HR+/HER2-negative Breast Cancer
Conditions
Keywords
PI3K-alpha, breast cancer, metastatic breast cancer, PIK3CA, hormone receptor positive breast cancer
Brief 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. Phase 1a: what is the maximum tolerated dose and recommended dose for phase 2? 2. Phase 1a: how safe and tolerable is TOS-358 at different dose levels when taken orally once or twice per day? 3. 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.
Interventions
DRUGTOS-358
Covalent Phosphoinositide-3-Kinase (PI3K)-alpha Inhibitor
DRUGFulvestrant
Intramuscular SERD at standard doses
DRUGPalbociclib
CDK4/6 inhibitor at standard doses
DRUGRibociclib
CDK4/6 inhibitor at standard doses
Sponsors
Totus Medicines
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria * 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 * 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 Key
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR and duration of tumor control | Up to 24 months | Measures of efficacy of TOS-358 monotherapy and in combination with standard of care treatment in early line metastatic HR+HER2- breast cancer |
Countries
Spain, United States
Contacts
CONTACTClinical Trials
STUDY_DIRECTORZelanna Goldberg, MD
Totus Medicines
Outcome results
None listed