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

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.

Interventions

• 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

Primary outcome measures

• Phase 1 (dose-escalation): Maximum Tolerated Dose (MTD) [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 [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 outcome measures (12)

• Phase 1 (dose expansion): Objective Response Rate (ORR) 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]
• 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]
• 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]
• 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.]
• 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.]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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)]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Japan · 11 centers

• National Cancer Center Hospital East — Kashiwa-shi
• Tohoku University Hospital — Sendai
• Okayama University Hospital — Okayama
• Kansai Medical University Hospital — Hirakata-shi
• Osaka International Cancer Institute — Osaka
• Shizuoka Cancer Center — Shizuoka
• National Cancer Center Hospital — Chuo-ku
• The Cancer Institute Hospital of JFCR — Koto-ku
• … and 3 more centers

United States · 9 centers

• Chao Family Comprehensive Cancer Center — Orange
• Stanford Cancer Center — Stanford
• Massachusetts General Hospital — Boston
• Henry Ford Hospital — Detroit
• START Midwest - Cancer & Hematology Centers of Western Michigan — Grand Rapids
• Laura and Isaac Perlmutter Cancer Center at NYU Langone Health — New York
• Memorial Sloan Kettering Cancer Center — New York
• The Sarah Cannon Research Institute/Tennessee Oncology — Nashville
• … and 1 more center

South Korea · 1 center

• Samsung Medical Center — Seoul

Identifiers

NCT: NCT04683250 · HM06-19-26

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗