RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study

Christoph P Beier, Christina Schmid, Thierry Gorlia, Christine Kleinletzenberger, Dagmar Beier, Oliver Grauer, Andreas Steinbrecher, Birgit Hirschmann, Alexander Brawanski, Christopher Dietmaier, Tanja Jauch-Worley, Oliver Kölbl, Torsten Pietsch, Martin Proescholdt, Petra Rümmele, Armin Muigg, Günther Stockhammer, Monika Hegi, Ulrich Bogdahn, Peter Hau, Christoph P Beier, Christina Schmid, Thierry Gorlia, Christine Kleinletzenberger, Dagmar Beier, Oliver Grauer, Andreas Steinbrecher, Birgit Hirschmann, Alexander Brawanski, Christopher Dietmaier, Tanja Jauch-Worley, Oliver Kölbl, Torsten Pietsch, Martin Proescholdt, Petra Rümmele, Armin Muigg, Günther Stockhammer, Monika Hegi, Ulrich Bogdahn, Peter Hau

Abstract

Background: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for.

Methods: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression.

Results: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison.

Conclusion: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

Trial registration: ClinicalTrials.gov NCT00944801.

Figures

Figure 1
Figure 1
CONSORT flow diagram.
Figure 2
Figure 2
Overall survival of RNOP-09 patients as compared to historical control. Kaplan-Meier estimates of overall survival according to treatment group. The unadjusted hazard ratio for death among patients treated with PEG-Dox and prolonged administration of TMZ as compared with those treated in the EORTC26981/NCIC-CE.3 trial was 0.83 (CI: 0.60-1.16; p = 0.28).

References

    1. Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17:2572–2578.
    1. Stupp R, Mason WP, Bent MJ van den, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330.
    1. Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Kieslich A. Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 2008;68:5706–5715. doi: 10.1158/0008-5472.CAN-07-6878.
    1. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003. doi: 10.1056/NEJMoa043331.
    1. Wolff JE, Trilling T, Molenkamp G, Egeler RM, Jurgens H. Chemosensitivity of glioma cells in vitro: a meta analysis. J Cancer Res Clin Oncol. 1999;125:481–486. doi: 10.1007/s004320050305.
    1. Neuwelt EA, Pagel M, Barnett P, Glassberg M, Frenkel EP. Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification. Cancer Res. 1981;41:4466–4470.
    1. Siegal T, Horowitz A, Gabizon A. Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg. 1995;83:1029–1037. doi: 10.3171/jns.1995.83.6.1029.
    1. Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002;94:25–36. doi: 10.1002/cncr.10201.
    1. Cabanes A, Tzemach D, Goren D, Horowitz AT, Gabizon A. Comparative study of the antitumor activity of free doxorubicin and polyethylene glycol-coated liposomal doxorubicin in a mouse lymphoma model. Clin Cancer Res. 1998;4:499–505.
    1. Fabel K, Dietrich J, Hau P, Wismeth C, Winner B, Przywara S, Steinbrecher A, Ullrich W, Bogdahn U. Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Cancer. 2001;92:1936–1942. doi: 10.1002/1097-0142(20011001)92:7<1936::AID-CNCR1712>;2-H.
    1. Hau P, Fabel K, Baumgart U, Rummele P, Grauer O, Bock A, Dietmaier C, Dietmaier W, Dietrich J, Dudel C. Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer. 2004;100:1199–1207. doi: 10.1002/cncr.20073.
    1. Chua SL, Rosenthal MA, Wong SS, Ashley DM, Woods AM, Dowling A, Cher LM. Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme. Neuro Oncol. 2004;6:38–43. doi: 10.1215/S1152851703000188.
    1. Glas M, Koch H, Hirschmann B, Jauch T, Steinbrecher A, Herrlinger U, Bogdahn U, Hau P. Pegylated liposomal doxorubicin in recurrent malignant glioma: analysis of a case series. Oncology. 2007;72:302–307. doi: 10.1159/000113052.
    1. Hau P, Koch D, Hundsberger T, Marg E, Bauer B, Rudolph R, Rauch M, Brenner A, Rieckmann P, Schuth J. Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma. Neurology. 2007;68:688–690. doi: 10.1212/.
    1. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–1280.
    1. Vlassenbroeck I, Califice S, Diserens AC, Migliavacca E, Straub J, Di Stefano I, Moreau F, Hamou MF, Renard I, Delorenzi M. Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. J Mol Diagn. 2008;10:332–337. doi: 10.2353/jmoldx.2008.070169.
    1. Vail DM, Chun R, Thamm DH, Garrett LD, Cooley AJ, Obradovich JE. Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model. Clin Cancer Res. 1998;4:1567–1571.
    1. Grant R, Liang BC, Slattery J, Greenberg HS, Junck L. Chemotherapy response criteria in malignant glioma. Neurology. 1997;48:1336–1340.
    1. Remlinger KA. Cutaneous reactions to chemotherapy drugs: the art of consultation. Arch Dermatol. 2003;139:77–81. doi: 10.1001/archderm.139.1.77.
    1. Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000;89:1037–1047. doi: 10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>;2-Z.
    1. Koukourakis MI, Koukouraki S, Fezoulidis I, Kelekis N, Kyrias G, Archimandritis S, Karkavitsas N. High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer. 2000;83:1281–1286. doi: 10.1054/bjoc.2000.1459.
    1. Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin. Rationale for use in solid tumours. Drugs. 1997;54(Suppl 4):15–21. doi: 10.2165/00003495-199700544-00005.
    1. Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke B, Kortmann RD, Steinbach JP, Hundsberger T, Wick W, Meyermann R. Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03. J Clin Oncol. 2006;24:4412–4417. doi: 10.1200/JCO.2006.06.9104.
    1. a service of the U.S. National Institutes of Health.
    1. Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick W. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol. 2007;25:3357–3361. doi: 10.1200/JCO.2007.10.7722.
    1. Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P, Muracciole X, Braguer D, Ouafik L, Martin PM. Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol. 2007;25:1470–1475. doi: 10.1200/JCO.2006.07.4807.
    1. Reardon DA, Nabors LB, Stupp R, Mikkelsen T. Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme. Expert Opin Investig Drugs. 2008;17:1225–1235. doi: 10.1517/13543784.17.8.1225.

Source: PubMed

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