A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies

Obinutuzumab has been shown to be faster than and superior to both rituximab and ofatumumab in inducing direct cell death in malignant B-cells. This was demonstrated by phosphatidylserine exposure and propidium iodide staining [with analysis by fluorescence-activated cell sorting (FACS) and time-lapse microscopy] in a panel of CD20-expressing tumor cell lines [39, 43]. While some researchers have questioned the validity of using FACS to assess mAb-induced direct cell death (because of potential mechanical interference with mAb-mediated homotypic adhesion) [47], multiple studies, using a variety of methods (including FACS), have confirmed that, overall, obinutuzumab induces greater direct cell death than type I mAbs [48‐53] and occurs without disruption of homotypic aggregates [43, 54].

The mechanisms that may underlie the ability of type II anti-CD20 mAbs to directly evoke programmed cell death (PCD) are still poorly understood, but have been investigated in several studies [39, 48, 55]. Honeychurch et al. demonstrated actin-dependent, lysosome-mediated induction of PCD by type II mAbs, such as obinutuzumab or tositumomab, which was directly correlated with the production of reactive oxygen species (ROS) [48]. In contrast, type I mAbs, such as rituximab, induced only minimal levels of ROS and PCD. Generation of ROS mediated by nicotinamide adenine dinucleotide phosphate oxidase, independently of mitochondria, was unaffected by B-cell lymphoma 2 (BCL-2) overexpression and took place downstream of mAb-induced actin cytoskeletal reorganization and lysosome membrane permeabilization. The results thus indicated a newly characterized cell death pathway that is independent of the classical hallmarks of apoptosis and has the potential to bypass mechanisms of apoptotic resistance, thereby eliminating malignant cells that are refractory to conventional chemo- or immunotherapy. A similar mechanism of cell death has also been described for other antibodies targeting B-cell surface antigens, such as HLA-DR or CD37 [56, 57]. In a separate study, Cheadle and colleagues found that PCD induced by type II agents such as obinutuzumab is a form of immunogenic cell death that is characterized by the release of damage-associated pattern molecules, including heat shock protein 90 and adenosine triphosphate. It is believed that this mechanism of PCD could enhance the immune response by inducing dendritic cell mutation and subsequent T-cell proliferation [49].

In contrast to these data, which are largely based on NHL cell lines, ex vivo studies utilizing CLL primary samples suggest that direct cell death induction is not the major mechanism of obinutuzumab-mediated B-cell depletion in CLL [50, 55, 58‐61]. This observation may be a consequence of the lower proliferative state of non-stimulated CLL cells, as compared to NHL cell lines. Thus, in CLL, immune effector-mediated mechanisms (as described below) may play a more important role than direct cell death induction in mediating the antiproliferative effects of obinutuzumab. In line with this assumption, a study has demonstrated that CD40 stimulation can sensitize CLL cells to lysosomal cell death induction by obinutuzumab, providing evidence that drug sensitivity in CLL cells can be modulated by microenvironmental stimuli [55].

Antibody-mediated CDC is initiated by fixing of C1q (the initiating component of the classical complement pathway) to the Fc portion of target-bound antibodies. This triggers a cascade that in turn leads to the formation of C3 and C5 convertase and ultimately to the membrane attack complex (MAC). The MAC then causes cell lysis by disrupting the plasma membrane of the target cell [62].

The ability of CD20 antibodies to mediate CDC appears to be determined by the effect of mAb binding and cross-linking on the redistribution of the target antigen into lipid rafts on the surface of the target cell. The density and positioning of the antigen-antibody complexes influence C1q binding and, in turn, the complement cascade [62]. Complement recruitment as such is a key characteristic distinction between type I CD20 mAbs, such as rituximab and ofatumumab, which mediate strong CDC, and type II CDC antibodies like obinutuzumab, which only mediate weak CDC activity in cellular assays [39, 42, 43]. CDC is therefore not thought to contribute meaningfully to the overall activity of obinutuzumab [38, 62]. Interestingly, the limited capacity of obinutuzumab to fix complement via its Fc portion may further enhance its capability to bind to FcγRIII and mediate ADCC [63].

Glycoengineering as well as subsequent enhancement of affinity for FcγRIIIa (an activating Fc receptor expressed primarily on NK cells) was confirmed as the predominant determinant of the superior ADCC activity of obinutuzumab over type I anti-CD20 mAbs in a series of experiments using NHL cell lines and human PBMCs expressing the V158/V158 or F158/F158 FcγRIIIa receptor [43]. While obinutuzumab was superior to rituximab and ofatumumab in terms of potency and overall cell killing, the ADCC activity of a non-glycoengineered version of obinutuzumab was similar to that of rituximab and ofatumumab, confirming the additional benefit conferred by glycoengineering [43]. Notably, the induction of ADCC was found to be particularly more potent with obinutuzumab than rituximab in the presence of nonspecific human IgG at physiological concentrations, as found in human blood [39].

In an assessment of ADCP, Herter et al. used FACS analysis to show that obinutuzumab, rituximab, and ofatumumab have comparable overall phagocytic activity in NHL cell lines and primary human monocyte-derived macrophages (MDMs) [44]. Rafiq et al. have demonstrated the phagocytic activity of obinutuzumab against membrane-dyed CLL cells undergoing flow cytometry, although ofatumumab and rituximab produced greater phagocytosis than obinutuzumab in these experiments [50]. In a recent report, intravital imaging revealed improved Kupffer cell-mediated phagocytosis of B-cells as an important in vivo mode of action of glycoengineered anti-CD20 mAbs, such as obinutuzumab, which underlies their improved activity compared with non-Fc-engineered antibodies [64].

ADCC is carried out mainly by NK cells, which carry inhibitory killer cell immunoglobulin-like receptors (KIRs) that interact with exposed epitopes on the class I human leukocyte antigen (HLA). Experiments using peripheral blood mononuclear cells (PBMCs) from healthy donors, primary CLL cells from patients, and a variety of cell lines have shown that, because of its Fc modification, obinutuzumab can compensate for inhibitory KIR/HLA interactions [65]. This results in the recruitment of additional NK cells for ADCC, and target cell depletion is not negatively impacted by KIR/HLA interactions [65]. Genotyping of patients participating in the CLL11 study (comparing chlorambucil, rituximab-chlorambucil, and obinutuzumab-chlorambucil in previously untreated patients with CLL) has shown that the prognosis for patients with a low number of KIR/HLA interactions is better than that for patients with a higher number of such interactions [66]. Taken together, these results indicate that ADCC is a key mode of action for obinutuzumab and is influenced by the number of the inhibitory interactions.

Unlike type I anti-CD20 mAbs, type II agents are found to undergo reduced CD20 internalization (Fig. 1) [67]. Indeed, increased stability of surface-accessible CD20 was noted with obinutuzumab relative to both rituximab and ofatumumab using FACS in a human DLBCL cell line and in blood from patients with CLL [43]. Ultimately, this may further enhance the immune effector cell-mediated mechanisms of type II anti-CD20 mAbs, independently of, but in conjunction with, glycoengineering. Furthermore, type II anti-CD20 mAbs may be less susceptible to the development of resistance mechanisms affecting effector-cell-mediated cytotoxicity. The impact of trogocytosis on reducing the efficacy of type II mAbs through shaving of CD20 molecules from the cell surface requires further investigation.

Measurement of overall B-cell depletion in whole blood allows all mechanisms of action of therapeutic antibodies to be assessed in a single assay. Potent B-cell depleting activity in peripheral blood and lymphoid tissue superior to that of rituximab has been reported with obinutuzumab in non-human primate models [39]. In addition, Mössner et al. showed obinutuzumab to be significantly (10–25 times) more potent and 1.5–2.5 times more effective (p < 0.001) than rituximab in depleting B-cells in whole blood from healthy human donors [39]. These results were then confirmed using primary malignant B-cells from a patient with CLL [39]. Superior B-CLL cell depletion in whole blood with obinutuzumab was demonstrated independently by several other research groups [50, 58, 60, 61], whereas Bologna et al. showed that obinutuzumab treatment depleted B-cells in whole blood from CLL patients to a similar extent to rituximab, but at a much faster rate [59]. These findings may reflect the different experimental methods that were used but overall demonstrate the enhanced B-cell-depleting activity of obinutuzumab. Recently, Ysebaert et al. described the effects of rituximab and obinutuzumab on B-cell depletion in 96 CLL patient samples with different prognostic factors [68]. Median proportions of B-cell depletion after whole-blood assay were 22% with rituximab and 63% with obinutuzumab (p < 0.001), independent of their prognostic factors [68].

Finally, obinutuzumab has shown superiority over rituximab in vivo in various human lymphoma xenograft models [39]. Dose-dependent efficacy in the range of 1–30 mg/kg was noted in a staged aggressive SU-DHL4 DLBCL model, with complete tumor regression in all animals and lasting tumor eradication in 90% at the highest dose of 30 mg/kg. In contrast, tumor regression was not shown at any equivalent dose of rituximab [39] or with ofatumumab [43]. In this model, second-line obinutuzumab treatment was also effective in inhibiting the progression of tumors that had progressed under first-line treatment with rituximab and that were no longer responsive to rituximab [39] or ofatumumab [43]. Superior efficacy of obinutuzumab over rituximab or ofatumumab has also been shown in an aggressive disseminated MCL model [39, 43].

Herting et al. described the antitumor activity of obinutuzumab and rituximab alone and in combination with bendamustine, fludarabine, chlorambucil, doxorubicin, and cyclophosphamide/vincristine in subcutaneous murine xenograft models using Z138 MCL and WSU-DLCL2 DLBCL tumors [69]. As obinutuzumab had high single-agent activity in these models, suboptimal doses were used in order to observe combination effects. Superior tumor growth inhibition was achieved with obinutuzumab plus bendamustine over rituximab plus bendamustine, and statistically significant effects versus the respective single treatments were also observed (Fig. 3). In addition, obinutuzumab showed significantly greater activity than rituximab when combined with fludarabine, chlorambucil, or cyclophosphamide/vincristine. Obinutuzumab monotherapy was as effective as, or more effective than, rituximab plus chemotherapy in vivo [69].

Obinutuzumab given as monotherapy has been investigated in the GAUGUIN study (NCT00517530), a multicenter phase Ib/II clinical trial in patients with B-cell malignancies [70‐73]. The primary objective of the phase Ib part of the study was to investigate the safety and tolerability of escalating intravenous doses of obinutuzumab in patients with CD20-positive lymphoid malignancies, including NHL and CLL. This was followed by a phase II part to study efficacy and safety. Patients were adults aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.

The first two reports from GAUGUIN (Table 1) communicated phase I [70] and II [71] results from patients with relapsed/refractory iNHL, most of whom had FL. In the phase I part, 21 patients (median of five prior therapies, 20/21 with prior rituximab) received escalating doses of obinutuzumab monotherapy over eight 21-day cycles. The majority of adverse events (AEs) were infusion-related reactions (IRRs), nearly all of which were of grade 1–2 in severity (Table 1).

IRRs with obinutuzumab, like those seen with rituximab, have been attributed to cytokine release. In previous studies of rituximab, patients with IRRs were found to release greater amounts of interleukin (IL)-8, IL-6, and tumor necrosis factor-alpha than those without IRRs [76‐78]. Patients with a baseline absolute lymphocyte count of ≥50 × 10⁹/l appear to have a particularly high risk of developing IRRs [76‐78]. The incidence and severity of IRRs in patients treated with obinutuzumab is reportedly greater than with rituximab and has been linked to immediate and marked release of IL-6 and IL-8 that is limited to the first infusion and is accompanied by rapid destruction of circulating B-cells and disappearance of circulating NK cells from the peripheral blood [79].

In GAUGUIN, 18 grade 3–4 AEs occurred in 7 patients; all treatment-related grade 4 events were neutropenias, while most grade 3 AEs were hematologic events and IRRs. Notably, there were no dose-limiting toxicities (DLTs). Two of nine rituximab-refractory patients showed a tumor response, and the best overall response rate (ORR) was 43%, with five complete responses (CRs) and four partial responses indicating the promising activity of obinutuzumab.

Phase II data from relapsed/refractory iNHL patients (n = 40; Table 1) showed promising efficacy and acceptable tolerability, particularly in the higher dose group (1600/800 mg) over a median observation time of 33.7 months [71]. Of the phase II patients, 90% had stage III or IV disease and had received a median of two prior rituximab treatments (range 0–5); 45% and 55% were refractory to their last treatment or to rituximab, respectively. End-of-treatment ORRs in rituximab-refractory patients were 8% in the 400/400 mg group and 50% in the 1600/800 mg group. The two CRs were seen in the higher dosage group.

The phase II GAUGUIN study for patients with aggressive forms of B-cell NHL showed similar tolerability and promising efficacy (Table 1) [72]. These patients (25 with DLBCL and 15 with MCL) had received a median of three prior treatments (range 1–17), and 25 (63%) were rituximab-refractory. Of the 25 rituximab-refractory patients, 4 (16%) had objective responses to induction treatment and one responded during follow-up. Four of the five responses were achieved at the 1600/800 mg dose. The best ORR in all patients with aggressive B-cell NHL was 30%. Median response duration (all responders) was 9.8 months; there was no relevant difference in progression-free survival (PFS) between dosage groups after a median of 14.2 months (range 0.3–36.1 months) of observation. Based on both these results and on pharmacokinetic modeling, which showed that obinutuzumab 1000 mg per cycle with additional 1000 mg doses on days 8 and 15 of cycle 1 can achieve exposures similar to the 1600/800 mg regimen used in GAUGUIN [80], a simplified flat-dose 1000 mg schedule was adopted for subsequent phase II and III investigation [81]. It has been hypothesized that differences in CD20 binding, activation of biological pathways, and underlying mechanisms of action compared with type I anti-CD20 mAbs permit the use of flat dosing for obinutuzumab rather than conventional body surface area-based dosing [80]. The 1000-mg flat-dose schedule for obinutuzumab, which has been implemented as the standard dose in clinical trials, rapidly achieves CD20 target saturation in all patients tested, with serum concentrations maintained at this therapeutic level throughout the treatment course [80].

Among 13 phase I patients with relapsed/refractory CLL in the separately reported GAUGUIN CLL study, there was a median response duration of 10.5 months (range 8.5–37 months) in eight partial responders (for a best ORR of 62%; Table 1) [73]. Among 20 patients with CLL who were recruited to phase II, the best ORR was substantially lower (6/20; 30%). This has been linked to a higher baseline tumor burden and consequent lower treatment exposure than in phase I [73]. Median response duration was 8.9 months (range 0.8–26.1 months). Tolerability was acceptable in other groups of patients, with IRRs being the most common AEs (Table 1). Most notably, all CLL patients treated in the GAUGUIN study experienced a rapid and sustained elimination of B-cells in the peripheral blood, which was independent of the dose applied. These findings provided the rationale for investigating obinutuzumab in the phase III CLL11 trial. Data from CLL11 and other dedicated studies in patients with CLL are presented later in this review.

Further data in larger numbers of patients with relapsed iNHL were obtained from the multicenter GAUSS study (NCT00576758) [74]. The initial phase I component of this trial evaluated obinutuzumab doses of 200–2000 mg given once weekly for 4 weeks (induction) followed by maintenance therapy every 3 months for 2 years in 22 patients with relapsed B-cell NHL (including 10 with FL) or CLL [82]. The best ORR was 32%, with a response observed in 15% of rituximab-refractory patients. The maximum tolerated dose was not reached. A flat dose of 1000 mg was selected for the phase II part of GAUSS based on the phase I data and other clinical experience. As summarized in Table 1, 175 patients with relapsed iNHL were enrolled to phase II, of whom 149 had FL. The ORR at the end of induction was higher with obinutuzumab than with rituximab, as shown by investigator assessments at the end of the induction period (45% vs. 33%; p = 0.08) and by a blinded independent review panel (45% vs. 27%; p = 0.01) (Table 1). There was no significant difference between treatments for the secondary endpoint of PFS, but the study was not powered to detect differences. AEs were balanced between the two groups, but there were more IRRs and coughs in the obinutuzumab group (Table 1) [74].

An additional phase I study in 12 Japanese patients, of whom 8 had FL, also showed no DLTs [75]. B-cell depletion was seen in all patients and persisted for the duration of treatment. No disease progression was observed during the treatment period. Moreover, the majority of AEs were of grade 1 or 2 in severity; as in other studies, IRRs predominated (Table 1).

Following the promising activity of obinutuzumab in phase I and II single-agent studies, a number of studies have been carried out in the combination therapy setting. The phase Ib GAUDI study (NCT00825149) examined the safety and antitumor activity of two doses of obinutuzumab (G) (400/400 mg or 1600/800 mg) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; G-CHOP), or with fludarabine and cyclophosphamide (FC; G-FC), as induction therapy in 56 patients with relapsed/refractory FL (Table 2) [83]. These patients had received up to six prior treatments. Patients were allocated to either CHOP or FC by their physicians on the basis of clinical need and the physician’s judgment; allocation to the two obinutuzumab dose regimens was randomized. As seen in the previously described phase I and II monotherapy studies, IRRs were the most common AEs and were predominantly of mild severity (Table 2). Two patients from the G-FC 400/400 mg arm and three from the G-FC 1600/800 mg arm discontinued treatment because of AEs; one other patient in the latter group discontinued because of insufficient response. All rituximab-refractory patients responded to treatment, and the high ORRs noted (Table 2) supported future phase III investigation [83].

As G-CHOP was seen to have a safety profile similar to R-CHOP (rituximab combined with CHOP), the design of the GAUDI study was amended to compare the safety of obinutuzumab plus CHOP or bendamustine in 81 treatment-naïve patients with FL (Table 2) [84]. After 2 years’ maintenance in initial responders who went on to receive obinutuzumab 1000 mg as monotherapy, high CR rates were seen in both treatment arms and opportunistic infections were infrequent [84].

G-CHOP was also investigated in the first-line setting in 80 patients with advanced DLBCL in the GATHER study (NCT01414855) (Table 2) [85]. The ORR and CR rates as determined by investigators were 83% and 55%, respectively (Table 2). IRRs, most of which were grade 1–2 in intensity, were typically observed during the first cycle.

The phase III GADOLIN study (NCT01059630) (Table 2) compared bendamustine monotherapy (120 mg/m² on day 1 and 2, for up to six 28-day cycles) with obinutuzumab (1000 mg on day 1, 8, and 15 of cycle 1 and on day 1 of cycles 2–6 in 28-day cycles) plus bendamustine (90 mg/m² on day 1 and 2, for up to six 28-day cycles) induction and obinutuzumab maintenance (1000 mg every 2 months for 2 years or until progression in patients achieving stable disease or better with induction) in 396 patients with rituximab-refractory iNHL who had received a median of two prior treatments [86]. At a preplanned interim analysis for efficacy, enrollment was stopped and the trial was analyzed in full, as the primary endpoint had been met. Median observation time was 20.3 months for bendamustine alone and 21.9 months for obinutuzumab plus bendamustine. Recruitment had been ongoing between data cutoff and interim analysis, and a significant number of patients were still undergoing treatment. PFS was significantly longer with combination therapy (median not reached) than with bendamustine alone (median 14.9 months) as assessed by an IRF [primary endpoint; hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.40–0.74; p = 0.0001].

Subgroup analyses and secondary endpoints (including PFS by investigator and OS) were consistent and supportive of the primary endpoint. There were no significant differences in IRF-assessed ORR or CR rate at the end of induction. Whether this was due to the differences between groups in bendamustine dosage or to the different modes of action of obinutuzumab and bendamustine was uncertain (Table 2). The prognostic relevance of minimal residual disease (MRD) status in 93 biomarker-evaluable patients with FL in GADOLIN was also investigated [88]. MRD analysis measures the small number of malignant cells that remain after treatment. MRD status was associated with clinical CR rate and improved PFS, and significantly more patients were MRD-negative after induction with obinutuzumab plus bendamustine than after bendamustine alone (82% vs. 43%; p < 0.0001). Median OS was not reached in either arm at the time of reporting, but there were more deaths due to disease progression with bendamustine alone than with obinutuzumab plus bendamustine [86]. Overall, grade ≥3 AEs were more common in the obinutuzumab plus bendamustine group, but grade ≥3 thrombocytopenia and anemia were more frequent in the bendamustine-only group (Table 2).

Emerging data from GADOLIN also suggest improvements in health-related quality of life [89]. The time taken to a ≥6-point worsening from baseline on the Functional Assessment of Cancer Treatment-Lymphoma Trial Outcome Index (FACT-Lym TOI) was 8.0 months in the combination therapy arm and 4.6 months with bendamustine alone. A higher proportion of patients reported meaningful improvements on the lymphoma subscale, lymphoma TOI, and total score with obinutuzumab plus bendamustine than with bendamustine alone [89].

Ongoing phase III combination therapy studies with obinutuzumab include GALLIUM (first-line advanced iNHL; NCT01332968) and GOYA (first-line DLBCL; NCT01287741). GALLIUM aims to assess the efficacy and safety of obinutuzumab plus chemotherapy versus rituximab plus chemotherapy followed by maintenance immunotherapy. After induction, responders will progress to maintenance therapy with their randomized antibody treatment alone, given every 2 months until disease progression or for a maximum of 2 years. In May 2016, at a prespecified interim analysis, the GALLIUM Independent Data Monitoring Committee recommended analysis of the study data as the primary endpoint of investigator-reported PFS had been met [90]. This is the second head-to-head comparative trial against rituximab that has shown a positive result for obinutuzumab, the first being the CLL11 study (described below). In the phase III GOYA trial, previously untreated patients with DLBCL were randomized to obinutuzumab 1000 mg every 21 days (with two additional doses on day 8 and day 15 of cycle 1) or rituximab 375 mg/m² every 21 days for eight cycles in addition to 6–8 cycles of CHOP chemotherapy. Recruitment of 1418 patients was completed in 2014. After the final analysis in July 2016, Roche issued a press release to say that the study’s primary endpoint of improvement in investigator-assessed PFS had not been met. Detailed results are expected to be announced at ASH 2016.

A number of studies have investigated the use of obinutuzumab in patients with CLL. The GAGE study (NCT01414205), a randomized, phase II study in 80 symptomatic, untreated CLL patients, demonstrated significant antitumor activity with both 1000 mg and 2000 mg dosages of obinutuzumab. End of induction response was superior with the higher dosage (Table 3) [91]. The results suggested a possible dose-response relationship, but this requires further investigation and longer follow-up. Obinutuzumab has also shown manageable toxicity and promising activity in combination with either bendamustine or FC in the phase Ib GALTON study (NCT01300247) in 41 patients with previously untreated CLL [92].

In the phase III CLL11 study (Table 3), 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale or an estimated creatinine clearance of 30–69 ml/min were randomized to chlorambucil alone, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil for six 28-day cycles [93]. The main study followed a safety run-in designed to ensure that chlorambucil-containing chemoimmunotherapy regimens were safe in recruited older patients with comorbidities [94]. IRRs and neutropenia were identified as potential risks during the run-in, but none of the specified stopping criteria were met, and the main study was opened for randomization in April 2010.

Both combinations increased PFS significantly over chlorambucil monotherapy; obinutuzumab plus chlorambucil, but not rituximab plus chlorambucil, prolonged OS significantly (Table 3) [95]. Obinutuzumab plus chlorambucil also conferred longer PFS (Table 3) [93, 95] and a higher CR rate (21% vs. 7%) [93] than rituximab plus chlorambucil, and it was associated with significantly and substantially increased time to next treatment (Table 3) [95].

AEs were reported at higher frequencies with obinutuzumab plus chlorambucil than with either of the other two treatments, but toxicities were manageable and the risk of infection was not increased over rituximab plus chlorambucil or chlorambucil alone. Among patients for whom MRD data were available, the proportion who were MRD-negative in bone marrow and peripheral blood at the end of treatment was markedly higher with obinutuzumab plus chlorambucil than with rituximab plus chlorambucil treatment (bone marrow, 18% vs. 3%; peripheral blood, 36% vs. 3%) [96]. MRD in peripheral blood at the end of treatment was an independent prognostic factor for both PFS (HR 5.29; 95% CI 3.48–8.04; p < 0.001) and OS (HR 3.04; 95% CI 1.53–6.03; p = 0.002).

The GREEN study (NCT01905943) is an ongoing, open-label, multicenter, phase IIIb study in patients with previously untreated or relapsed/refractory CLL receiving obinutuzumab alone or in combination with chemotherapy (bendamustine, FC, or chlorambucil). One of the objectives of this study is to investigate the potential of alternative obinutuzumab administration protocols for reducing IRRs. Emerging results suggest that the safety profile of obinutuzumab plus bendamustine is manageable if the appropriate measures are taken (e.g., monitoring at-risk patients for tumor lysis syndrome after the first infusion) [97, 98].

The safety of SDI of obinutuzumab after cycle 1 was evaluated in the GATHER study (first-line advanced DLBCL) (Table 2) [85]. After treatment at the regular infusion rate was deemed safe, based on 20 patients who received the standard-rate infusion with G-CHOP therapy, patients who met the SDI inclusion criteria (who had not experienced a serious and/or grade ≥3 IRR and had a lymphocyte count ≤5000/µl) were treated at the SDI rate. Initially three patients in the cohort received obinutuzumab over 120 min; if none of the three experienced IRRs of grade ≥3, the 90-min infusion was then tested for the remaining patients. Overall, 51 of 80 patients (64%) experienced IRRs, most of which were of grade 1–2 in severity and reported in cycle 1. There were no IRRs of grade ≥3 with the 90-min infusion [85].

SDI with obinutuzumab in combination with chemotherapy (CHOP) is also being investigated in a phase II study in Japanese patients (Table 2) receiving first-line therapy for various types of CD20-positive B-cell NHL. In cycle 1, all patients receive obinutuzumab 1000 mg on day 1 over 4.25 h and on days 8 and 15 over 3.25 h. Patients who meet the criteria for SDI (no serious and/or grade ≥3 IRRs in the first three infusions and lymphocyte count ≤5000/µl prior to SDI) receive their next obinutuzumab infusion over 1.5 h. The primary objectives of the study are to evaluate infusion tolerability, pharmacokinetics, and change in cytokine levels over time.