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 HR +/HER2- breast cancerUp to 3 prior lines of therapy for metastatic diseaseWilling and able to provide written informed consent for this studyAdults ≥ 18 years old at time of consentKnown PIK3CA mutations or amplifications as determined at a CAP/CLIA-certified or equivalently accredited diagnostic laboratory using a validated testMeasurable or evaluable disease by RECIST 1.1Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1Life expectancy ≥ 6 months, as determined by the investigatorAdequate bone marrow, liver, and kidney function within 14 days prior to first dose of investigational productFasting 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
- Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2Known active central nervous system (CNS) metastasesPTEN mutations
Clinical Study Information for Healthcare Providers
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