Clinical trial NCT05683418: A Study to Evaluate the Safety and Tolerability of TOS-358 in Adults With Select Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Squamous Cell Carcinoma of Head and Neck
Urothelial Carcinoma
Endometrial Cancer
HR+/HER2-negative Breast Cancer
Lead sponsor: Totus Medicines
Sponsor class: INDUSTRY
First posted: 2023-01-13
Enrollment: 241
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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
Primary purpose: TREATMENT

Brief summary: 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?

Detailed description: 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.

Primary outcomes:
measure: Determine the rate of dose-limiting toxicities (DLTs)
timeFrame: First 21 days of treatment
measure: Incidence and severity of adverse events (AEs) and specific laboratory abnormalities graded according to NCI CTCAE v5
timeFrame: Start of treatment to 30 days after last dose
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of Southern California, Norris Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Barcelona
country: Spain
facility: NEXT Oncology - Hospital Quironsalud Barcelona - PPDS
city: Barcelona
country: Spain
facility: START Barcelona HM Nou Delfos
city: Barcelona
country: Spain
facility: Instituto de Investigacion Oncologica Vall dHebron (VHIO) - EPON
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: START MADRID Hospital Universitario Fundacion Jimenez Diaz - EDOS
city: Madrid
country: Spain
facility: START MADRID Hospital Universitario HM Sanchinarro - CIOCC
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Pozuelo de Alarcon
country: Spain
facility: NEXT Oncology - Hospital Quironsalud Madrid - PPDS
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
affiliation: Totus Medicines
name: Zelanna Goldberg, MD
role: STUDY_DIRECTOR
References: