A Study to Evaluate the Safety and Tolerability of TOS-358 in Adults with Select Solid Tumors

The goal of this clinical trial is to evaluate the safety of TOS-358 in adults with select solid tumors who meet study enrollment criteria. The main questions it aims to answer are:

1. what is the maximum tolerated dose and recommended dose for phase 2?
2. how safe and tolerable is TOS-358 at different dose levels when taken orally once or twice per day?

This study will be conducted in two parts: a dose finding portion to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of TOS-358 administered orally on once a day (QD) and twice daily (BID) schedules, and a dose expansion portion to evaluate safety and tolerability in tumor-specific cohorts administered TOS-358 at the recommended phase 2 dose and schedule.

Adult subjects with histologically confirmed diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer, squamous cell carcinoma of the head and neck, urothelial cancer, or endometrial cancer with known PIK3CA mutations or amplifications (as determined at a College of American Pathologists/clinical laboratory improvement amendments \[CAP/CLIA\]-certified or equivalently accredited diagnostic laboratory using a validated test), who meet all of the eligibility criteria will be enrolled in the Phase 1 portion of the study.

In the dose finding portion of the study, TOS-358 will be evaluated as a single-agent at multiple dose levels administered orally until disease progression, unacceptable toxicity, or until meeting any other reason for discontinuation as specified in the protocol.

Eligibility Criteria:
Key Inclusion Criteria

* Locally advanced, recurrent, or metastatic, incurable (any number of previous lines of therapy is allowed), histologically or cytologically confirmed; HR +/HER2- breast cancer; squamous cell carcinoma of the head and neck; urothelial cancer; or endometrial cancer
* Willing and able to provide written informed consent for this study
* Adults ≥ 18 years old at time of consent
* Known PIK3CA mutations or amplifications as determined at a CAP/CLIA-certified or equivalently accredited diagnostic laboratory using a validated test
* Measurable disease by RECIST 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Life expectancy ≥ 3 months, as determined by the investigator
* Adequate bone marrow, liver, and kidney function within 14 days prior to first dose of investigational product
* Fasting plasma glucose \< 126 mg/dL AND hemoglobin A1c (HbA1c) \< 6.5%
* Available archived or fresh tumor tissue sample for detection of PIK3CA mutation by central laboratory test

Key Exclusion Criteria

* Recent systemic anticancer treatment prior to start of treatment (EXCEPTION: Patients with breast cancer who were receiving a fulvestrant-containing regimen at the time of informed consent may remain on fulvestrant while receiving study treatment)
* Prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway, except for patients with breast cancer
* Second malignancy (solid or hematologic) within the past 3 years except: Adequately treated basal cell or squamous cell skin cancer; carcinoma in situ of the cervix, or prostate cancer with Gleason score \< 6 and undetectable prostate specific antigen over 12 months; ductal breast carcinoma in situ with full surgical resection (ie, negative margins); treated medullary or papillary thyroid cancer; metaplastic breast cancer
* History of diabetes of any type
* Cushing syndrome
* Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to the first dose of investigational product
* Known active central nervous system (CNS) metastases.