Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study

Ralph V Boccia, Lucio N Gordan, Gemma Clark, Julian D Howell, Steven M Grunberg, Sancuso Study Group, Petyo Chilingirov, Tatyana V Koynova, Hristina Markova, Mariya Racheva, Violina Taskova, Antoaneta Tomova, Hristo Tsekov, Valentina I Tzekova, Valentina N Yanakieva, Lubos Petuzelka, Jaroslav Vanasek, Raju Titus Chacko, Chirag Desai, Boman Dhabhar, Raghunadharao Digumarti, Rejnish Kumar, Anish Maru, Shawnas Bahnou Noor Mohamed, Kumar Ranjan Mohapatra, Shona Nag, Meenu Walia, Paula Cabrera, Jazmin Figueroa, Edwin Franco-Gonzalez, Ana Laura Rodriguez, Evelia Sanchez, Maciej Krzakowski, Andrzej Mruk, Janusz Rolski, Ciprian Aldea, Florinel Badulescu, Tudor Eliade Ciuleanu, Mircea Dediu, Doina Elena Motan Ganea, Lucian Miron, Delia Ruta Muresan, Monica Patran, Kudrat M Abdulkadirov, Yulia A Alexeeva, Mikhail L Gershanovich, Nicolay V Iiyin, Elena V Karyagina, Alla S Lisyanskaya, Alfia S Nizamutdinova, Sergey V Orlov, Laslo Roman, Tatiana V Shneider, Vladimir L Vinokurov, Andrei U Zaritskiy, Snezana Bosnjak, Dragutin Donat, Roberto Arevalo-Araujo, Veena Charu, Ayse Dincer, Susan Ferguson, Nashat Y Gabrail, Glen R Justice, Cameron K Tebbi, Ralph V Boccia, Lucio N Gordan, Gemma Clark, Julian D Howell, Steven M Grunberg, Sancuso Study Group, Petyo Chilingirov, Tatyana V Koynova, Hristina Markova, Mariya Racheva, Violina Taskova, Antoaneta Tomova, Hristo Tsekov, Valentina I Tzekova, Valentina N Yanakieva, Lubos Petuzelka, Jaroslav Vanasek, Raju Titus Chacko, Chirag Desai, Boman Dhabhar, Raghunadharao Digumarti, Rejnish Kumar, Anish Maru, Shawnas Bahnou Noor Mohamed, Kumar Ranjan Mohapatra, Shona Nag, Meenu Walia, Paula Cabrera, Jazmin Figueroa, Edwin Franco-Gonzalez, Ana Laura Rodriguez, Evelia Sanchez, Maciej Krzakowski, Andrzej Mruk, Janusz Rolski, Ciprian Aldea, Florinel Badulescu, Tudor Eliade Ciuleanu, Mircea Dediu, Doina Elena Motan Ganea, Lucian Miron, Delia Ruta Muresan, Monica Patran, Kudrat M Abdulkadirov, Yulia A Alexeeva, Mikhail L Gershanovich, Nicolay V Iiyin, Elena V Karyagina, Alla S Lisyanskaya, Alfia S Nizamutdinova, Sergey V Orlov, Laslo Roman, Tatiana V Shneider, Vladimir L Vinokurov, Andrei U Zaritskiy, Snezana Bosnjak, Dragutin Donat, Roberto Arevalo-Araujo, Veena Charu, Ayse Dincer, Susan Ferguson, Nashat Y Gabrail, Glen R Justice, Cameron K Tebbi

Abstract

Purpose: A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV).

Patients and methods: Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%.

Results: Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation.

Conclusions: The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron.

Trial registration: ClinicalTrials.gov NCT00273468.

Figures

Fig. 1
Fig. 1
Flow of participants through the study SS, all patients who received ≥1 dose of study treatment. FAS, all SS patients who had ≥1 efficacy assessment after the start of chemotherapy. PPS, all FAS patients without protocol violations that directly impinged on or affected the primary endpoint. Protocol violations leading to exclusion from the PPS included changes in the planned chemotherapy regimen, receipt of banned concomitant medications, >50% patch detachment and incorrect study drug administration
Fig. 2
Fig. 2
Complete control of CINV in predefined subgroups of the PPS. CS corticosteroids

References

    1. Hainsworth JD. The use of ondansetron in patients receiving multiple-day cisplatin regimens. Semin Oncol. 1992;19:48–52.
    1. De Mulder PH, Roila F, Kris MG, Marty MM. Consensus regarding multiple day and rescue antiemetic therapy. Support Care Cancer. 1998;6:248–252. doi: 10.1007/s005200050162.
    1. Dearnaley DP, Judson I, Root T (2002) Handbook of adult cancer chemotherapy schedules, 2nd edn. Oxon, UK, TMG Healthcare Communications, in collaboration with The Royal Marsden NHS Trust
    1. Herrstedt J, Sigsgaard TC, Nielsen HA, Handberg J, Langer SW, Ottesen S, Dombernowsky P. Randomized, double-blind trial comparing the antiemetic effect of tropisetron plus metopimazine with tropisetron plus placebo in patients receiving multiple cycles of multiple-day cisplatin-based chemotherapy. Support Care Cancer. 2007;15:417–426. doi: 10.1007/s00520-006-0158-y.
    1. Navari RM. Prevention of emesis from multiple-day and high-dose chemotherapy regimens. J Natl Compr Canc Netw. 2007;5:51–59.
    1. Lefevre G, Sedek G, Jhee SS, Leibowitz MT, Huang HL, Enz A, Maton S, Ereshefsky L, Pommier F, Schmidli H, Appel-Dingemanse S. Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer's disease patients. Clin Pharmacol Ther. 2008;83:106–114. doi: 10.1038/sj.clpt.6100242.
    1. Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet. 1988;14:287–310. doi: 10.2165/00003088-198814050-00002.
    1. Kraut L, Fauser AA. Anti-emetics for cancer chemotherapy-induced emesis: potential of alternative delivery systems. Drugs. 2001;61:1553–1562. doi: 10.2165/00003495-200161110-00003.
    1. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. Oncologist. 2007;12:1143–1150. doi: 10.1634/theoncologist.12-9-1143.
    1. Einhorn LH, Grunberg SM, Rapoport B, Rittenberg C, Feyer P. Antiemetic therapy for multiple-day chemotherapy and additional topics consisting of rescue antiemetics and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support Care Cancer. 2010
    1. Howell J, Smeets J, Drenth HJ, Gill D. Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy-induced nausea and vomiting. J Oncol Pharm Pract. 2009;15:223–231. doi: 10.1177/1078155209104063.
    1. Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, Aapro MS, Gandara D, Lindley CM. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103–109.
    1. Eisenberg P, Figueroa-Vadillo J, Zamora R, Charu V, Hajdenberg J, Cartmell A, Macciocchi A, Grunberg S. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473–2482. doi: 10.1002/cncr.11817.
    1. Gralla R, Lichinitser M, Van der Vegt S, Sleeboom H, Mezger J, Peschel C, Tonini G, Labianca R, Macciocchi A, Aapro M. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570–1577. doi: 10.1093/annonc/mdg417.
    1. European Medicines Agency (2009) European public assessment report for Aloxi: scientific discussion. . Accessed March 2010
    1. FDA Center for Drug Evaluation and Research (2002) Approval package for palonosetron: statistical review. . Accessed March 2010
    1. Jordan K, Hinke A, Grothey A, Voigt W, Arnold D, Wolf HH, Schmoll HJ. A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis. Support Care Cancer. 2007;15:1023–1033. doi: 10.1007/s00520-006-0186-7.
    1. International Conference on Harmonisation (1998) Data analysis considerations: Analysis sets. pp 21–27
    1. Handberg J, Wessel V, Larsen L, Herrstedt J, Hansen HH. Randomized, double-blind comparison of granisetron versus granisetron plus prednisolone as antiemetic prophylaxis during multiple-day cisplatin-based chemotherapy. Support Care Cancer. 1998;6:63–67. doi: 10.1007/s005200050134.
    1. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist. 2003;8:187–198. doi: 10.1634/theoncologist.8-2-187.
    1. Blower PR. Granisetron: relating pharmacology to clinical efficacy. Support Care Cancer. 2003;11:93–100.

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