Phase I Study Of Inotuzumab Ozogamicin (InO) Combined With R-GDP For Relapsed/Refractory CD22+ B-Cell Non-Hodgkin Lymphoma (B-NHL)
Authors: Sangha Randeep , Davies Andrew , Dang Nam H. , Ogura Michinori , MacDonald David A. , Volkert Angela , Ananthakrishnan Revathi , Luu Kenneth , Boni Joseph P. , Vandendries Erik , YT Goh Yeow-Tee 
Published: October 2019

Abstract

Background
CD22 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.

Methods
Part 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.

Results
Fifty-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).

Conclusions
InO 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.