Reference Detail

Ref Type

Journal Article

PMID

(28976556)

Authors

Bédard PL, Davies MA, Kopetz S, Juric D, Shapiro GI, Luke JJ, Spreafico A, Wu B, Castell C, Gomez C, Cartot-Cotton S, Mazuir F, Dubar M, Micallef S, Demers B, Flaherty KT

Title

First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in patients with advanced solid tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer	124	2	2018 01 15	315-324	Cancer

URL

Abstract Text

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).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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SAR260301	SAR260301	4	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SAR260301		SAR 260301\|SAR-260301	PIK3CB inhibitor 8	SAR260301 is PI3K beta-selective inhibitor, which has been demonstrated to inhibit tumor growth in xenograft models (PMID: 24387221, PMID: 28976556).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References