title: Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme.
abstract: Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavours, with low response rates and survival rarely exceeding 6 months. There are no standard chemotherapeutic regimens and new therapeutic approaches have to be found. We report an open-label, uncontrolled, multicentre phase II trial of lonidamine (LND) and diazepam in 16 patients with GBM at first relapse and a Karnofsky performance status > or = 70. The treatment regimen consisted of LND 450 mg/day and diazepam 15 mg/day orally of every 28-day cycle until progression or unacceptable toxicity. Patients received a median of three cycles (range, 1-12). No complete or partial response was observed. Therefore, according to the design of the study, no additional patients were enrolled and the trial was closed. Nevertheless, seven stabilizations (50%) were observed. Median time to progression was 8 weeks (range, 5-19 weeks). Median overall survival from recurrence was 15 weeks (range, 14-61 weeks). No grade 3-4 toxicity, except somnolence, was observed and there were no therapy-related deaths. Dose reduction for diazepam due to somnolence (grade III) was performed in 9 patients. The combination of LND and diazepam is well tolerated. LND and diazepam, acting on two distinct mitochondrial sites involved in cellular energy metabolism, may exert a cytostatic effect on tumour growth as shown by the high percentage of stable patients. The LND-diazepam at the used dosing schedule did not show a complete or partial response. LND plus diazepam may be interesting in the adjuvant setting or associated to chemotherapy to act on different targets and increase the therapeutic index.
authors.affiliation: Department of Oncology, Hôpital Européen Georges Pompidou, Paris, France. stephane.oudard@hop.egp.ap-hop-paris.fr
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.forename: Antoine
authors.initials: A
authors.lastname: Carpentier
authors.forename: Eugeniu
authors.initials: E
authors.lastname: Banu
authors.forename: François
authors.initials: F
authors.lastname: Fauchon
authors.forename: Denis
authors.initials: D
authors.lastname: Celerier
authors.forename: Marie F
authors.initials: MF
authors.lastname: Poupon
authors.forename: Bernard
authors.initials: B
authors.lastname: Dutrillaux
authors.forename: Jean M
authors.initials: JM
authors.lastname: Andrieu
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Delattre
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003975:Diazepam / Q000008:administration & dosage; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate
chemical_list: D007191:Indazoles; D003975:Diazepam; C016371:lonidamine