Phase I Trial of SAR245408 (S08), a Pan-Phosphatidylinositol 3 Kinase (PI3K) Inhibitor, in Patients with Chronic Lymphocytic Leukemia (CLL) and Lymphoma (2011)

Abstract Abstract 2683 Background: Dysregulation of the class I phosphatidylinositol 3-kinases (PI3Ks) has been implicated in cancer pathogenesis in many cell types, and the PI3K pathway is constitutively activated in CLL and often in other non-Hodgkin lymphomas. SAR245408 (XL147) is a potent and selective inhibitor of all four class I PI3K isoforms, with IC50s (nM) of α: 39, β: 383, γ: 36, and δ: 23, compared to mTOR: &gt;15000. In vitro and in vivo, SAR245408 inhibits phosphorylation of downstream targets of PI3K, including pAKT and pEBP1. As part of a phase 1 single-agent study in solid tumors (NCT00486135), we administered SAR245408 to a dedicated expansion cohort of patients with relapsed/refractory lymphoma and CLL. Methods: SAR245408 was administered orally, once daily, with continuous dosing in monthly cycles. A total of 15 patients were enrolled at 3 centers. A cohort of 3 patients was enrolled initially, with the remaining 12 patients subsequently enrolled following a safety review. Results: The median age of the patients was 66 years (range 28–81), 40% were male and 60% female. Among the 15 patients, 33% (n=5) had refractory CLL and 67% (n=10) had various relapsed lymphomas, including diffuse large B-cell lymphoma (n=4), follicular lymphoma (n=2), Hodgkin lymphoma (n=2), Waldenstrom's macroglobulinemia (n=1), and B-cell prolymphocytic leukemia (n=1). Fourteen patients (93%) had stage 3–4 disease. Among the 12 patients with data available, 6 (50%) had received 3 or more prior therapies, 10 (83%) had been exposed rituximab, and 11 (92%) to alkylating agents. Overall, the median hemoglobin was 11.3g/dL (range 9.2–14.1), and the median platelet count was 113 × 103/μl (range 66–470). For the 5 patients with CLL, the median starting absolute lymphocyte count was 1.9 × 103/μl (range 0.9–22.3), the median starting hemoglobin was 10.8 g/dL (range 9.2–14.1) and the median platelet count was 83 × 103/μl (range 66–143). Two CLL patients had an 11q deletion and one had a 17p deletion. Two of 4 CLL patients tested for IgVH status were unmutated, and 2 of 2 tested for ZAP70 were positive. Four of 5 patients with CLL had been treated with fludarabine combination chemotherapy. A median of 4 treatment cycles of SAR245408 were delivered on study, with 8 patients currently continuing treatment. Causes of study discontinuation included disease progression (n= 6) and a serious adverse event (n=1, with recurrent hospitalization for pneumonia). Adverse events were infrequent; those of any grade occurring in &gt;10% of patients included diarrhea, hyperglycemia, headache, and lymphopenia. Hematologic toxicity was uncommon, with grade 3–4 neutropenia observed in 4/15 patients (26.7%) and grade 3–4 thrombocytopenia observed in 1 of 15 (6.7%). Hyperglycemia was grade 3–4 in 1 patient (6.7%) and grade 1–2 in 1 patient (6.7%). Follow-up to assess response is ongoing and updated data will be presented. Analyses of pharmacokinetic and pharmacodynamic data, as well as potential predictive biomarkers, are in progress. Conclusions: These preliminary data suggest that SAR245408, an oral pan-PI3K inhibitor, is generally well tolerated in heavily pretreated relapsed/refractory CLL and lymphoma. Ten additional patients have been enrolled in the expansion cohort to better define the activity of SAR245408 and further studies are warranted. Disclosures: Brown: Calistoga, Pharmacyclics, Celgene: Consultancy; Celgene, Genzyme, GSK: Research Funding. DeCillis:Exelixis: Employment. Rockich:Sanofi: Employment. Egile:Sanofi: Employment. Kelly:Sanofi: Employment. Xu:Sanofi: Employment. Lager:Sanofi: Employment, GSK - Equity ownership.