A Phase I Dose Expansion Cohort Study of the Safety, Pharmacokinetics and Pharmacodynamics of SAR245409 (S09), An Orally Administered PI3K/mTOR Inhibitor, in Patients with Lymphoma

Dysregulation of phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR pathway signaling by various mechanisms, including PIK3CA mutations, PTEN deficiency and p70S6K amplification, has been implicated in the pathogenesis of lymphoma. In this context, although inhibition of specific PI3K isoforms has shown efficacy in some B-cell malignancies, targeting multiple components of this pathway may offer significant therapeutic benefits. SAR245409 (XL765) is a potent inhibitor of class I PI3K isoforms (α, β, γ, δ) that also inhibits mTOR, which has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Preliminary data for lymphoma patients treated with SAR245409 are presented.

Patients with refractory or relapsed lymphomas were enrolled in a lymphoma-specific expansion cohort to receive SAR245409 orally (NCT00485719). The duration of each cycle was 28 days. Cycle 1 safety data determined the dose-limiting toxicities by CTCAE v 3.0. Samples were collected for pharmacokinetic and pharmacodynamic analyses. Tumor response was assessed every 8 weeks by International Working Group response criteria, including PET for diffuse large B-cell lymphoma (DLBCL) and Hodgkin Disease (HD).

Sixteen patients with non-Hodgkin lymphoma were enrolled: mantle cell lymphoma (MCL) n=6, follicular lymphoma n=5, DLBCL n=2, HD n=1, follicular transformed lymphoma n=1, and anaplastic T-cell/null cell lymphoma n=1. There were 12 males/4 females with a median age of 69 years (range, 20–90). Among 15 patients, 10 (66.7%) had received 3 or more prior regimens. Sixteen patients were evaluable for safety and tolerability. The most common related adverse events (>10% of patients) were nausea (25%), diarrhea (12.5%), and elevated liver enzymes (ALT 18.8% and AST 18.8%). Drug-related grade ≥3 ALT elevation occurred during the second cycle in 2 patients (12.5%) and resolved with drug discontinuation. The pharmacokinetic parameters of SAR245409, including the median tmax and mean t1/2 at steady state, were consistent with those seen in solid tumor patients. Two MCL patients remained on study >12 months, with 1 showing robust pharmacodynamic modulation of PI3K and ERK pathway signaling. Evaluation of pharmacokinetic, pharmacodynamic, and potential predictive biomarkers is ongoing.

In this phase 1 dose-expansion cohort study in lymphoma, SAR245409 was generally well tolerated and showed promise in several lymphoma subtypes. Further clinical development as a single agent or in combination regimens in select patients with NHL is warranted.

Papadopoulos:Sanofi, Exelixis: Research Funding. Rasco:Sanofi, Exelixis: Research Funding. Patnaik:Sanofi, Exelixis: Research Funding. Tabernero:Sanofi: Consultancy, Honoraria. Rajangam:Exelixis: Employment. Rockich:Sanofi: Employment. Egile:Sanofi: Employment. Kelly:Sanofi: Employment. Xu:Sanofi: Employment. Lager:Sanofi: Employment, GSK - Equity Ownership.