Phase I study of inotuzumab ozogamicin (INO) combined with R-GDP for relapsed CD22+ B-cell non-Hodgkin lymphoma (B-NHL).

Abstract

2574 Background: CD22 is expressed on most B-NHL. INO, an anti-CD22 antibody linked to calicheamicin, has activity in refractory B-NHL. This study hypothesized that INO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for relapsed CD22+ B-NHL was safe and tolerable. Methods: Patients (pts) with relapsed CD22+ B-NHL treated with ≥1 prior R-chemo regimen were enrolled 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-d cycle for up to 6 cycles. Dose-limiting toxicity (DLT) included febrile neutropenia, grade (Gr) 4 ANC lasting ≥7 d, Gr 4 platelets ≥7 d, Gr ≥3 platelets with bleeding and transfusion support, Gr ≥3 QTc prolongation, Gr 4 AST/ALT, Gr 2 bilirubin ≥7 d, G-CSF during cycle 1, Gr ≥3 clinically significant or drug-related nonhematologic toxicity ≥7 d, and Gr ≥2 drug-related nonhematologic toxicity causing dose delay of ≥7 d. Results: Thirty-seven pts were treated: 15 DLBCL, 11 FL, 7 MCL, 1 MZL, 1 SLL, and 2 indolent B-NHL. Characteristics: aged 33 to 81 y (median 65 y); 34 with ECOG PS £1; median of 2 prior chemo regimens (range 1-6); 5 refractory to prior therapy. No DLTs were observed at the starting dose of G 500 mg/m2, P 37.5 mg/m2 (n = 6); 2 DLTs (febrile neutropenia, Gr 2 platelets) at G 1000 mg/m2, P 37.5 mg/m2 (n = 3); no DLTs at G 1000 mg/m2, P 0 mg/m2 (n = 6); 2 DLTs (febrile neutropenia; Gr 4 ANC ≥7 d) at G 500 mg/m2, P 50 mg/m2 (n = 8); and 2 DLTs (Gr 3 hypokalemia, Gr 4 neutropenic sepsis) at G 500 mg/m2, P 75 mg/m2 (n = 4). In a maximum tolerated dose (MTD) confirmation cohort of 10 additional pts, 3 pts had DLTs (2 with Gr 4 platelets, 1 with febrile neutropenia); thus MTD was determined to be INO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2, D 40 mg, P 50 mg/m2. Gr ≥3 adverse events included thrombocytopenia (68%), neutropenia (54%), lymphopenia (32%), anemia (27%), leukopenia (24%), hypokalemia (22%), fatigue (11%), and febrile neutropenia (11%). Median treatment cycle was 4 (range 1-6). There were 8 complete and 9 partial responses. Conclusions: INO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2) and P (50 mg/m2). Preliminary efficacy is being explored in the ongoing MTD expansion cohort. Clinical trial information: NCT01055496.