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Updated: Feb 21, 2026
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in patients with advanced solid tumors
Philippe L Bédard1, Michael A Davies2, Scott Kopetz2
1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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. © 2017 American Cancer Society.
Insights
The PI3Kβ-selective inhibitor SAR260301 showed an acceptable safety profile in a first-in-human study but was terminated due to rapid clearance and insufficient exposure for antitumor activity.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Phosphoinositide 3-kinase (PI3K) β is a key target in phosphatase and tensin homolog (PTEN)-deficient tumors.
- SAR260301 is a potent PI3Kβ-selective inhibitor investigated for cancer treatment.
Purpose of the Study:
- To determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301.
- To assess target engagement and evaluate the effect of food on PK.
Main Methods:
- First-in-human study with dose escalation in patients with advanced solid tumors.
- Bayesian design with overdose control based on dose-limiting toxicities.
- Evaluation of adverse events, tumor response, PK, pharmacodynamics, and food effect; physiologically-based PK modeling used.
Main Results:
- Twenty-one patients received SAR260301 at doses up to 440 mg/m² twice daily; maximum tolerated dose was not reached.
- Most frequent adverse events: nausea, vomiting, diarrhea (14% each).
- Pharmacologically active concentrations were achieved, but rapid clearance prevented sustained exposure for preclinical antitumor activity; food decreased exposure.
Conclusions:
- SAR260301 demonstrated an acceptable safety profile but clinical development was halted due to rapid clearance and unachievable target PI3K pathway inhibition.
- Highlights the critical role of pharmacokinetic and pharmacodynamic assessments in early drug development.
