Download Original article Palonosetron improves prevention of

Original article
Annals of Oncology 14: 1570–1577, 2003
DOI: 10.1093/annonc/mdg417
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
R. Gralla1, M. Lichinitser2, S. Van der Vegt3, H. Sleeboom4, J. Mezger5, C. Peschel6, G. Tonini7,
R. Labianca8, A. Macciocchi9 & M. Aapro10*
1
New York Lung Cancer Alliance, New York, NY, USA; 2Cancer Research Center, Moscow, Russia; 3Ziekenhuis Ondenrijn, Van Heuven Goedhartlaan, Utrecht;
Ziekenhuis Leyenburg, Den Haag, The Netherlands; 5St Vincentius-Kliniken, Karlsruhe; 6Klinikum rechts der Isar der Technischen Universität München, Munich,
Germany; 7Oncology Department Campus, Bio-Medico University, Rome; 8Ospedali Riuniti di Bergamo, Unitá Operativa di Oncologia Medica, Bergamo, Italy;
9
Helsinn Healthcare SA, Lugano; 10IMO, Clinique de Genolier, Genolier, Vaud, Switzerland
4
Received 10 June 2003; revised 17 July 2003; accepted 21 July 2003
Background: 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 (0–24 h) (81.0% versus 68.6%, respectively), delayed (24–120 h)
(74.1% versus 55.1%) and overall (0–120 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
Introduction
Four selective 5-HT3 (serotonin-3) receptor antagonists are available
for use in North America and/or Europe for the prevention of
acute chemotherapy-induced nausea and vomiting (CINV): dolasetron, ondansetron, granisetron and tropisetron. Although these
agents have some pharmacological differences in 5-HT3 receptor
binding affinity, selectivity and metabolism, these minor variations have not resulted in clinically meaningful differences in
efficacy amongst them. Therefore, according to current evidencebased and consensus guidelines, these 5-HT3 receptor antagonists
*Correspondence to: Dr M. Aapro, IMO, Clinique de Genolier, 1 Route du
Muids, CH-1272 Genolier, Vaud, Switzerland. Tel: +41-22-3669136;
Fax: +41-22-3669131; E-mail: [email protected]
© 2003 European Society for Medical Oncology
are equivalent with regard to efficacy and are therapeutically
interchangeable when used at equipotent doses [1–4].
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 [7–11]. 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
1571
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) [12–14]. 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.
Patients and methods
Patient selection
Eligible patients were ≥18 years of age with histologically or cytologically
confirmed malignant disease, either chemotherapy naïve or non-naïve (having
experienced a maximum of mild nausea previously) and scheduled to receive
moderately emetogenic chemotherapy. The inclusion/exclusion criteria can be
summarized as follows: patients who were scheduled to receive chemotherapy
with any dose of carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan or
mitoxantrone; methotrexate >250 mg/m2; cyclophosphamide <1500 mg/m2;
doxorubicin >25 mg/m2; or cisplatin <50 mg/m2 (infused over 1–4 h). Patients
with hepatic, renal or cardiovascular impairment were enrolled at the investigator’s discretion. Patients were excluded if they were unable to understand or
cooperate with study procedures. Other exclusion criteria were as follows: the
taking of any drug with antiemetic activity within 24 h prior to treatment until
day 5 (including corticosteroids); evidence of seizure disorder requiring anticonvulsants (unless clinically stable with no seizure activity); vomiting, retching
or National Cancer Institute (NCI) Common Toxicity Criteria grade 2 or 3
nausea in the 24 h preceding chemotherapy; or were scheduled for radiation of
upper abdomen or cranium on days 2–6.
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 investigator’s 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 24–120-h time period and the
cumulative overall 0–120-h time period, as well as CR rates during successive
24-h time periods (i.e. 24–48, 48–72, 72–96, 96–120 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 0–24,
24–120 and 0–120 h intervals; number of emetic episodes daily and cumulatively for the 24–120 and 0–120 h intervals; time to first emetic episode; severity
of nausea measured daily for the 0–120 h interval by a four-point Likert scale
(used in previous studies to evaluate patient perceptions of cancer treatmentrelated side-effects) [21–23]; 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 0–120-h interval; and quality of life (QoL), measured via a modified
functional living index—emesis (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 24–96-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 24–30 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 δ 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 onesided test of equivalence (α = 0.0125), a sample size of 180 evaluable patients
1572
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 Fisher’s exact test were also conducted. The χ2 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 Kruskal–Wallis 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 Kaplan–Meier 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 (α = 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.
Results
Patient characteristics and baseline demographics
Demographic data and baseline characteristics for patients in the
ITT cohort are presented in Table 1. Of the 570 patients randomized, seven did not receive study medication. Therefore, a
total of 563 patients were evaluable for efficacy in the ITT cohort.
Of these patients, 562 were evaluable for safety. Five patients
withdrew from the study: one in the palonosetron 0.25 mg group
(patient’s decision), two in the palonosetron 0.75 mg group (one,
patient’s decision; one, non-serious AE), and two in the ondansetron group (one, patient’s decision; one, serious AE). The percentages of patients with protocol violations were similar in the three
treatment groups, with the majority of violations (4.7%) in all
treatment groups due to the taking of rescue medication before the
first emetic episode on study day 1.
The majority (72.1%) of patients evaluated were female,
Caucasian (98.9%) and had received chemotherapy previously
(58.4%). The most common cancer type was breast cancer (57%
of patients), followed by lung (8%), bladder (5%), colon (4%),
rectal (3%), small-cell lung (3%) and gastric (3%) cancer. The
most common chemotherapeutic agents administered on study
day 1 (received by >10% of patients) were cyclophosphamide
(63%), doxorubicin (48%), cisplatin (18%), methotrexate (16%)
and carboplatin (12%). All three treatment groups were comparable regarding the type and dose of chemotherapy administered.
No patient received prophylactic corticosteroids.
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).
Secondary efficacy parameters
Complete response: study days 2–5 (delayed CINV). For the
delayed (24–120 h) and overall (0–120 h) time periods, the proportion of patients achieving a CR was significantly greater for
palonosetron 0.25 mg compared with ondansetron (Table 2). For
the daily assessments through study day 4 (96 h), CR rates were
significantly higher with palonosetron 0.25 mg than ondansetron.
Palonosetron 0.75 mg was as effective as ondansetron at all time
points.
Complete control: study days 1–5 (acute and delayed CINV). Palonosetron 0.25 mg and 0.75 mg produced significantly higher CC
rates compared with ondansetron during the delayed (24–120 h)
interval (66.7% versus 50.3%; P = 0.001), and the overall (0–120 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).
1573
Table 1. Demographic data and baseline characteristics (ITT cohort, n = 563)
Variable
Age, years (mean ± SD)
Height, cm (mean ± SD)
Weight, kg (mean ± SD)
Palonosetron 0.25 mg
(n = 189)
56.1 ± 11.7
165.0 ± 7.2
Palonosetron 0.75 mg
(n = 189)
54.8 ± 10.1
165.4 ± 8.5
Ondansetron 32 mg
(n = 185)
55.3 ± 10.8
165.5 ± 8.1
71.7 ± 13.3
69.4 ± 13.6
71.0 ± 13.0
54 (28.6)
51 (27.0)
52 (28.1)
135 (71.4)
138 (73.0)
133 (71.9)
Gender, n (%)
Male
Female
Karnofsky index, % (mean ± SD)
88.9 ± 9.6
89.5 ± 10.7
88.5 ± 10.9
Ethnicity, n (%)
White, Caucasian
186 (98.4)
188 (99.5)
183 (98.9)
Black
0 (0.0)
0 (0.0)
0 (0.0)
Hispanic
1 (0.5)
0 (0.0)
1 (0.5)
Asian
2 (1.1)
0 (0.0)
0 (0.0)
Other
0 (0.0)
1 (0.5)
1 (0.5)
132 (69.8)
132 (69.8)
127 (68.6)
Ex-smoker
28 (14.8)
19 (10.1)
23 (12.4)
Smoker
28 (14.8)
38 (20.1)
35 (18.9)
No
89 (47.1)
84 (44.4)
78 (42.2)
Rarely
75 (39.7)
71 (37.6)
73 (39.5)
Occasionally
15 (7.9)
27 (14.3)
23 (12.4)
9 (4.8)
7 (3.7)
11 (5.9)
Tobacco use, n (%)
Non-smoker
Alcohol use, n (%)
Regularly
Chemotherapeutic history, n (%)
Naïve
Non-naïve
76 (40.2)
80 (42.3)
78 (42.2)
113 (59.8)
109 (57.7)
107 (57.8)
ITT, intention-to-treat; SD, standard deviation.
Additional secondary end points
Palonosetron 0.25 mg was consistently superior to ondansetron
(P ≤0.05) in the number of emetic episodes [during the acute
(0–24 h), delayed (24–120 h) and overall (0–120 h) intervals, as
well as on study days 2 and 3], the proportion of patients with no
emetic episodes (study days 1–3 and delayed and overall intervals)
(Figure 2) and the proportion of nausea-free patients (study days
3–5). For these same end points, palonosetron 0.75 mg was superior
to ondansetron on study day 3, delayed and overall intervals (% no
emesis), and study days 4–5 (% no nausea). Only a few patients
required rescue medication during the delayed (24–120 h) period
(palonosetron 0.25 mg, 15.9%; palonosetron 0.75 mg, 22.8%;
ondansetron, 24.3%) and during the overall (0–120 h) period
(18.5%, 23.8% and 27.0%, respectively) (P ≥0.05 for each study
day and during the cumulative delayed and overall study periods),
with metoclopramide used most frequently.
A subset analysis by gender showed a trend in males for higher
CR rates, higher CC rates, less severe nausea, longer time to treatment failure, longer time to first emetic episode and less rescue
medication compared with female patients. A subset analysis by
chemotherapeutic history showed that chemotherapy-naïve
patients tended to have less severe nausea than non-naïve patients.
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 patient’s 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
50.3
0.1192
97.5% CIs for the difference between palonosetron 0.25 mg or 0.75 mg dose group and the ondansetron group indicate palonosetron superiority.
P values represent adjusted post hoc, two-sided, Fisher’s exact test comparisons of palonosetron with ondansetron. Comparisons are significant at the 0.025 level.
CI, confidence interval; ITT, intention-to-treat; OND, ondansetron; PAL, palonosetron.
b
55.1
0.0730
–3.6% to 20.5%
58.7
<0.001
–2.4% to 21.3%
64.6
<0.001
7.4% to 30.7%
69.3
Overall, 0–120
7.5% to 30.3%
74.1
Delayed, 24–120
PAL minus OND 97.5% CI
1.8% to 22.8%
81.0
%
Acute, 0–24
a
68.6
0.3067
%
PAL minus OND 97.5% CI
–6.1% to 15.9%
73.5
%
P value
0.0085
Palonosetron 0.75 mg (n = 189)
b
a
Palonosetron 0.25 mg (n = 189)
Time period, h
Table 2. Complete response (no emetic episode and no use of rescue medication) rates (ITT cohort, n = 563)
a
P value
b
Ondansetron 32 mg (n = 185)
1574
Figure 1. Kaplan–Meier plot of time to treatment failure. P = 0.0003 for
pairwise difference (log-rank) between palonosetron 0.25 mg and
ondansetron.
Figure 2. Proportion of patients with no emetic episodes during the acute,
delayed and overall time periods. *P ≤0.05 compared with ondansetron (χ2
test; intention-to-treat cohort, n = 563).
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.
Fifteen patients (five per treatment group) experienced serious
AEs; all were assessed by the investigators as not related to, or
unlikely to be related to, study medication. No significant changes
related to study drug were observed with respect to laboratory
1575
Table 3. Treatment-related adverse eventsa reported by >2% of patients (safety cohort, n = 562)
Adverse reaction
Headache
PAL 0.25 mg (n = 187)
PAL 0.75 mg (n = 188)
OND 32 mg (n = 187)
n
%
n
%
n
%
9
4.8
10
5.3
10
5.3
Dizziness
1
0.5
0
0.0
6
3.2
Constipation
3
1.6
6
3.2
3
1.6
a
Adverse events judged by the investigator to have a definite, possible, probable or unknown relationship to study
medication.
PAL, palonosetron; OND, ondansetron.
parameters, vital sign measurements and ECG recordings, with no
pronounced differences in these parameters observed between
treatment groups. The mean post-dose change from baseline in
QTc (Fridericia correction) was 1 ms for palonosetron 0.25 mg,
2 ms for palonosetron 0.75 mg and 5 ms for ondansetron. Overall,
no significant safety concerns were raised in this study.
Discussion
Conventional thinking regarding the activity of the available
5HT3 receptor antagonists is that they are all similar. The results
of this study suggest that palonosetron’s major pharmacological
differences may translate into improved control of CINV in
patients receiving moderately emetogenic chemotherapy. In this
study, a single i.v. dose of palonosetron was superior to ondansetron in preventing acute CINV, as indicated by the CR rates and a
number of secondary efficacy assessments within the 24 h following chemotherapy administration. This advantage was observed
comparing palonosetron to the highest recommended i.v. dose of
ondansetron. CR rates observed in this study for ondansetron were
similar to those reported previously, with earlier studies reporting
CR rates ranging from 69% to 73% for acute emesis (following a
single dose) and 45% for delayed emesis (following multiple
doses) [24, 25]. The consistency of these CR rates with those
reported in the current study (69% for acute emesis, 50% for
delayed emesis) highlights the validity of the current study.
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 24–120-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 patient’s 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, 28–30]. 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 dose–response 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.
Acknowledgements
This study was sponsored by Helsinn Healthcare SA, Lugano,
Switzerland.
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
1576
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 PhilippsUniversität, 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.
References
1. Forni C, Ferrari S, Loro L et al. Granisetron, tropisetron, and ondansetron
in the prevention of acute emesis induced by a combination of cisplatin–
adriamycin and by high-dose ifosfamide delivered in multi-day continuous
infusions. Support Care Cancer 2000; 8: 131–133.
2. Gralla RJ, Osoba D, Kris MG et al. Recommendations for the use of
antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol
1999; 17: 2971–2994.
3. Koeller JM, Aapro MS, Gralla RJ et al. Antiemetic guidelines: creating a
more practical approach. Support Care Cancer 2002; 10: 519–522.
4. Watters J, Riley M, Pedley I et al. The development of a protocol for the
use of 5-HT3 antagonists in chemotherapy-induced nausea and vomiting.
Clin Oncol 2001; 13: 422–426.
5. Walton SM. Advances in use of the 5-HT3 receptor antagonists. Exp Opin
Pharmacother 2000; 1: 207–223.
6. Hesketh PJ. Comparative review of 5-HT3 receptor antagonists in the
treatment of acute chemotherapy-induced nausea and vomiting. Cancer
Invest 2000; 18: 163–173.
7. The Italian Group for Antiemetic Research. Dexamethasone, granisetron,
or both for the prevention of nausea and vomiting during chemotherapy
for cancer. N Engl J Med 1995; 332: 1–5.
8. The Italian Group for Antiemetic Research. Dexamethasone alone or in
combination with ondansetron for the prevention of delayed nausea and
vomiting induced by chemotherapy. N Engl J Med 2000; 342: 1554–1559.
9. Johnston D, Latreille J, Laberge F et al. Preventing nausea and vomiting
during days 2–7 following high dose cisplatin chemotherapy (HDCP). A
study by the National Cancer Institute of Canada Clinical Trials Group
(NCIC CTG). Proc Am Soc Clin Oncol 1995; 14: 529 (Abstr 1745).
10. Kaizer L, Warr D, Hoskins P et al. Effect of schedule and maintenance on
the antiemetic efficacy of ondansetron combined with dexamethasone in
acute and delayed nausea and emesis in patients receiving moderately
emetogenic chemotherapy: a phase III trial by the National Cancer Institute
of Canada Clinical Trials Group. J Clin Oncol 1994; 12: 1050–1057.
11. Osoba D, Zee B, Pater J et al. Determinants of postchemotherapy nausea
and vomiting in patients with cancer. J Clin Oncol 1997; 15: 116–123.
12. Miller RC, Galvan M, Gittos MW et al. Pharmacological properties of
dolasetron, a potent and selective antagonist at 5-HT3 receptors. Drug
Dev Res 1993; 28: 87–93.
13. Wong EH, Clark R, Leung E et al. The interaction of RS 25259-197, a
potent and selective antagonist, with 5-HT3 receptors, in vitro. Br J Pharmacol 1995; 114: 851–859.
14. Van Wijngaarden I, Tulp MTM, Soudijn W. The concept of selectivity in
5-HT receptor research. Eur J Pharmacol 1990; 188: 301–312.
15. Piraccini G, Stolz R, Tei M et al. Pharmacokinetic features of a novel
5-HT3-receptor antagonist: palonosetron (RS 25259-197). Proc Am Soc
Clin Oncol 2001; 20: 400a (Abstr 1595).
16. GlaxoSmithKline. Zofran® (ondansetron hydrochloride injection) prescribing information. Research Triangle Park, NC: GlaxoSmithKline
2001.
1577
17. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention
of chemotherapy-induced nausea and vomiting. A comparison of their
pharmacology and clinical efficacy. Drugs 1998; 55: 173–189.
18. Aventis Pharmaceuticals. Anzemet® (dolasetron mesylate injection) prescribing information. Bridgewater, NJ: Aventis Pharmaceuticals 2002.
19. Roche Laboratories. Kytril® (granisetron hydrochloride injection) prescribing information. Nutley, NJ: Roche Laboratories 2000.
20. Macciocchi A, Gallagher S. A phase II dose-ranging study to assess single
intravenous doses of palonosetron for the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. Proc Am Soc Clin
Oncol 2002; 21: 471a (Abstr 1480).
21. Clark JA, Wray N, Brody B et al. Dimensions of quality of life expressed
by men treated for metastatic prostate cancer. Soc Sci Med 1997; 45:
1299–1309.
22. Lindley C, McCune JS, Thomason TE et al. Perception of chemotherapy
side effects: cancer versus noncancer patients. Cancer Pract 1999; 7: 59–65.
23. Rollison B, Strang P. Pain, nausea, and anxiety during intra-uterine brachytherapy of cervical carcinomas. Support Care Cancer 1995; 3: 205–207.
24. Gebbia V, Cannata G, Testa A et al. Ondansetron versus granisetron in the
prevention of chemotherapy-induced nausea and vomiting. Cancer 1994;
74: 1945–1952.
25. Perez EA, Hesketh P, Sandbach J et al. Comparison of single-dose oral
granisetron versus intravenous ondansetron in the prevention of nausea
and vomiting induced by moderately emetogenic chemotherapy: a multi-
center, double-blind, randomized parallel study. J Clin Oncol 1998; 16:
754–760.
26. Hajdenberg J, Figueroa-Vadillo J, Macciocchi A, Grunberg S. Safety and
efficacy of fixed-dose palonosetron in preventing acute and delayed
emesis following moderately emetogenic chemotherapy: a phase III
study. Presented at The 37th American Society of Health-System Pharmacists Midyear Clinical Meeting; December 8–12, 2002; Atlanta, GA.
International Pharmaceutical Abstracts 2002; 37: P-643-E.
27. Aapro MS, Thuerlimann B, Sessa C et al. A randomized, double-blind
trial to compare the clinical efficacy of granisetron with metoclopramide,
both combined with dexamethasone in the prophylaxis of chemotherapyinduced delayed emesis. Ann Oncol 2003; 14: 291–297.
28. Audhuy B, Cappelaere P, Martin M et al. A double-blind, randomised
comparison of the anti-emetic efficacy of two intravenous doses of
dolasetron mesilate and granisetron in patients receiving high dose cisplatin
chemotherapy. Eur J Cancer 1996; 32A: 807–813.
29. Hesketh P, Navari R, Grote T et al. Double-blind, randomized comparison
of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in
patients with cancer. J Clin Oncol 1996; 14: 2242–2249.
30. Navari R, Gandara D, Hesketh P et al. Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis.
J Clin Oncol 1995; 13: 1242–1248.