BACKGROUND: Glufosfamide is a new alkylating agent in which the active
      metabolite of isophosphoramide mustard is covalently linked to
      beta-D-glucose to target the glucose transporter system and increase
      intracellular uptake in tumor cells. We investigated this drug in a
      multicenter prospective phase II trial in recurrent glioblastoma
      multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent
      GBM following surgery, radiotherapy and no more than one prior line of
      chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2)
      administered as a 1-h intravenous infusion. Treatment success was defined
      as patients with either an objective response according to Macdonald's
      criteria or 6 months progression-free survival. Toxicity was assessed with
      the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one
      eligible patients were included. Toxicity was modest, the main clinically
      relevant toxicities being leukopenia (CTC grade >3 in five patients) and
      hepatotoxicity (in three patients). No responses were observed; one
      patient (3%; 95% confidence interval 0 to 17%) was free from progression
      at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under
      the curve and glufosfamide clearance in patients treated with
      enzyme-inducing antiepileptic drugs, but no effect of these drugs on
      maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did
      not show significant clinical antitumor activity in patients with
      recurrent GBM

Baron, B.

Bent, M.J. (Martin) van den

Brandes, A. (Alba)

Carpentier, A.F.

Chollet, P.

Desir, J.P.

Dittrich, C. (Christian)

Frappaz, D.

Frenay, M. (Marc)

Fumoleau, P. (Pierre)

Grisold, W. (Wolfgang)

Jonge, M.J.A. (Maja) de

Lacombe, D. (Denis)

Lesimple, T.

Oliveira, J.

Schuessler, M.

Stupp, R. (Roger)

Erasmus University Digital Repository

Annals of Oncology 14: 1732–1734, 2003Original article DOI: 10.1093/annonc/mdg491© 2003 European Society for Medical OncologyEuropean Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiformeM. J. van den Bent1*, W. Grisold2, D. Frappaz3, R. Stupp4, J. P. Desir5, T. Lesimple6, C. Dittrich2, M. J. A. de Jonge1, A. Brandes7, M. Frenay8, A. F. Carpentier9, P. Chollet10, J. Oliveira11, B. Baron12, D. Lacombe12, M. Schuessler13 & P. Fumoleau14On behalf of the EORTC New Drug Development Group and Brain Tumor Group, Brussels, Belgium*Correspondence to: Dr M. J. van den Bent, Department of Neuro-Oncology, Daniel den Hoed Cancer Center/Erasmus University Medical Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands. Tel: +31-10-4391415; Fax: +31-10-4391031; E-mail: m.vandenbent@erasmusmc.nl1Daniel den Hoed Cancer Center/Erasmus University Medical Center, Rotterdam, The Netherlands; 2LBI-ACR Vienna and Kaiser Franz Josef Spital, Vienna, Austria; 3Centre Léon Bérard, Lyon, France; 4Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 5Centre Georges-François-Leclerc, Dijon; 6Centre Eugène Marquis, Rennes, France; 7Medical Oncology Department University Hospital-Padova, Padova, Italy; 8Centre Lacassagne, Nice; 9CHU Pitié-Salpétrière, Paris; 10Centre Jean Perrin, Clermont-Ferrand, France; 11IPO Francisco Gentil-Centro de Lisboa, Portugal; 12EORTC Data Center, Brussels, Belgium; 13Baxter Oncology GmbH, Frankfurt/Main, Germany; 14Centre René Gauducheau, Nantes-St Herblain, FranceReceived 23 April 2003; revised 17 June 2003; accepted 12 August 2003Background: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramidemustard is covalently linked to β-D-glucose to target the glucose transporter system and increase intracellularuptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblas-toma multiforme (GBM).Patients and methods: Eligible patients had recurrent GBM following surgery, radiotherapy and no morethan one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m2 administered as a 1-hintravenous infusion. Treatment success was defined as patients with either an objective response according toMacdonald’s criteria or 6 months progression-free survival. Toxicity was assessed with the Common ToxicityCriteria (CTC) version 2.0.Results: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicitiesbeing leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses wereobserved; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmaco-kinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treatedwith enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasmahalf-life.Conclusion: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GBM.Key words: chemotherapy, glioblastoma multiforme, glufosfamide, recurrentIntroductionDespite many trials to improve the outcome of patients with high-grade glioma, the prognosis of this disease remains dismal. Inparticular, the prognosis of glioblastoma is poor, with a mediansurvival of 9–12 months. Once the tumor recurs following initialtreatment further treatment options are limited. Even chemo-therapy with temozolomide, recently approved for this indication,offers a low response rate (5–10%) with ∼20% of patients remainingfree from progression at 6 months after the start of treatment [1, 2].This shows the clear need for better medical treatment for thisdisease, which requires the investigation of new and promisingagents in well-designed phase II trials.Glufosfamide is a new alkylating agent in which the activemetabolite isophosphoramide mustard is linked to β-D-glucose[3]. Glufosfamide does not require metabolic activation byhepatic microsomal enzymes such as the oxazaphosphorinescyclophosphamide and ifosfamide. There is evidence that theNa-D-glucose cotransporter SAAT1 mediates the transport ofglufosfamide into human tumor cells and this mechanism maylead to accumulation of  the drug in tumor cells [3, 4]. Togetherwith the elevated metabolic rate and glucose consumption rate oftumor cells, this targeting mechanism probably contributes to therelative selectivity of glufosfamide for tumor cells. The drug wasfound to be active against the glioblastoma multiforme (GBM)1733cell line HTB 14 (A. R. Hanauske, Baxter Oncology, data on file).In phase I studies renal tubular acidosis and neutropenia were thedose-limiting toxicities. The recommended phase II dose was4500 mg/m2 when given as a 6-h infusion or 5000 mg/m2 whengiven as a 60-min infusion [4, 5]. In phase I studies evidence ofantitumor activity in resistant solid tumors was observed. As partof a broad phase II program to investigate the activity of glufosfa-mide in solid tumors, the European Organization for Research andTreatment of Cancer (EORTC) New Drug Development Groupand Brain Tumor Group investigated this drug in recurrent GBM(EORTC study 16994G-26002).Patients and methodsPatients were eligible if they had: a histologically proven GBM at first surgery;recurrent or progressive disease after radiation therapy; at least one bidimen-sionally measurable target lesion requiring a contrast enhancing lesion with adiameter of at least 2 cm on magnetic resonance imaging (MRI) or computedtomography scan; no more than one line of prior chemotherapy, either givenadjuvant or at first recurrence; no prior high-dose radiotherapy (>65 Gy),stereotactic radiosurgery or internal radiotherapy; no surgery or radiotherapywithin the last 3 months prior to registration; stable or decreasing dose of steroidsfor at least 1 week; adequate hematological, hepatic and cardiac function; normalrenal function as assessed by serum creatinine <150 µmol/l and a creatinineclearance of ≥60 ml/min as determined by the formula of Cockcroft and Gault;World Health Organization (WHO) performance status 0–2; age ≥18 years;given written informed consent. All participating centers obtained approval ofthe local medical ethical board prior to study activation.Before the start of treatment all patients were centrally registered at theEORTC Data Center in Brussels. The treatment consisted of glufosfamide5000 mg/m2 administered as a 60-min intravenous infusion every 3 weeks, fora minimum of 6 months in case of stabilization of the disease or for at least twocycles after confirmation of an objective response. No nephroprotectivehydration schedule was foreseen in these patients. Response was evaluatedafter every two cycles with MRI scanning.The primary end point of the study was the success rate. A ‘success’ wasdefined as either an objective response according to Macdonald’s criteria orabsence of progression for at least 6 months [6, 7]. Secondary end pointsincluded toxicity, the pharmacokinetic profile of glufosfamide, the estimationof progression-free survival and response duration.Using the one-step Fleming design, while considering a success rate of <5%as unacceptable, 28 patients were needed to assure with 90% power and atype I error of 10% that if the success rate is ≥20% the regimen can berecommended for further investigation in phase III studies [8]. All analyseswere restricted to patients that started treatment. The success rate and its 95%confidence interval (CI) were calculated by pooling, in all eligible patients,those patients with complete response (CR) or partial response (PR) and thosepatients with stable disease (SD) for at least 6 months. Progression-freesurvival (PFS), overall survival (OS) and duration of response were to beestimated by the Kaplan–Meier method and calculated from the start ofchemotherapy [9]. OS was measured until the date of death or last follow-upexamination otherwise. PFS was measured until the first sign of radiological orclinical progression (whichever came first) or death or last follow-up visitotherwise. Toxicity was assessed according to the Common Toxicity Criteria(CTC), version 2.0. The relationship of any toxicity was scored as either likelyrelated to the treatment, unlikely related or relationship not assessable. Duringcycle one, blood samples for pharmacokinetic analysis were drawn at 0 h (pre-dose), at 1 h (immediately post-infusion), at 3 h and at 8 h.ResultsBetween February and August 2001, 32 patients were registeredby 12 institutions. Median age was 56 years (range 30–71 years);the WHO performance status was 0 in five patients, 1 in 22patients and 2 in five patients. Twenty-five patients had receivedprior chemotherapy, following radiotherapy in 17 patients and atfirst recurrence in eight patients. One patient was consideredineligible because the serum bilirubin on the day of entry was >1.5the upper limit of normal. All patients started treatment. A total of94 cycles were administered (median two cycles; range 1–8).Most reported toxicities were considered unrelated to the treat-ment. In four patients (five cycles) retreatment was delayed,which was due to neutropenia (CTC grade 2) in three patients. Therelative dose intensity of glufosfamide was between 90% and110% of the theoretical dose for all patients but one. Grade 3 or 4hematological toxicity (leukopenia or neutropenia) was observedin six patients (16 cycles). Three patients developed a grade 3hepatotoxicity, with a predominant increase of alanine amino-transferase and γ-glutamyltransferase. The ineligible patient witha baseline increase in bilirubin (CTC grade 2) developed a grade 3increase in bilirubin, with full recovery after discontinuation oftreatment. One other patient developed a grade 2 creatinineincrease with a grade 2 proteinuria. One patient developed a grade3 infection and one patient grade 3 vomiting. Several grade 3electrolyte disturbances were observed (hyponatremia, hypo- andhypercalemia, hypermagnesemia, hypophosphatemia) and onegrade 4 hypocalemia.At the time of this report, all but one patient have progressed and17 patients have died. No responses were observed, 10 patients hadno change after two cycles and one patient (3%; 95% CI 0 to 17%)remained free from progression at 6 months.Four patients were excluded from the pharmacokinetic analysis,because they had erroneously received a nephroprotective hydrationschedule which may influence pharmacokinetic parameters. Amoderate inter-individual variability was observed in the remaining27 patients. Table 1 shows pharmacokinetic parameters for allnon-hydrated patients. Patients treated with enzyme-inducingantiepileptic drugs (EIAED; carbamazepine, phenytoine, pheno-barbital, oxcarbazepine) showed a statistically significantdecrease of ∼15% of the glufosfamide clearance and the areaunder the curve (AUC; P = 0.043) as compared with patients notusing these agents. No significant differences were observed inglufosfamide maximum concentration and plasma half-life time.DiscussionGlufosfamide showed a low hematological and non-hematologicaltoxicity profile in GBM patients. The relatively large volume thatwas administrated in a short time (1000 ml in 60 min) did notcause increased edema or neurological deterioration during orshortly after the infusion, events that have been observed in braintumor patients receiving hydration before cisplatin [10]. The pre-dominant toxicity consisted of neutropenia and hepatotoxicity. Inone patient a grade 2 renal toxicity was observed. Glufosfamidewas well tolerated in this group of patients. No objectiveresponses were observed, and only one of 31 patients (3%; 95%1734CI 0 to 17%) remained free from progression at 6 months after thestart of treatment. The pharmacokinetic analysis in this studyshowed overall a profile comparable to results obtained in phase Iand II studies in patients with non-neurological solid tumors (datanot shown). In the group of patients treated with EIAED, a slight(15%) increase in clearance and AUC was observed. Glufosfamideis not metabolized through interaction with CYP3A4 cytochromeand beforehand no interaction was expected. The differences aresmall however, especially in view of the more pronounced andclinically relevant interactions observed with paclitaxel and CPT-11[11, 12]. Whether the presently observed interaction is of clinicalrelevance remains to be established. Its shows, however, the rele-vance of pharmacokinetic studies in studies on medical treatmentof brain tumors, even if beforehand no interaction is expected.In studies on primary brain tumors, Macdonald’s criteria havebeen widely accepted as the primary end point [6]. Several recenttrials on GBM used the percentage of patients remaining free fromprogression at 6 months as the primary end point, using a largedatabase with negative phase II trials on GBM as a referencesource [1, 2]. The advantage of the latter criterion is that itacknowledges the clinical benefit of SD for a patient with adisease in which a rapidly progressive course is the rule [7, 13].The use of this criterion also allows comparison to future trialswith new agents in which a true response is not to be expected. Wefelt reluctant to leave out the objective response criterion (partialor complete response) because true responses (partial or com-plete), regardless of duration, would still imply clinical activity ofglufosfamide. We therefore combined both end points and con-sidered as a treatment ‘success’ any patient in which either a partialor complete response was observed, or in which 6 months PFSwas obtained. Unfortunately, only one patient in the present studymet these conditions.In conclusion, treatment with glufosfamide was in general welltolerated but did not show significant activity in GBM. Thepresent study does not support further investigations of glufosfamidein recurrent GBM.AcknowledgementsThe authors thank L. Lantican and R. Selvais (EORTC Data Center,Brussels, Belgium) for data management and assistance with thedaily conduct of the trial; J. P. Droz and C. Terret (Centre LéonBérard, Lyon, France) for the inclusion and treatment of patientsin this trial; and P. Bachman (Baxter Oncology GmbH) for assist-ance with the preparation and guidance of the trial. This study wassponsored by Baxter Oncology GmbH, Frankfurt, Germany. Theresults were presented at the 93rd Annual Meeting of the Ameri-can Association of Cancer Research, April 2002, San Francisco.References1. Yung WKA, Albright RE, Olson J et al. A phase II study of temozolomidevs. procarbazine in patients with glioblastoma multiforme at first relapse.Br J Cancer 2000; 83: 588–593.2. Brada M, Hoang-Xuan K, Rampling R et al. Multicenter phase II trial oftemozolomide in patients with glioblastoma multiforme at first relapse.Ann Oncol 2000; 12: 259–266.3. Veyhl M, Wagner K, Volk C et al. Transport of the new chemotherapeuticagent β-D-glucosylisophopharmide mustard (D-19575) into tumor cells ismediated by the Na+-D-glucose cotransporter SAAT1. Proc Natl Acad SciUSA 1998; 95: 2914–2919.4. Depenbrock H, Dumez H, van Oosterom AT et al. Phase I clinical andpharmacokinetic study of glufosfamide administered as a short time infu-sion every three weeks in patients with solid tumors. Proc Am Soc ClinOncol 2001; 20: 118a (Abstr 468).5. Briasoulis E, Judson I, Pavlidis N et al. Phase I trial of 6-hour infusion ofglufosfamide, a new alkylating agent with potentially enhanced selectivityfor tumors that overexpress transmembrane glucose transporters: a studyof the European Organization of Research and Treatment of Cancer EarlyClinical Studies Group. J Clin Oncol 2000; 18: 3535–3444.6. Macdonald DR, Cascino TL, Schold SC, Cairncross JG. Response criteriafor phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8: 1277–1280.7. Yung WKA, Prados M, Yaya-Tur R et al. Multicenter phase II trial oftemozolomide in patients with anaplastic astrocytoma or anaplasticoligoastrocytoma at first relapse. J Clin Oncol 1999; 17: 2762–2771.8. Fleming TR. One-sample multiple testing procedures for phase II clinicaltrials. Biometrics 1982; 38: 143–151.9. Kaplan EL, Meier P. Nonparametric estimation from incomplete observa-tions. J Am Stat Assoc 1958; 53: 457–481.10. Walker RW, Cairncross JG, Posner JB. Cerebral herniation in patientsreceiving cisplatin. J Neuro-Oncol 1988; 6: 61–65.11. Chang SM, Kuhn JG, Rizzo J et al. Phase I study of paclitaxel in patientswith recurrent malignant glioma: a North American brain tumor consortiumreport. J Clin Oncol 1998; 16: 2188–2194.12. Friedman HS, Petros WP, Friedman A et al. Irinotecan therapy in adultswith recurrent or progressive malignant glioma. J Clin Oncol 1999; 17:1516–1525.13. Osoba D, Brada M, Yung WKA, Prados MD. Health related quality of lifein patients with anaplastic astrocytoma during treatment with temozolo-mide. Eur J Cancer 2000; 36: 1788–1795.Table 1. Results of pharmacokinetic analysis in the 27 non-hydrated patients: mean values (ranges)aSamples from 27 patients included.bSamples from 17 patients included.AUC, area under the curve; Cmax, maximum concentration; EIAED, enzyme-inducing antiepileptic drugs; P value, difference between patients with and without EIAED; t½, terminal half-life.No. of patientsCmax (µg/ml) t½ (h) AUC (µg·h/ml) Clearance (ml/min/m2)All patients 26 479 (382–696)a 1.8 (1.3–2.9) 1487 (1086–2204) 57 (38–77)With EIAED 10 451 (384–500) 1.7 (1.4–2.2) 1341 (1086–1669) 62 (48–77)Without EIAED 16 495 (382–696)b 1.9 (1.3–2.9) 1579 (1114–2204) 54 (38–71)P value 0.145 0.206 0.043 0.043

European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme

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European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme

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