Safety and Tolerability of Obinutuzumab (GA101) with Shorter Duration of Infusion in Japanese Patients with Previously Untreated CD20-Positive B-Cell Non-Hodgkin's Lymphoma (NHL)-Comparison with GAO4915g (GATHER) and BO21005 (GOYA) Studies

Background

Obinutuzumab (GA101) is a novel humanized, glycoengineered Type II anti-CD20 monoclonal antibody. It has greater direct cell death induction and antibody-dependent cell-mediated cytotoxicity and lower complement-dependent cytotoxicity than Type I anti-CD20 antibody rituximab. Studies of obinutuzumab in patients (pts) with previously untreated or relapsed/refractory NHL demonstrated clinical activity with an acceptable safety profile. Infusion-related reactions (IRRs) were the most common adverse event, typically associated with the first infusion. Obinutuzumab 1000 mg is being administered over 4 hrs 15 min for the first infusion on Cycle 1 Day 1, and over 3 hrs 15 min for subsequent infusions. Shortening administration times can result in greater patient convenience and more efficient use of infusion facilities. To evaluate the tolerability of a Shorter Duration of Infusion (SDI), we conducted a Phase II study (JO29737, JapicCTI-152848, 'GATS') of G-CHOP (obinutuzumab in combination with CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone]) in Japanese pts with previously untreated CD20-positive B-cell NHL.

Methods

This study included adult pts with previously untreated CD20-positive B-cell NHL. Treatment consisted of 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, with additional doses on Days 8 and 15 of Cycle 1) plus standard CHOP on Day 1 of Cycles 1-6. Obinutuzumab SDI is administered over 1 hr 30 min. Obinutuzumab was administered as an SDI from Cycle 2 to pts who met the following criteria: (1) No ≥ Gr 3 IRR related to obinutuzumab during regular infusions (RI) in Cycle 1, and (2) Lymphocyte count ≤ 5000/µL in peripheral blood prior to SDI. Primary endpoints were tolerability of SDI, pharmacokinetics (PK) of obinutuzumab. Tolerability of SDI was assessed by incidence of ≥ Gr 3 IRR in Cycle 2. Secondary endpoints were overall safety profile and efficacy. IRRs were defined as AEs related to obinutuzumab occurring during infusion or within 24 hrs from the end of infusion. Results were compared to the multicenter, open-label, randomized GOYA study (phase III, RI G-CHOP), and the multicenter, open-label, single-arm GATHER study (phase II, SDI G-CHOP). The GOYA study included 111 Japanese pts.

Results

At database lock date, 35 pts were enrolled and treated, including 19 diffuse large B-cell lymphoma, 13 follicular lymphoma, and 3 other histologies; median age was 66 yrs (range, 35-78); 12/35 female; Ann Arbor stage I 11.4%, II 25.7%, III 20.0%, IV 42.9%; 7/35 positive bone marrow involvement. In 7 pts, treatment was prematurely discontinued due to AE (n=3; infected dermal cyst, bronchiolitis, and pneumonia　aspiration, 1 pt each), progressive disease (n=2), or physician's decision (n=2). Thirty-three pts received at least one SDI of obinutuzumab, given in Cycle 2 and subsequent cycles in 31 pts. Overall, 48.6% of pts (17/35) experienced IRRs. They were Gr 1/2 in all cases and occurred most commonly on Day 1 Cycle 1 (RI). No SDI-associated IRR was observed in Cycle 2, and very rare cases (2 pts) were noted in Cycles 6, 7, and 8. IRRs occurring in ≥5% pts were pyrexia (25.7%), chills (8.6%), and nausea, blood pressure increased, and headache (5.7%). Gr ≥3 AEs observed in ≥10% of pts were neutropenia (40.0%), neutrophil count decreased (25.7%), febrile neutropenia (17.1%), and leukopenia (14.3%). Obinutuzumab concentration just after Cycle 2 SDI was the same level as the concentration in Cycle 8. This shows PK reached a steady state at Cycle 2 and was not affected by shortening of administration. From PK analysis in the GATS study, AUC_7day was 4170±885 µg·day/mL and t_1/2 was 15.4±7.0 day, similar to the GATHER values (AUC_7day, 3300±1130 µg·day/mL; t_1/2, 23.0±15.9 day) after considering individual variability. No ethnic difference was observed. Overall response rate was 82.9% (29/35) (CR 62.9% [22/35], PR 20.0% [7/35]); 2 pts were not evaluable for response.

Conclusions

Obinutuzumab can be safely administered as SDI. No SDI-associated IRR was observed in Cycle 2. A few IRRs were observed with SDI in later cycles, but all were tolerable and manageable. RI and SDI have comparable safety, PK, and efficacy profiles in Japanese and non-Japanese.