Philippe L Bédard1, Michael A Davies2, Scott Kopetz2, Dejan Juric3, Geoffrey I Shapiro4, Jason J Luke5, Anna Spreafico1, Bin Wu6, Christelle Castell7, Corinne Gomez8, Sylvaine Cartot-Cotton8, Florent Mazuir8, Michel Dubar9, Sandrine Micallef10, Brigitte Demers11, Keith T Flaherty3. 1. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 2. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3. Massachusetts General Hospital Cancer Center, Boston, Massachusetts. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 5. Department of Medicine, University of Chicago Cancer Center, Chicago, Illinois. 6. Department of Oncology, Sanofi, Cambridge, Massachusetts. 7. Department of Translational Medicine, Sanofi, Vitry sur Seine, France. 8. Department of Drug Disposition, Sanofi, Alfortville, France. 9. Department of Translational Informatics, Sanofi, Chilly-Mazarin, France. 10. Department of Biostatistics Oncology, Sanofi R&D, Vitry sur Seine, France. 11. Department of Oncology - Early Development, Sanofi, Vitry sur Seine, France.
Abstract
BACKGROUND: Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737). METHODS: Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions. RESULTS: Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure. CONCLUSIONS: SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24.
BACKGROUND: Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737). METHODS: Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions. RESULTS: Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure. CONCLUSIONS:SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24.
Authors: Tihitina Y Aytenfisu; Hannah M Campbell; Mayukh Chakrabarti; L Mario Amzel; Sandra B Gabelli Journal: Curr Top Microbiol Immunol Date: 2022 Impact factor: 4.737