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

RET-altered Non Small Cell Lung Cancer Clinical Trial

— (MARGARET)  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04683250
• Other study ID #: HM06-19-26
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 16, 2020
• Est. completion date: September 2025

Study information

• Verified date: March 2023
• Source: Helsinn Healthcare SA
• Contact: Michael Karl
• Phone: +49 8709 943 761
• Email: Michael.Karl[@]iconplc.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 202
• Est. completion date: September 2025
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Congenital Abnormalities
• 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
• TAS0953/HM06
Phase 2: oral, recommended dose twice a day, continuous daily dosing, cycles lasting 21 days

Locations

Country	Name	City	State
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	National Cancer Center Hospital East	Kashiwa-shi	Chiba
Japan	The Cancer Institute Hospital of JFCR	Koto-ku	Tokyo
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Henry Ford Hospital	Detroit	Michigan
United States	START Midwest - Cancer & Hematology Centers of Western Michigan	Grand Rapids	Michigan
United States	The University of Texas M. D. Anderson Cancer Center	Houston	Texas
United States	The Sarah Cannon Research Institute/Tennessee Oncology	Nashville	Tennessee
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone Health	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Chao Family Comprehensive Cancer Center	Orange	California
United States	Stanford Cancer Center	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Helsinn Healthcare SA	ICON Clinical Research

Countries where clinical trial is conducted

United States,  Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	Phase 2: Objective Response Rate (ORR) by independent data monitoring committee (IDMC)	Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by IDMC	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	Phase 1 (dose expansion): Objective Response Rate (ORR) by IDMC	Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by IDMC	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	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	Phase 1 (dose-escalation): AUC0-24		Day -1 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): AUC0-infinity		Day -1 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): AUC0-12 at steady state		Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Maximum drug concentration (Cmax)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Trough drug concentration at 12 hours (Ctrough)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Time to maximum plasma concentration (tmax)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Terminal half-life (t1/2)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Accumulation factor based on Cmax (Rmax)		Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Accumulation factor based on Ctrough (Rmin)		Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Terminal rate constant (lambda_z)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Volume of Distribution (Vz/F)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Systemic clearance (CL/F)		Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Amount excreted in 0-24 hour urine (Ae0-24)		Day -1 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-escalation): Renal Clearance (CL_R)		Day -1 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-expansion): AUC0-12 at steady state		Day 8 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-expansion): Maximum drug concentration (Cmax)		Day 8 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough)		Day 8 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax)		Day 8 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-expansion): Terminal rate constant (lambda_z)		Day 8 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 1 (dose-expansion): Terminal half-life (t1/2)		Day 8 and Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 2 Population PK: Typical value of absorption rate constant (Ka)		Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 2 Population PK: Typical value of CL/F		Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	Phase 2 Population PK: Typical value of volume of distribution (V/F)		Day 15 of Cycle 1 (each cycle is 21 days)
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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)