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

Eligibility Criteria:
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.