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

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

Detailed Description
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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 colorectal cancer, gastric cancer, non-small cell lung cancer, human epidermal growth factor receptor 2 (HER2) negative breast cancer, squamous cell carcinoma of the head and neck, urothelial cancer, or select gynecologic cancers (ovarian cancer, cervical 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.

Official Title
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A Study to Evaluate the Safety and Tolerability of the Covalent Phosphoinositide-3-Kinase (PI3K)-Alpha Inhibitor, TOS-358, in Adult Subjects With Select Solid Tumors

Conditions
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Colorectal Cancer, Gastric Cancer, HER2-negative Breast Cancer, Non-small Cell Lung Cancer, Squamous Cell Carcinoma of Head and Neck, Urothelial Carcinoma, Cervical Cancer, Ovarian Cancer, Endometrial Cancer

Intervention / Treatment
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* Drug: TOS-358


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Locally advanced, recurrent, or metastatic, incurable (any number of previous lines of therapy is allowed), histologically or cytologically confirmed: colorectal cancer; gastric cancer; non-small cell lung cancer; HER2- breast cancer; squamous cell carcinoma of the head and neck; urothelial cancer; or select gynecologic cancer (ovarian cancer, cervical 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) < 5.7% 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 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 Body mass index (BMI) ≥ 30 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.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: TOS-358 Single Agent Arm: Part 1(multiple ascending doses, QD or BID): locally advanced, recurrent or metastatic select solid tumors with PIK3CA mutation per local assessment; Part 2 (RP2D determined in Part 1) Patients with locally advanced, recurrent or metastatic select solid tumors with PIK3CA mutation per local assessment will be enrolled protocol defined groups
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TOS-358 Single Agent Arm<br>Multiple doses of TOS-358 for oral administration. | Drug: TOS-358<br>* Covalent Phosphoinositide-3-Kinase (PI3K)-alpha Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the rate of dose-limiting toxicities (DLTs) |  | First 21 days of treatment | 
| Incidence and severity of adverse events (AEs) and specific laboratory abnormalities graded according to NCI CTCAE v5 |  | Start of treatment to 30 days after last dose |