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Ester Simeone - One of the best experts on this subject based on the ideXlab platform.
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three year follow up of advanced melanoma patients who received ipilimumab plus Fotemustine in the italian network for tumor biotherapy nibit m1 phase ii study
Annals of Oncology, 2015Co-Authors: A M Di Giacomo, P A Ascierto, P Queirolo, Lorenzo Pilla, Ruggero Ridolfi, M Santinami, A Testori, Ester Simeone, Massimo Guidoboni, Andrea MaurichiAbstract:ABSTRACT Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of the combination of ipilimumab and Fotemustine in metastatic melanoma patients with or without brain metastases. The addition of Fotemustine to ipilimumab does not impair its immunomodulatory activity. Background In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with Fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. Patients and methods This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with Fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3+CD4+ICOS+CD45RO+ or CD45RA+ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. Results Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1–18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naive’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points.BRAF status did not correlate with clinical outcome. Conclusions Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with Fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EudraCT number 2010-019356-50. CinicalTrials.gov NCT01654692.
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combined vemurafenib and Fotemustine in patients with braf v600 melanoma progressing on vemurafenib
Oncotarget, 2014Co-Authors: Paola Queirolo, Ester Simeone, Francesco Spagnolo, Virginia Picasso, Laura Spano, Enrica Tanda, Valeria Fontana, Laura Giorello, Domenico Franco Merlo, Antonio M GrimaldiAbstract:// Paola Queirolo 1 , Francesco Spagnolo 2 , Virginia Picasso 1 , Laura Spano 1 , Enrica Tanda 1 , Valeria Fontana 3 , Laura Giorello 3 , Domenico Franco Merlo 3 , Ester Simeone 4 , Antonio Maria Grimaldi 4 , Marcello Curvietto 4 , Michele Del Vecchio 5 , Paolo Bruzzi 3 , Paolo Antonio Ascierto 4 1 Department of Medical Oncology, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 2 Department of Plastic and Reconstructive Surgery, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 3 Department of Epidemiology, Biostatistics and Clinical Trials, IRCCS AOU San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 4 Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione “G. Pascale”, Napoli, Italy 5 Department of Medical Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy Correspondence to: Francesco Spagnolo, email: francesco.spagnolo85@gmail.com Keywords: vemurafenib, BRAF, Fotemustine, melanoma, treatment beyond progression Received: February 29, 2016 Accepted: June 30, 2016 Published: July 13, 2016 ABSTRACT Background: BRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of Fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor. Patients and Methods: In this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and Fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS. Results: Thirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients. This trial is registered with ClinicalTrials.gov number NCT01983124. Conclusion: The combination of vemurafenib plus Fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients.
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PROTOCOL Open Access
2013Co-Authors: Antonio Daponte, Ester Simeone, Simona Signoriello, Luigi Maiorino, Bruno Massidda, Antonio Maria Grimaldi, Corrado Caracò, Antonio Cossu, Gerardo Botti, Antonella PetrilloAbstract:Phase III randomized study of Fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanom
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Phase III randomized study of Fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma.
Journal of translational medicine, 2013Co-Authors: Antonio Daponte, Ester Simeone, Simona Signoriello, Luigi Maiorino, Bruno Massidda, Antonio Maria Grimaldi, Corrado Caracò, Antonio Cossu, Giuseppe Palmieri, Gerardo BottiAbstract:Background The effect of the addition of Fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial.
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ipilimumab and Fotemustine in patients with advanced melanoma nibit m1 an open label single arm phase 2 trial
Lancet Oncology, 2012Co-Authors: A M Di Giacomo, P A Ascierto, Lorenzo Pilla, M Santinami, Ester Simeone, Pier Francesco Ferrucci, Diana Giannarelli, Antonella Marasco, Licia Rivoltini, S NicolettiAbstract:Summary Background Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus Fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m 2 intravenous Fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and Fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. Findings 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7–57·6), as did ten with brain metastases (50·0%, 27·2–72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation The combination of ipilimumab plus Fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding Bristol-Myers Squibb.
A M Di Giacomo - One of the best experts on this subject based on the ideXlab platform.
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three year follow up of advanced melanoma patients who received ipilimumab plus Fotemustine in the italian network for tumor biotherapy nibit m1 phase ii study
Annals of Oncology, 2015Co-Authors: A M Di Giacomo, P A Ascierto, P Queirolo, Lorenzo Pilla, Ruggero Ridolfi, M Santinami, A Testori, Ester Simeone, Massimo Guidoboni, Andrea MaurichiAbstract:ABSTRACT Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of the combination of ipilimumab and Fotemustine in metastatic melanoma patients with or without brain metastases. The addition of Fotemustine to ipilimumab does not impair its immunomodulatory activity. Background In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with Fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination. Patients and methods This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with Fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3+CD4+ICOS+CD45RO+ or CD45RA+ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status. Results Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months [95% confidence interval (CI) 7.1–18.7 months] and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naive’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points.BRAF status did not correlate with clinical outcome. Conclusions Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with Fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab. EudraCT number 2010-019356-50. CinicalTrials.gov NCT01654692.
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immune correlates of metastatic melanoma patients treated with ipilimumab in combination with Fotemustine in the phase ii nibit m1 study
Journal for ImmunoTherapy of Cancer, 2013Co-Authors: Cristina Maccalli, A M Di Giacomo, Diana Giannarelli, Hugues J M Nicolay, Filippo Capocefalo, Ester Fonsatti, Carla Chiarucci, Ornella Cutaia, Giorgio Parmiani, Michele MaioAbstract:Meeting abstracts Ipilimumab (IPI) in combination with Fotemustine (FTM) has shown a promising clinical activity in metastatic melanoma (MM) patients (pts) enrolled in the NIBIT-M1 trial (Di Giacomo, et al., Lancet Oncology, 2012). This study investigated changes in immunological parameters in the
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ipilimumab and Fotemustine in patients with advanced melanoma nibit m1 an open label single arm phase 2 trial
Lancet Oncology, 2012Co-Authors: A M Di Giacomo, P A Ascierto, Lorenzo Pilla, M Santinami, Ester Simeone, Pier Francesco Ferrucci, Diana Giannarelli, Antonella Marasco, Licia Rivoltini, S NicolettiAbstract:Summary Background Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus Fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m 2 intravenous Fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and Fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. Findings 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7–57·6), as did ten with brain metastases (50·0%, 27·2–72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation The combination of ipilimumab plus Fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding Bristol-Myers Squibb.
Dirk Schadendorf - One of the best experts on this subject based on the ideXlab platform.
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acquired resistance of melanoma cells to the antineoplastic agent Fotemustine is caused by reactivation of the dna repair gene mgmt
International Journal of Cancer, 2001Co-Authors: Markus Christmann, Dirk Schadendorf, Matthias Pick, Hermann Lage, Bernd KainaAbstract:Acquired resistance to antineoplastic agents is a frequent obstacle in tumor therapy. Malignant melanoma cells are particularly well known for their unresponsiveness to chemotherapy; only about 30% of tumors exhibit a transient clinical response to treatment. In our study, we investigated the molecular mechanism of acquired resistance of melanoma cells (MeWo) to the chloroethylating drug Fotemustine. Determination of O6-methylguanine-DNA methyltransferase (MGMT) activity showed that MeWo cells that acquired resistance to Fotemustine upon repeated treatment with the drug display high MGMT activity, whereas the parental cell line had no detectable MGMT. The resistant cell lines exhibit cross-resistance to other O6-alkylating agents, such as N-methyl-N′-nitro-N-nitrosoguanidine. Acquired resistance to Fotemustine was alleviated by treatment with the MGMT inhibitor O6-benzylguanine demonstrating that reactivation of MGMT is the main underlying cause of acquired alkylating drug resistance. As compared with control cells, both MGMT mRNA and MGMT protein were expressed at a high level in Fotemustine resistant cells. Southern blot analysis proved that the MGMT gene was not amplified. There was also only an insignificant difference in the CpG methylation pattern of the MGMT promoter whereas a clear hypermethylation in the body of the gene was observed in Fotemustine resistant cells. The conclusion that hypermethylation is responsible for reactivation of the MGMT gene gained support by the finding that MGMT activity significantly declined and cells reverted (partially) to the parental sensitive phenotype upon treatment with 5-azacytidine. This is the first report of acquired resistance to a chloroethylating antineoplastic drug of melanoma cells due to gene hypermethylation. © 2001 Wiley-Liss, Inc.
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alterations of dna repair in melanoma cell lines resistant to cisplatin Fotemustine or etoposide
Journal of Investigative Dermatology, 2000Co-Authors: Thomas M Runger, Dirk Schadendorf, Steffen Emmert, Caroline Diem, Bernd Epe, Doris HellfritschAbstract:Resistance to chemotherapy is a common phenomenon in malignant melanoma. In order to assess the role of altered DNA repair in chemoresistant melanoma, we investigated different DNA repair pathways in one parental human melanoma line (MeWo) and in sublines of MeWo selected in vitro for drug resistance against four commonly used drugs (cisplatin, Fotemustine, etoposide, and vindesine). Host cell reactivation assays with the plasmid pRSVcat were used to assess processing of different DNA lesions. With ultraviolet-irradiated plasmids, no significant differences were found, indicating a normal (nucleotide excision) repair of DNA photoproducts. With singlet oxygen-treated plasmid, the Fotemustine- and cisplatin-resistant lines exhibited a significantly increased (base excision) repair of oxidative DNA damage. With Fotemustine-treated plasmid, the Fotemustine-resistant subline did not exhibit an increased repair of directly Fotemustine-induced DNA damage. Similar results were obtained with cisplatin-induced DNA crosslinks in the cisplatin-resistant line. The Fotemustine- and etoposide-resistant sublines have been shown to exhibit a reduced expression of genes involved in DNA mismatch repair. We used a "host cell microsatellite stability assay" with the plasmid pZCA29 and found a 2.0-fold to 2.5-fold increase of microsatellite frameshift mutations (p < or = 0.002) in the two resistant sublines. This indicates microsatellite instability, the hallmark of an impaired DNA mismatch repair. The increased repair of oxidative DNA damage might mediate an increased chemoresistance through an improved repair of drug-induced DNA damage. In contrast, a reduced DNA mismatch repair might confer resistance by preventing futile degradation of newly synthesized DNA opposite alkylation damage, or by an inability to detect such damage and subsequent inability to undergo DNA-damage-induced apoptosis.
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combined treatment of stage iv melanoma patients with amifostine and Fotemustine a pilot study
Melanoma Research, 1998Co-Authors: P Mohr, A Makki, Eckhard W Breitbart, Dirk SchadendorfAbstract:Amifostine (Ethyol) is a new chemoprotective agent that has been shown to have significant activity in the prevention of nephro-, oto-, neuro- and haemotoxicity. In preclinical models as well as in clinical trials carried out in patients suffering from various malignancies, the adverse effects and signs of toxicity related to a number of cytostatic drugs, including cisplatin, cyclophosphamide, carboplatin and mitomycin C, were prevented. In Europe Fotemustine (Muphoran) is widely used in the treatment of brain metastases in melanoma patients. However, the dose is often limited by severe bone marrow toxicity after induction cycles, particularly in heavily pretreated patients. In order to test whether amifostine treatment might promote bone marrow protective effects when combined with Fotemustine chemotherapy, we conducted a preliminary study in 10 patients suffering from stage IV disseminated malignant melanoma. The patients received amifostine (740 mg/m2) prior to Fotemustine chemotherapy (100 mg/m2). Six of the patients had failed one or two other prior chemotherapy regimens. Seven patients had brain metastases. Among the 10 patients treated with amifostine and Fotemustine, no major clinical responses (complete response or partial response) were achieved, with four patients showing stabilization of the disease over more than 3 months. No patient in the amifostine plus Fotemustine treatment group showed severe myelosuppression (WHO grade III/IV), in contrast to a historical control group treated with Fotemustine alone, in which about 40% developed major thrombocytopenia and about 45% developed severe leucopenia (WHO grade III/IV). Therefore, we conclude that the combination of amifostine with Fotemustine was well tolerated in this small series of patients and further studies are warranted to test the amelioration of myelosuppression by the addition of amifostine.
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human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin Fotemustine vindesine or etoposide modulation of proto oncogene expression
Anticancer Research, 1997Co-Authors: M A Kern, Heike Helmbach, Metin Artuc, D Karmann, Klaus Jurgovsky, Dirk SchadendorfAbstract:Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. In order to establish a reproducable model system for studying the exact mechanisms conferring chemoresistance, we selected drug-resistant sublines in vitro derived from one parental human melanoma (MeWo) cell line. Four commonly used chemotherapeutic drugs (vindesine, etoposide, Fotemustine, cisplatin) with different modes of action were choosen and stable sublines exhibiting four different levels of resistance against each drug were selected by continuous exposure over two years. Analysis of the drug-resistant sublines regarding their pharmacological characteristics and cross-resistance pattern revealed an up to 26-fold increased relative resistance against the alkylating agent Fotemustine (MeWo FOTE ) and an up to 35.7-fold increased relative resistance against topoisomerase-II-inhibiting etoposide (MeWo ETO ). Cisplatin selection (MeWo CIS ) resulted in a 6-fold higher resistance compared to parental MeWo cells, whereas vindesine exposure (MeWo VIND ) increased relative resistance up to 10.2-fold. Sublines selected separately for resistance to the DNA-damaging agents Fotemustine, cisplatin and etoposide demonstrated strong cross-resistance. In comparison to the parental cell line drug-resistant sublines showed altered expression patterns of proto-oncogenes. Levels of p53 mRNA decreased with increasing resistance to vindesine, etoposide and Fotemustine. Expression of bcl-2 family members (bax, bcl-x) was modulated by Fotemustine, etoposide and cisplatin. In addition the expression of members of the fos (c-fos) and jun (c-jun, jun-D) gene family encoding transcription factors of the AP-I complex was altered in all drug-resistant sublines. The pattern of expression varied with the inducing stimulus and this was paralleled by changes in the transactivation potential of AP-1. Our results reinforce the central role of AP-1 in drug resistance probably through its participation in a programmed cellular stress response.
Alfredo Marinelli - One of the best experts on this subject based on the ideXlab platform.
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biweekly Fotemustine schedule for recurrent glioblastoma in the elderly activity and toxicity assessment of a multicenter study
CNS oncology, 2019Co-Authors: Raffaele Addeo, Alfredo Marinelli, Giuseppe Lamberti, G Simonetti, Patrizia Iodice, Liliana Montella, Salvatore Cappabianca, P Gaviani, Michele Caraglia, Salvatore Del PreteAbstract:Aim: To assess the efficacy and safety of alternative Fotemustine administration schedule in elderly patients with recurrent glioblastoma. Patients & methods: Patients aged >65 years with recurrent glioblastoma received Fotemustine (80 mg/m2; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety. Results: 58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3-4 hematological toxicities occurred. Conclusion: The alternative Fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.
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high dose Fotemustine in temozolomide pretreated glioblastoma multiforme patients a phase i ii trial
Medicine, 2018Co-Authors: Alfredo Marinelli, Carlo Buonerba, Giuseppe Di Lorenzo, Giuseppe Lamberti, Luigi Cerbone, Nadia Cordua, Gianfranco Peluso, Sabino De PlacidoAbstract:AbstractBackground:Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively invest
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Can high-dose Fotemustine reverse MGMT resistance in glioblastoma multiforme?
Journal of Neuro-Oncology, 2010Co-Authors: Chiara Gallo, Carlo Buonerba, Giuseppe Di Lorenzo, Valeria Romeo, Sabino De Placido, Alfredo MarinelliAbstract:Glioblastoma multiforme (GBM), the highest grade malignant glioma, is associated with a grim prognosis-median overall survival is in the range 12-15 months, despite optimum treatment. Surgery to the maximum possible extent, external beam radiotherapy, and systemic temozolomide chemotherapy are current standard treatments for newly diagnosed GBM, with intracerebral delivery of carmustine wafers (Gliadel). Unfortunately, the effectiveness of chemotherapy can be hampered by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which confers resistance both to temozolomide and nitrosoureas, for example Fotemustine and carmustine. MGMT activity can be measured by PCR and immunohistochemistry, with the former being the current validated technique. High-dose chemotherapy can deplete MGMT levels in GBM cells and has proved feasible in various trials on temozolomide, in both newly diagnosed and recurrent GBM. We here report the unique case of a GBM patient, with high MGMT expression by immunohistochemistry, who underwent an experimental, high-dose Fotemustine schedule after surgery and radiotherapy. Although treatment caused two episodes of grade 3-4 thrombocytopenia, a complete response and survival of more than three years were achieved, with a 30% increase in dose intensity compared with the standard Fotemustine schedule.
B Gerard - One of the best experts on this subject based on the ideXlab platform.
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clinical experience of Fotemustine cisplatin and high dose tamoxifen in patients with metastatic malignant melanoma
Melanoma Research, 1998Co-Authors: K A Semb, C Lucas, Steinar Aamdal, T Bohmann, B GerardAbstract:Inspired by the high response rates achieved with the DBCT regimen (dacarbazine [DTIC], carmustine [BCNU], cisplatin and tamoxifen [TAM]), we administered the nitrosourea compound Fotemustine, cisplatin and TAM (FCT regimen) to 69 patients with metastatic melanoma. Fotemustine (100 mg/m2) and cisplatin (100 mg/m2) were administered every 4 weeks, preceded by TAM 160 mg daily for 7 days from the second course onwards. Pharmacokinetic blood sampling was performed in 14 patients during the initial two cycles to compare the pharmacokinetic behaviour of Fotemustine with or without TAM. Previous chemo- or radiotherapy was allowed, and patients with brain metastases or concomitant other malignancies were included. Four complete and 11 partial responders were observed among 66 evaluable patients, yielding a response rate of 22.7% (95% confidence interval 12.9 32.5%). The median survival time was 6.4 months (range 0.1-52+ months). The main toxicities were thrombocytopenia, protracted nausea/vomiting and ototoxicity. Renal toxicity was generally mild, but possibly contributed to two deaths. Seven patients experienced deep venous thrombosis during the study. TAM had no influence on the pharmacokinetics of Fotemustine. The activity of the FCT regimen was clearly inferior to that initially reported with DBCT treatment. However, a recent publication concludes that the latter achieves a considerably lower response rate when administered to a larger patient group. We believe our results reflect the true activity of FCT and similar regimens when administered routinely to unselected patients. Considering the number of potentially serious side effects, we cannot recommend the moderately active FCT regimen as a palliative treatment option for melanoma patients.
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Fotemustine in the treatment of brain primary tumors and metastases
Cancer Investigation, 1994Co-Authors: David Khayat, Bruno Giroux, Jocelyne Berille, Veronique Cour, B Gerard, Marlis Sarkany, Philippe Bertrand, Jeanpierre BizzariAbstract:Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using Fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma. In recurrent malignant glioma, Fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose Fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, Fotemustine has been used intraarterially, with 10 objective responses observed among 26 evaluable patients. In brain metastases of non-small cell lung cancer, Fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, Fotemustine is still under study, but preliminary results are promising. In cerebral metastases of disseminated malignant melanoma, Fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%. Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.
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activity and unexpected lung toxicity of the sequential administration of two alkylating agents dacarbazine and Fotemustine in patients with melanoma
European Journal of Cancer, 1993Co-Authors: B Gerard, C Lucas, Jeanpierre Bizzari, Steinar Aamdal, S Leyvraz, S M Lee, Maurizio DincalciAbstract:We report the results and discuss the toxicity of clinical trials based on a single concept: the decrease in O6alkyl DNA alkyltransferase (O6AT) resistance mechanism when a chloroethylating agent is used sequentially after a methylating agent. This decrease in O6AT being dose dependent, several increasing doses of dacarbazine (DTIC) have been tested (400 mg/m2 to 1000 mg/m2 every 4 weeks, 3-4 h before Fotemustine (100 mg/m2 intravenously every 4 weeks). These results (mean overall response rate 27%) compared with reference regimes, demonstrate that DTIC is able to increase the alkylating power of Fotemustine: same range of response rate with only half of the two drug doses compared to an alternated combination, high activity rate especially in lung metastases (10/42 complete responses + 13/42 partial responses), different pattern for haematotoxicity, and occurrence of a new side-effect: acute lung toxicity as adult respiratory distress syndrome (ARDS). This lung toxicity was totally unexpected since several hundreds of patients had been so far treated with Fotemustine as single agent or in other combinations with DTIC without any case of acute or delayed lung toxicity. Prophylactic administration of corticoids was not effective and monitoring of the respiratory function was of no predictive value. Due to the additional depleting effects of DTIC on at least two main defence mechanisms--the O6AT system and cytosolic and/or nuclear glutathione--we suppose that the sequence is able to increase the alkylating power of Fotemustine to an excessive extent and/or that the detoxication capacity of the cell against DTIC and/or Fotemustine metabolites is overwhelmed. Other depletors of the O6AT activity which do not generate metabolites that compete for the same detoxication pathway as the chloroethylnitrosourea (CENU) metabolites should be tested.