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Obinutuzumab (Gazyva)

Obinutuzumab ia a humanised monoclonal antibody designed to attach to CD20, a protein found only on B-cells. It attacks targeted cells both directly and together with the body's immune system.

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Web Resources: Obinutuzumab
Latest Research Publications

Web Resources: Obinutuzumab (7 links)

Latest Research Publications

Cheson BD, Trask PC, Gribben JG, et al.
Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone.
Ann Hematol. 2017; 96(2):253-259 [PubMed] Free Access to Full Article Related Publications
We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL.

Edelmann J, Gribben JG
Obinutuzumab for the treatment of indolent lymphoma.
Future Oncol. 2016; 12(15):1769-81 [PubMed] Related Publications
Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody designed for strong induction of direct cell death and antibody-dependent cell-mediated cytotoxicity. The Phase III GADOLIN trial tested the clinical efficacy of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy in rituximab-refractory indolent non-Hodgkin lymphoma versus treatment with bendamustine alone. It demonstrated significantly longer progression-free survival for the obinutuzumab-containing regimen in this difficult to treat patient group. Based on the results of this trial, US FDA approval was most recently granted for obinutuzumab in the treatment of follicular lymphoma that has relapsed after or was refractory to a rituximab-containing regimen. This article summarizes the available data on chemistry, pharmacokinetics, clinical efficacy and safety of obinutuzumab in the treatment of indolent non-Hodgkin lymphoma.

Reda G, Orofino N, Cassin R, et al.
Treating chronic lymphocytic leukemia with obinutuzumab: safety and efficacy considerations.
Expert Opin Drug Saf. 2016; 15(6):865-73 [PubMed] Related Publications
INTRODUCTION: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL).
AREAS COVERED: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy. Moreover, a comparison with other anti-CD20 MoAb is performed. The principal available studies on obinutuzumab are reviewed, focusing on CLL. A PubMed literature search (August 2002 to September 2015) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL.
EXPERT OPINION: Obinutuzumab, a third-generation anti-CD20 MoAb, is a safe and effective treatment for elderly patients who are un-fit for fludarabine-based regimen. Its use, proven in the CLL11 study and the results of many ongoing trials evaluating other obinutuzumab-based regimen can lead obinutuzumab to be a candidate to replace rituximab as the first-line treatment option.

Burger JA
Obinutuzumab: the more the merrier?
Blood. 2016; 127(1):6-8 [PubMed] Free Access to Full Article Related Publications
In this issue of Blood, Byrd et al present data from a randomized phase 2 study in which 78 previously untreated patients with chronic lymphocytic leukemia (CLL) received 8 cycles of either 1000 mg (the current standard dose) or 2000 mg of the anti-CD20 monoclonal antibody (mAb) obinutuzumab. The authors report a higher overall response rate with higher doses of obinutuzumab (67% vs 49%), but there was no significant difference in progression-free survival (PFS) between groups.

Snowden A, Hayden I, Dixon J, Gregory G
Prevention and management of obinutuzumab-associated toxicities: Australian experience.
Int J Nurs Pract. 2015; 21 Suppl 3:15-27 [PubMed] Related Publications
Patients with chronic lymphocytic leukaemia (CLL) are typically diagnosed at an advanced age and may have multiple co-existing conditions, augmenting the challenges of treating their CLL. Aggressive cytotoxic therapies are often poorly tolerated in this patient population. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody indicated in combination with chlorambucil for previously untreated CLL. The approval of this drug was based on the pivotal CLL11 trial, which demonstrated longer progression-free survival vs. rituximab/chlorambucil and chlorambucil alone in patients with significant co-existing medical conditions and/or poor renal function. However, a higher risk of infusion-related reactions (IRRs) was demonstrated with obinutuzumab-based therapy. We highlight important nursing care considerations to help prevent and successfully manage IRRs and other important adverse events, to improve the treatment experience of patients receiving obinutuzumab infusions and to enable them to complete their treatment and receive optimal benefit. Premedication, drug handling, dosing, administration, monitoring and documentation are discussed.

Cartron G, Hourcade-Potelleret F, Morschhauser F, et al.
Rationale for optimal obinutuzumab/GA101 dosing regimen in B-cell non-Hodgkin lymphoma.
Haematologica. 2016; 101(2):226-34 [PubMed] Free Access to Full Article Related Publications
Obinutuzumab (GA101) is a type II, glycoengineered anti-CD20 monoclonal antibody for the treatment of hematologic malignancies. Obinutuzumab has mechanisms of action that are distinct from those of rituximab, potentially translating into improved clinical efficacy. We present the pharmacokinetic and clinical data from the phase I/II GAUGUIN and phase I GAUDI studies that were used to identify the obinutuzumab dose and regimen undergoing phase III assessment. In phase I (GAUGUIN and GAUDI), non-Hodgkin lymphoma patients received up to a maximum 9 fixed doses (obinutuzumab 50-2000 mg). In GAUGUIN phase II, patients received obinutuzumab 400/400 mg or 1600/800 mg [first dose day (D)1, D8, cycle (C) 1; second dose D1, C2-C8]. The influence of demographic factors on pharmacokinetics and drug exposure on tumor response and toxicity were analyzed using exploratory graphical analyses. Obinutuzumab serum concentrations with 1600/800 mg were compared with a 1000 mg fixed-dose regimen (D1, D8 and D15, C1; D1, C2-C8) using pharmacokinetic modeling simulations. Factors related to CD20-antigenic mass were more influential on obinutuzumab pharmacokinetics with 400/400 versus 1600/800 mg. Higher serum concentrations were observed with 1600/800 versus 400/400 mg, irrespective of CD20-antigenic mass. Tumor shrinkage was greater with 1600/800 versus 400/400 mg; there was no significant increase in adverse events. Fixed dose 1000 mg with an additional C1 infusion resulted in similar serum concentrations to 1600/800 mg in model-based analyses. The obinutuzumab 1000 mg fixed-dose regimen identified in this exploratory analysis was confirmed in a full covariate analysis of a larger dataset, and is undergoing phase III evaluation. GAUGUIN and GAUDI are registered at www.clinicaltrials.gov (clinicaltrials.gov identifier:00517530 and 00825149, respectively).

García-Muñoz R, López-Díaz-de-Cerio A, Feliu J, et al.
Follicular lymphoma: in vitro effects of combining lymphokine-activated killer (LAK) cell-induced cytotoxicity and rituximab- and obinutuzumab-dependent cellular cytotoxicity (ADCC) activity.
Immunol Res. 2016; 64(2):548-57 [PubMed] Related Publications
Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity. We analyzed the LAK cell-induced cytotoxicity and rituximab (R)- and obinutuzumab (GA101)-induced ADCC activity. We show that LAK cells generated from FL patients induce cytotoxicity against tumor cell lines. R and GA101 enhance cytolysis through ADCC activity of LAK cells. Impaired LAK cell cytotoxicity and ADCC activity were detected in 50 % of patients. Percentage of NK cells in LAK infusions were correlated with the R- and GA101-induced ADCC. Our results indicate that the combination of R or GA101 and LAK cells should be an option as frontline maintenance therapy in patients with FL.

Byrd JC, Flynn JM, Kipps TJ, et al.
Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia.
Blood. 2016; 127(1):79-86 [PubMed] Free Access to Full Article Related Publications
Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205.

Awasthi A, Ayello J, Van de Ven C, et al.
Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL.
Br J Haematol. 2015; 171(5):763-75 [PubMed] Related Publications
Obinutuzumab is a novel glycoengineered Type-II CD20 monoclonal antibody. CD20 is expressed in approximately 100% of children and adolescents with Burkitt lymphoma (BL) and 40% with precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL). We evaluated the anti-tumour activity of obinutuzumab versus rituximab against rituximab-resistant (Raji 4RH) and -sensitive (Raji) BL and pre-B-ALL (U698-M) cells in vitro and in human BL or Pre-B-ALL xenografted mice. We demonstrated that obinutuzumab compared to rituximab significantly enhanced cell death against Raji 35·6 ± 3·1% vs. 25·1 ± 2·0%, (P = 0·001), Raji4RH 19·7 ± 2·2% vs. 7·9 ± 1·5% (P = 0·001) and U-698-M 47·3 ± 4·9% vs. 23·2 ± 0·5% (P = 0·001), respectively. Obinutuzumab versus rituximab also induced a significant increase in antibody-dependent cellular cytotoxicity (ADCC) with K562-IL15-41BBL expanded NK cells against Raji 73·8 ± 8·1% vs. 56·81 ± 4·6% (P = 0·001), Raji-4RH 40·0 ± 1·6% vs. 0·5 ± 1·1% (P = 0·001) and U-698-M 70·0 ± 1·6% vs. 45·5 ± 0·1% (P = 0·001), respectively. Overall survival in tumour xenografted mice receiving 30 mg/kg of obinutuzumab was significantly increased when compared to those receiving 30 mg/kg of rituximab in BL; Raji (P = 0·05), Raji4RH (P = 0·02) and U698-M (P = 0·03), respectively. These preclinical data suggest obinutuzumab is significantly superior to rituximab in inducing cell death, ADCC and against rituximab-sensitive/-resistant BL and pre-B-ALL xenografted mice. Taken together, these preclinical results provide evidence to suggest that future investigation of obinutuzumab is warranted in patients with relapsed/refractory CD20(+) BL and/or pre-B-ALL.

Dupuis J
Obinutuzumab in chronic lymphocytic leukemia.
Future Oncol. 2015; 11(18):2503-13 [PubMed] Related Publications
Obinutuzumab is the second next-generation monoclonal anti-CD20 antibody (after ofatumumab) to enter clinical practice in chronic lymphocytic leukemia. Its superiority in association with chlorambucil as compared with chlorambucil alone has led to its approval as a first-line treatment for chronic lymphocytic leukemia, for patients who are not candidates for a more intensive treatment.

Sehn LH, Goy A, Offner FC, et al.
Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study.
J Clin Oncol. 2015; 33(30):3467-74 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Obinutuzumab (GA101), a novel glycoengineered type II anti-CD20 monoclonal antibody, demonstrated responses in single-arm studies of patients with relapsed/refractory non-Hodgkin lymphoma. This is the first prospective, randomized study comparing safety and efficacy of obinutuzumab with rituximab in relapsed indolent lymphoma. The primary end point of this study was the overall response rate (ORR) in patients with follicular lymphoma after induction and safety in patients with indolent lymphoma.
PATIENTS AND METHODS: A total of 175 patients with relapsed CD20(+) indolent lymphoma requiring therapy and with previous response to a rituximab-containing regimen were randomly assigned (1:1) to four once-per-week infusions of either obinutuzumab (1,000 mg) or rituximab (375 mg/m(2)). Patients without evidence of disease progression after induction therapy received obinutuzumab or rituximab maintenance therapy every 2 months for up to 2 years.
RESULTS: Among patients with follicular lymphoma (n = 149), ORR seemed higher for obinutuzumab than rituximab (44.6% v 33.3%; P = .08). This observation was also demonstrated by a blinded independent review panel that measured a higher ORR for obinutuzumab (44.6% v 26.7%; P = .01). However, this difference did not translate into an improvement in progression-free survival. No new safety signals were observed for obinutuzumab, and the incidence of adverse events was balanced between arms, with the exception of infusion-related reactions and cough, which were higher in the obinutuzumab arm.
CONCLUSION: Obinutuzumab demonstrated a higher ORR without appreciable differences in safety compared with rituximab. However, the clinical benefit of obinutuzumab in this setting remains unclear and should be evaluated within phase III trials.

Illidge T, Klein C, Sehn LH, et al.
Obinutuzumab in hematologic malignancies: lessons learned to date.
Cancer Treat Rev. 2015; 41(9):784-92 [PubMed] Related Publications
The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.

Seiter K, Mamorska-Dyga A
Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia.
Clin Interv Aging. 2015; 10:951-61 [PubMed] Free Access to Full Article Related Publications
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. Fludarabine-based regimens demonstrate higher response rates in younger patients but have a significant risk of infection and are thus poorly tolerated by older, frail patients. Anti-CD20 monoclonal antibodies have added to the efficacy of chemotherapy in CLL. Obinutuzumab is a potent Type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular toxicity and direct cell death compared with rituximab. In Phase I studies, infusion reactions and neutropenia were the predominant toxicities. Phase II studies demonstrated efficacy both as a single agent and in combination with chemotherapy in patients with CLL. The CLL11 trial was a Phase III randomized trial of chlorambucil alone or with either obinutuzumab or rituximab in elderly, unfit patients. Progression-free survival (the primary end point) was 26.7 months for patients receiving obinutuzumab plus chlorambucil versus 16.3 months for those receiving rituximab plus chlorambucil and 11.1 months for those receiving chlorambucil alone (P<0.001). Overall survival was improved for patients receiving obinutuzumab plus chlorambucil versus chlorambucil alone (P=0.002). This trial led to the US Food and Drug Administration (FDA) approval of obinutuzumab in this patient population.

Morabito F, Gentile M, Seymour JF, Polliack A
Ibrutinib, idelalisib and obinutuzumab for the treatment of patients with chronic lymphocytic leukemia: three new arrows aiming at the target.
Leuk Lymphoma. 2015; 56(12):3250-6 [PubMed] Related Publications
Over the last 20 years there have been sustained and dramatic improvements in the therapy of chronic lymphocytic leukemia (CLL). Until 1990, therapy for CLL was based on alkylating agents, chlorambucil and cyclophosphamide, which did not impact meaningfully on overall survival. The more recent therapeutic regimens, built on combination chemoimmunotherapy, achieve complete responses in 40-50% of cases. However, these regimens are limited in their applicability mostly to the treatment of younger and physically fit patients due to their associated toxicity. Furthermore, since disease progression and drug resistance are considered inevitable, CLL remains incurable. Fortunately, significant progress in the understanding of CLL biology has enabled the development of new molecular drugs targeting the B-cell receptor signaling pathway, such as ibrutinib and idelalisib, which have shown impressive results in patients with relapsed/refractory disease or with TP53 mutation/deletion. Furthermore, obinutuzumab, a type II anti-CD20 antibody, which results in direct cell death and antibody-dependent cell-mediated cytotoxicity, also has proven efficacy when used in combination with chlorambucil in previously untreated and unfit patients. All these three new drugs have recently received FDA approval for the treatment of CLL. This review focuses on the role of ibrutinib, idelalisib and obinutuzumab in therapy of CLL.

Sanford DS, Wierda WG, Burger JA, et al.
Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.
Clin Lymphoma Myeloma Leuk. 2015; 15(7):385-91 [PubMed] Free Access to Full Article Related Publications
Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

Brown JR, O'Brien S, Kingsley CD, et al.
Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial.
Blood. 2015; 125(18):2779-85 [PubMed] Free Access to Full Article Related Publications
Obinutuzumab is a type 2, glycoengineered, anti-CD20 antibody recently approved with chlorambucil for the initial therapy of chronic lymphocytic leukemia (CLL). In this nonrandomized, parallel-cohort, phase 1b, multicenter study, we explored the safety and preliminary efficacy of obinutuzumab-bendamustine (G-B) or obinutuzumab fludarabine cyclophosphamide (G-FC) for the therapy of previously untreated fit patients with CLL. Patients received up to 6 cycles of G-B (n = 20) or G-FC (n = 21). The primary end point was safety, with infusion-related reactions (88%, grade 3-4 20%) being the most common adverse event and grade 3-4 neutropenia in 55% on G-B and 48% on G-FC. Mean cycles completed were 5.7 for G-B and 5.1 for G-FC, with 2 and 7 early discontinuations, respectively. The objective response rate (ORR) for G-B was 90% (18/20) with 20% complete response (CR) and 25% CR with incomplete marrow recovery (CRi). The ORR for G-FC was 62% (13/21), with 10% CR and 14% CRi, including 4 patients not evaluable. With a median follow-up of 23.5 months in the G-B cohort and 20.7 months in the G-FC cohort, no patient has relapsed or died. We conclude that obinutuzumab with either B or FC shows manageable toxicity and has promising activity. This study was registered at www.clinicaltrials.gov as #NCT01300247.

Hoy SM
Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia.
Drugs. 2015; 75(3):285-96 [PubMed] Related Publications
Obinutuzumab (Gazyva(®); Gazyvaro(®)) is an intravenously administered, glycoengineered, humanized, type II, anti-CD20 monoclonal antibody of the IgG1 subclass. It is available in the EU and the USA as combination therapy with oral chlorambucil in adults with previously untreated chronic lymphocytic leukaemia (CLL). In a multinational phase III study in this patient population, obinutuzumab plus chlorambucil significantly prolonged progression-free survival compared with oral chlorambucil alone and intravenous rituximab plus oral chlorambucil. Significant advantages with obinutuzumab plus chlorambucil over chlorambucil alone and rituximab plus chlorambucil were also observed in event-free survival, the time to a new anti-leukaemia treatment and overall response. The overall survival benefit with obinutuzumab plus chlorambucil is as yet unclear, although the most recent analysis suggests a benefit over chlorambucil alone. In the phase III study, obinutuzumab plus chlorambucil had a manageable tolerability profile in accordance with what would be expected for an anti-CD20 antibody. Neutropenia and infusion-related reactions were the most frequently reported grade 3 or higher treatment-emergent adverse events. In the majority of patients, infusion-related reactions were mild to moderate in severity and occurred predominantly during the first infusion and were managed by slowing or temporarily halting the infusion. Thus, current evidence suggests that obinutuzumab plus chlorambucil is a welcome addition to the treatment options currently available for adults with previously untreated CLL and is recommended by the National Comprehensive Cancer Network guidelines as the preferred first option for some, including those with comorbidities.

Chung C, Lee R
Ibrutinib, obinutuzumab, idelalisib, and beyond: review of novel and evolving therapies for chronic lymphocytic leukemia.
Pharmacotherapy. 2014; 34(12):1298-316 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a neoplasm resulting from the progressive accumulation of functionally incompetent monoclonal B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. It is the most common leukemia in Western countries and typically occurs in elderly patients. Initial treatment of CLL often includes a first-generation anti-CD20 antibody (rituximab) with chemotherapy and is the current standard of treatment for "younger" old adults (< 70 yrs of age) or older, clinically fit patients. However, because disease progression and drug resistance are inevitable, patients typically die from their disease or treatment-related complications. Improved understanding of the B-cell receptor signaling pathway, which is essential for normal B-cell growth and tumorigenesis, has led to the development of targeted therapies, with improved short-term clinical outcomes. Ibrutinib, obinutuzumab, and idelalisib, three novel agents recently approved by the U.S. Food and Administration for CLL, all have the potential to change the treatment paradigm. In this article, we describe the pathogenesis of CLL and some of its prognostic factors. Emphasis is on the pharmacology, dosing, clinical efficacy, safety, and place of therapy of ibrutinib, obinutuzumab, and idelalisib. Investigational agents that target different parts of the CLL pathogenic pathway are also described.

Illidge T, Cheadle EJ, Donaghy C, Honeychurch J
Update on obinutuzumab in the treatment of B-cell malignancies.
Expert Opin Biol Ther. 2014; 14(10):1507-17 [PubMed] Related Publications
INTRODUCTION: The anti-CD20 mAb rituximab has revolutionized the treatment of B-cell malignancies, improving outcome for patients. Despite these improvements, the majority of patients still relapse and become refractory to rituximab. Further efforts to improve anti-CD20 mAb efficacy have recently focused on obinutuzumab /GA101, a novel anti-CD20 mAb glycoengineered to display enhanced Fc-mediated effector mechanisms and induce direct cell death.
AREAS COVERED: We provide an overview of the current insights into the mechanisms of action of obinutuzumab focusing on how structural modifications and differences to rituximab led to designation of obinutuzumab as a type II antibody. We summarize data from preclinical studies and recent clinical trials including the Phase III trial in chronic lymphocytic leukemia (CLL), which led to FDA approval in November 2013.
EXPERT OPINION: Clinical data are now emerging confirming the promise of the initial preclinical data that demonstrated superior efficacy of obinutuzumab over rituximab at similar dosing. The emerging randomized Phase III data from older comorbid patients with previously untreated CLL demonstrated significant improvements in molecular remission rates and median progression-free survival of obinutuzumab plus chlorambucil versus rituximab plus chlorambucil. This emerging data provide reasons to be optimistic that outcomes for patients with B-cell malignancies can be further improved with obinutuzumab.

Rioufol C, Salles G
Obinutuzumab for chronic lymphocytic leukemia.
Expert Rev Hematol. 2014; 7(5):533-43 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a frequent hematological malignancy that is incurable using standard approaches. Two anti-CD20 monoclonal antibodies (mAb), rituximab and ofatumumab, have been approved for CLL treatment. A new glycoengineered type II humanized anti-CD20 mAb, obinutuzumab (GA101), has been developed and demonstrates increased activity against B-cell malignancies by inducing direct cell death and better antibody-dependent cellular cytotoxicity. In a recent randomized Phase III study in patients with newly diagnosed CLL and coexisting conditions, obinutuzumab plus chlorambucil demonstrated significant improvement in progression-free survival and several other outcome parameters, in contrast to rituximab plus chlorambucil. Grade 3-4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Obinutuzumab represents a promising new option for patients with CLL and must be investigated with other chemotherapy regimens or with new targeted agents.

Cartron G, de Guibert S, Dilhuydy MS, et al.
Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study.
Blood. 2014; 124(14):2196-202 [PubMed] Related Publications
GAUGUIN evaluated the safety and efficacy of obinutuzumab (GA101) monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In phase 1 (dose escalation), 13 patients received obinutuzumab 400 to 1200 mg (days 1 and 8 of cycle 1; day 1 of cycles 2-8). In phase 2, 20 patients received a fixed dose of 1000 mg (days 1, 8, and 15 of cycle 1; day 1 of cycles 2-8). Infusion-related reactions occurred in nearly all patients, but few were grade 3/4. Grade 3/4 neutropenia occurred in 7 patients in phase 1 (but was not dose-related) and in 4 patients in phase 2. Overall end-of-treatment response (all partial responses) was 62% (phase 1) and 15% (phase 2); best overall response was 62% and 30%, respectively. Phase 2 median progression-free survival was 10.7 months and median duration of response was 8.9 months. In summary, obinutuzumab monotherapy is active in patients with heavily pretreated relapsed/refractory CLL.

Shah A
Obinutuzumab: a novel anti-CD20 monoclonal antibody for previously untreated chronic lymphocytic leukemia.
Ann Pharmacother. 2014; 48(10):1356-61 [PubMed] Related Publications
OBJECTIVE: To review and summarize data on obinutuzumab, which was approved by the Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL).
DATA SOURCES: A PubMed literature search (August 2002 to March 2014) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. Data were also obtained through the FDA briefing documents and American Society of Hematology abstracts.
STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to human studies published in English. Priority was placed on trials of obinutuzumab in previously untreated CLL.
DATA SYNTHESIS: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody, with a higher affinity for CD20 epitope, leading to superior cytotoxicity compared with rituximab. The FDA approval was based on a phase III, randomized trial of chlorambucil monotherapy (n = 118), chlorambucil plus obinutuzumab (n = 333), or rituximab (n =330) in previously untreated elderly CLL patients. Obinutuzumab was administered intravenously as 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 for subsequent cycles. Median progression-free survival was 26.7 months in the chlorambucil plus obinutuzumab arm. The incidence of grade 3 or higher adverse events in the obinutuzumab plus chlorambucil arm was as follows: neutropenia (33%), infusion-related reactions (20%), thrombocytopenia (10%), and infections (7%).
CONCLUSION: Obinutuzumab in combination with chlorambucil is a safe and effective new treatment option for previously untreated elderly CLL patients. It should become the new preferred therapy for these patients with significant comorbidities who are not candidates for fludarabine-based therapy.

Rogers KA, Jones JA
Obinutuzumab for the treatment of chronic lymphocytic leukemia.
Drugs Today (Barc). 2014; 50(6):407-19 [PubMed] Related Publications
Obinutuzumab is a novel therapeutic anti-CD20 monoclonal antibody recently approved by the United States Food and Drug Administration (FDA) for use in combination with chlorambucil as first-line treatment of chronic lymphocytic leukemia (CLL). It is distinguished from other anti-B-lymphocyte antigen CD20 (anti-CD20) therapeutic antibodies in current clinical use by its type II properties and glycoengineered Fc region. In vitro these unique properties translate into higher rates of antibody-dependent cytotoxicity and direct cell death compared to rituximab, and obinutuzumab demonstrates improved efficacy in human lymphoma xenograft models and whole blood lymphocyte depletion assays. FDA approval was based upon results from a randomized phase III trial comparing treatment with single-agent chlorambucil to the combination of chlorambucil and either rituximab or obinutuzu-mab. The obinutuzumab arm resulted in higher rates of complete remission and significant improvements in progression-free survival versus either comparator regimen. The majority of patients in the obinutuzumab and chlorambucil arm finished all six planned treatment cycles, and therapy was well tolerated. Toxicities of obinutuzumab are similar to those of other anti-CD20 antibodies, although infusion-related reactions and neutropenia appear to be more common. This trial establishes chemoimmunotherapy with obinutuzumab and chlorambucil as an attractive treatment option for CLL patients, particularly those with comorbid medical illnesses or advanced age. Obinutuzumab remains under study in combination with both chemotherapy and novel agents for CLL and non-Hodgkin's lymphoma, where it is expected to find additional clinical applications.

Owen CJ, Stewart DA
Obinutuzumab for B-cell malignancies.
Expert Opin Biol Ther. 2014; 14(8):1197-205 [PubMed] Related Publications
INTRODUCTION: We analyse data for the use of obinutuzumab in the treatment of CD20(+) lymphoproliferative disorders with a focus on chronic lymphocytic leukaemia (CLL). Targeted therapy against CD20 with the mAb rituximab led to significant improvements in survival for patients with B-cell non-Hodgkin lymphoma (NHL) and is the current mainstay of treatment for CD20(+) malignancies. Despite this, many patients relapse or become refractory after rituximab-containing therapies, so efforts have been made to develop better anti-CD20 mAbs. Obinutuzumab recently demonstrated superiority over rituximab in the only published Phase III study comparing the two antibodies.
AREAS COVERED: Obinutuzumab is a humanised, anti-CD20 mAb being compared to rituximab in several Phase III studies. An overview of obinutuzumab, its mechanisms of action and results of Phase I-III studies are presented.
EXPERT OPINION: The demonstration of superiority of obinutuzumab over rituximab in the CLL11 Phase III study is potentially practice-changing. Obinutuzumab has also proven safe and efficacious in CD20(+) NHL in Phase I/II studies and results of Phase III studies in NHL are eagerly awaited. The potential implications of improved outcomes for CLL and NHL with the introduction of this more potent anti-CD20 antibody are tremendous given the impressive results obtained after the introduction of rituximab over a decade ago.

Lin X, Zhu H, Luo Z, et al.
Near-infrared fluorescence imaging of non-Hodgkin's lymphoma CD20 expression using Cy7-conjugated obinutuzumab.
Mol Imaging Biol. 2014; 16(6):877-87 [PubMed] Related Publications
PURPOSE: Obinutuzumab is the first fully humanized and glycoengineered monoclonal antibody (mAb) directly targeting CD20 antigen, which is expressed on B cell lymphocytes and the majority of non-Hodgkin's lymphoma (NHL). This study aims to design a diagnostic molecular probe, Cy7-Obinutuzumab (Cy7-Obi), in which Cy7 is a near-infrared fluorescent dye. This probe is used to noninvasively image CD20 antigen expressed in NHL cells.
PROCEDURES: Cy7-Obi probe was synthesized through nucleophilic substitution reaction between NHS-Cy7 and obinutuzumab. After purification, the conjugate was fully characterized by a series of methods. The immunoreactivity and molecular specificity of the probe were confirmed using flow cytometry and in vitro microscopy on Raji (CD20-positive) cells. For in vivo imaging, Cy7-Obi probe (1 nmol) was injected intravenously in severe combined immunodeficiency (SCID) mice bearing Raji tumors which overexpress CD20 (n = 3) and was imaged with near-infrared fluorescence (NIRF) at 6, 9, 12, 24, 60, and 96 h post-probe injection. For pre-block, obinutuzumab (3.25 mg) was injected intravenously in tumor-bearing mice 6 h before the administration of Cy7-Obi probe.
RESULTS: The synthesized Cy7-Obi probe in this paper mimics obinutuzumab in both structure and function. Flow cytometry analysis of the probe and obinutuzumab on Raji cells showed minor difference in binding affinity/specificity with CD20. The probe showed significant fluorescence signal when it was examined on Raji cells using in vitro microscopy. The fluorescence signal can be blocked by pretreatment with obinutuzumab. The probe Cy7-Obi also showed high tumor uptake when it was examined by in vivo optical imaging on Raji tumor-bearing mice. The tumor uptake can be blocked by pretreatment with obinutuzumab (n = 3, p < 0.05). The in vivo imaging results were also confirmed by ex vivo imaging of dissected organs. Finally, the probe Cy7-Obi has shown excellent tumor targeting and specificity through immunofluorescence analysis.
CONCLUSIONS: We have shown that humanized Cy7-Obi probe can be used for NIRF imaging successfully. The probe may be an effective and noninvasive diagnostic molecular probe capable of tracking CD20 overexpression in NHL.

Kakkar AK, Balakrishnan S
Obinutuzumab for chronic lymphocytic leukemia: promise of the first treatment approved with breakthrough therapy designation.
J Oncol Pharm Pract. 2015; 21(5):358-63 [PubMed] Related Publications
Obinutuzumab (also known as GA101, afutuzumab, Gazyva) is a humanized, glycoengineered type II monoclonal antibody targeted against CD20. The US Food and Drug Administration has approved obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first treatment to receive approval under the agency's breakthrough therapy designation, a program intended to facilitate and expedite the review and development of therapies for serious and life-threatening conditions. In preclinical studies, obinutuzumab has showed superior efficacy, as compared with rituximab, by inducing direct cell death and increased antibody-dependent cellular cytotoxicity activity with less complement-dependent cytotoxicity. Regulatory approval of obinutuzumab is based on a phase III (CLL11) study that demonstrated improved outcomes with a combination of obinutuzumab with chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities. Obinutuzumab plus chlorambucil induced deeper and longer remissions than rituximab plus chlorambucil combination as evidenced by prolongation of progression-free survival and higher complete response and molecular response rates. Marketing applications for obinutuzumab have also been submitted to other regulatory authorities including the European Medicines Agency.

Lee HZ, Miller BW, Kwitkowski VE, et al.
U.S. Food and drug administration approval: obinutuzumab in combination with chlorambucil for the treatment of previously untreated chronic lymphocytic leukemia.
Clin Cancer Res. 2014; 20(15):3902-7 [PubMed] Related Publications
On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11-0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy-designated drug to receive FDA approval.

Obinutuzumab breaks through to FDA approval.
Cancer Discov. 2014; 4(1):OF6 [PubMed] Related Publications
The U.S. Food and Drug Administration approved the monoclonal antibody obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first to receive approval under the agency's breakthrough therapy designation, created in July 2012.

Goede V, Fischer K, Busch R, et al.
Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.
N Engl J Med. 2014; 370(12):1101-10 [PubMed] Related Publications
BACKGROUND: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions.
METHODS: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival.
RESULTS: The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased.
CONCLUSIONS: Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).

Cameron F, McCormack PL
Obinutuzumab: first global approval.
Drugs. 2014; 74(1):147-54 [PubMed] Related Publications
Obinutuzumab (Gazyva™) is an intravenously administered, humanized and glycoengineered, type II anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. It is approved in the US for use in combination with chlorambucil for the first-line treatment of chronic lymphocytic leukaemia (CLL), and has been filed for approval in the EU in this indication. The antibody is based on GlycArt Biotechnology's (later Roche Glycart AG) proprietary GlycoMAb® technology, which uses glycoengineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death. Obinutuzumab is a type II anti-CD20 antibody that induces enhanced direct cell death. The monoclonal antibody is in worldwide phase III development with Roche and its subsidiaries, Genentech and Chugai Pharmaceutical, as well as Biogen Idec, for diffuse large B-cell lymphoma and non-Hodgkin's lymphoma generally, and is also in phase III development in countries outside of the US and EU for CLL.

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