The purpose of this study is to assess the safety and efficacy of the combination of ofatumumab and bendamustine in patients with previously untreated or relapsed chronic lymphocytic leukemia. Patients received IV ofatumumab (cycle 1: 300 mg day 1 and 1,000 mg day 8; cycles 2–6: 1,000 mg on day 1 every 28 days) and IV bendamustine 90 mg m −2 (previously untreated) or 70 mg m −2 (relapsed) on days 1 and 2 of each 28‐day cycle, for up to 6 cycles. Forty‐four previously untreated and 53 relapsed patients were enrolled. Median age was 62.5 years (previously untreated) and 68 years (relapsed); relapsed patients had received a median of 1 (range 1–11) prior therapy. The investigator‐assessed overall response rate was 95% (43% complete response [CR]) for the previously untreated, and 74% (11% CR) for the relapsed patients. The regimen was well tolerated with 89% (previously untreated) and 85% (relapsed patients) receiving all 6 cycles. No unexpected toxicities were reported. Grade 3/4 events occurred in 57% of previously untreated, and 72% of relapsed patients. At ∼29 months’ follow‐up, the median progression‐free survival (PFS) was not reached for the previously untreated population, and the 28‐month PFS estimate was 72.3%. The median PFS for the relapsed population was 22.5 months (95% CI: 14.0–27.3 months). The combination of ofatumumab and bendamustine was well tolerated and effective in these previously untreated or relapsed populations. Am. J. Hematol. 91:900–906, 2016. © 2016 Wiley Periodicals, Inc.

Background Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options.Methods We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1: 1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189.Findings We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22.4 months (95% CI 19.0-25.2) in the group assigned to chlorambucil plus ofatumumab compared with 13.1 months (10.6-13.8) in the group assigned to chlorambucil only (hazard ratio 0.57, 95% CI 0.45-0.72; p<0.0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group.Interpretation Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy.

e22085 Background: Ofatumumab is an anti-CD20 monoclonal antibody that induces cell lysis primarily through complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). Given ADCC is regulated by Fc-gamma receptors (FCGRs), two nonsynonymous variants were evaluated in 5 clinical studies for an association with ofatumumab efficacy. Methods: Germline DNA was collected for ofatumumab-treated subjects with DLBCL from OMB110927 and OMB110928 (81% (227/281)), and with CLL from OMB110911, OMB115991 and OMB114242 (89% (353/397)). FCGR3A V158F and FCGR2A H131R genotypes generated by validated TaqMan and Sanger sequencing assays were evaluated for association with improved ofatumumab efficacy. One-tailed tests were performed under an additive genetic model by exact logistic regression for overall response (OR) and a Cox proportional hazards model for progression-free survival (PFS). The significance threshold for the primary objective assessing FCGR3A 158V on OR was p < 0.05 in CLL and DLBCL. The threshold for remaining objectives was p < 0.02 in CLL and p < 0.01 in DLBCL. Results: In the primary DLBCL meta-analysis using the OMB110927 investigator-assessed and OMB110928 independent review committee OR evaluations, a non-significant improvement in OR to ofatumumab (n = 225; p = 0.059, odds ratio = 0.69 (95% CI 0.44, 1.10)) as well as a non-significant improvement in PFS (p > 0.01 hazards ratio = 0.82 (95% CI 0.62, 1.09)) was seen with FCGR3A V allele carriage. A post-hoc meta-analysis of the investigator-assessed efficacy endpoints in both DLBCL studies yielded a statistically significant improvement in OR (n = 225; p = 0.029, odds ratio = 0.62 (95% CI 0.38, 1.01)). There was no evidence of an effect of this variant on ofatumumab efficacy in CLL (p > 0.05). Also, there was no evidence of an effect of FCGR2A H131R on ofatumumab response in CLL (p > 0.02) or DLBCL (p > 0.01). Conclusions: A trend for improvement in response to ofatumumab with FCGR3A 158V allele carriage was observed in DLBCL. These results suggest a role of ADCC in ofatumumab treatment of DLBCL subjects, and subject to independent confirmation, that this variant may have value as a candidate marker for improved efficacy in that setting.

Ofatumumab is a human monoclonal antibody that binds to a unique CD20 epitope on the surface of B lymphocytes, resulting in efficient lysis of CD20‐expressing cells via complement‐dependent cytotoxicity and antibody‐dependent cell‐mediated cytotoxicity. The potential effect of ofatumumab on cardiac repolarization and the relationship between ofatumumab concentration and change in corrected QT interval (ΔQTcF) were evaluated in data from three clinical trials in 82 patients with chronic lymphocytic leukemia receiving ofatumumab alone (n = 14), ofatumumab with chemotherapy (n = 33), and chemotherapy alone (n = 35). Because of ofatumumab accumulation, baseline QTcF interval was recorded prior to the first infusion for each patient. No patient had a post‐baseline QTcF interval >480 milliseconds or a ΔQTcF >60 milliseconds; five patients (four on ofatumumab) had a ΔQTcF between 30 and 60 milliseconds. At cycle 6 (week 21; 308 μg/mL), there was an increase in QTcF in patients on ofatumumab treatment, with an estimated between‐treatment difference (90% CI) of 12.5 (4.5, 20.5) milliseconds. However, at the visit with the highest median concentration (week 8; 1386 μg/mL), median ΔQTcF was 4.8 milliseconds. There was no significant relationship between ofatumumab plasma concentration and ΔQTcF. Ofatumumab did not have a clinically significant effect on cardiac repolarization.

The primary objective was to determine if a single dose of casopitant 90 mg added to ondansetron and dexamethasone would improve the control of chemotherapy-induced nausea and vomiting (CINV) over 0–120 h following initiation of oxaliplatin-based moderately emetic chemotherapy (MEC) compared to ondansetron and dexamethasone alone.

Background Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens.Methods The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries. All 810 patients enrolled in the trial received dexamethasone and ondansetron. Patients were randomly assigned to also receive placebo (n=269), single oral dose of casopitant mesylate (150 mg oral, n=271), or 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on (lay 1 plus 50 mg oral on days 2 and 3, n=270). Randomisation was done using a central telephone system at the study level, because some centres were expected to recruit only a few patients during the study period. The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h after receiving HEC. Efficacy analysis was done on the modified intention-to-treat population (n=800), which included all patients who received placebo or study drug and HEC (n=265 control, n=266 single-dose oral casopitant mesylate, n=269 3-day intravenous and oral casopitant mesylate). Safety was reported in 802 patients who received either placebo or study medication. This study is registered with ClinicalTrials.gov, NCT00431236.Findings Significantly more patients in each casopitant group achieved complete response in cycle 1 of HEC treatment than did those in the control group (175 [66%] patients in the control group, 228 [86%] in the single-dose oral casopitant mesylate group [p<0.0001 vs control], and 214 (80%] in the 3-day intravenous plus oral casopitant mesylate group (p=0.0004 vs control]). This improvement was sustained over multiple cycles of HEC. Adverse events occurred in 205 (77%) patients in the single-dose oral casopitant mesylate group and 203 (75%) patients in the 3-day intravenous and oral casopitant mesylate group compared with 194 (73%) of patients in the control group. The most common serious adverse events were neutropenia (n=5 [3%] in the control group, n=3 [1%] in the single-dose oral casopitant mesylate group, and n=11 [4%] in the 3-day intravenous plus oral casopitant mesylate group), febrile neutropenia (n=1 [<1%] in the control group, n=4 [1%] in the single-dose oral casopitant mesylate group, and n=6 [2%] in the 3-day intravenous plus oral casopitant mesylate group), and dehydration (n=4 [2%] in the control group, n=2 [<1%] in the single-dose oral casopitant mesylate group, and n=1 [<1%] in the 3-day intravenous plus oral casopitant mesylate group).Interpretation A three-drug regimen including a single oral dose or 3-day intravenous plus oral regimen of casopitant mesylate plus dexamethasone and ondansetron significantly reduced CINV events in patients receiving HEC compared with a two-drug regimen of dexamethasone and ondansetron.