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

Study Overview
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Brief Summary
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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.

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

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

Intervention / Treatment
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* Drug: TAS0953/HM06
* Drug: TAS0953/HM06


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAS0953/HM06 Phase 1<br>Dose escalation and dose expansion until recommended Phase 2 dose determined | Drug: TAS0953/HM06<br>* Phase 1: oral, starting dose 20mg twice a day, until recommended phase 2 dose, continuous daily dosing, cycles lasting 21 days<br>|
| Experimental: TAS0953/HM06 Phase 2<br>Treatment phase at recommended Phase 2 dose in three different populations | Drug: TAS0953/HM06<br>* Phase 2: oral, recommended dose twice a day, continuous daily dosing, cycles lasting 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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. | 
| 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. | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| Phase 1 (dose-escalation): AUC0-24 |  | Day -1 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): AUC0-infinity |  | Day -1 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): AUC0-12 at steady state |  | Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Maximum drug concentration (Cmax) |  | Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Trough drug concentration at 12 hours (Ctrough) |  | Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Time to maximum plasma concentration (tmax) |  | Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Terminal half-life (t1/2) |  | Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Accumulation factor based on Cmax (Rmax) |  | Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Accumulation factor based on Ctrough (Rmin) |  | Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Terminal rate constant (lambda_z) |  | Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Volume of Distribution (Vz/F) |  | Day -1 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Systemic clearance (CL/F) |  | 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) |  | Day -1 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-escalation): Renal Clearance (CL_R) |  | Day -1 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-expansion): AUC0-12 at steady state |  | Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-expansion): Maximum drug concentration (Cmax) |  | Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough) |  | Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax) |  | Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-expansion): Terminal rate constant (lambda_z) |  | Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 1 (dose-expansion): Terminal half-life (t1/2) |  | Day 8 and Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 2 Population PK: Typical value of absorption rate constant (Ka) |  | Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 2 Population PK: Typical value of CL/F |  | Day 15 of Cycle 1 (each cycle is 21 days) | 
| Phase 2 Population PK: Typical value of volume of distribution (V/F) |  | 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). |  | 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) |  | 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) |  | 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). |  | 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) |  | 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) |  | 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) |