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 orally available, highly selective covalent inhibitor of phosphoinositide 3-kinase alpha (PI3Kα; PIK3CA) in clinical development for solid tumors harboring PIK3CA mutations or amplifications. A first-in-human, multicenter phase 1/1b study (NCT05683418) is ongoing in biomarker-selected solid tumors. Initial dose-escalation data were presented in 2024. (ejcancer.com)

Mechanism of action

Target and modality: TOS-358 forms a covalent bond with PI3Kα (wild-type and mutant), driving deep and durable pathway inhibition of PI3K/AKT/mTOR signaling. In biochemical and cell-based studies, it showed sub–10 nM potency against PI3Kα and sustained target engagement after washout, consistent with covalent binding. (ejcancer.com)
Pharmacodynamic evidence: A target-occupancy assay demonstrated that near-complete (>95%) suppression of PI3Kα is associated with sustained downstream pathway inhibition (pAKT, pS6) across models. (aacrjournals.org)
Preclinical profile: Across numerous PDX/CDX models of PI3Kα‑mutant cancers, TOS‑358 produced superior antitumor activity versus reversible PI3Kα inhibitors and, in animal studies, did not induce marked hyperglycemia at efficacious doses. (aacrjournals.org)

Clinical development

Trial design: The first-in-human study (TOS‑358‑001; NCT05683418) includes phase 1a dose escalation (QD and BID) followed by phase 1b tumor‑specific expansions in PIK3CA‑mutant/amplified cancers (e.g., HR+/HER2– breast, urothelial, endometrial, SCCHN). Objectives include determination of MTD/RP2D, characterization of safety/PK/PD, and preliminary antitumor activity by RECIST 1.1. (aacrjournals.org)

Efficacy

Early signals: In the phase 1a presentation at ESMO Congress 2024 (Abstract 625P; data cutoff April 2024), investigators reported “initial monotherapy clinical activity” across several PIK3CA‑mutant cancer subtypes. Numeric response rates were not provided in the abstract. (oncologypro.esmo.org)

Safety

Tolerability in phase 1a (ESMO 2024): Among 28 treated patients (doses 10–30 mg QD; 5–15 mg BID), adverse events were mostly low‑grade, dose‑dependent, and manageable without dose reduction; the QD MTD was 20 mg, and no MTD was reached with BID dosing at the time of reporting. Target engagement exceeded 90% across dose levels. (oncologypro.esmo.org)

Note: A 2025 company communication stated completion of dose escalation with high target engagement, no grade 3/4 toxicities at low doses, and an unconfirmed complete response; these statements come from a sponsor press release rather than a peer‑reviewed or conference‑vetted dataset. (fox8.com)

HealthScout AI Analysis

Goal: Evaluate safety, tolerability, and determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of the covalent PI3Kα inhibitor TOS-358 given orally once daily or twice daily in adults with select solid tumors harboring PIK3CA alterations.

Patients: Adults (≥18 years) with locally advanced, recurrent, or metastatic, incurable solid tumors including HR+/HER2− breast cancer, squamous cell carcinoma of the head and neck, urothelial cancer, or endometrial cancer. Patients must have measurable disease by RECIST 1.1, ECOG 0–1, adequate organ function, life expectancy ≥3 months, fasting glucose <126 mg/dL and HbA1c <6.5%, and a CAP/CLIA-confirmed PIK3CA mutation or amplification with available tumor tissue for central testing. Key exclusions include prior PI3K/AKT/mTOR inhibitors (except allowed for breast cancer), recent systemic therapy, active CNS metastases, diabetes, significant cardiac disease, and certain recent second malignancies.

Design: Phase 1, multicenter, open-label study with a dose-escalation (3+3) component to define MTD/RP2D on QD and BID schedules, followed by tumor-specific dose-expansion cohorts at the RP2D. Nonrandomized, single-arm allocation.

Treatments: TOS-358 single agent administered orally at multiple dose levels on QD or BID schedules until progression or unacceptable toxicity. TOS-358 is a first-in-class covalent, irreversible inhibitor of PI3Kα designed to achieve sustained >95% target inhibition, potentially overcoming limitations of reversible PI3K inhibitors. Early phase data from dose escalation report high target engagement, initial signals of activity including an unconfirmed complete response, and several patients progression-free beyond six months, with a favorable tolerability profile and no grade 3–4 toxicities observed at lower doses such as 5 mg BID.

Outcomes: Primary endpoints are the rate of dose-limiting toxicities during the first 21 days and the incidence and severity of adverse events and lab abnormalities per NCI CTCAE v5 from treatment start to 30 days post last dose.

Burden on patient: High. As a first-in-human phase 1 dose-escalation study, participants can expect frequent on-site visits, intensive safety monitoring, serial pharmacokinetic blood draws, and protocol-mandated labs to assess metabolic parameters and organ function. Archival or fresh tumor tissue is required, and expansion cohorts may require additional biopsies for correlative studies. Imaging at regular intervals for RECIST assessments and potential travel to specialized centers add logistical demands beyond standard care.

Last updated: Oct 2025

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.