Japan
      • Recruiting
      • Okayama University Hospital
      • Contact: Kadoaki Ohashi, MD; Phone Number: +81-86-223-7151; Email: pbto124g@s.okayama-u.ac.jp
  • Osaka
    • Hirakata-shi, Osaka, Japan
      • Recruiting
      • Kansai Medical University Hospital
      • Contact: Takayasu Kurata, MD; Phone Number: +81-72-804-0101; Email: uratat@hirakata.kmu.ac.jp
    • Osaka, Osaka, Japan
      • Recruiting
      • Osaka International Cancer Institute
      • Contact: Kazumi Nishino, MD; Phone Number: +81-6-6945-1181; Email: kazumi.nishino@oici.jp
  • Shizuoka
    • Shizuoka, Shizuoka, Japan
      • Recruiting
      • Shizuoka Cancer Center
      • Contact: Akira Ono, MD; Phone Number: +81-55-989-5222; Email: a.ono@scchr.jp
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Recruiting
      • National Cancer Center Hospital
      • Contact: Yuki Shinno, MD; Phone Number: +81-3-3542-2511; Email: yshinno@ncc.go.jp
    • Koto-ku, Tokyo, Japan, 135-8550
      • Recruiting
      • The Cancer Institute Hospital Of JFCR
      • Contact: Shigehisa Kitano, MD; Phone Number: +81-3-3520-0111; Email: shigehisa.kitano@jfcr.or.jp
• South Korea
  • Seoul, South Korea
    • Recruiting
    • Samsung Medical Center
    • Contact: Jong-Mu Sun, MD; Phone Number: +82-02-3410-6518; Email: tntntn3@gmail.com
• United States
  • California
    • Orange, California, United States, 92868-3298
      • Terminated
      • Chao Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305-5826
      • Terminated
      • Stanford Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Terminated
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Terminated
      • Henry Ford Hospital
    • Grand Rapids, Michigan, United States, 49546
      • Terminated
      • START Midwest - Cancer & Hematology Centers of Western Michigan
  • New York
    • New York, New York, United States, 10065
      • Terminated
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • Terminated
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Terminated
      • The Sarah Cannon Research Institute/Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030-4009
      • Terminated
      • The University of Texas M. D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Ages Eligible for Study:

- Adult patient (The definition of adulthood shall comply with the regulatory requirements of each region)

Inclusion Criteria:

Phase I - Common inclusion criteria for Dose-Escalation / Dose-Expansion:

• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
• Available RET-gene abnormalities determined on tissue biopsy or liquid biopsy. If deemed appropriate by the investigator, determination on a pleural cell block or cell pellet is also acceptable.
• Adequate hematopoietic, hepatic and renal function

Phase I Dose-Escalation - Specific inclusion criteria:

• Advanced solid tumors
• Measurable and/or non-measurable disease as determined by RECIST 1.1
• If patient has brain and/or leptomeningeal metastases, (s)he should be asymptomatic.

Phase I Dose-Expansion - Specific inclusion criteria:

• Patient with RET gene fusion :

  • Cohort 1, 3: locally advanced or metastatic NSCLC patients naïve to RET selective inhibitors and no prior systemic anti-cancer treatment. Patients who have been treated with neo-adjuvant or adjuvant chemotherapy may be included if it has been completed at least 6 months prior to the first dose of the study.
  • Cohort 2, 4: locally advanced or metastatic NSCLC patients with RET gene fusion and prior exposure to RET selective inhibitors.
• Measurable disease as determined by RECIST 1.1

• If patient has brain and/or leptomeningeal metastases,(s)he should have:

  • asymptomatic untreated brain/leptomeningeal metastases off steroids and anticonvulsant for at least 7 days or
  • asymptomatic brain metastases already treated with local therapy and be clinically stable on steroids and anticonvulsant for at least 7 days before study drug administration.

Phase II :

• Available RET-gene abnormalities determined on tissue or liquid biopsy

• Locally advanced or metastatic:

  • NSCLC patients with primary RET gene fusion and prior exposure to RET selective inhibitors;
  • NSCLC patients with RET gene fusion and without prior exposure to RET selective inhibitors
  • patients with advanced solid tumors that harbour RET gene abnormalities (other than NSCLC patients with primary RET gene fusions) and has failed all the available therapeutic options
• Eastern Cooperative Oncology Group (ECOG) performance score of 0-2
• Measurable disease as determined by RECIST 1.1

• If patient has brain and/or leptomeningeal metastases,(s)he should have:

  • asymptomatic untreated brain/leptomeningeal metastases off steroids and anticonvulsant for at least 7 days or
  • asymptomatic brain metastases already treated with local therapy and be clinically stable on steroids and anticonvulsant for at least 7 days before study drug administration.
• Adequate hematopoietic, hepatic and renal function

Exclusion Criteria:

Common exclusion criteria for Phase 1 and Phase 2

• Investigational agents or anticancer therapy within 5 half-lives prior to the first dose of study drug
• Major surgery (excluding placement of vascular access) within 4 weeks prior to the first dose of study drug or planned major surgery during the course of study treatment.
• Whole Brain Radiotherapy within 14 days or other palliative radiotherapy within 7 days prior to the first dose of study drug, or persisting side effects of such therapy, in the opinion of the Investigator.
• Clinically significant, uncontrolled, cardiovascular disease including myocardial infarction within 3 months prior to Day 1 of Cycle 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart Failure (CHF) New York Heart Association (NYHA) class III-IV, and severe uncontrolled arterial hypertension, according to the Investigator's opinion.
• QT interval corrected using Fridericia's formula (QTcF) >470 msec; personal or family history of prolonged QT syndrome or history of Torsades de pointes (TdP). History of risk factors for TdP
• Treatment with strong CYP3A4 inhibitors within 1 week prior to the first dose of study drug or strong CYP3A4 inducers within 3 weeks prior to the first dose of study drug.

Phase I Dose-Expansion - and Phase II specific exclusion criteria:

• Presence of known EGFR, KRAS, ALK, HER2, ROS1, BRAF and METex14 activating mutations.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAS0953/HM06 Phase 1; Dose escalation and dose expansion until recommended Phase 2 dose determined	Drug: TAS0953/HM06; Phase 1: oral, starting dose 20mg twice a day, until recommended phase 2 dose, continuous daily dosing, cycles lasting 21 days; Drug: TAS0953/HM06; Phase 2: oral, recommended dose twice a day, continuous daily dosing, cycles lasting 21 days
Experimental: TAS0953/HM06 Phase 2; Treatment phase at recommended Phase 2 dose in three different populations	Drug: TAS0953/HM06; Phase 1: oral, starting dose 20mg twice a day, until recommended phase 2 dose, continuous daily dosing, cycles lasting 21 days; Drug: TAS0953/HM06; Phase 2: oral, recommended dose twice a day, continuous daily dosing, cycles lasting 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 (dose-escalation): Maximum Tolerated Dose (MTD)	Incidence rate and category of dose limiting toxicities (DLTs)	At the end of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-expansion): Recommended Phase 2 dose (RP2D)		At the end of Cycle 1 (each cycle is 21 days), and at the end of every subsequent cycle (each cycle is 21 days) for approximately 10 months (or earlier if patient discontinues the study)
Phase 2: Objective Response Rate (ORR) by independent central review	Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by independent central review	Approximately every 6 weeks for 6 months, then every 9 weeks during treatment, 7 days after the last dose, and every 3 months after the last dose (up to an average of 2 years) in patients without progressive disease.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: ORR by Investigator	Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by Investigator	Approximately every 6 weeks for 6 months, then every 9 weeks during treatment, 7 days after the last dose, and every 3 months after the last dose (up to an average of 2 years) in patients without progressive disease
Phase 2: Disease Control Rate (DCR)	Proportion of patients with confirmed complete response (CR), partial response (PR) and Stable Disease according to RECIST 1.1 as assessed by Investigator	Approximately every 6 weeks for 6 months, then every 9 weeks during treatment, 7 days after the last dose, and every 3 months after the last dose (up to an average of 2 years) in patients without progressive disease
Phase 2: Time to Tumor Response (TTR)	Time from first dose to first documentation of objective tumor response (CR or PR)	From date of randomization until the date of first documentation of objective tumor response, assessed up to an average of 2 years.
Phase 2: Progression Free Survival (PFS)	Time from first dose to first documentation of objective disease progression or to death due to any cause, whichever occurs first	From date of randomization until the date of first documented progression or death due to any cause, whichever occurs first, assessed up to an average of 2 years.
Phase 2: Time to Progression (TTP)	Time from first dose to objective tumor progression	From date of randomization until the date of first documented progression, assessed up to an average of 2 years
Phase 2: Duration of Response (DOR)	Time from first documentation of tumor response (CR + PR) to disease progression or death due any cause whichever occurs first	From first documentation of objective tumor response (CR or PR) until the date of first documented progression or death due to any causes, whichever occurs first, assessed up to an average of 2 years
Phase 2: Overall Survival (OS)	Time from first dose to date of death due to any cause	From date of randomization until the date of death due to any cause, assessed up to an average of 2 years
Phase 2: Central Nervous System (CNS) ORR (C-ORR)	Rate of confirmed CR and PR relative to patients with brain lesions at study entry	Approximately every 6 weeks for 6 months, then every 9 weeks during treatment, 7 days after the last dose, and every 3 months after the last dose (up to an average of 2 years) in patients without progressive disease
Phase 2: Central Nervous System DOR (C-DOR)	Time from documentation of intracranial tumor response to disease progression or death due to any cause whichever occurs first	From first documentation of objective tumor response (CR or PR) until the date of first documented progression or death due to any causes, whichever occurs first, assessed up to an average of 2 years
Phase 2: Time to CNS progression	Time from the first dose to the first radiological evidence of CNS disease progression	From date of randomization until the date of first documented progression, assessed up to an average of 2 years
Phase 1 (dose-escalation): Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12)		Day -1 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): AUC0-24		Day -1 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): AUC0-infinity		Day -1 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): AUC0-12 at steady state		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Maximum drug concentration (Cmax)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Trough drug concentration at 12 hours (Ctrough)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Time to maximum plasma concentration (tmax)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Terminal half-life (t1/2)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Accumulation factor based on Cmax (Rmax)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Accumulation factor based on Ctrough (Rmin)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Terminal rate constant (lambda_z)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Volume of Distribution (Vz/F)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Systemic clearance (CL/F)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Amount excreted in 0-24 hour urine (Ae0-24)		Day -1 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-escalation): Renal Clearance (CL_R)		Day -1 of Cycle 1 (each cycle is 21 days)
Phase 2 Population PK: Typical value of absorption rate constant (Ka)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 2 Population PK: Typical value of CL/F		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 2 Population PK: Typical value of volume of distribution (V/F)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1: Incidence of abnormal electrocardiograms (ECG QT interval). QT will be corrected for heart rate (QTc) using Fridericia's formula (QTcF).		On Day 1, Day 8 (only in dose escalation), Day 15 in cycle 1, Day 1 of any subsequent cycles (each cycle is 21 days) during treatment, for approximately 10 months (or earlier if the patient discontinues from the study), and 7 days after last dose
Phase 1: Incidence of treatment-emergent adverse events (TEAEs)		From the time of informed consent, for approximately 10 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose)
Phase 1: Incidence of serious adverse events (SAEs)		From the time of informed consent, for approximately 10 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose)
Phase 2: Incidence of abnormal electrocardiograms (ECG QT interval). QT will be corrected for heart rate (QTc) using Fridericia's formula (QTcF).		On Day 1 and Day 15 in cycle 1, Day 1 of any subsequent cycles (each cycle is 21 days) during treatment, for approximately 2 years (or earlier if the patient discontinues from the study), and 7 days after last dose
Phase 2: Incidence of treatment-emergent adverse events (TEAEs)		From the time of informed consent for approximately 2 years (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose)
Phase 2: Incidence of serious adverse events (SAEs)		From the time of informed consent for approximately 2 years (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose)
Phase 1 (dose expansion): Objective Response Rate (ORR) by independent central review	Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by independent central review	Approximately every 6 weeks for 6 months, then every 9 weeks during treatment, 7 days after the last dose, and every 3 months after the last dose (up to an average of 2 years) in patients without progressive disease
Phase 1 (dose-expansion): AUC0-12 at steady state		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-expansion): Maximum drug concentration (Cmax)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-expansion): Terminal rate constant (lambda_z)		Day 15 of Cycle 1 (each cycle is 21 days)
Phase 1 (dose-expansion): Terminal half-life (t1/2)		Day 15 of Cycle 1 (each cycle is 21 days)

Collaborators and Investigators

• Sponsor: Taiho Pharmaceutical Co., Ltd.
• Collaborators: Linical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2020
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: December 4, 2020
• First Submitted That Met QC Criteria: December 23, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 28, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Congenital Abnormalities; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: HM06-19-26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No