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V. Leblond et al.
(as G-Clb; in November 2013 in the US and May 2014 in Europe) for this indication.8,9
Following its approval in CLL, a large study (GREEN) was undertaken to further inform the risk-benefit profile of obinutuzumab in a broad population of patients that is representative of that encountered in everyday practice. GREEN (clinicaltrials.gov identifier: 01905943) is an ongoing phase IIIb safety study of obinutuzumab, as a single agent or in combination with chemotherapy, in fit [defined as a Cumulative Illness Rating Scale (CIRS) score of ≤6 and cre- atinine clearance (CrCl) ≥70 mL/minute (min)] and unfit (defined as a CIRS score of >6 and/or CrCl <70 mL/min) patients with previously untreated (first-line) or relapsed/refractory (R/R) CLL. This study is collecting safety data for the largest cohort of CLL patients treated with obinutuzumab to date.
This paper reports data for the primary objective of the GREEN study (a primary analysis snapshot), which was to assess the overall safety and tolerability of obinutuzumab- based treatment. An exploratory objective was to investi- gate the effectiveness of different approaches (including a modified initial obinutuzumab dosage, slower infusion rate and additional steroid pre-medication) to reduce infu- sion-related reactions (IRRs), which were observed during obinutuzumab infusion in the CLL11 trial, particularly during the first administration.2
Methods
Design
GREEN is a non-randomized, non-comparative, open-label study. Patients received intravenous obinutuzumab 1000 mg, alone or with chemotherapy [investigator’s choice of fludarabine- cyclophosphamide (FC), Clb or bendamustine (benda), based pri- marily on fitness; see Online Supplementary Appendix], on days 1 (split over 2 consecutive days), 8 and 15 of cycle 1, and on day 1 of cycles 2-6 (six 28-day cycles). Alternative administration approaches for the first obinutuzumab infusion were studied in three first-line cohorts to assess their effect on IRR mitigation (Online Supplementary Appendix). Patients received intravenous prednisolone (or equivalent) 1 hour (h) pre-dose on day 1/day 2 of cycle 1.
Risk minimization measures, including prophylaxis and investi- gator training (Online Supplementary Appendix), were instigated for patients considered at risk of tumor lysis syndrome (TLS; defined initially as nodes ≥10 cm, or ≥5-<10 cm with lymphocytes ≥25×109/L; definition later expanded for G-benda-treated patients following 2 fatal TLS cases) (Online Supplementary Appendix). Neutropenia prophylaxis was also recommended (Online Supplementary Appendix).
GREEN was conducted according to the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws/regula- tions. Study documentation was approved by institutional review boards/ethics committees at each site. Patients gave written informed consent.
Patients
Patients were aged 18 years or over with CLL requiring treat- ment [National Cancer Institute/International Workshop on Chronic Lymphocytic Leukemia (NCI/iwCLL) criteria10], an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate hematologic function (see Online Supplementary Appendix for eligibility criteria).
Study procedures
Adverse events (AEs) were graded by NCI Common Terminology Criteria for AEs version 4.0. Response was assessed by investigators according to NCI/iwCLL criteria10 at the final response assessment, scheduled 84 days after the last dose of study medication.
Statistical analysis
The primary end point was safety/tolerability. Safety outcomes included AEs, grade ≥3 AEs (primary outcome of interest), serious AEs (SAEs), and AEs of special/particular interest (AESIs/AEPIs). Overall response rate (ORR) and complete response [(CR; includ- ing CR with incomplete marrow recovery (CRi)] at the final response assessment were among the secondary efficacy end points (Online Supplementary Appendix). Time-to-event end points are not presented due to insufficient follow up (median, 20.8-28.8 months, depending on treatment); post-treatment fol- low up is still ongoing for patients who have not discontinued the study.
IRRs were defined as any AE occurring during/within 24 h of obinutuzumab infusion and considered related to obinutuzumab. IRR incidence in first-line patients was an exploratory end point.
Safety was evaluated in patients treated with at least one dose of study medication. Response was assessed in the intent-to-treat (ITT) population comprising all enrolled patients. A sample size of 950 patients [630 first-line (approximately equal proportions of fit and unfit) and 320 R/R patients] was planned [based on adequate precision, by 95% Clopper-Pearson confidence intervals (CIs), to estimate incidence rate of grade ≥3 AEs if the observed rate was 1-25%], with no formal statistical hypothesis testing. As a non-randomized study, treatment comparability was not applica- ble.
Data are presented using descriptive statistics. Incidence rates and two-sided 95% Clopper-Pearson CI were calculated for grade ≥3 AEs and ORRs.
Additional AEs and response amendments were reported late by some sites. While not captured here, updates are reported in the Online Supplementary Appendix.
Results
Patients
Patients were enrolled between October 2013 and March 2016 at 169 centers in 31 countries in Africa, North and South America, Asia and Europe. This primary analy- sis took place after all treated patients had finished study treatment and undergone a final response assessment (data cut-off for primary snapshot analysis, December 29, 2016).
The ITT population comprised 972 patients and the safety population included 971 patients [630 (64.8%) first- line, including 339 (34.9%) fit (CIRS ≤6 and CrCl ≥70 mL/min) and 291 (29.9%) unfit (CIRS >6 and/or CrCl <70 mL/min) patients; and 341 (35.1%) R/R patients]; one first-line patient was enrolled but not treated and there- fore not included in the safety population. Seven patients from one site in Romania were excluded from the analy- ses due to non-compliance with Good Clinical Practice guidelines.
At the data cut-off, 195 (20.1%; 80 first-line and 115 R/R) ITT patients had discontinued the study and 777 (79.9%; 551 first-line and 226 R/R) were still on study (all in follow up). Primary reasons for study discontinuation included death [n=105 (10.8%); 40 first-line and 65 R/R], withdrawal of consent (n=63, 6.5%), AE (n=10, 1.0%),
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haematologica | 2018; 103(11)