Clinical trial NCT04683250: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: RET-altered Non Small Cell Lung Cancer
RET-altered Solid Tumors
Lead sponsor: Taiho Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2020-12-24
Enrollment: 244
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose escalation phase followed by a dose expansion phase (Phase 1), then followed by a Phase 2 at the recommended dose
Primary purpose: TREATMENT

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.


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 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.

Primary outcomes:
measure: Phase 1 (dose-escalation): Maximum Tolerated Dose (MTD)
timeFrame: At the end of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): Recommended Phase 2 dose (RP2D)
timeFrame: 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)
measure: Phase 2: Objective Response Rate (ORR) by independent central review
timeFrame: 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:
measure: Phase 1 (dose expansion): Objective Response Rate (ORR) by independent central review
timeFrame: 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
measure: Phase 2: ORR by Investigator
timeFrame: 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
measure: Phase 2: Disease Control Rate (DCR)
timeFrame: 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
measure: Phase 2: Time to Tumor Response (TTR)
timeFrame: From date of randomization until the date of first documentation of objective tumor response, assessed up to an average of 2 years.
measure: Phase 2: Progression Free Survival (PFS)
timeFrame: 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.
measure: Phase 2: Time to Progression (TTP)
timeFrame: From date of randomization until the date of first documented progression, assessed up to an average of 2 years
measure: Phase 2: Duration of Response (DOR)
timeFrame: 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
measure: Phase 2: Overall Survival (OS)
timeFrame: From date of randomization until the date of death due to any cause, assessed up to an average of 2 years
measure: Phase 2: Central Nervous System (CNS) ORR (C-ORR)
timeFrame: 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
measure: Phase 2: Central Nervous System DOR (C-DOR)
timeFrame: 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
measure: Phase 2: Time to CNS progression
timeFrame: From date of randomization until the date of first documented progression, assessed up to an average of 2 years
measure: Phase 1 (dose-escalation): Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12)
timeFrame: Day -1 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): AUC0-24
timeFrame: Day -1 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): AUC0-infinity
timeFrame: Day -1 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): AUC0-12 at steady state
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Maximum drug concentration (Cmax)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Trough drug concentration at 12 hours (Ctrough)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Time to maximum plasma concentration (tmax)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Terminal half-life (t1/2)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Accumulation factor based on Cmax (Rmax)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Accumulation factor based on Ctrough (Rmin)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Terminal rate constant (lambda_z)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Volume of Distribution (Vz/F)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Systemic clearance (CL/F)
timeFrame: Day -1 and Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Amount excreted in 0-24 hour urine (Ae0-24)
timeFrame: Day -1 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-escalation): Renal Clearance (CL_R)
timeFrame: Day -1 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): AUC0-12 at steady state
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): Maximum drug concentration (Cmax)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): Terminal rate constant (lambda_z)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1 (dose-expansion): Terminal half-life (t1/2)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 2 Population PK: Typical value of absorption rate constant (Ka)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 2 Population PK: Typical value of CL/F
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 2 Population PK: Typical value of volume of distribution (V/F)
timeFrame: Day 15 of Cycle 1 (each cycle is 21 days)
measure: Phase 1: Incidence of abnormal electrocardiograms (ECG QT interval). QT will be corrected for heart rate (QTc) using Fridericia's formula (QTcF).
timeFrame: 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
measure: Phase 1: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: 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)
measure: Phase 1: Incidence of serious adverse events (SAEs)
timeFrame: 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)
measure: Phase 2: Incidence of abnormal electrocardiograms (ECG QT interval). QT will be corrected for heart rate (QTc) using Fridericia's formula (QTcF).
timeFrame: 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
measure: Phase 2: Incidence of treatment-emergent adverse events (TEAEs)
timeFrame: 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)
measure: Phase 2: Incidence of serious adverse events (SAEs)
timeFrame: 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)
Other outcomes:
Locations:
city: Orange
country: United States
facility: Chao Family Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest - Cancer & Hematology Centers of Western Michigan
state: Michigan
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: The Sarah Cannon Research Institute/Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: The University of Texas M. D. Anderson Cancer Center
state: Texas
city: Kashiwa-shi
country: Japan
facility: National Cancer Center Hospital East
state: Chiba
city: Sendai-shi
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Okayama-shi
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Hirakata-shi
country: Japan
facility: Kansai Medical University Hospital
state: Osaka
city: Osaka-shi
country: Japan
facility: Osaka International Cancer Institute
state: Osaka
city: Shunto-gun
country: Japan
facility: Shizuoka Cancer Center
state: Shizuoka
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
Study officials:
References: