Safety and Clinical Activity of the Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) in Combination with Rituximab in Follicular Lymphoma or Diffuse Large B-Cell Lymphoma: Preliminary Report of a Phase 1/2 Study (2008)

Abstract Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized CD22 antibody, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Inotuzumab ozogamicin targets B-cell malignancies since they often express CD22. In a previously reported phase 1 dose-escalation trial in patients with CD22-positive B-cell non-Hodgkin’s lymphoma (NHL), the maximum tolerated dose (MTD) was determined to be 1.8 mg/m2 every 4 weeks. Responses were seen in patients with both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). This ongoing study consisted of a limited dose escalation (DE) portion to confirm the MTD of inotuzumab ozogamicin when combined with rituximab, followed by an expanded MTD cohort to further define safety and efficacy. Patients with FL and DLBCL who relapsed or progressed after 1 or 2 prior therapies were eligible. Prior rituximab treatment was required and prior autologous transplant allowed if &amp;gt;6 months from enrollment. Rituximab refractory patients, as defined by progression within 6 months of the first dose of rituximab, were excluded. Patients received rituximab 375 mg/m2 on day 1 of each 28-day cycle and inotuzumab ozogamicin on day 2 at doses of 0.8 mg/m2 (n=5), 1.3 mg/m2 (n=3), and 1.8 mg/m2 (n=7) for a maximum of 8 cycles. After confirmation of the MTD dose at 1.8 mg/m2 ditional patients were enrolled in an expanded MTD cohort. Safety data and preliminary efficacy data were collected. As of June 2008, the DE portion was completed and the study is enrolling in the MTD portion. To date, 61 patients have been treated: median age 63 yr (range 33–85 yr), 62% men. All 61 patients were evaluable for safety and currently 30 patients (16 FL, 14 DLBCL) in the expanded MTD cohort were evaluable for tumor response based on available data. 20% of patients discontinued treatment due to an adverse event (AE), which included hematologic AEs (8 patients) or elevation of ³1 liver function test (5 patients). The overall safety profile was characterized by AEs that were manageable; the most common drug-related AEs (all grades) were thrombocytopenia (41%), nausea (38%), fatigue (36%), AST increased (26%), and neutropenia (25%). Grade 3/4 AEs that occurred in 5% of patients included thrombocytopenia (21%), neutropenia (15%), and lymphopenia (7%). Tumor responses were seen in all DE cohorts and the MTD cohort, and the response rates in evaluable patients are shown in the Table. The 6-month progressionfree survival rate was 100% for FL and 66% DLBCL for all patients in the MTD cohort. The safety profile of inotuzumab ozogamicin plus rituximab exhibits a similar profile seen in the previous inotuzumab ozogamicin monotherapy study. The main toxicity was clinically manageable, self-limited thrombocytopenia. The preliminary efficacy in recurrent/refractory FL and DLBCL is promising and may indicate a durable response. These data support the continuing development of inotuzumab ozogamicin in combination with rituximab in the management of NHL. Table: Best Overall Response, Evaluable* Patients in the Dose Escalation (DE) and MTD Cohorts FL, n (%) DLBCL, n (%) DE MTD DE MTD Response 0.8 (n=1) 1.3 (n=2) 1.8 (n=3) Total (n=6) 1.8 (n=16) 0.8 (n=3) 1.3 (n=1) 1.8 (n=2) Total (n=6) 1.8 (n=14) CR=complete response; CRu=CR unconfirmed; ORR=objective response rate (CR/CRu+partial response) *Best response during treatment and follow up. Evaluable patients had 32 doses inotuzumab ozogamicin and a response assessment CR/CRu 1 (100) 1 (50) 1 (33) 3 (50) 7 (44) 1 (33) 0 1 (50) 2 (33) 6 (43) ORR 1 (100) 2 (100) 2 (67) 5 (83) 14 (88) 1 (33) 1 (100) 2 (100) 4 (67) 10 (71)