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Cancer Therapy: Clinical

Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma

Michinori Ogura, Kensei Tobinai, Kiyohiko Hatake, Andrew Davies, Michael Crump, Revathi Ananthakrishnan, Taro Ishibashi, M. Luisa Paccagnella, Joseph Boni, Erik Vandendries and David MacDonald
Michinori Ogura
Nagoya Daini Red Cross Hospital, Nagoya, Japan.
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  • For correspondence: mi-ogura@naa.att.ne.jp
Kensei Tobinai
National Cancer Center Hospital, Tokyo, Japan.
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Kiyohiko Hatake
Cancer Institute Hospital, Tokyo, Japan.
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Andrew Davies
Cancer Sciences Division, Somers Cancer Research Building, University of Southampton, Southampton, United Kingdom.
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Michael Crump
Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
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Revathi Ananthakrishnan
Inventiv Health, Cambridge, Massachusetts.
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Taro Ishibashi
Pfizer Japan, Tokyo, Japan.
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M. Luisa Paccagnella
Pfizer Inc, Groton, Conneticut.
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Joseph Boni
Pfizer Inc, Collegeville, Pennsylvania.
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Erik Vandendries
Pfizer Inc, Cambridge, Massachusetts.
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David MacDonald
Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada.
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DOI: 10.1158/1078-0432.CCR-15-2488
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Abstract

Purpose: To evaluate the safety, preliminary efficacy, and pharmacokinetics of inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, in combination with the immunochemotherapeutic regimen, rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma (NHL).

Experimental Design: In part 1 (n = 16), patients received inotuzumab ozogamicin plus R-CVP on a 21-day cycle with escalating doses of cyclophosphamide first then inotuzumab ozogamicin. Part 2 (n = 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 = 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/m2. The most common treatment-related grade ≥3 AEs in the MTD cohort (n = 38) were hematologic: neutropenia (74%), thrombocytopenia (50%), lymphopenia (42%), and leukopenia (47%). Among the 48 patients treated in the study, 13 discontinued due to AEs, most commonly thrombocytopenia (n = 10). Overall, 13 patients died, including one death due to treatment-related pneumonia secondary to neutropenia. Among patients receiving the MTD (n = 38), the overall response rate (ORR) was 84% (n = 32), including 24% (n = 9) with complete response; the ORR was 100% for patients with indolent lymphoma (n = 27) and 57% for those with aggressive histology lymphoma (n = 21).

Conclusions: Inotuzumab ozogamicin at 0.8 mg/m2 plus full dose R-CVP was associated with manageable toxicities and demonstrated a high rate of response in patients with relapsed/refractory CD22+ B-cell NHL. The study is registered at ClinicalTrials.gov (NCT01055496). Clin Cancer Res; 1–10. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • 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.

  • Received October 13, 2015.
  • Revision received March 18, 2016.
  • Accepted April 13, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst August 12, 2016
doi: 10.1158/1078-0432.CCR-15-2488

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Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma
Michinori Ogura, Kensei Tobinai, Kiyohiko Hatake, Andrew Davies, Michael Crump, Revathi Ananthakrishnan, Taro Ishibashi, M. Luisa Paccagnella, Joseph Boni, Erik Vandendries and David MacDonald
Clin Cancer Res August 12 2016 DOI: 10.1158/1078-0432.CCR-15-2488

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Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma
Michinori Ogura, Kensei Tobinai, Kiyohiko Hatake, Andrew Davies, Michael Crump, Revathi Ananthakrishnan, Taro Ishibashi, M. Luisa Paccagnella, Joseph Boni, Erik Vandendries and David MacDonald
Clin Cancer Res August 12 2016 DOI: 10.1158/1078-0432.CCR-15-2488
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Clinical Cancer Research
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