Dr. Eisenberg has participated in clinical trials and received consulting fees and honoraria from Helsinn Healthcare SA (Lugano, Switzerland), MGI Pharma (Bloomington, Minnesota), GlaxoSmithKline (Research Triangle Park, North Carolina), Merck (Whitehouse Station, New Jersey), Roche (Basel, Switzerland), and Aventis Pharmaceuticals (Bridgewater, New Jersey). Dr. Cartmell is a clinical investigator for MGI Pharma. Dr. Macciocchi is an employee of Helsinn Healthcare SA. Dr. Grunberg is a consultant to Helsinn Healthcare SA and has received honoraria from MGI Pharma.
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
Article first published online: 16 OCT 2003
Copyright © 2003 American Cancer Society
Volume 98, Issue 11, pages 2473–2482, 1 December 2003
How to Cite
Eisenberg, P., Figueroa-Vadillo, J., Zamora, R., Charu, V., Hajdenberg, J., Cartmell, A., Macciocchi, A. and Grunberg, S. (2003), Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist. Cancer, 98: 2473–2482. doi: 10.1002/cncr.11817
- Issue published online: 17 NOV 2003
- Article first published online: 16 OCT 2003
- Manuscript Accepted: 1 SEP 2003
- Manuscript Revised: 11 AUG 2003
- Manuscript Received: 5 MAY 2003
- Helsinn Healthcare SA
- 5-HT3 receptor antagonist;
- chemotherapy-induced nausea and vomiting;
Palonosetron, a highly selective and potent 5-HT3 receptor antagonist with a strong binding affinity and a long plasma elimination half-life (approximately 40 hours), has shown efficacy in Phase II trials in preventing chemotherapy-induced nausea and vomiting (CINV) resulting from highly emetogenic chemotherapy. The current Phase III trial evaluated the efficacy and safety of palonosetron in preventing acute and delayed CINV after moderately emetogenic chemotherapy.
In the current study, 592 patients were randomized to receive a single, intravenous dose of palonosetron 0.25 mg, palonosetron 0.75 mg, or dolasetron 100 mg, 30 minutes before receiving moderately emetogenic chemotherapy. The primary efficacy endpoint was the proportion of patients with a complete response (CR; defined as no emetic episodes and no rescue medication) during the first 24 hours after chemotherapy. Secondary endpoints included assessment of prevention of delayed emesis (2–5 days postchemotherapy).
In the current study, 569 patients received study medication and were included in the intent-to-treat efficacy analyses. CR rates during the first 24 hours were 63.0% for palonosetron 0.25 mg, 57.1% for palonosetron 0.75 mg, and 52.9% for dolasetron 100 mg. CR rates during the delayed period (24–120 hours after chemotherapy) were superior for palonosetron compared with dolasetron. Adverse events (AEs) were mostly mild to moderate and not related to study medication, with similar incidences among groups. There were no serious drug-related AEs.
A single dose of palonosetron is as effective as a single dose of dolasetron in preventing acute CINV and superior to dolasetron in preventing delayed CINV after moderately emetogenic chemotherapy, with a comparable safety profile for all treatment groups. Cancer 2003. © 2003 American Cancer Society.
It is well established that the majority of cancer patients who undergo moderately or highly emetogenic cytotoxic treatment without receiving prophylactic antiemetics will experience chemotherapy-induced nausea and vomiting (CINV). Although the exact mechanisms of CINV are not fully known, it is clear from preclinical experiments and more than 15 years of clinical investigations that serotonin plays a major role in initiating nausea and vomiting associated with emetogenic chemotherapy. Emetogenic chemotherapy damages the gastrointestinal mucosa, causing the release of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells in the small intestine, which, in turn, activates 5-HT3 receptors located on vagal afferents.1 Activated vagal afferent fibers send signals to the brain stem vomiting centers, initiating emesis.1 The introduction of 5-HT3 receptor antagonists into clinical oncology in the 1990s led to significant improvements in control rates for acute nausea and vomiting associated with emetogenic chemotherapy, and 5-HT3 receptor antagonists are now considered part of the standard of care. As single agents for antiemetic prophylaxis of acute CINV (occurring within 24 hours of chemotherapy) in patients receiving moderately emetogenic chemotherapy, 5-HT3 receptor antagonists are reported to have complete response (CR) rates (i.e., no emesis, no use of rescue medication) of 50–70%.2 Although they are commonly prescribed after the first day of chemotherapy, the effectiveness of 5-HT3 receptor antagonists as single agents in preventing delayed CINV (occurring > 24 hours after chemotherapy) associated mainly with cisplatin-based chemotherapy and (to a lesser extent) with other chemotherapeutic agents is less well established. Four 5-HT3 receptor antagonists are currently approved for use in the United States and/or Europe: ondansetron, granisetron, tropisetron, and dolasetron. These agents have some pharmacologic differences in receptor binding affinity, selectivity, and metabolism. Despite these nuances, the minor pharmacologic differences of these agents have not translated into clinically meaningful differences among them. Therefore, according to current evidence-based guidelines (American Society of Clinical Oncology, Multinational Association of Supportive Care in Cancer) and consensus guidelines (American Society of Health-System Pharmacists, National Comprehensive Cancer Network), these 5-HT3 receptor antagonists are considered therapeutically equivalent and interchangeable when used at equipotent doses.3–7
Although 5-HT3 receptor antagonists are part of the current standard of care for patients receiving chemotherapy, a substantial proportion of patients today continue to experience both acute and particularly delayed CINV after moderately or highly emetogenic chemotherapy.7, 8 Therefore, there is still a need to develop new agents to improve control rates and patient care. Although other neurotransmitter pathways besides serotonin are clearly involved in CINV (e.g., substance P and the neurokinin-1 receptor mechanisms),9 one question has not been fully explored: will major pharmacologic improvements in a novel 5-HT3 receptor antagonist lead to improved clinical outcomes in patients receiving emetogenic chemotherapy compared with a currently available 5-HT3 receptor antagonist?
Palonosetron is a highly potent, second-generation, selective 5-HT3 receptor antagonist. It has been shown to have approximately a 100-fold stronger binding affinity for the 5-HT3 receptor compared with other agents in the class10 and an extended plasma elimination half-life of approximately 40 hours. A dose-ranging Phase II trial of palonosetron designed to identify the minimal effective dose(s) was performed in patients receiving highly emetogenic chemotherapy. Two doses were identified for Phase III investigation.11 The objective of the current Phase III trial was to evaluate the efficacy and safety of single, fixed, intravenous (i.v.) doses of palonosetron 0.25 mg and 0.75 mg compared with a single i.v. dose of dolasetron 100 mg in preventing acute and delayed CINV after administration of moderately emetogenic chemotherapy.
MATERIALS AND METHODS
This was a Phase III, multicenter, randomized, double-blind, parallel, stratified, comparative trial. Eligible patients were 18 years or older with histologically or cytologically confirmed malignant disease and a Karnofsky index of greater than or equal to 50%. They were scheduled to receive a single dose of at least 1 of the following moderately emetogenic agents administered on Day 1: carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, mitoxantrone, methotrexate (> 250 mg/m2), cyclophosphamide (< 1500 mg/m2), doxorubicin (> 25 mg/m2), or cisplatin (≤ 50 mg/m2). Patients who had experienced, at maximum, mild nausea with previous chemotherapy were eligible for enrollment per investigator discretion. Exclusion criteria included receipt of an investigational drug within 30 days before study entry; receipt of (within 24 hours of treatment initiation) or scheduled receipt of (up to Day 5) any drug with potential antiemetic properties; or National Cancer Institute Common Toxicity Criteria Grade 2 or 3 nausea within 24 hours preceding chemotherapy. Complete inclusion and exclusion criteria are presented in Table 1. Written informed consent was obtained from each patient before trial enrollment.
|Male or female, age ≥ 18 yrs, with histologically or cytologically confirmed malignant disease|
|Naive or nonnaive to chemotherapy, with a Karnofsky index ≥ 50%|
|Scheduled to receive a single dose of moderately emetogenic chemotherapy (i.e., any dose of carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, or mitoxantrone; or methotrexate > 250 mg/m2, cyclophosphamide < 1500 mg/m2, cyclophosphamide < 1500 mg/m2, doxorubicin > 25 mg/m2, or cisplatin ≤ 50 mg/m2) on study Day 1 administered over 1–4 hrs|
|Use of reliable contraceptive measures (for females of childbearing potential) and negative pregnancy test at baseline visit|
|Patients with hepatic, renal, or cardiovascular impairment eligible at the investigator's discretion|
|Patients experiencing, at maximum, mild nausea after previous chemotherapy eligible at the investigator's discretion|
|Provision of written informed consent|
|Inability to understand or cooperate with study procedures|
|Receipt of investigational drugs ≤ 30 days before study entry|
|Scheduled to receive any drug with antiemetic efficacy from 24 hrs before to 5 days after treatment|
|Seizure disorder requiring anticonvulsants unless clinically stable and free of seizure activity|
|Emesis, retching, or Grade 2 or 3a nausea ≤ 24 hrs before chemotherapy|
|Ongoing emesis due to any organic etiology|
|Moderate or severe nausea and emesis after any previous chemotherapy|
|Scheduled receipt of highly emetogenic chemotherapy (i.e., any dose of a nitrogen mustard, dacarbazine, or streptozotocin; or lomustine > 60 mg/m2, carmustine ≥ 250 mg/m2, or any other chemotherapy with an emetogenicity level of 5)|
|Scheduled receipt of any chemotherapeutic agent with an emetogenicity level ≥ 3 during study Days 2–6|
|Contraindications to 5-HT3 receptor antagonists|
|Enrollment in a previous study with palonosetron (RS-25259; Syntex, Palo Alto, CA)|
|Receipt of radiotherapy of the upper abdomen or cranium on study Days 2–6|
|Baseline QTc > 500 ms|
Patients were randomized using an interactive voice response system across all study sites according to specific procedures. In the current study, randomization was stratified by factors known to significantly affect response rates, including gender, previous chemotherapeutic exposure (naive vs nonnaive), and use of a pretreatment corticosteroid.
On Day 1, eligible patients were randomized to receive a single, fixed, i.v. dose of one of the following three treatments, administered as a bolus over 30 seconds, 30 minutes before the primary chemotherapeutic agent: palonosetron 0.25 mg, palonosetron 0.75 mg, or dolasetron 100 mg. Patients remained in the clinic or hospital for a minimum of 3 hours after study drug administration. By a late protocol amendment, and at the discretion of the investigator, a single dose of i.v. dexamethasone 20 mg (or, if unavailable, a single dose of oral dexamethasone 20 mg or i.v. methylprednisolone 125 mg), administered 15 minutes before chemotherapy, was permitted. After chemotherapy, rescue medication for the treatment of nausea and emesis also was permitted. Subjects were followed for 15 days. The study protocol received approval from the institutional review board or independent ethics committee at all investigational sites and was performed according to the Declaration of Helsinki.
Study Visits and Assessment Procedures
Baseline procedures were documented at a prestudy screening visit within 7 days preceding Day 1. Patients were assessed on three additional visits (day of study medication administration [Day 1] and two follow-up visits [Day 2 and Days 6–8]) and by two telephone contacts [Days 5 and 15]. Patient diaries were used to record emetic episodes, use of rescue medication, severity of nausea (evaluated daily until Day 5 via a 4-point Likert scale ranging from 0 [none] to 3 [severe]), and patient satisfaction with antiemetic therapy (evaluated daily until Day 5 via a 100-mm visual analog scale ranging from 0 [not at all satisfied] to 100 [totally satisfied]). The validated Functional Living Index-Emesis (FLIE) questionnaire, which specifically addresses the impact of nausea and emesis on daily functioning and quality of life (QOL),12 was completed by the patient on Day 2 (to evaluate the first 24 hours postchemotherapy) and Day 5 (to evaluate Days 2–4 postchemotherapy). Safety was assessed by recording adverse events (AEs; on site for 3 hours after study drug administration on Day 1 and at all subsequent contacts), vital sign measurements, laboratory tests (hematology, blood chemistry, urinalysis), physical examination, and 12-lead electrocardiogram (ECG) performed 24 hours and 1 week after study drug administration. A subset of patients (n = 30) had an additional ECG evaluation 15 minutes after study drug administration. The observation period for AEs was 14 days after study drug administration for all AEs and 30 days for serious AEs.
The primary efficacy endpoint in the current study was the proportion of patients considered to have achieved a complete response (CR; defined as no emetic episode and no use of rescue medication) during the first 24 hours after chemotherapy administration (acute period). Emetic episodes were recorded in standard fashion (unpublished data, 2003). Secondary endpoints included the proportion of patients with a CR during the delayed (24–120 hours) time period (Days 2–5) and the overall (0–120 hours) time period (Days 1–5), as well as during successive 24-hour time periods (i.e., 24–48, 48–72, 72–96, and 96–120 hours); the proportion of patients with complete control (CC; defined as no emetic episode, no need for rescue medication, and no more than mild nausea) during the acute, delayed, and overall time periods, as well as during successive 24-hour time periods; the number of emetic episodes, time to first emetic episode, time to first administration of rescue medication, time to treatment failure (time to first emetic episode or administration of rescue medication, whichever occurred first), severity of nausea, patient global satisfaction with antiemetic therapy, and QOL (FLIE).
The primary efficacy hypothesis of the study was that at least 1 dose of palonosetron was noninferior to the dolasetron dose using a maximum delta of 15% for a CR at 24 hours. The number of patients to be included in the study was estimated based on the assumption of a responder rate of 70% in the palonosetron and dolasetron groups and a difference of no more than 15% in the CR rate. For a 1-sided test of equivalence (α = 0.0125), a sample size of 180 evaluable patients per group was needed to ensure 80% power for each comparison (overall power, 90%). The number of patients was increased to 197 per group to account for the projected drop-out rate.
Cohorts for the analyses included an intent-to-treat (ITT) cohort, a per protocol (PP) cohort, and a safety cohort. The primary analysis was performed on the ITT cohort, which included all randomized patients who received chemotherapy and study medication. The PP cohort included all patients who completed the study at least until Day 1 and who were compliant with the study protocol. The PP analysis was performed for the primary efficacy parameter, demographic data, and baseline characteristics. The safety cohort included all treated patients who had at least one safety assessment after treatment with study drugs.
To assess noninferiority and adjust multiple comparisons for the primary endpoint of a CR rate at 24 hours, the lower bound of the 2-sided 97.5% confidence interval (CI) for the difference between the CR rates between each palonosetron dose and dolasetron was compared with a preset equivalence difference of −15%. Logistic regression was implemented to evaluate the influence of gender, chemotherapeutic history, corticosteroid use, and country/region of study on CR rates. The 24-hour rates were also compared directly using the Fisher exact test with an adjusted significance level of 0.025. Comparisons of CR rates at secondary time points (i.e., 24–120 hours, 0–120 hours, and daily for Days 2–5) were made using the same statistical methods as for the primary variable.
Complete control and the proportion of patients receiving rescue medication were analyzed using the chi-square test. Treatment group comparisons of the number of emetic episodes and the severity of nausea were analyzed using the Kruskal–Wallis test or the Wilcoxon test. In addition, post hoc analyses of the proportion of patients with no nausea and no emesis (variables recoded as none or any) were performed using the chi-square test. A Poisson regression analysis was performed for the number of emetic episodes, taking into account the use of rescue medication. Treatment group comparisons of time to first emetic episode and time to treatment failure were analyzed using Kaplan–Meier estimates and the log-rank test. The equivalence of the two palonosetron doses, with respect to CR during the first 24 hours and during all of the time periods, was tested in an exploratory way (α = 0.05). The bounds of the 2-sided 95% CI of the difference between the proportions of CR in the two doses were compared to the preset threshold (± 15%).
Laboratory values were analyzed using categoric changes from baseline with respect to toxicity grades. Toxicity grades were generated for hematology and blood chemistry parameters, displaying the data for the comparison baseline values versus the last value available. Changes in laboratory values 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 the differences from the baseline values for quantitative variables and the frequencies of treatment-emergent abnormalities. In particular, QT/QTc mean changes from Visit 1 (baseline) were calculated at each time point, including the maximum mean change from Visit 1. Other safety data were analyzed descriptively. All statistical analyses were performed using SAS software (Version 6.12; SAS Institute, Cary, NC).
Patients were evaluated between May 2000 and December 2001 in 61 centers in North America (United States and Mexico). Five hundred ninety-two patients were randomized to receive a single i.v. dose of one of three treatments, although nine of these patients did not receive treatment. Treatment groups received palonosetron 0.25 mg (n = 194), palonosetron 0.75 mg (n = 196), or dolasetron 100 mg (n = 193). Of the 583 patients treated, 14 were excluded from the ITT analysis: 1 due to receipt of chemotherapy with unacceptably low emetogenic potential and 13 due to enrollment at a disqualified investigative site. Therefore, 569 patients were included in the ITT cohort analysis.
Demographic data for the ITT cohort are presented in Table 2. As a result of stratification, the distribution of patients by gender, chemotherapeutic history, and corticosteroid use was similar among all treatment groups. The distribution of patients was similar according to ethnicity and alcohol consumption. Eighty-two percent of study patients were female. The most common types of malignant disease included breast carcinoma (approximately 64%), lung carcinoma (approximately 8%) and non-Hodgkin lymphoma (approximately 4%). The majority (67%) of patients were chemotherapy naive. Approximately 5% of patients received pretreatment with a corticosteroid (secondary to a late protocol amendment allowing concurrent corticosteroids). There were no relevant differences between treatment groups with respect to comorbid medical conditions (renal, hepatic, or cardiovascular impairment) or Karnofsky index. Of the chemotherapeutic treatments received on Day 1 by the ITT cohort, regimens containing anthracycline and cyclophosphamide were the ones that were most commonly administered, to 64% of patients (Table 3). The median dose of doxorubicin was 50 mg/m2 for all treatment groups. The median doses of cyclophosphamide were 500, 600, and 500 mg/m2 for the palonosetron 0.25 mg, palonosetron 0.75 mg, and dolasetron groups, respectively. Concomitant chemotherapy was generally similar among treatment groups.
|Characteristic||Palonosetron 0.25 mg (n = 189)||Palonosetron 0.75 mg (n = 189)||Dolasetron 100 mg (n = 191)|
|No. (%)||No. (%)||No. (%)|
|Age (yrs) (M ± SD)||53.3 ± 13.1||55.2 ± 13.1||53.6 ± 12.7|
|Height (cm) (M ± SD)||159.7 ± 9.6||160.1 ± 8.9||160.6 ± 9.0|
|Weight (kg) (M ± SD)||71.4 ± 17.2||71.1 ± 15.9||72.5 ± 18.3|
|Male||34 (18.0)||33 (17.5)||35 (18.3)|
|Female||155 (82.0)||156 (82.5)||156 (81.7)|
|White||57 (30.2)||62 (32.8)||59 (30.9)|
|Black||12 (6.3)||8 (4.2)||10 (5.2)|
|Hispanic||115 (60.8)||114 (60.3)||115 (60.2)|
|Asian||3 (1.6)||4 (2.1)||6 (3.1)|
|Other||2 (1.1)||1 (0.5)||1 (0.5)|
|None||124 (65.6)||125 (66.1)||134 (70.2)|
|Rare||25 (13.2)||30 (15.9)||24 (12.6)|
|Occasional||31 (16.4)||24 (12.7)||20 (10.5)|
|Regular||9 (4.8)||9 (4.8)||13 (6.8)|
|Naive||124 (65.6)||131 (69.3)||125 (65.4)|
|Nonnaive||65 (34.4)||58 (30.7)||66 (34.6)|
|Yes||11 (5.8)||12 (6.3)||8 (4.2)|
|No||178 (94.2)||177 (93.7)||183 (95.8)|
|Chemotherapeutic regimen||Palonosetron 0.25 mg (n = 189)||Palonosetron 0.75 mg (n = 189)||Dolasetron 100 mg (n = 191)|
|No. (%)||No. (%)||No. (%)|
|Anthracycline + cyclophosphamide||120 (63.5)||111 (58.7)||132 (69.1)|
|Carboplatin-based||30 (15.9)||38 (20.1)||26 (13.6)|
|Cyclophosphamide-based||11 (5.8)||16 (8.5)||11 (5.8)|
|Cisplatin (≤ 50 mg/m2)||14 (7.4)||8 (4.2)||7 (3.7)|
|Other||14 (7.4)||16 (8.5)||15 (7.9)|
Primary Efficacy Endpoint
The proportion of patients with a CR during the first 24 hours was numerically higher in the palonosetron 0.25 mg group (63.0% vs. 52.9%; 97.5% CI for the difference, [−1.7%, 21.9%]; P = 0.049) and in the palonosetron 0.75 mg group (57.1% vs. 52.9%; 97.5% CI for the difference, [−7.7%, 16.2%]; P = 0.412) compared with the dolasetron group (Table 4, Fig. 1). The primary hypothesis of noninferiority (i.e., equal or better efficacy) of both doses of palonosetron compared with dolasetron was proven for CR rates during the 0–24-hour period, as the lower bounds of the 97.5% CI of the difference between palonosetron and dolasetron were greater than the preset threshold (Table 4, Fig. 1).
|Time period (hrs)||PAL 0.25 mg (n = 189)||PAL 0.75 mg (n = 189)||DOL 100 mg (n = 191)|
|Response rate (%)||97.5% CI (PAL minus DOL)||P value||Response rate (%)||97.5% CI (PAL minus DOL)||P value||Response rate (%)|
|0–24||63.0||[−1.7%, 21.9%]||0.049||57.1||[−7.7%, 16.2%]||0.412||52.9|
|24–120||54.0||[3.4%, 27.1%]a||0.004b||56.6||[6.0%, 29.7%]a||< 0.001b||38.7|
|0–120||46.0||[0.3%, 23.7%]a||0.021b||47.1||[1.3%, 24.8%]a||0.012b||34.0|
Secondary Efficacy End Points
Significantly higher CR rates were observed for both doses of palonosetron compared with dolasetron during the delayed period (24–120 hours) and the overall period (0–120 hours; Table 4, Fig. 1). Comparisons of CR rates for delayed CINV during individual days revealed significantly higher rates for both doses of palonosetron compared with dolasetron on Days 2 and 3 and on Day 4 for palonosetron 0.75 mg. CC rates were also significantly higher for the palonosetron 0.25 mg and palonosetron 0.75 mg groups compared with dolasetron during the delayed 24–120-hour period (48.1%, 51.9%, and 36.1%, respectively; P = 0.018 and P = 0.002 for palonosetron 0.25 mg and 0.75 mg vs. dolasetron, respectively) and during the overall 0–120-hour period (41.8%, 42.9%, and 30.9%, respectively; P = 0.027 and P = 0.016 for palonosetron 0.25 mg and 0.75 mg vs. dolasetron, respectively). In addition, significantly higher CC rates were observed for palonosetron 0.25 mg and 0.75 mg compared with dolasetron on Day 2 (55.0% vs. 40.3%, P = 0.004 and 57.7% vs. 40.3%, P = 0.001, respectively) and Day 3 (62.4% vs. 48.2%, P = 0.005 and 68.3% vs. 48.2%, P = 0.001, respectively), with superiority also observed for palonosetron 0.75 mg on Day 4 (80.4% vs. 67.0%, P = 0.003).
Superiority of palonosetron compared with dolasetron was observed throughout the study for additional secondary end points. Patients treated with palonosetron 0.25 mg had significantly fewer emetic episodes compared with those treated with dolasetron during the acute (P = 0.0135), delayed (P = 0.0183), and overall (P = 0.0036) periods. This also was the case for patients treated with palonosetron 0.75 mg compared with patients treated with dolasetron during the delayed (P = 0.0002) and overall (P = 0.0016) periods. Consistent with this finding, significantly more patients treated with palonosetron had no emetic episodes during these delayed and overall intervals (P = 0.028 and P = 0.014 for palonosetron 0.25 mg and P = 0.001 and P = 0.004 for palonosetron 0.75, respectively). In addition, there was a greater proportion of patients with no emetic episodes on individual Days 1, 2, and 5 for palonosetron 0.25 mg and on Days 2 and 3 for palonosetron 0.75 mg compared with dolasetron (Fig. 2). The proportion of patients with no nausea was also significantly greater in both palonosetron groups on Days 2 and 3 (P < 0.05) and for palonosetron 0.75 mg on Day 4 as well (P = 0.002) (Fig. 3).
For all time points or intervals not mentioned, a similar trend favoring palonosetron compared with dolasetron was observed, although this difference did not reach statistical significance. Time to first emetic episode and time to treatment failure were significantly longer for both palonosetron doses compared with dolasetron (P < 0.05). The median time to first emetic episode was more than 120 hours for both palonosetron doses versus 41.5 hours for dolasetron. The median time to treatment failure for both palonosetron doses was more than twice as long as with dolasetron (51.1, 52.8, and 24.6 hours, respectively; Fig. 4). Results for additional secondary efficacy parameters not described in the current study will be presented in subsequent publications.
Both doses of palonosetron were equivalent for almost all efficacy assessments, suggesting that the 0.25 mg dose may be on the plateau of the dose-response curve. There was little additional incremental benefit beyond this dose.
Subgroup analyses of each palonosetron treatment group and the dolasetron treatment group by gender and chemotherapeutic history (stratification criteria) showed expected trends in efficacy differences. Compared with females, male patients tended to have higher CR and CC rates, less nausea, and longer times to first emetic episode. Male patients also needed less rescue medication. It is noteworthy, however, that males accounted for only 18% of the patient population. Compared with chemotherapy-naive patients, nonnaive patients showed a trend toward higher CR rates during the 0–24-hour period (palonosetron 0.25 mg group, 67.7% vs. 60.5%; dolasetron group, 65.2% vs. 46.4%; palonosetron 0.75 mg group, 60.3% vs. 55.7%). Patients who had received previous chemotherapy were eligible for enrollment in this trial if they had experienced no more than mild nausea. This might tend to select patients with less risk for subsequent problems with nausea or emesis after emetogenic chemotherapy. Compared with patients who did not receive corticosteroids, those who received corticosteroids showed a trend toward higher CR rates in the palonosetron 0.25 mg group (72.7% vs. 62.4%) and in the dolasetron group (62.5% vs. 52.5%), but not in the palonosetron 0.75 mg group (50.0% vs 57.6%). However, because only approximately 5% of patients received corticosteroids, these findings should be interpreted with caution.
The safety cohort comprised 582 patients. Palonosetron was well tolerated and no AE-related withdrawals were reported during the study. There were no clinically relevant differences between treatments with respect to overall incidence of AEs (both related and not related to treatment). Most (64.1%) were mild in intensity. In all 3 treatment groups, the most common AEs (whether or not related to the study drug) were headache (palonosetron 0.25 mg, 26.4% of patients; palonosetron 0.75 mg, 24.1%; dolasetron, 26.8%), followed by constipation (11.9%, 14.9%, and 9.3%, respectively) and fatigue (10.9%, 13.3%, and 12.4%, respectively). 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 dolasetron. Most (> 80%) AEs were not related to the study drug and there were no relevant differences between groups with regards to treatment-related AEs (i.e., adverse reactions; Table 5). The most common adverse reactions in all three treatment groups were headache and constipation.
|Adverse reaction||Palonosetron 0.25 mg (n = 193)||Palonosetron 0.75 mg (n = 195)||Dolasetron 100 mg (n = 194)|
|No.a (%)||No.a (%)||No.a (%)|
|Headache||28 (14.5)||30 (15.4)||32 (16.5)|
|Constipation||14 (7.3)||18 (9.2)||12 (6.2)|
|Anxiety||4 (2.1)||0 (0.0)||0 (0.0)|
|Diarrhea||3 (1.6)||3 (1.5)||4 (2.1)|
|Dizziness||3 (1.6)||2 (1.0)||4 (2.1)|
|Fatigue||2 (1.0)||2 (1.0)||4 (2.1)|
|Asthenia||1 (0.5)||4 (2.1)||1 (0.5)|
The incidence of serious AEs was low and there were no relevant differences between groups (2.1% [n = 4] of patients in the palonosetron 0.25 mg group, 6.7% [n = 13] in the palonosetron 0.75 mg group, and 4.6% [n = 9] in the dolasetron 100 mg group). None of the serious AEs reported were related to study medication. Three patients died during the observation period (1 in the palonosetron 0.25 mg group and 2 in the palonosetron 0.75 mg group). All deaths were attributed to cancer progression. No clinically relevant differences were found between treatment groups with respect to laboratory test results, vital sign changes, and ECG findings. As an example, the mean postdose change in QTc interval (Fridericia correction) from baseline was 3.4, 3.2, and 5.4 msec for palonosetron 0.25 mg, palonosetron 0.75 mg, and dolasetron, respectively.
The current study provides evidence that major pharmacologic differences in a novel 5-HT3 receptor antagonist, palonosetron, may translate into improved outcomes in patients receiving moderately emetogenic chemotherapy. Several features of the design of this clinical trial are worth exploring. First, we chose to enroll a heterogeneous population of patients receiving commonly administered, moderately emetogenic chemotherapy and did not limit the study to patients who were chemotherapy-naive. The higher response rates for patients who were chemotherapy-experienced are most likely related to the eligibility criteria. Patients with previous chemotherapy experience were allowed into the study if, according to the investigator, the patient had no more than mild nausea with previous chemotherapy. This exclusion of patients with more severe nausea from previous chemotherapy could explain the higher response rates to either palonosetron or dolasetron in this subpopulation compared with the chemotherapy-naive subpopulation. Second, study drugs were given only on Day 1 as single i.v. doses, which allowed us to explore the duration of palonosetron efficacy in the prevention of nausea and emesis during the 24–120-hour period (delayed phase) after chemotherapy. Palonosetron 0.25 mg produced numerically superior CR rates compared with dolasetron 100 mg during the acute period. However, for both the delayed and overall periods, as well as at each time point after 24 hours until 72 hours after chemotherapy, both doses of palonosetron administered as a single i.v. dose on Day 1 demonstrated both clinical and statistical superiority to a single i.v. dose of dolasetron 100 mg. This was observed consistently for all efficacy assessments. At 72 hours after chemotherapy administration, the efficacy differences among the regimens disappeared, most likely because of the considerably reduced risk of delayed emesis after moderately emetogenic chemotherapy after this time.
The palonosetron doses used in the current study were based on a Phase II dose-ranging study, which showed palonosetron 3.0 μg/kg (fixed dose of approximately 0.25 mg) to be the minimally effective dose for the prevention of highly emetogenic CINV. Doses up to 90 μg/kg (fixed dose of approximately 6.0 mg) were also safe and effective (Unpublished data, 2003). Findings from the Phase II study supported the selection of 3.0 μg/kg and 10 μg/kg (corresponding to fixed doses of approximately 0.25 mg and 0.75 mg, respectively) for use in the current Phase III study. Results of the current study showed that these two palonosetron doses were similar in overall efficacy, confirming that the 0.25 mg dose is on the plateau of the efficacy dose-response curve. In addition, both doses of palonosetron were similar to dolasetron in the incidence, pattern, and duration of reported AEs, most of which were mild and not related to study medication. There were also no clinically relevant differences between dolasetron and palonosetron with respect to laboratory, ECG, or vital sign changes.
Because CINV can persist for several days, a 5-HT3 receptor antagonist with a prolonged duration of action could be valuable. A Phase II study showed that palonosetron maintains efficacy in preventing CINV for some days after highly emetogenic chemotherapy.11 The 5-HT3 receptor binding affinity of palonosetron is approximately 100-fold greater than others in its class, making it more potent than other receptor antagonists (pKi 10.45 for palonosetron vs. 7.6 for dolasetron, 8.39 for ondansetron, and 8.91 for granisetron).10, 13 In addition, the extended plasma elimination half-life of palonosetron (approximately 40 hours)14 is substantially longer than first-generation agents (dolasetron, 7.5 hours; ondansetron, 4.0 hours; and granisetron, 8.9 hours).15–17 The strong 5-HT3 receptor binding affinity of palonosetron and prolonged half-life are potential explanations for its prolonged antiemetic activity. The prolonged efficacy of palonosetron seen in the current Phase III trial is in agreement with the Phase II findings.
In conclusion, the current study has demonstrated that single, fixed, i.v. doses of palonosetron 0.25 mg and 0.75 mg are effective and safe in preventing moderately emetogenic CINV. Palonosetron was more effective than single-dose dolasetron in preventing acute and delayed CINV. With its extended duration of action, excellent safety profile, and high response rates, palonosetron is a safe and potentially more effective alternative to currently marketed first-generation 5-HT3 receptor antagonists.
The authors thank the physicians of the 99-04 Palonosetron Study Group: Addo Ferdinand, Medcenter One (Bismarck, North Dakota); Adler Kent, Hematology & Oncology Associates (San Mateo, California); Afifi Mahmoud, Medical Arts Clinic (Minot, North Dakota); Agarwal Vandana (Pomona, California); Alexander Francisco M., Hospital General de Occidente (Zapopan, Mexico); Bergeron Mike,The Clinic (Lake Charles, Louisiana); Bertoli Luigi F., Clinical Research Consultants Inc. (Hoover, Alabama); Bhaskar, Birbal, Medical Oncology Care Associates (Orange, California); Bhoopalam Nirmala, Edward Hines Veterans Administration Hospital (Hines, Illinois); Capdeville Daniel, Hospital Regional Civil de León (León, Mexico); Cárdenas Sánchez Jesús, Centro Estatal de Cancerologia de Colima (Colima, Mexico); Castine Michael, Medical Oncology LLC (Baton Rouge, Louisiana); Cohn Allen, Rocky Mountain Cancer Care Centers (Denver, Colorado); Coleman Teresa, Eisenhower Army Medical Center (Fort Gordon, Georgia); Cortes Patricia, Centro Medico Nacional 20 de Noviembre ISSSTE (Mexico City, Mexico); Currie Mark, Lewis Gale Clinic (Salem, Virginia); Deutsch Margaret, nTouch Research - Wake Med. (Raliegh, North Carolina); Eckardt John, St. John's Mercy Medical Center (St. Louis, Missouri); Ethridge William, Yakima Regional Cancer Care Center (Yakima, Washington); Ferguson Susan, Cooper Green Hospital (Birmingham, Alabama); Gámez Ugalde Emilio, Hospital Central “Ignacio Morones Prieto” (San Luis Potosí, Mexico); Grote Thomas, Salem Research Group, Inc. (Winston-Salem, North Carolina); Hall Stephen, Reno Veterans Administration Medical Center (Reno, Nevada); Igancio Ibarra G., Hospital de Especialidades Gabriel Mancera (Mexico City,Mexico); Irwin David, Alta Bates Comprehensive Cancer Center (Berkley, California); Jhangiani Haresh, Pacific Coast Hematology-Oncology Medical Group (Fountain Valley, California); Kovacs Gabor, (Laguna Beach, California); LeBerthon Brian, California Cancer Medical Center (West Covina, California); Link John, Memorial Care Breast Cancer (Fountain Valley, California); López Hernández J., Hospital Centro Estatal de Cancerología (Durango, Mexico); Lowenthal Elizabeth A., Clinical Research Consultants Inc. (Hoover, Alabama); Martelo Orlando, Glens Falls Cancer Center (Glens Falls, New York); Modiano Manuel, Arizona Clinical Research Center Inc. (Tucson, Arizona); Moreno Ramírez Arturo, Hospital Universitario de Puebla (Puebla, Mexico); Morgan Gilberto, Centro Medico Nacional de Occidente (Guadalajara, Mexico); Olivares Guillermo, SIGLO XXI Servicio de Oncologia (Mexico City, Mexico); Ovilla Roberto, Hospital Angeles Interlomas (Huixquilucand, Mexico); Pendergrass Kelly, Oncology and Hematology Associates (Kansas City, Missouri); Peralta Sánchez Jesús, Centro Estatal de Cancerología (Chihuahua, Mexico); Phillips Nabil, (Tustin, California); Pluard Timothy, Missouri Cancer Care, PC (St. Charles, Missouri); Ramírez Márquez Marcelino, Hospital Regional de Morelos IMS (Chihuahua, Mexico); Rausch Gregory, Frederick Memorial Hospital (Frederick, Maryland); Robles Aviña Jorge, Hospital Central Sur de Alta Especialidad (Mexico City, Mexico); Rodríguez Ana Laura, Instituto Jalisiense de Cancerologia (Guadalajara, Mexico); Rooney James, Fallon Clinic Inc. (Worcester, Massachusetts); Rosales Francisco M., Hospital de Especialidades No. 71 IMSS (Torreón, Mexico); Saiers Joseph, Veterans Affairs Medical Center (Albuquerque, New Mexico); Sapra Ranjan, Shreenath Clinical Services (Fountain Valley, California); Senecal Frank, Hematology Oncology Northwest PC (Tacoma, Washington); Shah Ramesh, Florida West Coast Clinical Research Group (Tampa, Florida); Suárez Tirzo, Centro Anticanceroso de Mélrida (Mérida, Mexico); Thomas Mathew, Mid Dakota Clinic PC Cancer Treatment Center (Bismarck, North Dakota); Tripp Francisco José, Espec. La Raza IMSS (Mexico City, Mexico); Van Veldhuizen Peter, Veterans Affairs Medical Center (Kansas City, Missouri); Walsh Daniel, Altru Health System (Grand Forks, North Dakota); Wiznitzer Israel, Midwest Cancer Research Group Inc. (Skokie, Illinois); Yanagihara Ronald H., Gilroy Medical Plaza (Gilroy, California); Yeilding Allen L., Carraway Cancer Center (Birmingham, Alabama); Yunus Furhan, The Boston Cancer Center (Memphis, Tennessee);
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