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

Secondary

• 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)

• 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)