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
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Study Summary
Dose finding portion: To determine the maximum tolerated dose, and recommended phase 2 dose of TOS-358 administered orally on once a day and twice daily schedules Dose expansion portion: To evaluate safety and tolerability in tumor-specific cohorts administered TOS-358 at the recommended phase 2 dose and schedule To evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, and pharmacodynamics of TOS-358. The phase 1a was a 3+3 escalation to identify a minimum effective dose (MED) and a maximum tolerated dose (MTD) of TOS-358 when taken once daily (QD) or twice daily (BID). Tumor response was evaluated every 8 weeks by RECIST 1.1. PK was analyzed by non-compartmental analysis. PD was assessed by a TOS-358-specific target engagement assay. The phase 1 portion of the study follows a 3+3 dose escalation design and is intended to determine the minimum effective dose (MED) and the maximum tolerated dose (MTD) of TOS-358 when administered orally on a once daily (QD) or a twice daily (BID) schedule, and the recommended phase 2 dose (RP2D). The phase 1b portion to further assess the safety and tolerability of TOS-358 and to evaluate the initial efficacy of the investigational agent.
To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of TOS-358 in combination with fulvestrant and in combination with fulvestrant and CDK inhibitors in patients with PI3Ka-mutated, HR+/HER2- metastatic breast cancer.
To evaluate the safety, tolerability, and preliminary efficacy of TOS-358.
- 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 with no more than 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 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
- 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)
- For non-breast cancer: prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K-AKT-mTOR pathway,
- Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2 requiring antihyperglycemic medication
- Known active central nervous system (CNS) metastases.
Clinical Study Information for Healthcare Providers
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