RET-altered Non Small Cell Lung Cancer, RET-altered Solid Tumors
Conditions
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.
Interventions
DRUGTAS0953/HM06
Phase 1: oral, starting dose 20mg twice a day, until recommended phase 2 dose, continuous daily dosing, cycles lasting 21 days
Sponsors
Taiho Pharmaceutical Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation phase followed by a dose expansion phase (Phase 1), then followed by a Phase 2 at the recommended dose
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 (dose-escalation): Maximum Tolerated Dose (MTD) | At the end of Cycle 1 (each cycle is 21 days) | Incidence rate and category of dose limiting toxicities (DLTs) |
| 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 central review | 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. | Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by independent central review |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 (dose expansion): Objective Response Rate (ORR) by independent central review | 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 | 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 | 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 | Proportion of patients with confirmed complete response (CR) and or partial response (PR) according to RECIST 1.1 as assessed by Investigator |
| Phase 2: Disease Control Rate (DCR) | 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 | 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) | From date of randomization until the date of first documentation of objective tumor response, assessed up to an average of 2 years. | Time from first dose to first documentation of objective tumor response (CR or PR) |
| Phase 2: Progression Free Survival (PFS) | 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. | Time from first dose to first documentation of objective disease progression or to death due to any cause, whichever occurs first |
| Phase 2: Time to Progression (TTP) | From date of randomization until the date of first documented progression, assessed up to an average of 2 years | Time from first dose to objective tumor progression |
| Phase 2: Duration of Response (DOR) | 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 | Time from first documentation of tumor response (CR + PR) to disease progression or death due any cause whichever occurs first |
| Phase 2: Overall Survival (OS) | From date of randomization until the date of death due to any cause, assessed up to an average of 2 years | Time from first dose to date of death due to any cause |
| Phase 2: Central Nervous System (CNS) ORR (C-ORR) | 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 | Rate of confirmed CR and PR relative to patients with brain lesions at study entry |
| Phase 2: Central Nervous System DOR (C-DOR) | 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 | 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 | From date of randomization until the date of first documented progression, assessed up to an average of 2 years | Time from the first dose to the first radiological evidence of CNS disease progression |
| 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 15 of Cycle 1 (each cycle is 21 days) | — |
| Phase 1 (dose-expansion): Maximum drug concentration (Cmax) | Day 15 of Cycle 1 (each cycle is 21 days) | — |
| Phase 1 (dose-expansion): Trough drug concentration at 12 hours (Ctrough) | Day 15 of Cycle 1 (each cycle is 21 days) | — |
| Phase 1 (dose-expansion): Time to maximum plasma concentration (tmax) | Day 15 of Cycle 1 (each cycle is 21 days) | — |
| Phase 1 (dose-expansion): Terminal rate constant (lambda_z) | Day 15 of Cycle 1 (each cycle is 21 days) | — |
| Phase 1 (dose-expansion): Terminal half-life (t1/2) | 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) | — |
Countries
Australia, Japan, South Korea, United States
Contacts
CONTACTKazuo Koba
Outcome results
None listed