A PHASE I STUDY OF IBRUTINIB COMBINED WITH RITUXIMAB, IFOSFAMIDE, CARBOPLATIN, AND ETOPOSIDE IN PATIENTS WITH RELAPSED OR PRIMARY REFRACTORY DIFFUSE LARGE B‐CELL LYMPHOMA

Abstract

Background: In the post-rituximab era, half the patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) are ineligible for autologous stem cell transplantation (ASCT) secondary to unresponsive disease. The Bruton's tyrosine kinase inhibitor ibrutinib has single-agent activity in r/r DLBCL, predominately of the non-germinal center (non-GCB) phenotype. This phase I study is the first to evaluate the combination of ibrutinib with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in ASCT-eligible r/r DLBCL patients. Methods: Patients with r/r DLBCL are eligible for study. The phase I study design is a standard 3 × 3 dose escalation of ibrutinib at 420 mg (dose level [DL] #1), 560 mg (DL #2) and 840 mg (DL #3) on days 1-21 with standard dosing of R-ICE for 3 cycles, every 21 days. The primary objective is to determine the safety of ibrutinib + R-ICE. Secondary objectives include response according to Deauville (D) criteria. Results: Twenty patients have enrolled: 19 patients are evaluable for toxicity, and 18 are evaluable for response. The median age is 62 years (range 19-75 years). Histologies include: GCB DLBCL n = 3, non-GCB DLBCL n = 7, primary mediastinal large B-cell lymphoma n = 4 and transformed small lymphocytic lymphoma (tCLL/SLL) n = 5. Seventeen patients had primary refractory or relapsed DLBCL <12 months from initial diagnosis. There were no dose-limiting toxicities (DLTs) seen at DL #1 (n = 3), 2 (n = 3), or 3 (n = 13). The majority of patients (18/ 19) experienced transient grade 3 or 4 hematologic toxicities with hematopoietic recovery prior to each cycle. One patient had grade 3 atrial fibrillation and was removed from study. Fourteen of the 18 patients evaluable for response underwent R-ICE-primed CD34+ hematopoietic progenitor cells (HPCs) apheresis procedures on study; 13 successfully collected HPCs with a median of 5.5 × 106 CD34+/ kg (range 1.7-8.6). One HIV+ patient failed to collect HPCs in the setting of febrile illness. Four patients were intended to proceed to allogeneic transplant. of the 18 patients evaluable for response, n = 9 achieved complete metabolic remission (CMR, D1-3), n = 7 achieved partial remission (PR, D4), and n = 2 had stable disease (SD) for an overall response rate of 89%. Excluding the patient removed from study for toxicity, 6/6 patients (100%) with non-GCB phenotype disease achieved a CMR. At a median follow-up for survivors of (Figure Presented) 16 months, the 1-year PFS in transplanted patients and by intent-totreat (ITT) is 71% and 57%, respectively (Figure 1). Conclusion: Ibrutinib dosed at 840 mg daily in combination with R-ICE is well tolerated and enables HPC collection. Encouragingly, 89% of patients achieved a response; including 100% CMR in patients with non-GCB phenotype disease. These results compare favorably to historic cohorts. Later phase studies for this treatment program are warranted, particularly for r/r non-GCB patients.