The median age was 53

The median age was 53.5 years (range, 36-81). 10; lenalidomide as per cohort dose on days 1 to 21 of 28 for 18 cycles; and ibrutinib as per cohort dose daily until progression. Dose escalation used a 3+3 design from a starting dose level (DL) of lenalidomide 15 mg and ibrutinib 420 mg (DL0) to DL2 (lenalidomide 20 mg, ibrutinib 560 mg). Twenty-two patients were enrolled; DL2 was determined to be the recommended phase II dose. Although no protocol-defined dose-limiting toxicities were reported, a high incidence of rash was observed (all grades 82%, grade 3 36%). Eleven patients (50%) required dose reduction, 7 because of rash. The ORR for the entire cohort was 95%, and the 12-month progression-free survival was 80% (95% confidence interval, 57%-92%). Five patients developed new malignancies; 3 had known risk factors before enrollment. Given the increased toxicity and required dose modifications, as well as the apparent lack of additional clinical benefit to the rituximab-lenalidomide doublet, further WAY-362450 investigation of the regimen in this setting seems unwarranted. The study was registered with www.ClinicalTrials.gov as #”type”:”clinical-trial”,”attrs”:”text”:”NCT01829568″,”term_id”:”NCT01829568″NCT01829568. Introduction The standard approach for the treatment of advanced-stage follicular lymphoma, the most common of the indolent non-Hodgkin lymphomas (NHL), has traditionally consisted of chemoimmunotherapy. Although regimens such as R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) achieve overall response rates (ORR) of 90% in the front-line setting, patients inevitably relapse.1-4 Furthermore, these regimens are associated with acute and long-term toxicity, including but not limited to infection, myelosuppression, and neuropathy. Given the growing number of novel therapies with unique mechanisms of action, a multitargeted biological regimen may improve outcomes with fewer, less severe adverse events in this otherwise incurable disease. The Alliance for Clinical Trials in Oncology group, which includes the former Cancer and Leukemia Group B (CALGB), previously demonstrated the efficacy of the combination of rituximab and lenalidomide in follicular lymphoma. The CALGB 50401 phase 2 study reported an ORR of 76% (complete response [CR] 39%) and a 2-year time-to-progression of 52% in patients with relapsed disease.5 Preliminary data from the CALGB 50803 study indicated greater activity with the doublet in the front-line setting. Patients received rituximab 375 mg/m2 (cycle 1, days 1, 8, 15, and 22; cycles 4, WAY-362450 6, 8, and 10, day 1) and lenalidomide 20 mg (days 1-21 for twelve 28-day cycles), resulting in an ORR of 96% and a CR rate of 71%.6 An additional 6% achieved a CR by restaging 18FDG PET-CT scans (fluoro-deoxyglucose positron emission tomography combined with computed tomography), but were not included in the reported CR rate becase of lack of confirmatory bone marrow biopsies. The 2-year progression-free survival (PFS) was 89% among the 65 patients enrolled. Fowler et al noted similar response rates in a single-institution study, with a 3-year PFS of 79%.7 These impressive data supported the development of the phase 3 RELEVANCE trial of rituximab-lenalidomide vs rituximab-based chemoimmunotherapy (“type”:”clinical-trial”,”attrs”:”text”:”NCT01476787″,”term_id”:”NCT01476787″NCT01476787), which completed accrual in 2015. The Alliance sought to improve upon the efficacy of rituximab-lenalidomide with the addition of a B-cell receptor antagonist (BCR), ibrutinib. A first-in-class, selective, irreversible inhibitor of Bruton tyrosine kinase (BTK), ibrutinib is approved in chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstr?m macroglobulinemia. As a single agent, it has produced ORRs of 30% to 55% in early-phase clinical trials of heavily pretreated patients with relapsed WAY-362450 and refractory follicular lymphoma.8-10 Ibrutinib monotherapy is associated with minimal toxicity; the most common adverse events are mild edema, diarrhea, fatigue, and rash, with a small percentage of patients experiencing the more serious side effects of bleeding or atrial fibrillation. Given our mission to develop superior biological alternatives to conventional chemotherapy, the Alliance designed a multicenter phase 1 study of rituximab, lenalidomide, and ibrutinib Rabbit Polyclonal to HMGB1 in previously untreated follicular lymphoma. Utilization of a multitargeted approach against a cell surface marker, the tumor microenvironment, and an intracellular signaling pathway, may improve outcomes in this multiply relapsing disease. Methods Eligibility criteria Patients had previously untreated, histologically confirmed, World Health Organization classification grades 1, 2, or 3a follicular lymphoma, based on central review. Other inclusion criteria included age 18 years; Lugano classification bulky stage II.