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

• ClinicalTrials.gov Identifier: NCT04683250
• Recruitment Status: Recruiting
• First Posted: December 24, 2020
• Last Update Posted: March 3, 2023
• Sponsor: Helsinn Healthcare SA
• Collaborator: ICON Clinical Research
• Information provided by (Responsible Party): Helsinn Healthcare SA

Tracking Information

• First Submitted Date: December 4, 2020
• First Posted Date: December 24, 2020
• Last Update Posted Date: March 3, 2023
• Actual Study Start Date: December 16, 2020
• Estimated Primary Completion Date: March 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 23, 2020)

• Phase 1 (dose-escalation): Maximum Tolerated Dose (MTD) [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
  Incidence rate and category of dose limiting toxicities (DLTs)
• Phase 1 (dose-expansion): Recommended Phase 2 dose (RP2D) [ Time Frame: 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 data monitoring committee (IDMC) [ Time Frame: 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. ]
  Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by IDMC

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 23, 2020)

• Phase 1 (dose expansion): Objective Response Rate (ORR) by IDMC [ Time Frame: 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 ]
  Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by IDMC
• Phase 2: ORR by Investigator [ Time Frame: 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 ]
  Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by Investigator
• Phase 2: Disease Control Rate (DCR) [ Time Frame: 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 ]
  Proportion of patients with confirmed complete response (CR), partial response (PR) and Stable Disease according to RECIST 1.1 as assessed by Investigator
• Phase 2: Time to Tumor Response (TTR) [ Time Frame: From date of randomization until the date of first documentation of objective tumor response, assessed up to an average of 2 years. ]
  Time from first dose to first documentation of objective tumor response (CR or PR)
• Phase 2: Progression Free Survival (PFS) [ Time Frame: 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. ]
  Time from first dose to first documentation of objective disease progression or to death due to any cause, whichever occurs first
• Phase 2: Time to Progression (TTP) [ Time Frame: From date of randomization until the date of first documented progression, assessed up to an average of 2 years ]
  Time from first dose to objective tumor progression
• Phase 2: Duration of Response (DOR) [ Time Frame: 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 ]
  Time from first documentation of tumor response (CR + PR) to disease progression or death due any cause whichever occurs first
• Phase 2: Overall Survival (OS) [ Time Frame: From date of randomization until the date of death due to any cause, assessed up to an average of 2 years ]
  Time from first dose to date of death due to any cause
• Phase 2: Central Nervous System (CNS) ORR (C-ORR) [ Time Frame: 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 ]
  Rate of confirmed CR and PR relative to patients with brain lesions at study entry
• Phase 2: Central Nervous System DOR (C-DOR) [ Time Frame: 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 ]
  Time from documentation of intracranial tumor response to disease progression or death due to any cause whichever occurs first
• Phase 2: Time to CNS progression [ Time Frame: From date of randomization until the date of first documented progression, assessed up to an average of 2 years ]
  Time from the first dose to the first radiological evidence of CNS disease progression
• Phase 1 (dose-escalation): Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) [ Time Frame: Day -1 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): AUC0-24 [ Time Frame: Day -1 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): AUC0-infinity [ Time Frame: Day -1 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): AUC0-12 at steady state [ Time Frame: Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Maximum drug concentration (Cmax) [ Time Frame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Trough drug concentration at 12 hours (Ctrough) [ Time Frame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Time to maximum plasma concentration (tmax) [ Time Frame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Terminal half-life (t1/2) [ Time Frame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Accumulation factor based on Cmax (Rmax) [ Time Frame: Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Accumulation factor based on Ctrough (Rmin) [ Time Frame: Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Terminal rate constant (lambda_z) [ Time Frame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Volume of Distribution (Vz/F) [ Time Frame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Systemic clearance (CL/F) [ Time Frame: 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) [ Time Frame: Day -1 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-escalation): Renal Clearance (CL_R) [ Time Frame: Day -1 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-expansion): AUC0-12 at steady state [ Time Frame: Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-expansion): Maximum drug concentration (Cmax) [ Time Frame: Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough) [ Time Frame: Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax) [ Time Frame: Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-expansion): Terminal rate constant (lambda_z) [ Time Frame: Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 1 (dose-expansion): Terminal half-life (t1/2) [ Time Frame: Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 2 Population PK: Typical value of absorption rate constant (Ka) [ Time Frame: Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 2 Population PK: Typical value of CL/F [ Time Frame: Day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase 2 Population PK: Typical value of volume of distribution (V/F) [ Time Frame: 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). [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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). [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities
• Official Title: Phase I/II Study of the Selective RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

Dose escalation phase followed by a dose expansion phase (Phase 1), then followed by a Phase 2 at the recommended dose

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• RET-altered Non Small Cell Lung Cancer
• RET-altered Solid Tumors

Intervention

• 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

Study Arms

• Experimental: TAS0953/HM06 Phase 1
  Dose escalation and dose expansion until recommended Phase 2 dose determined
  Intervention: Drug: TAS0953/HM06
• Experimental: TAS0953/HM06 Phase 2
  Treatment phase at recommended Phase 2 dose in three different populations
  Intervention: Drug: TAS0953/HM06

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 23, 2020): 202
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2025
• Estimated Primary Completion Date: March 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 or liquid biopsy
• Documented progression of disease following existing therapies deemed by the Investigator to have demonstrated clinical benefit or unable to receive such therapies.
• 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:

• Locally advanced or metastatic non small cell lung cancer (NSCLC) patients with primary 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Michael Karl; +49 8709 943 761; Michael.Karl@iconplc.com

• Listed Location Countries: Japan, United States

Administrative Information

• NCT Number: NCT04683250
• Other Study ID Numbers: HM06-19-26
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Helsinn Healthcare SA
• Original Responsible Party: Same as current
• Current Study Sponsor: Helsinn Healthcare SA
• Original Study Sponsor: Same as current
• Collaborators: ICON Clinical Research
• Investigators: Not Provided
• PRS Account: Helsinn Healthcare SA
• Verification Date: March 2023