Younes A, et al. - In a two-part, open-label, phase 1/2a study, researchers investigated the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. Findings revealed an acceptable safety profile of the combination of ibrutinib and nivolumab. The combination had preliminary activity similar to that reported with single-agent ibrutinib in chronic lymphocytic leukemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. They observed promising clinical response in patients with Richter's transformation supporting further clinical assessment.

Methods

• Researchers performed this study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the US.
• In part A (dose escalation), they primarily determined the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to assess a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma.
• They used a modified toxicity probability interval design to investigate dose optimization.
• In part B expansion phase, they primarily established the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation.
• The primary analysis included all participants who received at least one dose of treatment; analyses were done by disease cohort.

Results

• Researchers enrolled 144 patients in the study between March 12, 2015 and April 11, 2017.
• Death before receiving study treatment was reported of three patients, leaving 141 patients for inclusion in the analysis, 14 in part A and 127 in part B.
• In the diffuse large B-cell lymphoma cohort, they reported one dose-limiting toxicity (grade 3 hyperbilirubinemia) at the 420 mg dose, which resolved after 5 days.
• Overall responses with the combination of ibrutinib and nivolumab were noted in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation.
• Diarrhea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]) were the most common all-grade adverse events.
• Adverse events that led to death were noted in 11 (8%) of 141 patients; none were reported as drug-related.
• Neutropenia (40 [28%] of 141 patients) and anemia (32 [23%]) were the most common grade 3–4 adverse events.
• Grade 3–4 neutropenia had incidence ranging from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukemia or small lymphocytic lymphoma; grade 3–4 anemia had incidence ranging from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation.
• Anemia (six [4%] of 141 patients) and pneumonia (five [4%]) comprised the most common serious adverse events.
• Rash (11 [8%] of 141 patients) and increased alanine aminotransferase (3 [2%]) were the most common grade 3–4 immune-related adverse events.