TAS-117 in Patients With Advanced Solid Tumors Harboring Germline PTEN Mutations

A Phase 2 Study of TAS-117 in Patients With Advanced Solid Tumors Harboring Germline PTEN Inactivating Mutations

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of TAS-117 in patients with advanced or metastatic solid tumors (excluding primary brain tumors) harboring germline PTEN inactivating mutations.

Study Overview

• Status: Terminated
• Conditions: Advanced or Metastatic Solid Tumors Irrespective of Gene Alterations; Advanced or Metastatic Solid Tumors With Germline PTEN Inactivating Mutations
• Intervention / Treatment: Drug: TAS-117; Drug: TAS-117; Drug: TAS-117

Detailed Description

Study TAS-117-201 is an open-label, single-arm Phase 2 study evaluating the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of TAS-117 in patients with advanced or metastatic solid tumors harboring germline PTEN inactivating mutations. The study will be conducted in two parts:

• Part A: Safety lead-in (Dose Escalation and Dose Regimen Confirmation)
• Part B: Single-arm Phase 2 study

Patients will receive TAS-117 orally every day or intermittently on a 21-day cycle

• Part A (Dose Escalation): up to 36 adult patients with advanced or metastatic solid tumors (excluding primary brain tumors) irrespective of gene alterations. The Dose Escalation consists of 2 cohorts: Daily Dose Regimen and Intermittent Dose Regimen.
• Part A (Dose Regimen Confirmation): approximately 6 adult or adolescent patients with advanced or metastatic solid tumors (excluding primary brain tumors) harboring germline PTEN inactivating mutations
• Part B (Phase 2): approximately 54 adult or adolescent patients with advanced or metastatic solid tumors (excluding primary brain tumors) harboring germline PTEN inactivating mutations

Treatment will continue until disease progression, unacceptable toxicity, or any other of the criteria for treatment discontinuation is met. For patients who discontinue treatment for reasons other than disease progression, tumor assessments should be continued until radiologic disease progression is documented or until initiation of subsequent new anticancer therapy (whichever occurs first).

Patients will be followed for survival every 12 weeks (±2 weeks) until survival events (deaths) have been reported for 75% of enrolled patients or the study is terminated early by the Sponsor.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna
• France
  • Ile De France
    • Villejuif, Ile De France, France, 98405
      • Institut Gustave Roussy
• United Kingdom
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute
• United States
  • California
    • Santa Monica, California, United States, 90403
      • Sarcoma Oncology Research Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Lerner Research Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

2. Dose Escalation in Part A

   1. ≥18 years of age.
   2. Histologically or cytologically confirmed advanced or metastatic solid tumors
   3. Has progressed after standard treatment for advanced or metastatic disease or was intolerant to or ineligible for available standard therapies.
   4. Patients with solid tumors irrespective of gene alterations.
   5. Patients with at least one measurable or non-measurable lesion per RECIST1.1

3. Dose and Regimen Confirmation in Part A and Phase 2 (Part B)

   1. ≥12 years of age. Patients age ≥12 and <18 years must have a body weight of ≥40 kg.
   2. Histologically confirmed advanced or metastatic solid tumors.
   3. Has progressed after standard treatment for advanced or metastatic disease or was intolerant or ineligible to available standard therapies.
   4. Patients with locally confirmed germline PTEN inactivating mutations determined from a blood sample.
   5. Patients with at least one measurable lesion per RECIST 1.1.

Exclusion Criteria

1. History or current evidence of interstitial lung disease that requires steroid medication.
2. Current evidence of diabetes mellitus that requires insulin therapy.
3. Prior treatment with PI3K/AKT/mTOR pathway inhibitors.
4. Patients with primary brain tumor.
5. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastasis.
6. Currently receiving chronic corticosteroid therapy of ≥10 mg/day of prednisone or its equivalent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAS-117 Dose Escalation Daily Dose Regimen (Part A: safety lead-in); Advanced or metastatic solid tumors irrespective of gene alterations	Drug: TAS-117; TAS-117 will be dosed orally every day on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed intermittently on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed orally every day or intermittently on a 21-day cycle
Experimental: TAS-117 Dose Escalation Intermittent Dose Regimen (Part A: safety lead-in); Advanced or metastatic solid tumors irrespective of gene alterations	Drug: TAS-117; TAS-117 will be dosed orally every day on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed intermittently on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed orally every day or intermittently on a 21-day cycle
Experimental: TAS-117 Dose and Regimen Confirmation (Part A: safety lead-in); Advanced or metastatic solid tumors with germline PTEN inactivating mutations	Drug: TAS-117; TAS-117 will be dosed orally every day on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed intermittently on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed orally every day or intermittently on a 21-day cycle
Experimental: TAS-117 Phase 2 (Part B); Advanced or metastatic solid tumors with germline PTEN inactivating mutations	Drug: TAS-117; TAS-117 will be dosed orally every day on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed intermittently on a 21-day cycle; Drug: TAS-117; TAS-117 will be dosed orally every day or intermittently on a 21-day cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events and dose-limiting toxicities (safety and tolerability) and MTD of TAS-117 in Part A	Number of patients with abnormal laboratory values, treatment emergent AEs, abnormal vital signs and ECG, and Dose-limiting toxicities (DLTs)	21 days for DLT evaluation, approximately 7 months for the others
Recommended Phase 2 Dose (RP2D) of TAS-117 in Part A		21 days for DLT evaluation, approximately 7 months for the others
Objective Response Rate (ORR) in Part B (including all patients with germline PTEN mutations in Part A)	ORR, defined as the proportion of patients experiencing a best overall response of CR or PR per RECIST 1.1.	Approximately 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events (safety) in Part B	Number of patients with abnormal laboratory values, treatment-emergent AEs, abnormal vital signs and ECG	Approximately 7 months
Disease Control Rate (DCR)	DCR, defined as the proportion of patients experiencing a best overall response of stable response (SD), PR, or complete response (CR).	Approximately 6 months
Duration of Response (DOR)	DOR, defined as the time from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.	Approximately 6 months
Progression Free Survival (PFS)	PFS, defined as the time from date of the first dose of study treatment to the date of disease progression based on Investigator assessment of radiographic images or death, whichever occurs first.	Approximately 6 months
Overall Survival (OS)	OS, defined as the time from the date of first dose to the death date.	Approximately 12 months
Pharmacokinetics (PK) profile of TAS-117 in Part A	maximum plasma concentration (Cmax)	21 days
Pharmacokinetics (PK) profile of TAS-117 in Part A	area under the plasma concentration-time curve (AUC)	21 days
Pharmacokinetics (PK) profile of TAS-117 in Part A	time to reach maximum plasma concentration (Tmax)	21 days
Pharmacokinetics (PK) profile of TAS-117 in Part A	terminal elimination half-life (T1/2)	21 days
Pharmacodynamics (PD) profile of TAS-117 in Part A	Evaluate Total and Phosphorylated AKT and PRAS40	21 days

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Publications and helpful links

General Publications

• Rodon J, Funchain P, Laetsch TW, Arkenau HT, Hervieu A, Singer CF, Murciano-Goroff YR, Chawla SP, Anthony K, Yamamiya I, Liu M, Halim AB, Benhadji KA, Takahashi O, Delaloge S. A phase II study of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations. Future Oncol. 2022 Sep;18(30):3377-3387. doi: 10.2217/fon-2022-0305. Epub 2022 Aug 30.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2021
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): March 6, 2023

Study Registration Dates

• First Submitted: February 16, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Metastatic solid tumor; Advanced solid tumor; PTEN; Adult patients; AKT inhibitor; TAS-117; Allosteric inhibitor; Germline PTEN; Inactivating mutation; Adolescent patients
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: TAS-117-201; 2020-004770-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No