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Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.

ABSTRACT: Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.

SUBMITTER: Barr PM

PROVIDER: S-EPMC4874222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Venetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine-rituximab (BR) in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). Patients and methods:BR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50-1200?mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy. Results:Sixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n?=?4) or respiratory failure (n?=?1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800?mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3?months [95% confidence interval (CI) 10.4-NR], not yet reached, and 10.7?months (95% CI 4.3-21.0), respectively. Conclusions:This study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL. Trial registered:Clinicaltrials.gov, NCT01594229.

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Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.

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