Cancer Therapy: Clinical Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22þ B-cell Non-Hodgkin Lymphoma Michinori Ogura 1 , Kensei Tobinai 2 , Kiyohiko Hatake 3 , Andrew Davies 4 , Michael Crump 5 , Revathi Ananthakrishnan 6 , Taro Ishibashi 7 , M. Luisa Paccagnella 8 , Joseph Boni 9 , Erik Vandendries 10 , and David MacDonald 11 Abstract Purpose: To evaluate the safety, preliminary efficacy, and phar- macokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immuno- chemotherapeutic regimen, rituximab, cyclophosphamide, vincris- tine, and prednisone (R-CVP), in patients with relapsed/refractory CD22þ B-cell non-Hodgkin lymphoma (NHL). Experimental Design: In part 1 (n ¼ 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozo- gamicin. Part 2 (n ¼ 10) confirmed the safety and tolerability of the maximum tolerated dose (MTD), which required a dose- limiting toxicity rate of <33% in cycle 1 and <33% of patients discontinuing before cycle 3 due to treatment-related adverse events (AEs). Part 3 (n ¼ 22) evaluated the preliminary efficacy of inotuzumab ozogamicin plus R-CVP. Results: The MTD was determined to be standard-dose R-CVP plus inotuzumab ozogamicin 0.8 mg/m 2 . The most common treatment-related grade 3 AEs in the MTD cohort (n ¼ 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 pati- ents treated in the study, 13 discontinued due to AEs, most com- monly thrombocytopenia (n ¼ 10). Overall, 13 patients died, including one death due to treatment-related pneumonia sec- ondary to neutropenia. Among patients receiving the MTD (n ¼ 38), the overall response rate (ORR) was 84% (n ¼ 32), including 24% (n ¼ 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n ¼ 27) and 57% for those with aggressive histology lymphoma (n ¼ 21). Conclusions: Inotuzumab ozogamicin at 0.8 mg/m 2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22þ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 22(19); 4807–16. Ó2016 AACR. Introduction Non-Hodgkin lymphoma (NHL) is estimated to be the sixth most common newly diagnosed cancer in the United States in 2015 (1). Although mAb-based therapies have advanced the treatment of many lymphoma subtypes (particularly B-cell NHL), relapse rates are high, and many patients are refractory to therapy (2–6). Combination treatments consisting of mAbs and chemotherapeutics have successfully treated relapsed/ refractory NHL; however, toxicity remains a significant limita- tion with these regimens (7–9). Combination therapies that are both safe and effective are needed to meet the challenges of treating relapsed/refractory NHL. The CD22 antigen is expressed by >90% of B-cell NHLs, is rapidly internalized, and is not shed into the extracellular environment (10–13). As such, it is an ideal target for mAb- based therapy for B-cell malignancies (10, 11). Inotuzumab ozogamicin (CMC-544) is a humanized immunoglobulin G4 anti-CD22 mAb conjugated to a derivative of calicheamicin, a potent cytotoxic antibiotic (12). Upon binding to inotuzumab ozogamicin, CD22 is rapidly internalized, releasing calichea- micin, which binds to DNA and induces double-strand DNA breaks, resulting in apoptosis (14–17). In contrast, the mech- anism of action of the anti-CD20 mAb, rituximab, involves activation of immune system defense mechanisms, as well as directly inducing apoptosis (18). These disparate mechanisms of action allow for the possibility of synergistic effects between inotuzumab ozogamicin and rituximab; such effects have been observed in preclinical studies (19). Previous phase I studies of inotuzumab ozogamicin demon- strated preliminary activity and manageable toxicity in patients 1 Nagoya Daini Red Cross Hospital, Nagoya, Japan. 2 National Cancer Center Hospital, Tokyo, Japan. 3 Cancer Institute Hospital, Tokyo, Japan. 4 Cancer Sciences Division, Somers Cancer Research Building, University of Southampton, Southampton, United Kingdom. 5 Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. 6 Inventiv Health, Cambridge, Massachusetts. 7 Pfizer Japan, Tokyo, Japan. 8 Pfizer Inc, Groton, Conneticut. 9 Pfizer Inc, Collegeville, Pennsylvania. 10 Pfizer Inc, Cambridge, Massachusetts. 11 Queen Eliza- beth II Health Sciences Center, Halifax, Nova Scotia, Canada. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Current address for M. Ogura: Tokai Central Hospital, Kakamigahara, Gifu, Japan; and current address for R. Ananthakrishnan: Pfizer Inc, Cambridge, Massachusetts. Prior presentation: Preliminary account of this study has been presented in part at the 2011 and 2012 American Society of Hematology (ASH) Annual Meetings and the 2013 Japanese Society of Hematology (JSH) Annual Meeting. Corresponding Author: Michinori Ogura, Department of Hematology, Tokai Central Hospital, 4-6-2 Higashijimacho, Sohara, Kakamigahara, Gifu, 504-8601, Japan. Phone: þ81-58-382-3101; Fax: þ81-58-382-1762; E-mail: mi-ogura@naa.att.ne.jp doi: 10.1158/1078-0432.CCR-15-2488 Ó2016 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 4807 on June 14, 2020. © 2016 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst May 6, 2016; DOI: 10.1158/1078-0432.CCR-15-2488