MEDI-551, a Humanized Monoclonal Anti-CD19, in Adults with Relapsed or Refractory Advanced B-Cell Malignancies: Results From a Phase 1/2 Study

Abstract

AbstractAbstract 3677 Background:MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa monoclonal antibody directed against CD19 and induces malignant clone destruction by antibody-dependent cellular cytotoxicity. This study evaluates the safety and preliminary efficacy profile of MEDI-551 in patients with relapsed/refractory B-cell malignancies. These include chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and multiple myeloma (MM). Objectives:To determine the safety profile and maximum tolerated dose (MTD) or optimal biological dose of MEDI-551 in patients with relapsed/refractory B-cell malignancies. Secondary objectives include pharmacokinetics, immunogenicity, and clinical activity of MEDI-551. Methods:In this phase 1/2 open-label multicenter, global dose-escalation and expansion study, patients with relapsed or refractory CLL, DLBCL, FL, or MM received MEDI-551 (at 0.5, 1, 2, 4, 8, or 12 mg/kg) by intravenous infusion administered over 28-day cycles using standard 3+3 dose escalation. Dose escalation continued until the MTD (≤12 mg/kg) was reached. Therapy continued for 2 cycles beyond complete response (CR), or until unacceptable toxicity or disease progression. Dose-limiting toxicity was defined as a MEDI-551-related adverse event (AE) that prevented completion of a full first cycle of MEDI-551, or as a grade 3 or higher toxicity (excluding hematologic toxicity) that could not be ascribed to another cause, such as disease progression or accident. Results:Of the 63 patients (CLL [12], DLBCL [23], FL [23], MM [5]) who received ≥1 dose of MEDI-551, 25 patients (CLL [3], DLBCL [6], FL [12], MM [4]) were enrolled in the phase 1 escalation portion (Jun 2010–Aug 2011). No MTD was achieved. The phase 2 expansion phase is ongoing. Median age of patients treated was 62 years. The median of completed treatment cycles was 4.0 with a maximum of 15 cycles. Dose intensity was approximately 98%. There were 6 deaths due to AEs (none were drug-related) and 9 subjects discontinued treatment (2 [neutropenia and infusion site reaction] were nonserious drug-related AEs). Most AEs were grade 1/2 with dose-independent frequency and severity (Table). 13 patients had serious treatment-emergent adverse events (TEAEs); pneumonia, sepsis, and bacteremia in 1 patient were considered drug-related. 7 patients had grade 4 TEAEs (2 with neutropenia were drug-related) and 7 had grade 5 events, none related to drug.Table:Treatment-emergent adverse events with highest severity by frequency (safety population)Adverse EventPatients, n (%) (N=63)Grade 1Grade 2Grade 3Grade 4Fatigue16 (25.4)9 (14.3)7 (11.1)––Diarrhea14 (22.2)12 (19.0)1 (1.6)1 (1.6)–Infusion reaction12 (19.0)2 (3.2)10 (15.9)––Nausea11 (17.5)9 (14.3)2 (3.2)––Cough9 (14.3)8 (12.7)1 (1.6)––Neutropenia9 (14.3)–3 (4.8)3 (4.8)3 (4.8)Thrombocytopenia9 (14.3)1 (1.6)5 (7.9)3 (4.8)–Dyspnea8 (12.7)7 (11.1)1 (1.6)––Headache8 (12.7)6 (9.5)2 (3.2)––Vomiting8 (12.7)6 (9.5)2 (3.2)––Abdominal pain7 (11.1)6 (9.5)–1 (1.6)–Pyrexia7 (11.1)6 (9.5)1 (1.6)––Anemia6 (9.5)1 (1.6)4 (6.3)1 (1.6)–Decreased appetite6 (9.5)6 (9.5)–––Of 43 patients in the evaluable for efficacy population (includes all patients who received any treatment of MEDI-551 and completed at least 1 post-baseline disease assessment), 5 had CR, 6 had partial responses (PR) and 21 had stable disease (SD; Figure 1). Median progression-free survival was ≈6 months (Figure 2). [Display omitted] [Display omitted] Conclusions:MEDI-551 demonstrated a safety profile warranting further study and no MTD was identified at the highest dose studied. The responses (CR: 11.6%; PR: 14.0%, objective response of 25.6% and SD of 48.8%) achieved in this single-agent study in heavily pretreated patients provide encouraging evidence of antitumor activity. Disclosures:Fanale:MedImmune: Research Funding. Kipps:MedImmune: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gregory:MedImmune (ALLRESEARCH FINDING PROCEEDS GO TO RUSH UVERSITY MEDICAL CENTER, NOT TOT ME PERSONALLY: Honoraria, Research Funding. Zhang:MedImmune: Employment. Goswami:MedImmune: Employment; AstraZeneca: Stocks, Stocks Other. Ibrahim:MedImmune: Employment; AstraZeneca: Stocks, Stocks Other. Yao:MedImmune: Employment. Herbst:MedImmune: Employment.