Trial: A Study to Evaluate the Safety and Tole…

Trial Details

Sponsor: Totus Medicines (industry)

Phase: 1

Start date: Feb. 15, 2023

Planned enrollment: 241

Trial ID: NCT05683418

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: TOS-358

Overview

TOS-358 is an investigational, first-in-class covalent inhibitor targeting phosphoinositide 3-kinase alpha (PI3Kα), developed by Totus Medicines for the treatment of solid tumors harboring PIK3CA mutations. (prnewswire.com)

Mechanism of Action

TOS-358 binds covalently and irreversibly to the PI3Kα enzyme, leading to sustained inhibition of its activity. This mechanism aims to achieve continuous >95% inhibition of PI3Kα, potentially overcoming limitations associated with reversible inhibitors. (totusmedicines.com)

Clinical Development

The clinical evaluation of TOS-358 is being conducted through the TOS-358-001 study (NCT05683418), a multicenter, open-label trial comprising two parts:

Phase 1a (Dose Escalation): Employs a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). (trial.medpath.com)
Phase 1b (Dose Expansion): Enrolls patients with specific tumor types known to harbor PIK3CA mutations or amplifications to further evaluate safety and preliminary efficacy at the RP2D. (trial.medpath.com)

Efficacy

Preliminary results from the Phase 1 dose-escalation study have demonstrated:

95% target engagement of PI3Kα in patients.
Initial clinical activity, including an unconfirmed complete response.
Several patients remaining progression-free for over six months. (biospace.com)

Safety

At doses as low as 5 mg twice daily, TOS-358 has shown:

No grade 3 or 4 toxicities.
A favorable safety and tolerability profile, with no significant hyperglycemia observed in preclinical models. (biospace.com)

HealthScout AI Analysis

Goal: The trial aims to evaluate the safety, tolerability, and optimal dosing (maximum tolerated dose and recommended phase 2 dose) of TOS-358, a covalent PI3Kα inhibitor, in adults with select advanced solid tumors with PIK3CA mutations or amplifications.

Patients: Eligible patients are adults (≥18 years) with histologically or cytologically confirmed, incurable, locally advanced, recurrent, or metastatic HR+/HER2- breast cancer, squamous cell carcinoma of the head and neck, urothelial cancer, or endometrial cancer with documented PIK3CA mutations or amplifications. Patients must have measurable disease by RECIST 1.1, ECOG performance status 0–1, adequate organ function, no active CNS metastases, and no prior treatment with PI3K, AKT, or mTOR inhibitors (with specific exceptions).

Design: This is a multicenter, open-label, phase 1 trial with a dose-escalation (3+3 design) component followed by a dose-expansion phase in tumor-specific cohorts. The primary purpose is to evaluate safety and establish optimal dosing. There is no randomization.

Treatments: TOS-358 is administered orally, either once or twice daily, as a single agent at various dose levels. TOS-358 is a first-in-class, covalent, and selective PI3Kα inhibitor designed for sustained >95% inhibition of its target. Early phase 1 clinical data demonstrate 95% target engagement, a favorable safety profile (no grade 3/4 toxicities at doses as low as 5 mg BID), and preliminary clinical activity including an unconfirmed complete response and several patients progression-free beyond six months. The agent is not associated with significant hyperglycemia in early studies.

Outcomes: Primary endpoints include the rate of dose-limiting toxicities (DLTs) during the first 21 days and the incidence and severity of adverse events and laboratory abnormalities (graded per NCI CTCAE v5) from the start of treatment to 30 days after the last dose. Secondary endpoints will likely include preliminary efficacy measures in the dose expansion phase, but safety and tolerability are the primary current focus.

Burden on patient: As a phase 1 study, patients can expect a high burden, including frequent clinic visits, safety and laboratory evaluations, ECGs, potentially frequent pharmacokinetic blood draws, and mandatory provision of tumor tissue for central analysis. There may also be additional scans, physical exams, and possible biopsies compared to standard care. Participation may require substantial time commitment and travel to sites conducting the trial.

Eligibility

Show 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.