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

Phase 2RecruitingNCT04683250

Taiho Pharmaceutical Co., Ltd.244 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

244

Conditions

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

Interventions

TAS0953/HM06DRUG

Phase 1: oral, starting dose 20mg twice a day, until recommended phase 2 dose, continuous daily dosing, cycles lasting 21 days

TAS0953/HM06DRUG

Phase 2: oral, recommended dose twice a day, continuous daily dosing, cycles lasting 21 days

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 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.

Locations (17)

Chao Family Comprehensive Cancer Center

Orange, California, United States

TERMINATED

Outcomes

Primary Outcomes

Phase 1 (dose-escalation): Maximum Tolerated Dose (MTD)

Incidence rate and category of dose limiting toxicities (DLTs)

Time frame: At the end of Cycle 1 (each cycle is 21 days)

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 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

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.

Secondary Outcomes

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

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

Central Contacts

Kazuo Koba

CONTACT

+08 8010113399 k-koba@taiho.co.jp

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Stanford Cancer Center

Stanford, California, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

TERMINATED

Henry Ford Hospital

Detroit, Michigan, United States

TERMINATED

START Midwest - Cancer & Hematology Centers of Western Michigan

Grand Rapids, Michigan, United States

TERMINATED

Laura and Isaac Perlmutter Cancer Center at NYU Langone Health

New York, New York, United States

TERMINATED

Memorial Sloan Kettering Cancer Center

New York, New York, United States

TERMINATED

The Sarah Cannon Research Institute/Tennessee Oncology

Nashville, Tennessee, United States

TERMINATED

The University of Texas M. D. Anderson Cancer Center

Houston, Texas, United States

TERMINATED

National Cancer Center Hospital East

Kashiwa-shi, Chiba, Japan

RECRUITING

...and 7 more locations

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

Phase 2: Time to Tumor Response (TTR)

Time from first dose to first documentation of objective tumor response (CR or PR)

Time frame: 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

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.

Phase 2: Time to Progression (TTP)

Time from first dose to objective tumor progression

Time frame: 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

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

Phase 2: Overall Survival (OS)

Time from first dose to date of death due to any cause

Time frame: 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

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

Phase 2: Time to CNS progression

Time from the first dose to the first radiological evidence of CNS disease progression

Time frame: 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)

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 15 of Cycle 1 (each cycle is 21 days)

Phase 1 (dose-expansion): Maximum drug concentration (Cmax)

Time frame: Day 15 of Cycle 1 (each cycle is 21 days)

Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough)

Time frame: Day 15 of Cycle 1 (each cycle is 21 days)

Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax)

Time frame: Day 15 of Cycle 1 (each cycle is 21 days)

Phase 1 (dose-expansion): Terminal rate constant (lambda_z)

Time frame: Day 15 of Cycle 1 (each cycle is 21 days)

Phase 1 (dose-expansion): Terminal half-life (t1/2)

Time frame: 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)