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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Advanced or Metastatic Solid Tumors Irrespective of Gene Alterations, Advanced or Metastatic Solid Tumors With Germline PTEN Inactivating Mutations

Intervention / Treatment
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* Drug: TAS-117
* Drug: TAS-117
* Drug: TAS-117
* Drug: TAS-117


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Dose Escalation in Part A ≥18 years of age. Histologically or cytologically confirmed advanced or metastatic solid tumors Has progressed after standard treatment for advanced or metastatic disease or was intolerant to or ineligible for available standard therapies. Patients with solid tumors irrespective of gene alterations. Patients with at least one measurable or non-measurable lesion per RECIST1.1 Dose and Regimen Confirmation in Part A and Phase 2 (Part B) ≥12 years of age. Patients age ≥12 and <18 years must have a body weight of ≥40 kg. Histologically confirmed advanced or metastatic solid tumors. Has progressed after standard treatment for advanced or metastatic disease or was intolerant or ineligible to available standard therapies. Patients with locally confirmed germline PTEN inactivating mutations determined from a blood sample. Patients with at least one measurable lesion per RECIST 1.1. Exclusion Criteria History or current evidence of interstitial lung disease that requires steroid medication. Current evidence of diabetes mellitus that requires insulin therapy. Prior treatment with PI3K/AKT/mTOR pathway inhibitors. Patients with primary brain tumor. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastasis. Currently receiving chronic corticosteroid therapy of ≥10 mg/day of prednisone or its equivalent.

Ages Eligible for Study
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Minimum Age: 12 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TAS-117, AKT inhibitor, Allosteric inhibitor, Advanced solid tumor, Metastatic solid tumor, PTEN, Germline PTEN, Inactivating mutation, Adolescent patients, Adult patients