Multicenter Phase 1b Dose-Escalation Study of Ibrutinib and Lenalidomide Combined with Dose-Adjusted EPOCH-R in Patients with Relapsed/Refractory DLBCL

Introduction

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor outcome and few achieve durable remission. DA-EPOCH-R (dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone with rituximab) is a regimen recommended by the NCCN guidelines for untreated and R/R DLBCL. The immunomodulator, lenalidomide, and the Bruton's tyrosine kinase inhibitor, ibrutinib, have both shown single-agent efficacy in non-germinal center B-cell-like (non-GCB) DLBCL, which is enriched for the activated B-cell [ABC] subtype, and are synergistic in vitro against ABC DLBCL. This nonrandomized, multicenter, open-label study is designed to evaluate the efficacy of ibrutinib in combination with lenalidomide and DA-EPOCH-R in subjects with R/R DLBCL. Part 1 of the study is designed to determine the maximum tolerated dose (MTD) of ibrutinib and lenalidomide with DA-EPOCH-R in R/R DLBCL. In Part 2, the efficacy of this combination will be evaluated in R/R ABC DLBCL. Here, we report the results of Part 1.

Methods

For Part 1, patients aged ≥18 years with pathologically confirmed R/R DLBCL were enrolled. The dose-escalation phase was conducted using a standard 3+3 design. Ibrutinib was administered at a fixed dose of 560 mg (Days 1-7) and lenalidomide was dose-escalated at doses of 0, 15, 20 and 25 mg (Dose Levels 1-4, respectively) and administered on Days 1-7 of each 21-day cycle. DA-EPOCH-R was given at standard doses. Treatment was continued in 21-day cycles for up to 6 cycles. The dose-limiting toxicity (DLT) assessment period was defined as the first 22 days of dosing (Day 1 of Cycle 1 through Day 1 of Cycle 2 [predose]). The primary endpoints were the MTD and safety and tolerability of the combination regimen; the secondary endpoint was overall response rate (ORR).

Results

Fifteen patients (13 male) were enrolled in Part 1. Median age was 58 years (range, 38-89) with 4 (27%) patients aged ≥65 years. Median time from initial diagnosis to first dose was 17.4 months (range, 7.4-65.5). Seven (47%) patients each had GCB and non-GCB DLBCL (subtype not reported for 1 patient). At baseline, 13 (87%) patients had stage III/IV disease; 8 (53%) had bulky disease ≥5 cm (2 >10 cm), and 10 (67%) were refractory to their last treatment. Patients had received a median of 3 prior regimens (range, 1-5). Dose escalation was completed through Dose Level 4. One DLT of diffuse alveolar damage was seen at the highest dose of lenalidomide tested. The MTD was not reached. Subjects in Part 2 will be treated with ibrutinib (560 mg) and lenalidomide (25 mg) on Days 1-7 combined with standard DA-EPOCH-R. Grade ≥3 adverse events (AEs) occurred in 14 (93%) patients. The most common grade ≥3 AEs (occurring in >20% of patients) were anemia (60%), febrile neutropenia (47%), leukopenia (40%), neutropenia (40%), thrombocytopenia (40%), hypokalemia (40%), and hypotension (33%). Serious AEs (SAEs) occurred in 14 patients (93%) including 2 cases (13%) of grade 2 atrial fibrillation. In 10 response evaluable patients (with at least one post-baseline radiological assessment), 2 patients had complete response (CR), 3 had partial response (PR), 2 patients had best response of stable disease, and 3 had progressive disease; 4 (67%) of 6 response evaluable non-GCB patients achieved objective response (CR/PR). Three patients continue treatment, 2 patients completed the protocol-specified treatment, and 10 patients discontinued treatment. Reasons for treatment discontinuation included AEs (n=3), progressive disease (n=3), stem cell transplant after achieving CR/PR (n=2), disease worsening (n=1), and death (n=1). Enrollment into Part 2 of the study has been initiated at Dose Level 4.

Conclusions

The Part 2 dose was established as 560 mg ibrutinib and 25 mg lenalidomide combined with standard DA-EPOCH-R. Ibrutinib in combination with lenalidomide and DA-EPOCH-R showed acceptable safety and tolerability and promising anti-tumor activity in patients with R/R DLBCL. The efficacy of this combination regimen will be further evaluated in Part 2 of this trial.