Phase I Study Of Inotuzumab Ozogamicin (InO) Combined With R-GDP For Relapsed/Refractory CD22+ B-Cell Non-Hodgkin Lymphoma (B-NHL)

Abstract

BackgroundCD22 is expressed on most B-NHL. Inotuzumab ozogamicin (InO) is a humanized anti-CD22 antibody conjugated with calicheamicin, a potent cytotoxic antitumor antibiotic with activity in relapsed/refractory B-NHL. This study explored the safety, tolerability and preliminary efficacy of InO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for subjects with CD22+ B-NHL. MethodsPart 1 (dose escalation phase, n = 27) enrolled patients (pts) with relapsed or refractory CD22+ B-NHL treated with ≥1 prior R-chemo regimen using an up-and-down independent dose-escalation schema for G and P. InO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-day cycle for up to 6 cycles. R-GDP (R 375 mg/m2 day 1; G 1000 mg/m2 days 1 and 8; D 40 mg days 1-4; P 75 mg/m2 day 1) is a regimen used in some patients with relapsed/refractory B-NHL. Part 2 (MTD confirmation cohort, n = 10) enrolled additional pts to further evaluate the safety and tolerability of the MTD determined in Part 1. Confirmation of the MTD required a dose-limiting toxicity (DLT) rate of < 33% in Cycle 1 and < 4 pts discontinuing prior to Cycle 3 due to adverse event (AE). Part 3 (MTD expansion cohort, n = 18) enrolled additional pts to further evaluate the preliminary efficacy of InO when given in combination with R-GDP. ResultsFifty-five pts were treated: 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL. Characteristics: aged 25 to 81 y (median 65 y); 51 with ECOG PS ≤1; median of 2 prior chemo regimens (range 1-6); 8 refractory to prior therapy. The dose-escalation phase (Part 1) identified the MTD as InO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2 (day 1 only), D 40 mg, P 50 mg/m2. This MTD was confirmed in Part 2, in which 3 pts had DLTs (2 with grade 4 platelets, 1 with febrile neutropenia). The most common treatment-related grade ≥3 AEs included thrombocytopenia (69%), neutropenia (56%), lymphopenia (22%), leukopenia (18%), anemia (16%), and febrile neutropenia (11%). Twenty-one pts completed all 6 treatment cycles; the median number of cycles completed was 4 (range 1-6). The most common AEs leading to dose reductions and temporary dose delays included thrombocytopenia, febrile neutropenia, and neutropenia. For the 55 pts enrolled, the overall response rate (ORR) was 45% (n = 25), including 22% of pts (n = 12) who achieved a complete response (CR). Of the 55 pts enrolled, 46 had both a baseline and at least 1 post-baseline assessment reported. In this population to date, the ORR was 54%, including 26% who achieved a CR. 2 pts remain on treatment at the time of data collection. Additional efficacy data are summarized in Table 1. Pharmacokinetic samples were collected for pts enrolled in the MTD confirmation and expansion cohorts. Fifty-three pts have discontinued treatment, including 21 who completed the planned number of cycles, 12 due to AE (including 8 pts with grade 2/3 thrombocytopenia that did not resolve to grade 1 or better within the 28-day dose delay window allowed per protocol, and 1 each grade 5 oesophageal obstruction, grade 2 skin lesion and grade 4 tumor lysis syndrome) and 12 due to PD. Fifteen deaths have been reported, 12 due to disease progression and 3 due to other causes, including graft-versus-host disease, toxicity after allograft, and sequelae of subdural hematoma not related to study drug (n = 1 each). ConclusionsInO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2 day 1 only) and P (50 mg/m2). Preliminary efficacy in the MTD expansion cohort is encouraging. Follow-up for PFS and OS is currently ongoing. Disclosures:Sangha:Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Pfizer: Honoraria. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ B-cell non-Hodgkin lymphoma; this drug is investigational and is not approved for use in any indication in any country. Davies:Pfizer: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ogura:Eli Lilly: Research Funding. Volkert:Pfizer Inc: Employment. Ananthakrishnan:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Goh:Gilead Scienes: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Honoraria, Membership on an entity's Board of Directors or advisory committees.