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Mark R Middleton - One of the best experts on this subject based on the ideXlab platform.
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a phase ii study of the potent parp inhibitor rucaparib pf 01367338 ag014699 with Temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Ruth Plummer, Neil Steven, Lucy Scott, Evan A Mulligan, Paul Lorigan, Mark R Middleton, NICOLA JANE CURTIN, Diane Wang, Richard Wilson, R DewjiAbstract:poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and Temozolomide showed that full-dose Temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m2 and oral Temozolomide 200 mg/m2 on days 1–5 every 28 days in patients with advanced metastatic melanoma. Patients with chemotherapy naive measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in Temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. This study showed that Temozolomide (150–200 mg/m2/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.
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phase ii open label randomized trial of the mek1 2 inhibitor selumetinib as monotherapy versus Temozolomide in patients with advanced melanoma
Clinical Cancer Research, 2012Co-Authors: John M. Kirkwood, Mark R Middleton, Jeffrey A Sosman, Lars Bastholt, Caroline Robert, James Larkin, Peter Hersey, Mireille Cantarini, Victoria Zazulina, Karin KemsleyAbstract:Purpose: To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus Temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma. Experimental Design: This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral selumetinib twice daily in 28-day cycles versus oral Temozolomide (200 mg/m 2 /d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival. Results: Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and Temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86–1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the Temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and Temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with Temozolomide. Conclusions: No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF / NRAS mutations, who received therapy with selumetinib or Temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors. Clin Cancer Res; 18(2); 555–67. ©2011 AACR .
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phase i study of the poly adp ribose polymerase inhibitor ag014699 in combination with Temozolomide in patients with advanced solid tumors
Clinical Cancer Research, 2008Co-Authors: Ruth Plummer, Mark R Middleton, Alan V Boddy, Chris Jones, Richard H Wilson, Jeff Evans, Anna Olsen, Nicola J Curtin, Peter J Mchugh, David R NewellAbstract:Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with Temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m 2 /d Temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and Temozolomide escalated to maximum tolerated dose or 200 mg/m 2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and Temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m 2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m 2 AG014699 and 200 mg/m 2 Temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with Temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and Temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.
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randomized phase ii study of Temozolomide given every 8 hours or daily with either interferon alfa 2b or thalidomide in metastatic malignant melanoma
Journal of Clinical Oncology, 2003Co-Authors: Sarah Danson, Paul Lorigan, Ana Arance, Andrew R Clamp, Malcolm R Ranson, Jackie Hodgetts, Lyn Lomax, L Ashcroft, Nick Thatcher, Mark R MiddletonAbstract:Purpose: Temozolomide is an imidazotetrazine with a mechanism of action similar to dacarbazine and equivalent activity in melanoma. It is well tolerated and is a candidate for combination chemotherapy and schedule manipulation. In this study, we combined Temozolomide with interferon alfa-2b and, separately, with thalidomide, and we administered Temozolomide alone in a compressed schedule. The objectives of this randomized phase II, two-center study were to determine response rates, overall survival, and tolerability of the regimens in patients with advanced metastatic melanoma. Patients and Methods: One hundred eighty-one patients with metastatic melanoma were randomly assigned to receive up to six 4-weekly cycles consisting of Temozolomide 200 mg/m2 every 8 hours for five doses, or Temozolomide 200 mg/m2 daily for days 1 to 5 plus interferon alfa-2b 5 MU (million International Units) subcutaneously three times a week, or Temozolomide 150 mg/m2 (increased after one cycle to 200 mg/m2) daily on days 1 to 5...
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randomized phase iii study of Temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma
Journal of Clinical Oncology, 2000Co-Authors: Mark R Middleton, J J Grob, N Aaronson, G Fierlbeck, W Tilgen, S Seiter, M Gore, Steinar Aamdal, Jonathan Cebon, Alan S CoatesAbstract:PURPOSE: : To compare, in 305 patients with advanced metastatic melanoma, Temozolomide and dacarbazine (DTIC) in terms of overall survival, progression-free survival (PFS), objective response, and safety, and to assess health-related quality of life (QOL) and pharmacokinetics of both drugs and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC). PATIENTS AND METHODS: Patients were randomized to receive either oral Temozolomide at a starting dosage of 200 mg/m2/d for 5 days every 28 days or intravenous (IV) DTIC at a starting dosage of 250 mg/m2/d for 5 days every 21 days. RESULTS: In the intent-to-treat population, median survival time was 7.7 months for patients treated with Temozolomide and 6.4 months for those treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52). Median PFS time was significantly longer in the Temozolomide-treated group (1.9 months) than in the DTIC-treated group (1.5 months) (P = .012; hazards ratio, 1.37; 95% CI, 1.07 to 1.75). No m...
Roger Stupp - One of the best experts on this subject based on the ideXlab platform.
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effect of tumor treating fields plus maintenance Temozolomide vs maintenance Temozolomide alone on survival in patients with glioblastoma a randomized clinical trial
JAMA, 2017Co-Authors: Roger Stupp, Sophie Taillibert, Andrew A Kanner, David M Steinberg, William L Read, Benoît LhermitteAbstract:Importance Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions Patients were randomized 2:1 to TTFields plus maintenance Temozolomide chemotherapy (n = 466) or Temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m 2 ) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-Temozolomide group and 4.0 months in the Temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P P Conclusions and Relevance In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance Temozolomide chemotherapy vs maintenance Temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration clinicaltrials.gov Identifier:NCT00916409
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maintenance therapy with tumor treating fields plus Temozolomide vs Temozolomide alone for glioblastoma a randomized clinical trial
JAMA, 2015Co-Authors: Roger Stupp, Sophie Taillibert, Andrew A Kanner, Santosh Kesari, David M Steinberg, Steven A Toms, Lynne P Taylor, Frank S Lieberman, A SilvaniAbstract:Importance Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. Objective To evaluate the efficacy and safety of TTFields used in combination with Temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. Design, Setting, and Participants After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus Temozolomide (n = 466) or Temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. Interventions Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m 2 /d) was given for 5 days of each 28-day cycle. Main Outcomes and Measures The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. Results The interim analysis included 210 patients randomized to TTFields plus Temozolomide and 105 randomized to Temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus Temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the Temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus Temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the Temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). Conclusions and Relevance In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance Temozolomide chemotherapy significantly prolonged progression-free and overall survival. Trial Registration clinicaltrials.gov Identifier:NCT00916409
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dose dense Temozolomide for newly diagnosed glioblastoma a randomized phase iii clinical trial
Journal of Clinical Oncology, 2013Co-Authors: Mark R Gilbert, Terri S Armstrong, Jeffrey Scott Wefel, Meihua Wang, Monika E. Hegi, Roger Stupp, Kenneth D Aldape, Kurt A Jaeckle, Minhee WonAbstract:Purpose Radiotherapy with concomitant and adjuvant Temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) Temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD Temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard Temozolomide (arm 1) or DD Temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
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Temozolomide versus standard 6 week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma the nordic randomised phase 3 trial
Lancet Oncology, 2012Co-Authors: Annika Malmstrom, Bjorn Henning Gronberg, Ufuk Abacioglu, Benoît Lhermitte, Björn Tavelin, Henrik Schultz, Christine Marosi, Didier Frappaz, Roger Stupp, Monika E. HegiAbstract:Summary Background Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. Methods Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive Temozolomide (200 mg/m 2 on days 1–5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. Findings 342 patients were enrolled, of whom 291 were randomised across three treatment groups (Temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (Temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with Temozolomide (8·3 months [95% CI 7·1–9·5; n=93] vs 6·0 months [95% CI 5·1–6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52–0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5–8·6; n=98], HR 0·85 [0·64–1·12], p=0·24). For all patients who received Temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3–9·4; n=119] vs 7·4 months [6·4–8·4; n=123]; HR 0·82, 95% CI 0·63–1·06; p=0·12). For age older than 70 years, survival was better with Temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for Temozolomide vs standard radiotherapy 0·35 [0·21–0·56], p vs standard radiotherapy 0·59 [95% CI 0·37–0·93], p=0·02). Patients treated with Temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0–11·4] vs 6·8 months [5·9–7·7]; HR 0·56 [95% CI 0·34–0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69–1·38]; p=0·81). As expected, the most common grade 3–4 adverse events in the Temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3–5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the Temozolomide group and one in the standard radiotherapy group) and one in the Temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. Interpretation Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both Temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from Temozolomide. Funding Merck, Lion's Cancer Research Foundation, University of Umea, and the Swedish Cancer Society.
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effects of radiotherapy with concomitant and adjuvant Temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase iii study 5 year analysis of the eortc ncic trial
Lancet Oncology, 2009Co-Authors: Roger Stupp, Martin J Van Den Bent, Barbara Fisher, Martin J B Taphoorn, Monika E. Hegi, Warren P Mason, Robert C Janzer, Samuel K Ludwin, Anouk Allgeier, Karl BelangerAbstract:BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant Temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant Temozolomide followed by up to six cycles of adjuvant Temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with Temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from Temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant Temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of Temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.
Martin J Van Den Bent - One of the best experts on this subject based on the ideXlab platform.
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adjuvant and concurrent Temozolomide for 1p 19q non co deleted anaplastic glioma catnon eortc study 26053 22054 second interim analysis of a randomised open label phase 3 study
Lancet Oncology, 2021Co-Authors: Martin J Van Den Bent, Alba A. Brandes, Marc Sanson, Wolfgang Wick, Mircea C S Tesileanu, Paul Clement, S Erridge, Michael A Vogelbaum, Anna K NowakAbstract:Summary Background The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant Temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent Temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. Methods This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0–2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral Temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral Temozolomide (12 4-week cycles of 150–200 mg/m2 Temozolomide given on days 1–5), or radiotherapy with both concurrent and adjuvant Temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent Temozolomide. This study is registered with ClinicalTrials.gov , NCT00626990 . Findings Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent Temozolomide, 186 to radiotherapy and adjuvant Temozolomide, and 188 to radiotherapy with concurrent and adjuvant Temozolomide). Median follow-up was 55·7 months (IQR 41·0–77·3). The second interim analysis declared futility of concurrent Temozolomide (median overall survival was 66·9 months [95% CI 45·7–82·3] with concurrent Temozolomide vs 60·4 months [45·7–71·5] without concurrent Temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73–1·28], p=0·76). By contrast, adjuvant Temozolomide improved overall survival compared with no adjuvant Temozolomide (median overall survival 82·3 months [95% CI 67·2–116·6] vs 46·9 months [37·9–56·9]; HR 0·64 [95% CI 0·52–0·79], p Interpretation Adjuvant Temozolomide chemotherapy, but not concurrent Temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. Funding Merck Sharpe & Dohme.
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interim results from the catnon trial eortc study 26053 22054 of treatment with concurrent and adjuvant Temozolomide for 1p 19q non co deleted anaplastic glioma a phase 3 randomised open label intergroup study
The Lancet, 2017Co-Authors: Martin J Van Den Bent, Marc Sanson, S Erridge, Michael A Vogelbaum, Anna K Nowak, Brigitta G Baumert, Alba A. BrandesAbstract:Summary Background The role of Temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant Temozolomide in adults with non-co-deleted anaplastic gliomas. Methods This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0–2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant Temozolomide (12 4-week cycles of 150–200 mg/m 2 Temozolomide given on days 1–5); or to receive radiotherapy with concurrent Temozolomide 75 mg/m 2 per day, with or without adjuvant Temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p Findings At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant Temozolomide was 0·65 (99·145% CI 0·45–0·93). Overall survival at 5 years was 55·9% (95% CI 47·2–63·8) with and 44·1% (36·3–51·6) without adjuvant Temozolomide. Grade 3–4 adverse events were seen in 8–12% of 549 patients assigned Temozolomide, and were mainly haematological and reversible. Interpretation Adjuvant Temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent Temozolomide treatment and molecular factors is needed. Funding Schering Plough and MSD.
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a phase i study of ly317615 enzastaurin and Temozolomide in patients with gliomas eortc trial 26054
Neuro-oncology, 2009Co-Authors: Roy Rampling, Clemens Stoffregen, Marc Sanson, Thiery Gorlia, Denis Lacombe, Christina Lai, Myriam Gharib, Walter Taal, Rodney Decker, Martin J Van Den BentAbstract:We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent Temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose Temozolomide (200 mg/m(2) for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly Temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with Temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels.
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effects of radiotherapy with concomitant and adjuvant Temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase iii study 5 year analysis of the eortc ncic trial
Lancet Oncology, 2009Co-Authors: Roger Stupp, Martin J Van Den Bent, Barbara Fisher, Martin J B Taphoorn, Monika E. Hegi, Warren P Mason, Robert C Janzer, Samuel K Ludwin, Anouk Allgeier, Karl BelangerAbstract:BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant Temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant Temozolomide followed by up to six cycles of adjuvant Temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with Temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from Temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant Temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of Temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.
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radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma
The New England Journal of Medicine, 2005Co-Authors: Roger Stupp, Martin J Van Den Bent, Karl Belanger, Barbara Fisher, Alba A. Brandes, Martin J B Taphoorn, Christine Marosi, Michael Weller, Warren P Mason, Ulrich BogdahnAbstract:methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily Temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant Temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus Temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-Temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus Temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus Temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.
Anna K Nowak - One of the best experts on this subject based on the ideXlab platform.
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adjuvant and concurrent Temozolomide for 1p 19q non co deleted anaplastic glioma catnon eortc study 26053 22054 second interim analysis of a randomised open label phase 3 study
Lancet Oncology, 2021Co-Authors: Martin J Van Den Bent, Alba A. Brandes, Marc Sanson, Wolfgang Wick, Mircea C S Tesileanu, Paul Clement, S Erridge, Michael A Vogelbaum, Anna K NowakAbstract:Summary Background The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant Temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent Temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. Methods This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0–2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral Temozolomide (75 mg/m2 per day), radiotherapy with adjuvant oral Temozolomide (12 4-week cycles of 150–200 mg/m2 Temozolomide given on days 1–5), or radiotherapy with both concurrent and adjuvant Temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent Temozolomide. This study is registered with ClinicalTrials.gov , NCT00626990 . Findings Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent Temozolomide, 186 to radiotherapy and adjuvant Temozolomide, and 188 to radiotherapy with concurrent and adjuvant Temozolomide). Median follow-up was 55·7 months (IQR 41·0–77·3). The second interim analysis declared futility of concurrent Temozolomide (median overall survival was 66·9 months [95% CI 45·7–82·3] with concurrent Temozolomide vs 60·4 months [45·7–71·5] without concurrent Temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73–1·28], p=0·76). By contrast, adjuvant Temozolomide improved overall survival compared with no adjuvant Temozolomide (median overall survival 82·3 months [95% CI 67·2–116·6] vs 46·9 months [37·9–56·9]; HR 0·64 [95% CI 0·52–0·79], p Interpretation Adjuvant Temozolomide chemotherapy, but not concurrent Temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. Funding Merck Sharpe & Dohme.
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interim results from the catnon trial eortc study 26053 22054 of treatment with concurrent and adjuvant Temozolomide for 1p 19q non co deleted anaplastic glioma a phase 3 randomised open label intergroup study
The Lancet, 2017Co-Authors: Martin J Van Den Bent, Marc Sanson, S Erridge, Michael A Vogelbaum, Anna K Nowak, Brigitta G Baumert, Alba A. BrandesAbstract:Summary Background The role of Temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant Temozolomide in adults with non-co-deleted anaplastic gliomas. Methods This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0–2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant Temozolomide (12 4-week cycles of 150–200 mg/m 2 Temozolomide given on days 1–5); or to receive radiotherapy with concurrent Temozolomide 75 mg/m 2 per day, with or without adjuvant Temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p Findings At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant Temozolomide was 0·65 (99·145% CI 0·45–0·93). Overall survival at 5 years was 55·9% (95% CI 47·2–63·8) with and 44·1% (36·3–51·6) without adjuvant Temozolomide. Grade 3–4 adverse events were seen in 8–12% of 549 patients assigned Temozolomide, and were mainly haematological and reversible. Interpretation Adjuvant Temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent Temozolomide treatment and molecular factors is needed. Funding Schering Plough and MSD.
Darell D Bigner - One of the best experts on this subject based on the ideXlab platform.
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Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model
Journal of Neuro-Oncology, 2013Co-Authors: Stephen T Keir, Henry S Friedman, Darell D Bigner, David A Reardon, Lloyd A. GrayAbstract:Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent Temozolomide, although resistance to this drug is common. The predominant mechanism of action of Temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to Temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of Temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered Temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are Temozolomide resistant, may be rendered more sensitive by this strategy.
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phase ii trial of Temozolomide plus o6 benzylguanine in adults with recurrent Temozolomide resistant malignant glioma
Journal of Clinical Oncology, 2009Co-Authors: Jennifer A Quinn, Darell D Bigner, Sara Xiaoyin Jiang, David A Reardon, Annick Desjardins, James J Vredenburgh, Jeremy N Rich, Sridharan Gururangan, Allan H Friedman, John H SampsonAbstract:Purpose This phase II trial was designed to define the role of O 6 -benzylguanine (O 6 -BG) in restoring Temozolomide sensitivity in patients with recurrent or progressive, Temozolomide-resistant malignant glioma and to evaluate the safety of administering O 6 -BG in combination with Temozolomide. Patients and Methods Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both Temozolomide and O 6 -BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O 6 -BG infusion at a dose of 120 mg/m 2 followed immediately by a 48-hour infusion at a dose of 30 mg/m 2 /d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O 6 -BG infusion at a dose of 472 mg/m 2 . The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. Results Sixty-six of 67 patients who enrolled were treated with Temozolomide and O 6 -BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. Conclusion O 6 -BG when added to a 1-day dosing regimen of Temozolomide was able to restore Temozolomide sensitivity in patients with Temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of Temozolomide sensitivity in patients with Temozolomide-resistant GBM.
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poly adp ribose polymerase 1 inhibition reverses Temozolomide resistance in a dna mismatch repair deficient malignant glioma xenograft
Molecular Cancer Therapeutics, 2005Co-Authors: Lynn C Cheng, Stephen T Keir, Stewart P Johnson, Eileen M Dolan, Jennifer A Quinn, Francis Aliosman, Csaba Szabo, Andrew L Salzman, Paul Modrich, Darell D BignerAbstract:Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of Temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repair-proficient [D-245 MG] or deficient [D-245 MG (PR)] xenografts, were treated with a combination of Temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg Temozolomide (0.75 LD(10)). This dose of Temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO-1001 had a more modest, yet statistically significant, increase in tumor growth delay in the mismatch repair-proficient xenografts. In these experiments, mice were treated with a lower amount of Temozolomide (88 mg/kg), which resulted in growth delays of 43.1 and 39.2 days. When the Temozolomide treatment was in combination with 200 mg/kg INO-1001, there was an increase in growth delay to 48.9 and 45.7 days, respectively. These results suggest that inhibition of PARP may increase the efficacy of Temozolomide in the treatment of malignant gliomas, particularly in tumors deficient in DNA mismatch repair.
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schedule dependent activity of Temozolomide plus cpt 11 against a human central nervous system tumor derived xenograft
Clinical Cancer Research, 2000Co-Authors: Vikas J Patel, Gertrude B Elion, Peter J Houghton, Stephen T Keir, Anthony E Pegg, Stewart P Johnson, Eileen M Dolan, Darell D Bigner, Henry S FriedmanAbstract:Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of Temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was Temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by Temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of Temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.
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activity of Temozolomide in the treatment of central nervous system tumor xenografts
Cancer Research, 1995Co-Authors: Henry S Friedman, Stephen T Keir, Anthony E Pegg, Eileen M Dolan, Darell D Bigner, Susan Marcelli, Joseph J Catino, Clifford S ScholdAbstract:Abstract The activity of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Temozolomide) in the treatment of a panel of xenografts derived from ependymoma, medulloblastoma, and childhood and adult high-grade glioma was evaluated in athymic nude mice bearing s.c. and intracranial tumors. Temozolomide administered daily for a total of five doses demonstrated marked activity against a panel of Mer+ xenografts despite marginal to moderate activity of 1,3-bis(2-chloroethyl)-1-nitrosourea. The growth delays produced by Temozolomide in these xenografts were 1.8–7.5-fold greater than those produced by procarbazine. Although Temozolomide demonstrated marginal activity against the Mer+ cell line D341 Med when a 5-day schedule was used, a high-dose 1-day schedule resulted in moderate activity. Temozolomide produced increases in median survival of 1285% (adult glioma D-54 MG), 323% (childhood glioma D-456 MG), and 68% (ependymoma D612 EP). Pretreatment of mice with O6-benzylguanine increased Temozolomide-induced mortality, requiring reduction of the dosage from 1200 to 750 mg/m2 on the single-day regimen. O6-Benzylguanine pretreatment of mice bearing Mer+ D341 Med increased the growth delay of Temozolomide, in duplicate experiments, from -3.1 to 4.8 and 1.1 to 4.9 days. These studies suggest that Temozolomide may be active in the treatment of a broad spectrum of central nervous system cancers, including Mer+ tumors resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea.
