HR+/HER2-negative Breast CancerPhase 1NCT05683418
A Study to Evaluate the Safety and Tolerability of TOS-358 in Women With HR+ HER2- Breast Cancer
A Phase 1 study testing TOS-358, Fulvestrant and Palbociclib in people with HR+/HER2-negative Breast Cancer, run by Totus Medicines at 18 sites in 2 countries.
Trial summary
The goal of this clinical trial is to evaluate the safety and efficacy of TOS-358 in women with HR+ HER2- metastatic breast cancer whose tumors have a mutation in PIK3CA and who meet all other study enrollment criteria. The main questions it aims to answer are: 1. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- HR+/HER2-negative Breast Cancer
- What is being tested?
- TOS-358, Fulvestrant and Palbociclib
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 241 participants
- Where
- 18 sitesin 2 countries
- Study dates
- 15 Feb 2023to Dec 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Locally advanced, recurrent, or metastatic HR +/HER2- breast cancer
- Up to 3 prior lines of therapy for metastatic disease
- 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 or evaluable disease by RECIST 1.1
Show all 11Show fewer
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy ≥ 6 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 <= 140 mg/dL AND hemoglobin A1c (HbA1c) <= 7.0%
- Available archived or fresh tumor tissue sample for detection of PIK3CA mutation by central laboratory test
Who cannot join
- Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2
- Known active central nervous system (CNS) metastases
- PTEN mutations
Trial locations and contacts
18 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
18 sites in 2 countries
United States9 sites, 9 recruiting
- Recruiting
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Victoria Weden, 617-975-7489, vweden@bidmc.harvard.edu
Gary Barahona, gbaraho1@bidmc.harvard.edu
- Recruiting
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Abigail Goldberg, abigail_goldberg@dfci.harvard.edu
Antonio Giordano, MD, PhD
- Recruiting
Northwestern Memorial Hospital
Chicago, Illinois, 60611
Essence Baymon, 312-695-9361, essence.baymon@northwestern.edu
Stella Estrella, (312) 695-1102, stella.estrella@northwestern.edu
- Recruiting
Virginia Cancer Specialists
Fairfax, Virginia, 22031
Alexander Spira, MD, 703-636-1473, alexander.spira@usoncology.com
Lilliana Payne, (703) 208-9396, Lilliana.Payne@usoncology.com
- Recruiting
Texas Oncology - Flower Mound
Flower Mound, Texas, 75028
Sarah Coates, (972) 537-4100, sarah.coates@usoncology.com
Vibha T Thomas, MD
- Recruiting
Comprehensive Cancer Centers of Nevada
Las Vegas, Nevada, 89169
AnaArlene Ramirez, RN, OCN, 702-952-3406, anaarlene.ramirez@usoncology.com
Eidan Gutierrez, Eidan.Gutierrez@usoncology.com
- Recruiting
Sarah Cannon Cancer Center
Nashville, Tennessee, 37203
Ethan Trull, (615) 828 - 7996, ethan.trull@scri.com
Tim Duff, (615) 329-7274, tim.duff@scri.com
- Recruiting
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
Jordan Berlin, MD, 1-800-811-8480, CIP@VUMC.ORG
Jordan Berlin, MD
- Recruiting
University of Pennsylvania
Philadelphia, Pennsylvania, 19106
Anais Iturralde, BSN, 215-829-6292, Anais.Iturralde@Pennmedicine.upenn.edu
Study Coordinator, PAhemoncResearch@uphs.upenn.edu
Spain9 sites, 9 recruiting
- Recruiting
NEXT Oncology - Hospital Quironsalud Barcelona - PPDS
Barcelona, 08023
Fabricio Racca, M.D., 34932746100, fracca@nextoncology.eu
Fabricio Racca, M.D.
- Recruiting
START Barcelona HM Nou Delfos
Barcelona, 08023
Tatiana Hernandez Guerrero, M.D., Ph.D., 34915504800, tatiana.hernandez@start-barcelona.com
Tatiana Hernandez Guerrero, M.D., Ph.D.
- Recruiting
Instituto de Investigacion Oncologica Vall dHebron (VHIO) - EPON
Barcelona, 08035
Guzmán Alonso Casal, M.D., 34932381661, galonso@nextoncology.eu
Guzmán Alonso Casal, M.D.
- Recruiting
Hospital Clinico San Carlos
Madrid, 28040
Jorge Bartolome Arcilla, M.D., 34913303649, jorge.bartolome@salud.madrid.org
Jorge Bartolome Arcilla, M.D.
- Recruiting
START MADRID Hospital Universitario Fundacion Jimenez Diaz - EDOS
Madrid, 28050
Bernard Doger, M.D., Ph.D., 34915504800, bernard.doger@startmadrid.com
Bernard Doger, M.D, Ph.D.
- Recruiting
START MADRID Hospital Universitario HM Sanchinarro - CIOCC
Madrid, 28050
Irene Moreno, M.D., 34917567825, irene.moreno@startmadrid.com
Irene Moreno, M.D.
- Recruiting
Clinica Universidad de Navarra
Pamplona, 31008
Jose Maria Lopez Picazo, M.D., 34948255400, jlpicazo@unav.es
Jose Maria Lopez Picazo, M.D.
- Recruiting
NEXT Oncology - Hospital Quironsalud Madrid - PPDS
Pozuelo de Alarcón, 28223
Valentina Boni, M.D., 34914521900, vboni@nextoncology.eu
Valentina Boni, M.D.
- Recruiting
Hospital Clinico Universitario de Valencia
Valencia, 46010
Valentina Gambardella, M.D., Ph.D., 34961973528, vgambardella@incliva.es
Valentina Gambardella, M.D., Ph.D.
About this study
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
The goal of this clinical trial is to evaluate the safety and efficacy of TOS-358 in women with HR+ HER2- metastatic breast cancer whose tumors have a mutation in PIK3CA and who meet all other study enrollment criteria. The main questions it aims to answer are:
- Phase 1a: what is the maximum tolerated dose and recommended dose for phase 2?
- Phase 1a: how safe and tolerable is TOS-358 at different dose levels when taken orally once or twice per day?
- Phase 1b: how safe and effective is TOS-358 when given with standard of care medicines for HR+HER2- metastatic breast cancer (fulvestrant and CDK4/6i)
Read the 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.
Women with histologically confirmed diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer with known PIK3CA mutations or amplifications and who meet all of the eligibility criteria will be enrolled in 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. In the Phase 1b portion, TOS-358 will be combined with fulvestrant +/- CDK4/6i.
- Conditions
- HR+/HER2-negative Breast Cancer
- Being tested
- TOS-358, Fulvestrant, Palbociclib, Ribociclib
- Keywords
- PI3K-alpha, breast cancer, metastatic breast cancer, PIK3CA, hormone receptor positive breast cancer
- Medical subject headings
- Hereditary Sensory and Autonomic Neuropathies, Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TOS-358Drug
Covalent Phosphoinositide-3-Kinase (PI3K)-alpha Inhibitor
FulvestrantDrug
Intramuscular SERD at standard doses
PalbociclibDrug
CDK4/6 inhibitor at standard doses
RibociclibDrug
CDK4/6 inhibitor at standard doses
| Study group | Role | What they receive |
|---|---|---|
| TOS-358 + fulvestrant | Experimental | TOS-358 + fulvestrant at standard dosing Receives: Drug: TOS-358; Drug: Fulvestrant |
| TOS-358 + fulvestrant + CDK4/6i | Experimental | TOS-358 + fulvestrant + CDK4/6i Receives: Drug: TOS-358; Drug: Fulvestrant; Drug: Palbociclib; Drug: Ribociclib |
| TOS-358 | Experimental | PIK3CA covalent inhibitor Receives: Drug: TOS-358 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determine the rate of dose-limiting toxicities (DLTs)
Measured: First 21 days of treatment
Incidence and severity of adverse events (AEs) and specific laboratory abnormalities graded according to NCI CTCAE v5
Measured: Start of treatment to 30 days after last dose
Secondary outcomes (1)
ORR and duration of tumor control
Measures of efficacy of TOS-358 monotherapy and in combination with standard of care treatment in early line metastatic HR+HER2- breast cancer
Measured: Up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jan 2023
- Study start15 Feb 2023
- Primary completionDec 2027 (estimated)
- Study completionDec 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HR+/HER2-negative Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- TOS-358 Single Agent Arm: Part 1 (multiple ascending doses, QD or BID): locally advanced, recurrent or metastatic HR+ breast, endometrial, urothelial or squamous cell carcinoma of the head and neck, with PIK3CA mutation per local assessment; Part 2 Patients with locally advanced, recurrent or metastatic HR+ HER2- breast cancer with PIK3CA mutation per local assessment will be enrolled in protocol defined groups in combination with fulvestrant +/- CDK4/6i.
- Masking
- None (open label)
- Enrolment
- 241 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Totus Medicines
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Zelanna Goldberg, MD, Study director, Totus Medicines
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05683418
- Sponsor's protocol ID
- TOS-358-001
- Other IDs
- 2023-505346-26-01, 2023
- Status last verified
- Apr 2026
- First submitted
- 12 Nov 2022
- Last updated
- 22 Apr 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05683418
- Acronym / sponsor ID
- TOS-358-001
- Conditions
- HR+/HER2-negative Breast Cancer
- Keywords
- PI3K-alpha, breast cancer, metastatic breast cancer, PIK3CA, hormone receptor positive breast cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 241 participants (estimated)
- Lead sponsor
- Totus MedicinesIndustry (pharma, biotech, devices)
- Study start
- 15 Feb 2023 (actual)
- Primary completion
- Dec 2027 (estimated)
- Study completion
- Dec 2027 (estimated)
- First posted
- 13 Jan 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to evaluate the safety and efficacy of TOS-358 in women with HR+ HER2- metastatic breast cancer whose tumors have a mutation in PIK3CA and who meet all other study enrollment criteria. The main questions it aims to answer are:
- Phase 1a: what is the maximum tolerated dose and recommended dose for phase 2?
- Phase 1a: how safe and tolerable is TOS-358 at different dose levels when taken orally once or twice per day?
- Phase 1b: how safe and effective is TOS-358 when given with standard of care medicines for HR+HER2- metastatic breast cancer (fulvestrant and CDK4/6i)
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.
Women with histologically confirmed diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer with known PIK3CA mutations or amplifications and who meet all of the eligibility criteria will be enrolled in 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. In the Phase 1b portion, TOS-358 will be combined with fulvestrant +/- CDK4/6i.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- TOS-358 Single Agent Arm: Part 1 (multiple ascending doses, QD or BID): locally advanced, recurrent or metastatic HR+ breast, endometrial, urothelial or squamous cell carcinoma of the head and neck, with PIK3CA mutation per local assessment; Part 2 Patients with locally advanced, recurrent or metastatic HR+ HER2- breast cancer with PIK3CA mutation per local assessment will be enrolled in protocol defined groups in combination with fulvestrant +/- CDK4/6i.
| Arm | Type | Receives |
|---|---|---|
| TOS-358 + fulvestrant | Experimental | Drug: TOS-358, Drug: FulvestrantTOS-358 + fulvestrant at standard dosing |
| TOS-358 + fulvestrant + CDK4/6i | Experimental | Drug: TOS-358, Drug: Fulvestrant, Drug: Palbociclib, Drug: RibociclibTOS-358 + fulvestrant + CDK4/6i |
| TOS-358 | Experimental | Drug: TOS-358PIK3CA covalent inhibitor |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Locally advanced, recurrent, or metastatic HR +/HER2- breast cancer
- Up to 3 prior lines of therapy for metastatic disease
- 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
Key exclusion criteria (3 listed)
- Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2
- Known active central nervous system (CNS) metastases
- PTEN mutations
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TOS-358Covalent Phosphoinositide-3-Kinase (PI3K)-alpha Inhibitor | Drug | TOS-358, TOS-358 + fulvestrant, TOS-358 + fulvestrant + CDK4/6i |
| FulvestrantIntramuscular SERD at standard doses | Drug | TOS-358 + fulvestrant, TOS-358 + fulvestrant + CDK4/6i |
| PalbociclibCDK4/6 inhibitor at standard doses | Drug | TOS-358 + fulvestrant + CDK4/6i |
| RibociclibCDK4/6 inhibitor at standard doses | Drug | TOS-358 + fulvestrant + CDK4/6i |
Primary outcome
Determine the rate of dose-limiting toxicities (DLTs)
Time frame: First 21 days of treatment
Incidence and severity of adverse events (AEs) and specific laboratory abnormalities graded according to NCI CTCAE v5
Time frame: Start of treatment to 30 days after last dose
1 secondary outcome
ORR and duration of tumor control
Time frame: Up to 24 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2026.
- Individual participant dataSharing planned: No
Related trials for HR+/HER2-negative Breast Cancer
Active, not recruitingPhase 1/2
Study of Oral MRT-2359 in Selected Cancer Patients
NSCLC, SCLC
RecruitingPhase 3
Adding an Immunotherapy Drug, MEDI4736 (Durvalumab), to the Usual Chemotherapy Treatment (Paclitaxel, Cyclophosphamide, and Doxorubicin) for Stage II-III Breast Cancer
Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8
Not yet recruitingPhase 1
A Study to Evaluate the Effects of GDC-4198 in Combination With Letrozole, Fulvestrant, or Giredestrant in Participants With Locally Advanced or Metastatic Hormone Receptor-Positive, HER2-Negatve Breast Cancer
Advanced or Metastatic Breast Cancer
RecruitingPhase 3
Phase 3 Study of RLY-2608 + Fulvestrant vs Capivasertib + Fulvestrant as Treatment for Locally Advanced or Metastatic PIK3CA-mutant HR+/HER2- Breast Cancer
PIK3CA Mutation, HER2- Negative Breast Cancer
Not yet recruiting
Prospective Study to Evaluate the Clinical Utility of ctDNA Tumor Fraction (TF) for Detection of Estrogen Receptor 1 (ESR1) Mutations in (Human Epidermal Growth Factor Receptor) HR+/HER2- Metastatic Breast Cancer (MBC)
Breast Cancer, Metastatic Breast Cancer
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Zelanna Goldberg, MD study director
Totus Medicines
18 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing TOS-358, Fulvestrant and Palbociclib in people with HR+/HER2-negative Breast Cancer, run by Totus Medicines at 18 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 22 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United States, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Clinical Trials (Please e-mail, clinicaltrials@totusmedicines.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determine the rate of dose-limiting toxicities (DLTs) (time frame: First 21 days of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Apr 2026.