1 New York Lung Cancer Alliance, New York, NY, USA; 2 Cancer Research Center, Moscow, Russia; 3 Ziekenhuis Ondenrijn, Van Heuven Goedhartlaan, Utrecht; 4 Ziekenhuis Leyenburg, Den Haag, The Netherlands; 5 St Vincentius-Kliniken, Karlsruhe; 6 Klinikum rechts der Isar der Technischen Universität München, Munich, Germany; 7 Oncology Department Campus, Bio-Medico University, Rome; 8 Ospedali Riuniti di Bergamo, Unitá Operativa di Oncologia Medica, Bergamo, Italy; 9 Helsinn Healthcare SA, Lugano; 10 IMO, Clinique de Genolier, Genolier, Vaud, Switzerland
Received 10 June 2003; revised 17 July 2003; accepted 21 July 2003
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Abstract |
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Although all first-generation 5-HT3 receptor antagonists demonstrate efficacy in preventing acute chemotherapy-induced nausea and vomiting (CINV), effective prevention of delayed CINV has not yet been achieved. This study compared the efficacy and tolerability of palonosetron, a novel, second-generation 5-HT3 receptor antagonist, with ondansetron.
Patients and methods:
In this multicenter, randomized, double-blind, stratified, phase III study, 570 adult cancer patients were randomized to receive a single i.v. dose of palonosetron 0.25 mg, palonosetron 0.75 mg or ondansetron 32 mg, each administered 30 min before initiation of moderately emetogenic chemotherapy. The primary end point was the proportion of patients with no emetic episodes and no rescue medication [complete response (CR)] during the 24 h after chemotherapy administration (acute period). Secondary end points included efficacy in treatment of delayed CINV (5 days post-chemotherapy) and overall tolerability.
Results:
563 patients were evaluable for efficacy. CR rates were significantly higher (P <0.01) for palonosetron 0.25 mg than ondansetron during the acute (024 h) (81.0% versus 68.6%, respectively), delayed (24120 h) (74.1% versus 55.1%) and overall (0120 h) (69.3% versus 50.3%) periods. CR rates achieved with palonosetron 0.75 mg were numerically higher but not statistically different from ondansetron during all three time intervals. Both treatments were well tolerated.
Conclusions:
A single i.v. dose of palonosetron 0.25 mg was significantly superior to i.v. ondansetron 32 mg in the prevention of acute and delayed CINV.
Key words: chemotherapy-induced nausea and vomiting, emesis, 5-HT3 receptor antagonist, ondansetron, palonosetron
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Introduction |
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All first-generation 5-HT3 receptor antagonists demonstrate considerable efficacy in preventing acute CINV [5], with acute response rates as single agents ranging from 50% to 70% [6]. The effectiveness of the 5-HT3 receptor antagonists as single agents in preventing delayed CINV is less well established, with a proportion of patients who receive these agents continuing to experience nausea and vomiting after receiving moderately or highly emetogenic chemotherapy [711]. Therefore, the development of new agents with the potential to more effectively prevent CINV is warranted. Of interest is whether distinct, major pharmacological differences in a 5-HT3 receptor antagonist would produce meaningful improvements over a currently available 5-HT3 receptor antagonist in controlling CINV in patients receiving emetogenic chemotherapy.
Palonosetron is a highly potent, selective, second-generation 5-HT3 receptor antagonist with a 5-HT3 receptor binding affinity that is 100-fold higher than other 5-HT3 receptor antagonists (pKi 10.5 compared with 8.91 for granisetron, 8.81 for tropisetron, 8.39 for ondansetron, 7.6 for dolasetron) [1214]. Palonosetron also has an extended plasma elimination half-life of
40 h [15], significantly longer than others in its class (ondansetron, 4 h [16]; tropisetron, 7.3 h [17]; dolasetron, 7.5 h [18]; granisetron, 8.9 h [19]). A prior dose-ranging phase II trial of palonosetron in patients receiving highly-emetogenic chemotherapy identified 0.25 and 0.75 mg as minimal effective doses for phase III investigation [20]. The current phase III, randomized, double-blind, stratified, non-inferiority study was conducted with the main objective of comparing the efficacy and tolerability of single, fixed, intravenous (i.v.) doses of palonosetron 0.25 and 0.75 mg with a single i.v. dose of ondansetron 32 mg in the prevention of acute and delayed CINV following administration of moderately emetogenic chemotherapy.
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Patients and methods |
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Study design and treatment regimen
This multicenter, phase III, randomized, controlled, double-blind, non-inferiority study was conducted in 58 European centers (Germany, Italy, UK, The Netherlands and Russia) from 1 August 2000 to 2 October 2001. On day 1, eligible patients were randomized using the TriaLine® interactive voice system to receive a single i.v. dose of palonosetron 0.25 mg, palonosetron 0.75 mg (each palonosetron dose was infused over 30 s) or ondansetron 32 mg infused over 15 min, administered 30 min before the first dose of moderately emetogenic chemotherapy. Patients were stratified at randomization by gender and prior chemotherapy experience. For the study to remain blind, a double-dummy technique was used. No patient received pretreatment with corticosteroids. After the start of chemotherapy, rescue medication was permitted at the investigators discretion. The study protocol was approved by the ethics committee at each participating site and the study was conducted according to the Declaration of Helsinki. All patients gave written informed consent.
Efficacy parameters
The primary end point of the study was the proportion of patients achieving a complete response (CR; defined as no emetic episode and no use of rescue medication) during the first 24 h following chemotherapy administration (i.e. efficacy in preventing acute CINV). An emetic episode was defined as one episode of vomiting or a sequence of episodes in very close succession not relieved by a period of relaxation of at least 1 min; any number of unproductive emetic episodes (retches) in any given 5 min period; or an episode of retching lasting <5 min combined with vomiting not relieved by a period of relaxation of at least 1 min. Secondary end points included the following: the proportion of patients achieving a CR during the delayed 24120-h time period and the cumulative overall 0120-h time period, as well as CR rates during successive 24-h time periods (i.e. 2448, 4872, 7296, 96120 h); the proportion of patients achieving complete control (CC; defined as no emetic episode, no need for rescue medication and no more than mild nausea) for the 024, 24120 and 0120 h intervals; number of emetic episodes daily and cumulatively for the 24120 and 0120 h intervals; time to first emetic episode; severity of nausea measured daily for the 0120 h interval by a four-point Likert scale (used in previous studies to evaluate patient perceptions of cancer treatment-related side-effects) [2123]; time to administration and need for rescue medication; time to treatment failure (first emetic episode or first need of rescue medication, whichever occurred first); patient global satisfaction with antiemetic therapy, as measured by a visual analog scale (VAS) daily for the 0120-h interval; and quality of life (QoL), measured via a modified functional living indexemesis (FLIE) questionnaire, which specifically addresses the impact of nausea and emesis on daily functioning, for the first 24 h and the standard FLIE for the 2496-h interval.
Study visits and evaluation procedures
Consenting patients were initially screened for eligibility within 7 days prior to study commencement. During this time period the following were recorded: physical examination; vital signs and weight; laboratory tests [complete blood count (CBC) with differential, platelet counts, blood chemistry and urine analysis]; past medical history; concomitant medications; and history of nausea and vomiting. Follow-up included clinic visits on day 2 (at 2430 h post-chemotherapy) and once between days 6 and 8. Follow-up, via the telephone, occurred on days 5 and 15. All subjects were followed for a total of 15 days. Patient diaries were used to record the following: emetic episodes; use of rescue medication; patient global satisfaction; and severity of nausea, which was evaluated daily until day 5 via a four-point Likert scale ranging from 0 (none) to 3 (severe).
Safety was assessed by the following: adverse event (AE) reporting for a period of 15 days (30 days for serious AEs); vital sign measurements; laboratory tests performed 24 h and 1 week after study drug administration (including hematology, blood chemistry, liver function tests and urine analysis); physical examination; and electrocardiogram (ECG) recordings performed 24 h and 1 week after study drug administration. A subset of patients (total, n = 49; palonosetron 0.25 mg group, n = 20; palonosetron 0.75 mg group, n = 15; ondansetron 32 mg group, n = 14) had an additional ECG evaluation 15 min after study drug administration (around the peak of plasma concentrations), according to study protocol.
Statistical analysis and sample size calculation
The primary efficacy hypothesis of the study was that at least one dose of palonosetron was non-inferior to the ondansetron dose using a maximum of 15% for CR at 24 h. The number of patients to be included in the study was estimated to be 567, who were distributed into three groups (i.e. 189 patients/group) based on the assumption of a responder rate of 70% in the palonosetron and ondansetron groups and a difference of
15% in the CR rate. For a one-sided test of equivalence (
= 0.0125), a sample size of 180 evaluable patients per group was needed to ensure 80% power for each comparison (overall power = 90%). Assuming a 5% dropout rate, 189 patients per group needed to be enrolled.
To demonstrate the non-inferiority of at least one dose of palonosetron to ondansetron, the lower boundary of the two-sided 97.5% confidence intervals (CI) for the difference (palonosetron minus ondansetron) between the proportion of patients achieving a CR during the first 24 h after chemotherapy administration was calculated and compared with the preset threshold (15% difference). Subsequent analyses comparing CR rates between each palonosetron dose and ondansetron by means of Fishers exact test were also conducted. The 2 test was utilized to analyze CC rates and the proportion of patients receiving rescue medication. Number of emetic episodes, severity of nausea, patient global satisfaction and QoL assessments were compared between treatment groups using the KruskalWallis or Wilcoxon tests. Differences between treatment groups with respect to time to first emetic episode, time to first administration of rescue medication and time to treatment failure were analyzed using KaplanMeier estimates and the log-rank test.
Analysis of the primary end point was performed for the intention-to-treat (ITT) cohort (all randomized patients who received chemotherapy and study drug) and the per-protocol (PP) cohort (all patients who completed study day 1 and who were compliant with the study protocol). Results for the ITT cohort analysis were interpreted in a confirmatory manner, whereas results of analyses performed for the PP cohort were only descriptive. All secondary efficacy analyses were performed for the ITT cohort and the results were interpreted in a descriptive manner. The proportion of patients achieving a CR at further time points was examined using the same statistical methods as for the primary efficacy variable. Subgroup analyses were used to identify differences in response based on gender and chemotherapeutic history. The equivalence of the two palonosetron doses with respect to CR was also evaluated ( = 0.05).
Changes in laboratory values with respect to toxicity grades were investigated for each time point within each group using the Wilcoxon signed rank test. All other safety parameters were analyzed descriptively, with ECG data summarized highlighting differences from baseline values for quantitative variables and frequencies of treatment-emergent abnormalities. Shift tables were used to evaluate categorical changes with respect to toxicity grades in hematology and blood chemistry parameters. Changes in laboratory values with respect to NCI-adapted toxicity grades were investigated within each group using the Wilcoxon matched pairs signed rank test. Vital signs and physical examination data were listed and summarized. ECG data were summarized highlighting differences from the baseline values for quantitative variables and the frequencies of treatment-emergent abnormalities. In particular, electrocardiographic intervals QT and QTc mean changes from baseline were calculated at each time point, including the maximum mean change from baseline.
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Results |
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Primary efficacy analysis
Complete response: study day 1 (acute CINV). The proportion of patients in the ITT cohort achieving a CR during the first 24 h after administration of moderately emetogenic chemotherapy is presented in Table 2. Non-inferiority of both doses of palonosetron compared with ondansetron was demonstrated, as the lower bounds of the 97.5% CI of the difference with ondansetron (1.8% and 6.1%, respectively) were greater than the preset threshold of 15% difference. Moreover, palonosetron 0.25 mg was statistically significantly superior to ondansetron in preventing acute emesis (lower bound of the 97.5% CI >0; P = 0.009).
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Complete control: study days 15 (acute and delayed CINV). Palonosetron 0.25 mg and 0.75 mg produced significantly higher CC rates compared with ondansetron during the delayed (24120 h) interval (66.7% versus 50.3%; P = 0.001), and the overall (0120 h) interval (63.0% versus 44.9%; P = 0.001). Palonosetron 0.25 mg was superior to ondansetron on study days 2 (P = 0.001), 3 (P = 0.001) and 4 (P = 0.003), with palonosetron 0.75 mg superior to ondansetron on study days 3 (P = 0.004) and 4 (P = 0.006). On all other days, both palonosetron doses were as effective as ondansetron.
Time to treatment failure
Time to treatment failure was significantly longer following treatment with palonosetron 0.25 mg than treatment with ondansetron (P <0.001) (Figure 1). Although the median time to treatment failure (time to first emetic episode or first use of rescue medication, whichever occurred first) was >120 h in all treatment groups, the first quartile of palonosetron 0.25 mg showed a time to treatment failure more than twice as long as that observed with ondansetron (46.5 versus 19.5 h, respectively).
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Adverse events
A total of 562 patients were evaluable for safety. Of the patients in the palonosetron 0.25 mg, palonosetron 0.75 mg and ondansetron groups, 114 (61.0%), 125 (66.5%) and 120 (64.2%) experienced at least one AE. Most AEs were mild in intensity, with the majority (84%) assessed as associated with the patients cancer and/or chemotherapy treatment and not related, or unlikely to be related, to study medication. Post hoc analysis revealed no differences in the duration of AEs commonly associated with 5-HT3 receptor antagonist therapy (i.e. headache, constipation, diarrhea, fatigue) in patients treated with palonosetron compared with ondansetron. Table 3 provides a list of treatment-emergent, drug-related AEs. Adverse reactions (i.e. AEs considered to be treatment related) occurred in 16% of patients in each of the palonosetron groups and in 13.9% of patients in the ondansetron group. The most common adverse reaction reported in all treatment groups was headache (palonosetron 0.25 mg, 4.8%; palonosetron 0.75 mg, 5.3%; ondansetron, 5.3%). There were two withdrawals during the study due to AEs, one non-serious AE (debility) assessed as possibly related to study medication in the palonosetron 0.75 mg group, and one serious AE (pulmonary embolism resulting in death) assessed as not related to study medication in the ondansetron group. Three other deaths were reported during the study; all were assessed as unlikely to be related to, or as definitely unrelated to, study medication.
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Discussion |
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Because the study drug was administered only on study day 1 as a single i.v. dose, we were able to explore the rate of delayed CINV and determine the efficacy of palonosetron in preventing CINV during the 24120-h period following administration of moderately emetogenic chemotherapy. Our results showed the superiority of palonosetron over ondansetron in preventing delayed CINV, as measured by CR and CC rates, as well as with respect to number of emetic episodes, per cent of patients with no nausea and time to treatment failure. It should be noted that both chemotherapy-naïve and non-naïve patients were included in this study to provide a more realistic, heterogeneous patient group, similar to that seen in the clinical setting.
Superiority of palonosetron in the prevention of delayed CINV has also been demonstrated in a similarly designed phase III trial of palonosetron and dolasetron in patients receiving moderately emetogenic chemotherapy [26]. The observed sustained efficacy of a single dose of palonosetron in preventing delayed emesis is a clinically important finding, as currently available 5-HT3 receptor antagonists do not demonstrate substantial efficacy in delayed emesis, despite repeated dosing [9, 10, 27] and concomitant use with corticosteroids [3]. The prolonged antiemetic efficacy of palonosetron is possibly related to its high 5-HT3 receptor binding affinity and long plasma elimination half-life of approximately 40 h.
All treatments were well tolerated, with no significant differences between groups. Most AEs (including serious AEs) were assessed as unlikely to be related to study medication, but rather to the patients underlying cancer or chemotherapeutic treatment. Consistent with previous studies of 5-HT3 receptor antagonists, headache was the most frequently reported drug-related AE (i.e. adverse reaction) in all treatment groups [4, 2830]. There were no significant treatment-related changes in laboratory measures, vital signs or ECG. No safety concerns were raised in this study.
Doses of palonosetron chosen for investigation in this study were based on a phase II dose-finding study, which revealed palonosetron 3.0 µg/kg (fixed dose of 0.25 mg) as the minimum effective dose for preventing CINV after administration of highly emetogenic chemotherapy, with doses up to 90 µg/kg (fixed dose of
6.0 mg) also safe and effective [20]. Findings from this phase II study supported the selection of 3.0 µg/kg and 10 µg/kg doses (corresponding to fixed doses of
0.25 mg and
0.75 mg, respectively) for use in the current phase III study. Our results show that palonosetron 0.25 and 0.75 mg are similar in overall efficacy, suggesting that the 0.25 mg dose can be found on the plateau of the efficacy doseresponse curve. The statistically non-significant difference in efficacy between palonosetron 0.25 mg and 0.75 mg is not unlike the results observed with other 5-HT3 receptor antagonists, such as dolasetron [28].
Our results demonstrate that a single i.v. dose of palonosetron results in prolonged protection against nausea and emesis following moderately emetogenic chemotherapy. Palonosetron is superior to ondansetron in preventing both acute and delayed CINV. Thus, palonosetron, a novel second-generation 5-HT3 receptor antagonist, would be a significant and important addition to antiemetic therapy.
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Acknowledgements |
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The following 99-03 Palonosetron Study Group investigators included patients in this study. Our sincere thanks go to the patients and the team that took care of them: G. Adam, Asklepios Klinik Triberg, Triberg, Germany; A.V. Arkhipov, Arkhangelsk Regional Oncology Center, Arkhangelsk, Russia; M. Assmann, Kreiskrankenhaus Riesa, Riesa; J.-E. Baier, Universitätsklinik St Joseph-Hospital, Bochum; F. Begemann, AK St Georg, Hamburg, Germany; G. Biasco, Azienda Ospedaliera S Orsola Malpigh, Bologna, Italy; N.V. Bogdanova, Hertzen Research Institute of Oncology, Moscow; V.I. Borisov, Moscow Clinical Oncology Center, Moscow, Russia; D. Braumann, Allgemeines Krankenhaus Altona, Hamburg; B. Brockmann, Humaine Klinik Dresden GmbH, Dresden, Germany; M.Y. Byakhov, Central Clinical Hospital of the Ministry of Transport n.a. Semashko, Moscow, Russia; S.L. Chawla, South Cleveland Hospital, Cleveland, UK; M. Clerico, Ospedale degli Infermi, Biella, Italy; H.J. Cordes, Gemeinschaftspraxis fur Hamatologie, Frankfurt/Main, Germany; D.J. Dodwell, Harrogate District Hospital, Harrogate, and Cookridge Hospital, Leeds, UK; G.D. Dolmatov, St Petersburg Oncology Center, St Petersburg, Russia; G. Ehninger, Technischen Uniklinik Carl Gustav Carus, Dresden, Germany; F.L.G. Erdkamp, Maasland Ziekenhuis, Sittard, The Netherlands; M.L. Gershanovich, Petrov Research Institute of Oncology, St Petersburg; V.A. Gorbunova, Russian Oncology Center N.N. Blokhin, Moscow, Russia; M. Gramatzki, Friedrich Alexander Universität, Erlangen; B. Heinrich, Hämatologische-Onkologische Praxis, Augsburg, Germany; N.V. Ilyin, Central Research Institute for Radiology of the Ministry of Health, St Petersburg; N.A. Karaseva, St Petersburg Oncology Center, St Petersburg, Russia; P.A. Karlov, St Petersburg Oncology Hospital 8, St Petersburg; D.B. Korman, Moscow City Hospital 40, Moscow, Russia; R. Labianca, Ospedali Riuniti di Bergamo, Bergamo, Italy; M.R. Lichinitser, Russian Oncology Center N.N. Blokhin, Moscow; A.N. Makhson, Moscow Oncology Clinical Hospital 62, Moscow; G.M. Manikhas, St Petersburg Oncology Center, St Petersburg; N.V. Medvedeva, St Petersburg Clinical Center of Advanced Medical Technologies, Hospital 31, St Petersburg, Russia; J. Mezger, St Vincentius Krankenhäuser, Karlsruhe, Germany; V.M. Moiseyenko, Petrov Research Institute of Oncology, St Petersburg, Russia; B. Morrica, Presidio Ospedaliero di Cremona, Cremona; G. Nastasi, Ospedale Pesenti Fenaroli, Alzano Lombardo; A. Neubauer, Klinikum der Philipps-Universität, Marburg, Germany; S.V. Odintsov, Central Clinical Hospital of the President, Administration of the Russian Federation, Moscow, Russia; C. Peschel, III Med. Klinik und Poliklinik der Technischen Universität München, München, Germany; G. Porcile, Ospedale S Lazzaro Alba, Alba (Cuneo); A. Santoro, Instituto Clinico Humanitas Milano, Milano, Italy; P. Schöffski, Medizinische Hochschule Hannover, Hannover, Germany; A.F. Seferyants, St Petersburg City Hospital 9, St Petersburg, Russia; E. Selak, Krankenhaus Paulinenstift, Wiesbaden, Germany; V.F. Semiglazov, Petrov Research Institute of Oncology, St Petersburg, Russia; H.P. Sleeboom, Ziekenhuis Leyenburg, Den Haag, The Netherlands; S.A. Tjulandin, Russian Oncology Center n.a. Blokhin, Moscow, Russia; M. Tondini, Ospedale di Vallecamonica, Esine; G. Tonini, Policlinico Universitario Campus Bio-Medico, Roma, Italy; K.D. van de Stadt, Spaarne Ziekenhuis, Heemstede; C. van der Heul, Sint Elisabeth Ziekenhuis, Tilburg; S.G.L. van der Vegt, Mesos Medisch Centrum, Utrecht; M. van Marwijk Kooy, Isala Klinieken, Zwolle; D. van Toorn, Gerle Ziekenhuizen, Apeldoorn, The Netherlands; L. Vassalli, Ospedali Civili di Brescia, Brescia, Italy; E.K. Voznyi, Research Institute of Roengenology and Radiation Therapy, Moscow; O.M. Vtoraya, Arkhangelsk Regional Oncology Center, Arkhangelsk, Russia; H. Wolf, Hämatologische Gemeinschaftspraxis, Dresden, Germany; A.U. Zaritsky, St Petersburg Medical University N.N. Pavlov, St Petersburg, Russia.
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Footnotes |
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