The Experts below are selected from a list of 1395 Experts worldwide ranked by ideXlab platform
Wolfgang Wick - One of the best experts on this subject based on the ideXlab platform.
-
Lomustine and Bevacizumab in Progressive Glioblastoma
New England Journal of Medicine, 2017Co-Authors: Wolfgang Wick, Walter Taal, Thierry Gorlia, Julien Domont, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, I Harting, Alba Brandes, Ahmed IdbaihAbstract:Background: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to Lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than Lomustine alone among patients at first progression of glioblastoma. Methods: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive Lomustine plus bevacizumab (combination group, 288 patients) or Lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. Results: A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P
-
Lomustine and bevacizumab in progressive glioblastoma
The New England Journal of Medicine, 2017Co-Authors: Wolfgang Wick, Walter Taal, Thierry Gorlia, Julien Domont, Alba A. Brandes, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, I Harting, Ahmed IdbaihAbstract:BackgroundBevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to Lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than Lomustine alone among patients at first progression of glioblastoma. MethodsWe randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive Lomustine plus bevacizumab (combination group, 288 patients) or Lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6-methylguanine–DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. ResultsA total of 437 patients underwent randomization. The median number of 6-week treatment cycles was...
-
Lomustine and bevacizumab in progressive glioblastoma
The New England Journal of Medicine, 2017Co-Authors: Wolfgang Wick, Walter Taal, Thierry Gorlia, Julien Domont, Alba A. Brandes, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, I Harting, Ahmed IdbaihAbstract:BACKGROUND: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to Lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than Lomustine alone among patients at first progression of glioblastoma. METHODS: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive Lomustine plus bevacizumab (combination group, 288 patients) or Lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6methylguanine–DNA methyltransferase (MGMT) was assessed. Healthrelated quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. RESULTS: A total of 437 patients underwent randomization. The median number of 6week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to Lomustine affected neither healthrelated quality of life nor neurocognitive function. The MGMT status was prognostic. CONCLUSIONS: Despite somewhat prolonged progressionfree survival, treatment with Lomustine plus bevacizumab did not confer a survival advantage over treatment with Lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann–La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939; EudraCT number, 201002321830.)
-
eortc 26101 phase iii trial exploring the combination of bevacizumab and Lomustine in patients with first progression of a glioblastoma
Journal of Clinical Oncology, 2016Co-Authors: Wolfgang Wick, Walter Taal, Thierry Gorlia, Ahmed Idbaih, Julien Domont, Alba A. Brandes, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, Mario CamponeAbstract:2001Background: Phase II data from BELOB suggested the combination of bevacizumab and Lomustine to produce an overall survival (OS) benefit for patients with progressive glioblastoma. EORTC 26101 aimed investigating whether the combination of bevacizumab and Lomustine improves OS in patients with first progression of a glioblastoma compared to Lomustine alone. Methods: Patients with progressive disease after standard chemoradiation at least 3 months off the concomitant part were randomized 2:1 between Lomustine 90 mg/m2 (cap. 160 mg with toxicity-driven escalation to cap. 200 mg from cycle 2 on) every six weeks plus 10 mg/kg bevacizumab every two weeks and Lomustine single agent 110 mg/m2(cap. 200 mg) every six weeks followed by best investigators choice at further progression. Targeted hazard ratio (HR) was 0.72 for the comparison of OS as the primary endpoint. Progression-free survival (PFS) was an important secondary endpoint. Neuroimaging according to a standard protocol was assessed locally and centr...
-
lb 05phase iii trial exploring the combination of bevacizumab and Lomustine in patients with first recurrence of a glioblastoma the eortc 26101 trial
Neuro-oncology, 2015Co-Authors: Wolfgang Wick, Aa Brandes, Walter Taal, Thierry Gorlia, Ahmed Idbaih, Julien Domont, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, Mario CamponeAbstract:LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND Lomustine IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and Lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to Lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with Lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between Lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and Lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of Lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the Lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to Lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the Lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.
Michael Weller - One of the best experts on this subject based on the ideXlab platform.
-
How did Lomustine become standard of care in recurrent glioblastoma?
Cancer Treatment Reviews, 2020Co-Authors: Michael Weller, Emilie Le RhunAbstract:Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management includes maximum safe surgical resection followed by involved-field radiotherapy plus concomitant and six cycles of maintenance temozolomide chemotherapy. Standards of care at recurrence are much less well defined. Minorities of patients are offered second surgery or re-irradiation, but data on a positive impact on survival from randomized trials are lacking. The majority of patients who are eligible for salvage therapy receive systemic treatment, mostly with nitrosourea-based regimens or, depending on availability, bevacizumab alone or in various combinations. In clinical trials, Lomustine alone has been increasingly used as a control arm, assigning this drug a standard-of-care position in the setting of recurrent glioblastoma. Here we review the activity of Lomustine in the treatment of diffuse gliomas of adulthood in various settings. The most compelling data for Lomustine stem from three randomized trials when Lomustine was combined with procarbazine and vincristine as the PCV regimen in the newly diagnosed setting together with radiotherapy; improved survival with PCV was restricted to patients with isocitrate dehydrogenase-mutant tumors. No other agent with the possible exception of regorafenib has shown superior activity to Lomustine in recurrent glioblastoma, but activity is largely restricted to patients with tumors with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Hematological toxicity, notably thrombocytopenia often limits adequate exposure.
-
Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide
2015Co-Authors: Martin Glas, Wolfgang Wick, Michael Weller, Ulrich Herrlinger, Joachim P Steinbach, Rolfdieter Kortmann, Johannes Rieger, Dorothee Wiewrodt, Guido Reifenberger, Tübingen Dr. Senckenbergisches InstiAbstract:Long-term survival of glioblastoma patients treated with radiotherapy and Lomustine plus temozolomid
-
phase iii study of enzastaurin compared with Lomustine in the treatment of recurrent intracranial glioblastoma
Journal of Clinical Oncology, 2010Co-Authors: Wolfgang Wick, Warren P Mason, Vinay K Puduvalli, Marc C Chamberlain, Antoine F Carpentier, Lawrence Cher, Michael Weller, Shengyan Hong, Luna MusibAbstract:Purpose This phase III open-label study compared the efficacy and safety of enzastaurin versus Lomustine in patients with recurrent glioblastoma (WHO grade 4). Patients and Methods Patients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or Lomustine (100 to 130 mg/m2, day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025. Results Enrollment was terminated at 266 patients (enzastaurin, n = 174; Lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and Lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients an...
-
prevention of irradiation induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase
Cancer Research, 2002Co-Authors: Wolfgang Wick, Antje Wick, Jorg B Schulz, J Dichgans, Hans Peter Rodemann, Michael WellerAbstract:Sublethal doses of irradiation enhance the invasiveness of human malignantglioma cells. This can be inhibited by subtoxic concentrations of temozolomide (TMZ) but not by Lomustine. Antagonism of irradiation-induced motility by TMZ is associated with the prevention of irradiation-induced αvβ3-integrin, matrix metalloproteinase-2 and MT1-matrix metalloproteinase-expression. Irradiation induces focal adhesion kinase (FAK) activation by phosphorylation, whereas TMZ promotes FAK cleavage. Inhibition of caspases prevents TMZ-induced FAK processing and restores the promigratory effect of irradiation, suggesting that the resistance of glioma cells to irradiation-induced caspase processing may determine the invasive responses of glioma cells to irradiation. In contrast, DAOY medulloblastoma cells, which respond with caspase activation to irradiation alone, do not show enhanced invasiveness when irradiated.
-
prevention of irradiation induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase
Cancer Research, 2002Co-Authors: Wolfgang Wick, Antje Wick, Jorg B Schulz, J Dichgans, Hans Peter Rodemann, Michael WellerAbstract:Sublethal doses of irradiation enhance the invasiveness of human malignantglioma cells. This can be inhibited by subtoxic concentrations of temozolomide (TMZ) but not by Lomustine. Antagonism of irradiation-induced motility by TMZ is associated with the prevention of irradiation-induced alpha(v)beta(3)-integrin, matrix metalloproteinase-2 and MT1-matrix metalloproteinase-expression. Irradiation induces focal adhesion kinase (FAK) activation by phosphorylation, whereas TMZ promotes FAK cleavage. Inhibition of caspases prevents TMZ-induced FAK processing and restores the promigratory effect of irradiation, suggesting that the resistance of glioma cells to irradiation-induced caspase processing may determine the invasive responses of glioma cells to irradiation. In contrast, DAOY medulloblastoma cells, which respond with caspase activation to irradiation alone, do not show enhanced invasiveness when irradiated.
Kristina Fritsch - One of the best experts on this subject based on the ideXlab platform.
-
high dose methotrexate based immuno chemotherapy for elderly primary cns lymphoma patients primain study
Leukemia, 2017Co-Authors: Kristina Fritsch, Benjamin Kasenda, Elisabeth Schorb, Peter Hau, Johannes Bloehdorn, Robert Mohle, S Low, Mascha Binder, Johannes Atta, Ulrich KellerAbstract:To investigate immuno-chemotherapy for elderly immuno-competent patients (. 65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m(2), days 1, 15, 29), high-dose methotrexate (3 g/m(2) days 2, 16, 30), procarbazine (60 mg/m(2) days 2-11) and Lomustine (110 mg/m(2), day 2)-R-MPL protocol. Owing to infectious complications, we omitted Lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less. grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.
-
immunochemotherapy with rituximab methotrexate procarbazine and Lomustine for primary cns lymphoma pcnsl in the elderly
Annals of Oncology, 2011Co-Authors: Kristina Fritsch, Gabriele Ihorst, Jurgen Finke, Benjamin Kasenda, Claudia Hader, Guido Nikkhah, Marco Prinz, Vanessa Haug, S Haug, Gerald IllerhausAbstract:Abstract Background Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system. In this article, we report the results of a pilot trial adding rituximab to the established regimen consisting of methotrexate, procarbazine, and Lomustine (R-MCP). Design and methods PCNSL patients ≥65 years without Karnofsky performance score (KPS) limit were included. R-MCP regimen consisted of rituximab (375 mg/m2 i.v. on days -6, 1, 15, and 29), methotrexate (3 g/m2 i.v., days 2, 16, and 30) followed by folinic rescue, procarbazine (60 mg/m2 orally, days 2–11), and Lomustine (110 mg/m2 orally, day 2). A maximum of three 43-day cycles were applied. Primary end point was response to treatment obtained by magnetic resonance imaging. Secondary end points were overall survival (OS) and progression-free survival (PFS). Results Twenty-eight patients were included (median age 75, median KPS 60%). Best documented response: complete remission in 18 of 28 (64%), partial remission in 5 of 28 (18%), stable disease in 1 of 28 (4%), and progressive disease in 2 of 28 (7%) patients. Response was not assessed in two patients. Two treatment-associated deaths were observed. After a median follow-up of 36 months, the 3-year PFS and OS was 31%. Conclusion R-MCP regimen is well tolerated and active in elderly patients with newly diagnosed PCNSL.
Ulrich Keller - One of the best experts on this subject based on the ideXlab platform.
-
high dose methotrexate based immuno chemotherapy for elderly primary cns lymphoma patients primain study
Leukemia, 2017Co-Authors: Kristina Fritsch, Benjamin Kasenda, Elisabeth Schorb, Peter Hau, Johannes Bloehdorn, Robert Mohle, S Low, Mascha Binder, Johannes Atta, Ulrich KellerAbstract:To investigate immuno-chemotherapy for elderly immuno-competent patients (. 65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m(2), days 1, 15, 29), high-dose methotrexate (3 g/m(2) days 2, 16, 30), procarbazine (60 mg/m(2) days 2-11) and Lomustine (110 mg/m(2), day 2)-R-MPL protocol. Owing to infectious complications, we omitted Lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less. grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.
Mario Campone - One of the best experts on this subject based on the ideXlab platform.
-
eortc 26101 phase iii trial exploring the combination of bevacizumab and Lomustine in patients with first progression of a glioblastoma
Journal of Clinical Oncology, 2016Co-Authors: Wolfgang Wick, Walter Taal, Thierry Gorlia, Ahmed Idbaih, Julien Domont, Alba A. Brandes, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, Mario CamponeAbstract:2001Background: Phase II data from BELOB suggested the combination of bevacizumab and Lomustine to produce an overall survival (OS) benefit for patients with progressive glioblastoma. EORTC 26101 aimed investigating whether the combination of bevacizumab and Lomustine improves OS in patients with first progression of a glioblastoma compared to Lomustine alone. Methods: Patients with progressive disease after standard chemoradiation at least 3 months off the concomitant part were randomized 2:1 between Lomustine 90 mg/m2 (cap. 160 mg with toxicity-driven escalation to cap. 200 mg from cycle 2 on) every six weeks plus 10 mg/kg bevacizumab every two weeks and Lomustine single agent 110 mg/m2(cap. 200 mg) every six weeks followed by best investigators choice at further progression. Targeted hazard ratio (HR) was 0.72 for the comparison of OS as the primary endpoint. Progression-free survival (PFS) was an important secondary endpoint. Neuroimaging according to a standard protocol was assessed locally and centr...
-
lb 05phase iii trial exploring the combination of bevacizumab and Lomustine in patients with first recurrence of a glioblastoma the eortc 26101 trial
Neuro-oncology, 2015Co-Authors: Wolfgang Wick, Aa Brandes, Walter Taal, Thierry Gorlia, Ahmed Idbaih, Julien Domont, Martin J B Taphoorn, Felix Sahm, Martin Bendszus, Mario CamponeAbstract:LB-05. PHASE III TRIAL EXPLORING THE COMBINATION OF BEVACIZUMAB AND Lomustine IN PATIENTS WITH FIRST RECURRENCE OF A GLIOBLASTOMA: THE EORTC 26101 TRIAL W. Wick1, AA. Brandes2, T. Gorlia3, M. Bendszus1, F. Sahm1, W. Taal4, M. Taphoorn5, J. Domont6, A. Idbaih7, M. Campone8, P.M. Clement9, R. Stupp10, M. Fabbro11, F. Dubois12, C. Bais13, D. Musmeci3, M. Platten1, M. Weller10, V. Golfinopoulos3, and M. van den Bent4; University Medical Center & German Cancer Research Center, Heidelberg, Germany; Medical Oncology Department, AUSL-Bologna-IRCCS Scienze Neurologiche, Bologna, Italia; EORTC Headquarters, Brussels, Belgium; Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; Medical Center Haaglanden, The Hague, The Netherlands The Netherlands; Institut Gustave Roussy, Villejuif, France; AP-HP, Hopital Universitaire La Pitie Salperiere and Sorbonne Universites, UPMC Univ Paris 06, Paris, France; Institut de Cancerologie de l’Ouest (ICO) Centre Rene Gauducheau, Saint-Herblain, France; U.Z. Leuven KU Leuven, Belgium; Zurich University Medical Center, Zurich, Switzerland; Institut regional du Cancer Montpellier, Montpellier, France; CHRU de Lille, Lille, France; Genentech Inc., South San Francisco, California, USA BACKGROUND: Phase II data from the BELOB trial indicated that the combination of bevacizumab and Lomustine might produce an overall survival (OS) benefit compared with either monotherapy for patients with first progression of a glioblastoma. The primary objective of the phase III part of EORTC 26101 is to investigate whether the addition of bevacizumab to Lomustine improves overall OS in patients with first progression of a glioblastoma compared to treatment with Lomustine alone. METHODS: Patients with progressive disease after standard chemo-radiotherapy with temozolomide at least 3 months off the concomitant part were randomized 2:1 between Lomustine 90 mg/m (cap. 160 mg) mg every six weeks plus 10 mg/kg bevacizumab every two weeks and Lomustine single agent 110 mg/m (cap. 200 mg) every six weeks followed by best investigators choice at further progression. In the absence of hematological toxicity . grade 1 during the first cycle in the combination arms, the dose of Lomustine could be escalated to 110 mg/m (cap 200 mg) in the second cycle. Neuroimaging according to a standard protocol was assessed locally and centrally. RESULTS: A total of 437 (288 and 149, respectively) patients were included. Median number of treatment cycles was 1 in the Lomustine arm and 3 in the combination arm. With 329 OS events (75.3%) OS was not superior in the combination therapy arm (hazard ratio (HR) 0.95 (confidence interval (CI) 0.74, 1.21), p 1⁄4 0.650, analyses stratified by EORTC online randomization system), whereas locally assessed progression-free survival (PFS) was longer with the addition of bevacizumab to Lomustine (HR 0.49 (CI 0.39, 0.61). Median efficacy outcomes were: OS 9.1 (8.1, 10.1) versus 8.6 (7.6, 10.4) months and PFS 4.2 (3.7, 4.3) versus 1.5 (1.5, 2.5) months in the combination arm versus the Lomustine arm respectively. Toxicity was in the expected range with more events in the combination arm being also longer on treatment. Crossover to bevacizumab occurred in 35.5% of patients in the control arm; whereas 19% of patients in the combination arm continued bevacizumab at progression. CONCLUSIONS: Bevacizumab treatment in patients with progressive glioblastoma despite prolonged PFS does not confer a survival advantage. The future challenge is to identify those patients deriving benefit from that treatment. Neuro-Oncology 17:v1–v1, 2015. doi:10.1093/neuonc/nov306 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.
-
phase iii randomized trial comparing the efficacy of cediranib as monotherapy and in combination with Lomustine versus Lomustine alone in patients with recurrent glioblastoma
Journal of Clinical Oncology, 2013Co-Authors: Tracy T Batchelor, Antje Wick, Burton L Nabors, Paul Mulholland, Surasak Phuphanich, Mario Campone, Tom Mikkelsen, Warren P Mason, Bart Neyns, Lynn S AshbyAbstract:Purpose A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recentin in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with Lomustine versus Lomustine in patients with recurrent glioblastoma. Patients and Methods Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus Lomustine (110 mg/m2); (3) Lomustine (110 mg/m2) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. Results The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone...
