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: >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.
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.
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 >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.
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.
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.
Asterisk with author names denotes non-ASH members.