An Open-Label, Phase I Study of R-CVP in Combination with Inotuzumab Ozogamicin in Patients with Relapsed/Refractory CD22-Positive B-Cell Non-Hodgkin Lymphoma,
Authors: Ogura Michinori , Uchida Toshiki , MacDonald David A , Hatake Kiyohiko , Davies Andrew , Sangha Randeep , Crump Michael , Thieblemont Catherine , Ishibashi Taro , Hua Steven , Paccagnella Luisa , Vandendries Erik R , Kobayashi Yukio , Tobinai Kensei 
Published: October 2019

Abstract
Abstract 3715

Background:
Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent antitumor antibiotic. CD22 is expressed on the majority of B-cell non-Hodgkin lymphomas (NHL). Although safety and preliminary efficacy data of INO as monotherapy and in combination with rituximab have previously been reported, there is no report of combination use of INO with chemotherapy. This phase I study evaluated the safety of INO in combination with chemotherapy (R-CVP regimen) in patients with relapsed or refractory CD22+ B-cell NHL. Preliminary efficacy data were also collected.
Patients and Methods: Patients with either relapsed or refractory CD22+ B-cell NHL and at least 1 prior treatment regimen, including rituximab and chemotherapy, were enrolled in a phase I dose-finding study (part 1), with a planned expansion cohort (n = 10) to confirm the safety and tolerability of the maximum tolerated dose (MTD; part 2), and a further expansion cohort (n = 20) to estimate antitumor activity (part 3). In the dose-escalation study, INO (0.8 mg/m2) was given on Day 2 with R-CVP (rituximab 375 mg/m2, vincristine 1.4 mg/m2, and escalating doses of cyclophosphamide 375, 550, and 750 mg/m2 all on Day 1; prednisone 40 mg/m2 on Days 1–5) q3wks. After the highest dose of cyclophosphamide was evaluated for safety, INO was escalated to 1.3 mg/m2. Dose reductions and/or dose delays were performed, as needed, based on toxicities. The current analysis presents the completed dose-escalation phase, with preliminary safety and efficacy data.

Results:
23 patients with follicular (FL; n = 15), mantle cell (n = 3), diffuse large B-cell (n = 3), or small lymphocytic (n = 1) lymphomas (missing diagnosis, n = 1) have been enrolled so far: 65% of patients were male, and the median age was 62 years (range, 42–74 years). In part 1 of the study, approximately 50% of patients had received 2 or more prior chemotherapy regimens, and all had received prior rituximab. As of the time of this analysis, 11 patients had completed at least 5 treatment cycles (ie, ≥105 days on study drug).
No dose-limiting toxicities (DLTs) were reported with INO 0.8 mg/m2 plus R-CVP at the lower doses of cyclophosphamide (375 and 550 mg/m2). At a dose level of INO 0.8 mg/m2 plus full-dose R-CVP (cyclophosphamide 750 mg/m2), 1 out of 6 patients had a DLT of grade 4 neutropenia requiring treatment with granulocyte colony-stimulating factor (G-CSF). At a dose level of INO 1.3 mg/m2 plus R-CVP, 2 out of 3 patients had a total of 3 DLTs (acute hepatitis, thrombocytopenia, and neutropenia requiring G-CSF). Therefore, the MTD was determined to be rituximab 375 mg/m2, vincristine 1.4 mg/m2, and cyclophosphamide 750 mg/m2 all given on Day 1, INO 0.8 mg/m2 given on Day 2, and prednisone 40 mg/m2 given on Days 1 through 5 of each 3-week cycle.
Treatment-emergent grade ≥3 adverse events included neutropenia (57%), lymphopenia (52%), leukopenia (35%), thrombocytopenia (30%), increased alanine aminotransferase (9%), increased aspartate aminotransferase (4%), decreased blood sodium (4%), fatigue (4%), febrile neutropenia (4%), hyperbilirubinemia (4%), hypoxia (4%), lethargy (4%), pleural effusion (4%), and pollakiuria (4%).
Enrollment is continuing in parts 2 and 3 of the study. Preliminary efficacy data from the escalation portion of the study (n = 15 evaluable patients) is notable for an overall response rate (ORR) of 87% (33% with complete response; 53% with partial response). In patients with FL, the ORR was 100% (45% with complete response).

Conclusions:
INO 0.8 mg/m2 appears to be tolerable when given in combination with full dose R-CVP chemotherapy. DLTs were hematologic and hepatic, and encouraging signs of antitumor activity have been reported.

Disclosures:
MacDonald: Roche Canada: Honoraria, Research Funding. Davies:Pfizer Inc: Research Funding. Sangha:Roche: Honoraria; Boehringer Ingelheim: Honoraria. Crump:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche Canada: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria. Thieblemont:Assistance Publique - Hôpitaux de Paris: Employment; Institut National du Cancer - INCa [French National Cancer Institute]: Research Funding. Ishibashi:Pfizer Inc: Employment, Equity Ownership. Hua:Pfizer Inc: Employment, Equity Ownership. Paccagnella:Pfizer Inc: Employment, Equity Ownership, Patents & Royalties. Vandendries:Pfizer Inc: Employment, Equity Ownership. Kobayashi:Ohtsuka Pharmaceutical: Research Funding; Nippon Shiyaku: Honoraria; BMS: Honoraria. Tobinai:Bayer: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Eli Lilly: Research Funding; Genzyme: Research Funding; GSK: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen: Research Funding; MSD: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Pfizer Inc: Research Funding; Symbio: Research Funding; Zenyaku: Research Funding.