Date: 2015-12-05
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando
Company: Genentech, a member of the Roche Group (USA - Switzerland)
Product: Gazyva™ (obinutuzumab - GA101)
Action
mechanism: Obinutuzumab is a glycoengineered, fully humanized IgG1 monoclonal antibody with potential antineoplastic activity. Obinutuzumab, a third generation type II anti-CD20 antibody, selectivity binds to the extracellular domain of the human CD20 antigen on malignant human B cells. The Fc region carbohydrates of the antibody, enriched in bisected non-fucosylated glycosylation variants, contribute to its higher binding affinity for human FcgammaRIII receptors compared to non-glycoengineered antibodies, resulting in enhanced antibody-dependent cellular cytotoxicity (ADCC) and caspase-independent apoptosis. In addition, modification of elbow hinge sequences within the antibody variable framework regions may account for the strong apoptosis-inducing activity of R7159 upon binding to CD20 on target cells. Preclinical studies demonstrate that GA101 induces significant B-cell depletion in peripheral blood as well as in lymphoid tissue. It also mediates high antitumor activity in preclinical NHL studies, both as a single agent and in conjunction with chemotherapy.
Genentech is investigating this agent with Biogen Idec.
Disease: chronic lymphocytic leukemia (CLL)
Therapeutic area: Cancer - Oncology
Country: USA - Germany
Trial
details: CLL11 is a Phase III, multicenter, open-label, randomized three-arm study investigating the safety and efficacy profile of GA101 plus chlorambucil compared to Rituxan® plus chlorambucil or chlorambucil alone in nearly 800 previously untreated people with chronic lymphocytic leukemia and coexisting medical conditions. The study is conducted in close collaboration with the German CLL Study Group (DCLLSG). The primary endpoint of the study is PFS with secondary endpoints including overall response rate (ORR), overall survival (OS), disease free survival (DFS), molecular remission and safety profile. Stage 1 included 589 patients and results were reported earlier this year and showed that GA101 plus chlorambucil doubled the time people lived without their disease worsening 23.0 vs. 10.9 months compared to chlorambucil alone (HR=0.14 CI 0.09-0.21 p<0.0001).
The study includes two separate stages. Stage 1 evaluated GA101 plus chlorambucil to chlormabucil alone, and included a pre-planned PFS futility analysis comparing GA101 plus chlorambucil to Rituxan plus chlorambucil. The goal of this futility analysis was to evaluate the likelihood that the study would meet its pre-specified endpoint criteria during Stage 2 analysis - improved efficacy (PFS) in the direct comparison of GA101 plus chlorambucil to Rituxan plus chlorambucil.
Patients will be randomized 2:2:1 to receive a maximum of six 28-day cycles of either RO5072759 (1000mg iv infusion, on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6) plus chlorambucil (0.5mg/kg orally, days 1 and 15 of cycles 1-6), or rituximab (iv infusion day 1, 375mg/m2 cycle 1, 500mg/m2 cycles 2-6) plus chlorambucil, or chlorambucil alone. Anticipated time on study treatment is >6 months and follow-up for disease-progression and safety will be at least 5 years. In the US, this trial is sponsored/managed by Genentech.
Stage 2 enrolled an additional 192 patients to enable the final direct comparison of GA101 versus MabThera/Rituxan, both in combination with chlorambucil. (NCT01010061)
Latest
news: * On December 5, 2015, Roche announced updated data from the pivotal CLL11 study confirming that Gazyva® (obinutuzumab) plus chlorambucil reduced the risk of disease worsening or death by more than half compared to Rituxan® (rituximab) plus chlorambucil (progression-free survival, PFS; HR=0.46, median PFS 28.7 months versus 15.7 months; p<0.0001). New results to be presented at the American Society of Hematology (ASH) Annual Meeting from a secondary endpoint that measured time to next treatment (TTNT) showed that, after completing the set six-month Gazyva® regimen, people remained treatment-free for nearly four years on average before needing the next treatment for their cancer (TTNT; 51.1 months, including the six-month initial treatment period). No unexpected safety signals were observed with Gazyva®. In the GREEN safety study, data from a subgroup analysis showed there were no unexpected safety signals when Gazyva was combined with bendamustine. In addition, nearly 80 percent of people responded to treatment with Gazyva plus bendamustine (overall response rate, ORR), and a third of people (32.3 percent) achieved a complete response (CR). A substantial number of people were also minimal residual disease (MRD)-negative when measured in the bone marrow or blood (28 percent and 59 percent, respectively), which means no cancer can be detected using a specific test. ORR and MRD-negativity were secondary endpoints of the study. Stage 1a Stage 2 Treatment Group G + Clb Clb Alone G + Clb R + Clb Median PFS 31.1 months 11.1 months 28.7 months 15.7 months HR 0.20 (95% CI 0.15-0.26) p<0.0001 0.46 (95% CI 0.38-0.55) p<0.0001 Median TTNT (measured from treatment initiation of six-month regimen until time of next treatment initiation) 51.1 months 15.1 months 51.1 months 38.2 months HR 0.24 (95% CI 0.17-0.34) p<0.0001 0.57 (95% CI 0.44-0.74) p<0.0001 OS Not reached 58.5 months Not reached Not reached HR 0.62 (95% CI 0.42-0.92) p=0.0167 0.77 (95% CI 0.57-1.05) p=0.0932 Safety No new safety signals were identified in this updated analysis. Previously reported most common Grade 3/4 adverse events were infusion-related reactions (IRRs) during the first infusion (21% vs. 0% [chlorambucil is an oral medicine]), low platelet count (thrombocytopenia, 11% vs. 3%) and low count of certain types of white blood cells (neutropenia, 34% vs. 16%) Previously reported Grade 3-5 adverse events were IRRs (20% vs. 4%), low count of certain types of white blood cells (neutropenia, 33% vs. 27%) and infections (7% vs. 7%) Treatment subgroup (n=158) Previously untreated, received G + B ORR 78.5% CR (including incomplete CR [CRi]) 32.3% MRD-negativity rates in the overall study population (ITT) 58.9% in blood 27.8% in bone marrow Safety No new safety signals were identified in this analysis. The most common serious adverse events were low count of certain types of white blood cells (neutropenia, 10.8%), fever (pyrexia, 7.6%), low count of certain types of white blood cells with fever (febrile neutropenia, 7%) and tumor lysis syndrome (TLS, 5.1%) * On November 7, 2013, Genentech, a member of the Roche Group, has announced new, positive data from the second stage of the CLL11 study. This Phase III study, conducted in cooperation with the German CLL Study Group, compared Gazyva™ (obinutuzumab), in combination with chlorambucil to Rituxan® (rituximab) in combination with chlorambucil for people with previously untreated chronic lymphocytic leukemia and co-existing medical conditions. The data showed that people treated in the Gazyva® arm lived nearly a year longer without their disease worsening (progression-free survival, or PFS).
For patients in the Gazyva® arm, median PFS was 26.7 months compared with 15.2 months for those in the Rituxan® arm (HR 0.39, CI 0.31-0.49, p<0.0001). No new safety signals were observed for either Gazyva® or Rituxan®. The data have been accepted for presentation during the Plenary Scientific Session of the 55th Annual Meeting of American Society of Hematology (Abstract #6). Additional data comparing the Gazyva and Rituxan treatment arms showed higher complete response rates (21 percent compared with 7 percent) and a ten-fold increase in the percentage of people achieving minimal residual disease (MRD) negativity (29.4 percent compared with 2.5 percent), which was defined as no detectable disease in the blood at the end of the treatment course.
In addition to the Stage 2 data being presented at ASH, an updated analysis from the first stage (Stage 1a) of the CLL11 study, which compared Gazyva in combination with chlorambucil to chlorambucil alone, will also be presented. This analysis showed that people treated with Gazyva in combination with chlorambucil lived longer (overall survival, or OS) compared to chlorambucil alone (HR 0.41, 95 percent 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.
* On July 24, 2013, Roche has announced positive results from the phase III CLL11 study. At a pre-planned interim analysis, an independent data monitoring committee determined that the study met its primary endpoint showing that GA101 plus chlorambucil helped people live significantly longer without their disease worsening (progression-free survival; PFS) compared to MabThera®/Rituxan® plus chlorambucil.
These final data were reached well ahead of the target completion date in 2014 as a result of the magnitude of difference seen between the two study arms. No new safety signals for GA101 or MabThera®/Rituxan® were identified in this analysis, and adverse events were similar to those observed in the first stage of the study which was previously reported earlier this year.
These data will be submitted for consideration to the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans, which is taking place December 7-10, 2013.
Based on an earlier analysis (stage 1 - see below) of the CLL11 study, marketing applications for GA101 were submitted to regulatory authorities including the FDA and EMA in April, 2013. Due to the significance of the positive trial results and the serious and life threatening nature of CLL, the FDA granted the GA101 application both Breakthrough Therapy Designation and Priority Review.
* On May 16, 2013, Roche has announced the first results from CLL11, a phase III study of the investigational medicine GA101 which is being conducted in collaboration with the German CLL Study Group (GCLLSG). The CLL11 study compared the combination of either GA101 or MabThera®/Rituxan® (rituximab) and chlorambucil, a standard chemotherapy, to chlorambucil alone in chronic lymphocytic leukemia (CLL).
GA101 combined with chlorambucil demonstrated a significant 86% reduction in the risk of disease progression, relapse or death. Additionally, the length of time during which people lived without their disease worsening (median progression-free survival, PFS) was more than doubled (23 months compared to 10.9 months, HR=0.14, 95% CI 0.09-0.21, p <.0001) when compared to chlorambucil alone. The full data, including the comparison of MabThera/Rituxan plus chlorambucil with chlorambucil alone will be presented in an oral session at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago on Tuesday, June 4. The study was conducted in collaboration with the German CLL Study Group (GCLLSG). 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. Specifically, the CLL11 trial data to be presented during ASCO showed the following:
• The addition of GA101 to chlorambucil led to a statistically significant reduction in the risk of disease progression or death of 86 percent (HR=0.14; p-value=<0.0001).
• The median PFS improved by more than a year from 10.9 months for chlorambucil alone to 23 months for GA101 plus chlorambucil.
• The addition of MabThera/Rituxan to chlorambucil significantly reduced the risk of disease progression or death during study follow-up by 68 percent (HR=0.32; p-value=<0.0001).
• Median PFS was 10.8 months for chlorambucil compared to 15.7 months for MabThera/Rituxan plus chlorambucil.
• At this time, no formal comparison between the GA101 and MabThera/Rituxan arms can be made as the number of PFS events required for that formal analysis has not yet been reached.
• No new safety signals were detected for either GA101 or MabThera/Rituxan.The most common grade 3/4 adverse events (AEs) for GA101 were infusion-related reactions (IRRs) and low cell count of certain white blood cells (neutropenia). The incidence and severity of IRRs decreased dramatically after the first infusion and no serious IRRs have been reported beyond the first infusion.
The most common AEs in the MabThera/Rituxan arm were infections and neutropenia. Based on the CLL11 data, marketing applications have been submitted to regulatory authorities including the European Medicines Association (EMA) and the FDA. The FDA has granted GA101 ‘Breakthrough Therapy Designation’. This designation is designed to expedite the development and review of medicines intended to treat serious diseases and to help ensure patients have access to them through FDA approval as soon as possible.
* On January 31, 2013, Genentech has announced positive results from Stage 1 of CLL11, a Phase III randomized study to investigate the efficacy and safety profile of the investigational medicine obinutuzumab (GA101) plus chlorambucil chemotherapy compared with chlorambucil alone in people with previously untreated chronic lymphocytic leukemia (CLL). An improvement in progression-free survival (PFS) was achieved as GA101 plus chlorambucil significantly reduced the risk of disease worsening or death compared to chlorambucil alone.
GA101 has been specifically designed as the first glycoengineered, type 2 anti-CD20 monoclonal antibody in development for B-cell malignancies. In pre-clinical development, GA101 has shown evidence of increased direct cell killing and antibody-dependent cellular cytotoxicity (ADCC). As a result, GA101’s clinical development program is designed to assess whether or not it is superior to Rituxan® (rituximab) in CLL and non-Hodgkin’s lymphoma (NHL). Data from CLL11 will be submitted for presentation at an upcoming medical meeting and submitted to European regulatory authorities and the FDA for potential approval.
