Positive data from the second stage of the phase III CLL11 trial, conducted in cooperation between Roche and the German CLL Study Group, compared obinutuzumab (Gazyva?, Genentech/Roche), a glyco-optimised type II CD20 blocker also known as GA101, in combination with chlorambucil to rituximab (Rituxan?, Genentech/Roche) in combination with chlorambucil for people with previously untreated chronic lymphocytic leukemia (CLL) and co-existing medical conditions. The data showed that people treated in the obinutuzumab arm lived nearly a year longer without their disease worsening (progression-free survival, or PFS).[1]
Chronic Lymphocytic Leukemia or CLL is one of the most common forms of blood cancer and in 2013, it is expected that there will be nearly 5,000 deaths from CLL in the United States. Nearly 95% of all cases of CLL start in white blood cells called B-cells that have a protein called CD20 on their surface.
New treatment options
Obinutuzumab is a new 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. The drug is now approved in combination with chlorambucil for people with previously untreated chronic lymphocytic leukemia and is additionally being investigated in a large clinical program, including multiple head-to-head Phase III studies compared to rituximab in indolent non-Hodgkin?s lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL).Obinutuzumab was originally discovered by Roche Glycart AG, a wholly owned, independent research unit of Roche. In September 2000 Glycart was founded as a spin-off company from the Swiss Federal Institute of Technology in Z?rich, Switzerland. Roche acquired the biotechnology company in the summer of 2005. In the United States, obinutuzumab is part of a collaboration between Genentech and Biogen Idec.
CLL11 trial
The CLL11 trial is a Phase III, multicenter, open-label, randomized three-arm study investigating the efficacy and safety profile of obinutuzumab plus chlorambucil, rituximab plus chlorambucil and chlorambucil alone in 781 previously untreated people with CLL and co-existing medical conditions who are in need of therapy. Stage I of the trial compared obinutuzumab plus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone (n=589). Stage II compared obinutuzumab plus chlorambucil directly with rituximab plus chlorambucil (n=663)
The primary endpoint of the study was PFS with secondary endpoints including overall response rate (ORR), overall survival (OS), disease free survival (DFS), minimal residual disease (MRD) and safety profile.
These new data are important because for the first time they showed that obinutuzumab significantly extended progression-free survival when directly compared against rituximab…
Trial results
For patients in the obinutuzumab arm, median PFS was 26.7 months compared with 15.2 months for those in the rituximab arm (HR 0.39, CI 0.31-0.49, p<0.0001). No new safety signals were observed for either obinutuzumab or rituximab. The data have been accepted for presentation during the Plenary Scientific Session of the 55th annual meeting of ASH?, the American Society of Hematology, held in New Orleans, Louisiana later this year. [1]
“Gazyva is the result of years of research for patients with chronic lymphocytic leukemia,” said Hal Barron, M.D., chief medical officer and head of Global Product Development at Genentech/Roche. “These new data are important because they showed for the first time that Gazyva significantly extended progression-free survival when directly compared against Rituxan.” Additional data comparing the obinutuzumab and rituximabtreatment arms showed higher complete response rates (21% compared with 7%) and a ten-fold increase in the percentage of people achieving minimal residual disease or MRD negativity (29.4% compared with 2.5%), which was defined as no detectable disease in the blood at the end of the treatment course.
In addition to the Stage II data being presented at the 55th annual meeting of ASH?, the American Society of Hematology, held in New Orleans, Louisiana later this year, an updated analysis from the first stage (Stage 1a) of the CLL11 study, which compared obinutuzumab in combination with chlorambucil to chlorambucil alone, will also be presented. This analysis showed that people treated with obinutuzumabin combination with chlorambucil lived longer (overall survival, or OS) compared to chlorambucil alone (HR 0.41, 95% CI 0.23-0.74, p=0.002). Given the median observation time of 23 months, median overall survival has not yet been reached in any of the study arms.
Breakthrough therapy designation
Obinutuzumabis the first drug with breakthrough therapy designation to receive U.S. Food and Drug Administration (FDA)approval. This designation was requested by the Genentech/Roche and granted soon after the biologic license application to support marketing approval was submitted to the FDA. The FDA can designate a drug a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.
The FDA also granted obinutuzumabpriority review because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. And the FDA granted obinutuzumaborphan product designation because it is intended to treat a rare disease.
?This approval represents an important new addition to the treatments for patients with CLL,? noted Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA?s Center for Drug Evaluation and Research. ?This approval reflects the promise of the Breakthrough Therapy Designation program, allowing us to work collaboratively with companies to expedite the development, review and availability of important new drugs.?
Roche has also submitted Marketing Authorization Applications to other regulatory authorities around the world, including the European Medicines Agency (EMA). Results for a variety of other trials withobinutuzumab will be presented at the ASH.[2][3][4] Other trials are still ongoing. [5][6][7]
For more information:
[1] Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, et al. Head-To-Head Comparison Of Obinutuzumab (GA101) Plus Chlorambucil (Clb) Versus Rituximab Plus Clb In Patients With Chronic Lymphocytic Leukemia (CLL) and Co-Existing Medical Conditions (Comorbidities): Final Stage 2 Results Of The CLL11 Trial [Abstract]
[2] Brown JR, O’Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, and Kipps TJ. Safety and Efficacy of Obinutuzumab (GA101) with Fludarabine/Cyclophosphamide (G-FC) or Bendamustine (G-B) in the Initial Therapy of Patients with Chronic Lymphocytic Leukemia (CLL): Results from the Phase Ib GALTON Trial (GAO4779g) [Abstract]
[3] Zelenetz AD, Mobasher M, Costa LJ, Flinn I, Flowers CR, Kaminski MS, Sandmann T, et al. Safety and Efficacy Of Obinutuzumab (GA101) Plus CHOP Chemotherapy In First-Line Advanced Diffuse Large B-Cell Lymp
homa: Results From The Phase II GATHER Study (GAO4915g) [Abstract]
[4] Radford J, Cartron G, Morschhauser F, Salles GA, Marcus R, Wenger MK, et al. Obinutuzumab (GA101) Plus CHOP or FC in Relapsed/Refractory Follicular Lymphoma: Final Data From the Maintenance phase of the Phase Ib GAUDI Study (BO21000) [Abstract]
Ongoing clinical trial
[5] NCT01010061 – CLL11: A Study of RO5072759 (GA101) With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia [Study Record Detail]
[6] NCT01998880 – CLL11: A Study of Rituximab With Chlorambucil or Chlorambucil Alone in Patients With Previously Untreated Chronic Lymphocytic Leukemia (Stage 1b)[Study Record Detail]
[7] NCT01113632 – Ofatumumab for Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma [Study Record Detail]
Photo:Obinutuzumab/Gazyva? Label.Photo courtesy: Roche.
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