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Phase 1 Dose Escalation of Ibrutinib and Buparlisib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma, Mantle-Cell Lymphoma, and Follicular Lymphoma

Conference Correspondent - ASCO 2017 - Chronic Lymphocytic Leukemia

In vitro studies of Bruton’s tyrosine kinase (BTK) and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). Investigators thereby initiated a phase 1/1b clinical trial to evaluate the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (RR) NHL.

Eligible patients had RR diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), or follicular lymphoma (FL) with Eastern Cooperative Oncology Group performance status ≤2, and adequate organ function. Oral ibrutinib and buparlisib were given daily on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was examined and based on Lugano Classification; however, complete response (CR) required both positron emission tomography resolution and at least partial response (PR) by computed tomography.

Phase 1 dose escalation was completed with 16 evaluable patients: 7 patients with DLBCL, 6 patients with MCL, and 3 patients with FL. Of the 7 patients with DLBCL, 1 had CR and 1 had stable disease. In the 3 patients with FL, all had stable disease. In the 6 patients with MCL, 4 had CR and 2 had PR. Ten patients discontinued treatment for progression (5 patients with DLBCL, 2 patients with MCL, and 3 patients with FL).

In regard to safety, 50% of patients had a ≥grade 3 related adverse event. Most common related adverse events were hyperglycemia, diarrhea, elevation of total bilirubin, and thrombocytopenia. Cytomegalovirus reactivation was also observed in 4 patients but none required therapy. Neurologic adverse events, including mood changes, depression, anxiety, anemia, and confusion, were observed in 7 patients.

The combination of ibrutinib and buparlisib, while generally well-tolerated, has the predicted toxicities of both BTK and PI3K inhibitors. Particularly, promising efficacy is observed in MCL. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg, although dose reductions for tolerability may be necessary for long-term oral therapies and may influence the recommended phase 2 dose.

Batlevi CL, et al. ASCO Abstract 7544.

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