A Multicenter Phase I Study of the Humanized Anti-CD19 Monoclonal Antibody, MEDI-551, in Patients with Relapsed or Refractory B-Cell Lymphoma and Multiple Myeloma
Authors: Ogura Michinori , Ando Kiyoshi , Uike Naokuni , Ogawa Yoshiaki , Uchida Toshiki , Abe Yasunobu , Morishita Takanobu , Kojima Minoru , Choi Ilseung , Yagawa Katsuro , Yokoi Yuki , Okamura Jun 
Published: October 2019

Abstract
Background: MEDI-551 is an affinity-optimized and afucosylated humanized IgG kappa anti-CD19 monoclonal antibody enhanced for antibody-dependent cellular cytotoxicity. In a previous multicenter, phase 1/2 trial conducted in the United States and Europe, an overall disease control (objective response + stable disease) rate of 73.5% was achieved with MEDI-551 in patients (N=83) with relapsed or refractory B-cell malignancies, and median progression-free survival was 9.4 months (95% CI, 3.9–18.6 months) (Forero-Torres A, et al. 2013, ASH meeting).
Objective: We conducted an open-label, multicenter, phase 1 dose escalation study of MEDI-551 in Japan in patients with relapsed or refractory B-cell lymphoma and myeloma to determine the safety profile, maximum tolerated dose (MTD) or optimal biologic dose (OBD), and the preliminary antitumor activity of MEDI-551.
Methods: Patients aged 20 years or older with relapsed or refractory chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or multiple myeloma (MM) were enrolled at 3 institutes in Japan. All patients received MEDI-551 (at 2, 4, or 8 mg/kg) intravenously on days 1 and 8 of the first 28-day cycle, then once every 28 days, with an additional dose cohort of 12 mg/kg added. Dose escalation continued to the maximum dose of 12 mg/kg or until MTD was reached. Therapy continued for 2 cycles after the achievement of complete response (CR) or until unacceptable toxicity or disease progression. Dose-limiting toxicity (DLT) was defined as a MEDI-551–related adverse event (AE) that inhibited completion of a full first cycle of MEDI-551, or as a grade ≥3 toxicity that could not be attributed to another cause.
Results: From April 2011 through June 30, 2014, a total of 20 patients, including 6 with DLBCL, 11 with FL, 2 with CLL, and 1 with MM, received study treatment across 4 dose levels (2-mg/kg cohort; n=3; 4-mg/kg cohort, n=7; 8-mg/kg cohort, n=4; 12-mg/kg cohort, n=6). Two DLTs, including one infusion-related reaction and one case of neutropenia/leukopenia, were observed at the 12-mg/kg dose; thus, the MTD was determined to be 8 mg/kg. The AEs most commonly reported (in ≥15% of patients) were infusion-related reaction, hypertriglyceridemia, leukopenia, nasopharyngitis, decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and rash. A serious AE of epiglottitis (not treatment-related) was observed on day 64 after 4 cycles of MEDI-551 12-mg/kg. No treatment-related deaths were reported. Two patients with 12-mg/kg were discontinued due to treatment-related AEs (infusion-related reaction, decreased neutrophil count). Among 20 patients evaluable for response, 2 and 10 patients achieved CR and partial response, respectively, with an overall response rate of 60%. Six patients (30%) had stable disease. Response was obtained in 3/6 patients with DLBCL, 0/2 with CLL, 9/11 with FL, and 0/1 with MM, and in 2/3 at the MEDI-551 2-mg/kg dose, 3/7 at 4 mg/kg, 3/4 at 8 mg/kg, and 4/6 at 12 mg/kg. Data from this phase I study are being finalized.
Conclusions: This phase I study demonstrated acceptable toxicity and preliminary but promising antitumor activity of MEDI-551, with an MTD of 8 mg/kg, in Japanese patients with relapsed or refractory DLBCL or FL.

Disclosures
Ogura: AstraZeneca: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Eizai: Research Funding; Symbio: Research Funding; Kyowahakko-Kirin: Research Funding; Chugai: Research Funding; Zenyaku: Research Funding; Otsuka: Research Funding; Dainippon Sumitomo: Research Funding; Jansen: Research Funding; Soraisia: Research Funding; Mundi: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Ando:Kyowahakko-Kirin: Research Funding. Yagawa:AstraZeneca: Employment; AstraZeneca: Stock ownership, Stock ownership Other. Yokoi:AstraZeneca: Employment; AstraZeneca: Stock ownership, Stock ownership Other.