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Annals of Oncology
doi:10.1093/annonc/mdm331
original article
Results of a multicenter randomized study to evaluate
the safety and efficacy of combined immunotherapy
with interleukin-2, interferon-a2b and histamine
dihydrochloride versus dacarbazine in patients
with stage IV melanoma
M. Middleton
1
, A. Hauschild
2
, D. Thomson
3
, R. Anderson
4
, S. Burdette-Radoux
5à
, K. Gehlsen
6§
,
K. Hellstrand
7
& P. Naredi
8
*
1
Department of Medical Oncology, Christie Hospital, Manchester, UK;
2
Department of Dermatology, University of Kiel, Kiel, Germany;
3
Department of Medical Oncology,
Princess Alexandra Hospital, Woolloongabba, Queensland, Australia;
4
Departments of Oncology, Umea
˚University Hospital, Umea
˚, Sweden;
5
Department of Oncology,
McGill University, Montreal, Canada;
6
EpiCept Corporation, San Diego, CA, USA;
7
Dept of Virology, University of Go
¨teborg, Go
¨teborg;
8
Departments of Surgery, Umea
˚
University Hospital, Umea
˚, Sweden
Received 23 February 2007; revised 14 May 2007; accepted 20 May 2007
Background: The safety and efficacy of immunotherapy with histamine dihydrochloride (HDC), interleukin-2 (IL-2)
and interferon-a2b (IFN) compared with dacarbazine (DTIC) in adult patients with stage IV melanoma was evaluated.
Patients and methods: Two hundred and forty-one patients were randomized to either receive repeated 4-week
cycles of IFN [3 MIU, s.c., once daily for 7 days], IL-2 (2.4 MIU/m
2
, s.c., twice a day for 5 days) and HDC (1 mg, s.c.,
twice a day for 5 days) or DTIC 850 mg/m
2
i.v. every 3 weeks. The primary endpoint was overall survival.
Results: Median survival was longer for patients receiving HDC/IL-2/IFN (271 days) than for patients receiving DTIC
(231 days), but this did not achieve statistical significance. Four patients receiving HDC/IL-2/IFN and nine receiving
DTIC experienced at least one grade 4 adverse event. Striking differences in overall survival were observed between
countries participating in the study.
Conclusion: Treatment with HDC/IL-2/IFN was safely administered on an outpatient basis, but this
immunotherapeutic regimen did not improve upon the response rate and overall survival seen with DTIC.
Key words: clinical trials, dacarbazine, histamine dihydrochloride, immunotherapy, interferon alpha, interleukin-2,
melanoma, phase III
introduction
Stage IV melanoma is associated with a 5–11 month median
survival duration and, despite response rates ranging from
10–50%, available treatments have failed to improve upon this
and are associated with significant toxicity. The lack of
efficacious treatments for advanced melanoma requires that
new approaches be tested.
Currently, there are two agents approved for use in
stage IV melanoma patients: dacarbazine (DTIC) in Europe
and the USA and high-dose intravenous interleukin-2 (IL-2)
in the USA. DTIC provides a 10–17% tumor response rate,
but these responses are generally of short duration, and
there is no evidence suggesting that DTIC has a significant
impact on overall survival in this patient population
[1–3].
The impact of high-dose IL-2 on the overall survival of
patients with stage IV melanoma is not known. Pooled data
from eight studies report a median survival of 11.4 months.
IL-2 administered at high doses is associated with severe
systemic side-effects [4]. Single-agent interferon-alpha (IFNa)
therapy, as well as single-agent IL-2 treatment, yields
response rates of approximately 15% in metastatic melanoma
with infrequent long-term responders and occasional long-term
survivors [5]. The combination of IFNaand IL-2 has been
reported to increase response rates [6] but this has not been
confirmed in a randomized phase III trial [7].
Immunosuppression within and around tumors has been
implicated as a major factor in preventing better clinical
outcomes using cytokines such as IL-2 and IFNa[8, 9]. One
original
article
*Correspondence to: Peter Naredi, Department of Surgery, Umea
˚University Hospital,
S-90185 Umea
˚, Sweden. Tel: +46 90 7851153; Fax: +46 90 7851156;
E-mail: peter.naredi@surgery.umu.se
Now at Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, UK
à
Now at Vermont Cancer Center, University of Vermont, Burlington, VT, USA
§
Now at Research Corporation Technologies, Tucson, AZ, USA
ª2007 European Society for Medical Oncology
Annals of Oncology Advance Access published August 20, 2007
by guest on June 4, 2013http://annonc.oxfordjournals.org/Downloaded from
mechanism by which tumors may suppress T-cell and natural
killer (NK)-cell function is through the recruitment of
monocyte/macrophages (MO) to the tumor site. These cells
produce reactive oxygen species (ROS), which can cause
down-regulation of the CD3ftransduction antigen in NK and
T cells along with significant NK-cell and T-cell apoptosis.
Histamines inhibit ROS production in MO, and thereby
protect NK-cells and T-cells from functional inhibition and
apoptosis. The use of histamine dihydrochloride (HDC) as
a counter-suppressive agent in combination with IL-2 and/or
IFNahas been under investigation in several phase 2 and
3 clinical trials [10–16].
The basis for this trial was in vitro and in vivo studies
suggesting that the combination of HDC and IL-2 yields
a more efficient lymphocyte-mediated destruction of several
human malignant target cells [17–21] than either compound
used as a single agent; these in vitro findings are supported by
clinical studies in melanoma demonstrating that cytotoxic
lymphocytes are more efficiently activated by systemic
treatment with HDC/IL-2 in vivo than by monotherapy with
IL-2 [22]. A recent randomized trial in acute myeloid leukemia
(AML) demonstrated a statistically significant improvement
in long-term leukemia-free survival for patients treated
post-consolidation with HDC and IL-2 compared with the
no-treatment control patients [16].
Clinical experience from a randomized phase 3 study in
stage IV melanoma patients reported that the combination of
histamine plus IL-2 improved the overall survival of stage IV
melanoma patients with liver metastases versus IL-2 alone
(9.4 vs. 5.1 months) but there was no survival benefit for the
overall population [12]. A second confirmatory phase 3 study
failed to show any survival benefit for patients with liver
metastases (P. Naredi). In a phase II study in stage IV
melanoma patients combining HDC/IL-2/IFN, the median
survival exceeded 11 months and complete responses were seen,
including in patients with liver metastases [14]. The present
study was designed to test this outpatient combination
immune-based treatment regimen containing low-dose IL-2,
low-dose IFNaand histamine compared with DTIC alone in
stage IV melanoma patients.
patients and methods
patients and eligibility
Inclusion criteria were: age >18 years; histologically proven American
Joint Committee on Cancer (AJCC) stage IV melanoma; life expectancy
of ‡3 months; clinically adequate bone marrow, kidney, cardiac and liver
function (hemoglobin >10.0 g/dl, white blood cell count (WBC) >2.5 ·10
9
cells/L, absolute neutrophil count (ANC) >1.5 ·10
9
cells/L, platelet count
>100 ·10
9
/L, partial thromboplastin time (PTT or activated partial
thromboplastin time in Australia) within normal limits, creatinine
clearance >60 ml/min, serum bilirubin <1.5 times the upper limit of normal
(ULN), alanine aminotransferase (ALT) or aspartate aminotransferase
(AST) <3 times the ULN, fasting serum glucose <160 mg/dl; Karnofsky
status score of ‡70). All patients signed an informed consent.
Patients were excluded if any of the following conditions applied: prior
treatment with DTIC or IL-2 (except IL-2 used as an adjuvant >1 year
before enrollment in this study); abnormal cardiac function assessed by
resting ECG; any other concurrent systemic anti-neoplastic therapy;
ongoing active other malignancy (except in situ carcinoma of the cervix,
localized squamous or basal cell skin carcinomas); metastatic central
nervous system (CNS) malignancy at randomization (patients with stable,
treated brain metastases were eligible); documented history of asthma
treated within the past 5 years; medical, sociological or psychological
impediment to compliance with protocol; pregnancy or breast-feeding;
positive serum HIV test or history of autoimmune disease; active peptic
ulcer disease or a history of prior bleeding ulcer disease.
study design
Patients were stratified on the basis of liver metastases at baseline
(present or absent) and then randomized to either HDC/IL-2/IFN or to
DTIC. Site-specific randomization codes were produced electronically for
each stratified group, and site personnel called a central randomization
desk. Randomization was conducted in consecutive sequence within each
center. This study was not blinded because of the physiologic effects of
HDC (such as flushing). The study was approved by the Institutional Ethics
Review Boards.
Histamine dihydrochloride 1 mg (Ceplene, Maxim Pharmaceuticals,
San Diego, CA, USA) was administered twice daily on days 1–5 of each
week of the 4-week treatment cycle. HDC was administered by slow
subcutaneous injection over a period of not less than 10 min and not
more than 30 min. IL-2 (Proleukin, Chiron Corporation, Emeryville, CA,
USA) was administered subcutaneously at a dosage of 2.4 MIU/m
2
twice
daily for days 1–5 of weeks 1 and 2 of each treatment cycle. IFN
(interferon-a2b, Intron-A, Schering Plough, Kenilworth, NJ, USA) was
administered subcutaneously at a daily dose of 3 MIU for days 1–7 of
each week of the treatment cycle. Before the first cycle a priming dose of
IFN for 5–7 days was given. Intravenous DTIC 850 mg/m
2
was delivered
on day 1 of each 3-week cycle. DTIC was administered according to
standard practice in each institution and was obtained from commercial
stock.
The duration of treatment for patients receiving HDC/IL-2/IFN was
expected to be 12 months, except in the event of progressive disease or
adverse effect (AE) resulting in study discontinuation. Duration of
treatment for patients who received DTIC and achieved a response was
left to the discretion of the investigator.
study endpoints
The intent-to-treat (ITT) population comprised all randomized patients
and the intent-to-treat liver metastases (ITT-LM) subgroup was defined
as all randomized patients who had liver metastases at baseline. The
primary efficacy endpoint was overall survival in the ITT population
calculated as the number of days from randomization to death. Those
patients without a documented date of death at the time of data cut-off
were censored at the last date on which the patient was known to be alive.
Secondary efficacy endpoints were overall survival in the ITT-LM
population, progression-free survival, objective response rate and duration
of response. Progression-free survival was calculated as the number of
days from randomization to the first documentation of progressive disease
(PD) or death. Those patients without documented PD or death at the
time of data cut-off were censored at the date of the last assessment of
disease response. Objective tumor response rate was calculated as the
number of patients with a confirmed complete response (CR) or partial
response (PR) divided by the number of patients randomized. Assessment
for a response occurred every 12 weeks after randomization with
confirmation of the response 4 weeks later. The duration of the objective
response was calculated as the number of days from the first documentation
of CR or PR until the first documentation of PD or death. Only patients
with a confirmed CR or PR were included in the analysis.
statistics
The primary analysis compared the overall survival in the two treatment
groups using the stratified log-rank test, stratified by the presence or
original article Annals of Oncology
2|Middleton et al.
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absence of liver metastases at baseline. The null hypothesis was that
distribution of overall survival be the same in the two treatment groups. All
Pvalues reported are two-sided. Kaplan-Meier curves were used to
summarize the survival distributions in the treatment groups, and the
median of the survival distributions with 95% confidence interval (CI) was
tabulated by treatment group.
A sample size of 96 patients in each group was required to provide 80%
power to detect a 50% increase in median survival time (7.0–10.5 months)
between the two treatment groups, with a type I error of 0.05. To allow
for an expected drop-out rate of 20%, enrollment of 240 patients
(120 per group) was planned to maintain the desired power.
Kaplan-Meier estimates of the survival rate in each treatment group
were calculated at 6, 12, 18, 24, 30 and 36 months, along with 95% CI.
The treatment groups were compared at each time point by using an
approximate ztest. The secondary endpoints of progression-free survival
and duration of objective response were analyzed by using the same
methods as for the primary analysis of overall survival. For duration of
response, only those patients with an objective tumor response
(confirmed CR or PR) were included in the analysis. The investigator’s
assessment of response was used to determine each patient’s best overall
response. The Fisher exact test was used to compare the treatment groups
for objective tumor response rates and for comparison of prognostic
factors between countries.
safety analysis
All patients who received at least 1 dose of study drug were included in
the safety analyses. Endpoints for assessment of safety included monitoring
the occurrence, frequency and severity of AE [according to Cancer and
Leukemia Group B (CALGB) expanded common toxicity criteria] and
their causal relationship to study drugs. Laboratory values, vital signs,
results of physical examinations and ECG, dose adjustments and treatment
withdrawals for safety reasons were included in the assessment of safety.
results
patient characteristics
A total of 241 patients were randomized from February 1998
to October 2000 (119 to HDC/IL-2/IFN and 122 to DTIC) at
43 centers in Australia (66 patients), Canada (23 patients),
Germany (52 patients), Israel (4 patients), Sweden (45 patients)
and the United Kingdom (51 patients). Follow-up continued
until June 2002, after which the trial database was locked.
The two treatment groups were similar with regard to sex,
race, age, WHO performance status, lactate dehydrogenase
(LDH) and location of disease. There were no significant
differences in key prognostic factors or demographic
characteristics between the two study groups (Table 1).
Patient participation by treatment cycle was defined as
receipt of at least one dose in a given cycle. Participation by
cycle was similar between the two treatment groups after the
first evaluation at week 12. However, there was a higher
drop-out rate in the HDC/IL-2/IFN group after the first cycle
(29% vs. 12% for DTIC). Five patients in the HDC/IL-2/IFN
and one patient in the DTIC arm completed 12 months of
treatment and three patients (all in the HDC/IL-2/IFN arm)
went on with extended treatment for a further 6 months.
efficacy
The primary measure of efficacy was the duration of survival
in the ITT population.
Table 1. Demographic summary: intent-to-treat (ITT) population
Characteristic ITT population
DTIC HDC/IL-2/IFN
N=122 N=119
Age (years)
Median 53 52
Range 23–74 20–73
Sex [n(%)]
Male 77 (63) 74 (62)
Female 45 (37) 45 (38)
WHO PS [n(%)]
0 75 (62) 71 (60)
1 46 (38) 48 (40)
2 1 (1) 0 (0)
Disease sites [n(%)]
a
Skin 31 (25) 29 (24)
Lymph nodes 55 (45) 61 (51)
Bone 17 (14) 9 (8)
Lung 68 (56) 61 (51)
Liver 59 (48) 60 (50)
Other 36 (30) 47 (40)
Number of organ sites
1 38 (31) 32 (27)
2 44 (36) 39 (33)
>2 40 (33) 47 (40)
Adjuvant therapy [n(%)] 6 (5) 5 (4)
LDH group [n(%)]
<ULN 54 (44) 58 (49)
‡ULN 50 (41) 47 (40)
Missing 18 (15) 14 (12)
DTIC, dacarbazine; HDC, histamine dihydrochloride; IL-2, interleukin-2;
IFN, interferon a2b; ITT, intent-to-treat population; N, total number of
patients in the specified population; n, number of patients with the
specified characteristic in that population; ULN, upper limit of normal;
WHO PS, WHO performance status.
a
Patients may be counted in multiple categories.
Figure 1. Kaplan–Meier survival distribution curves for the
intention-to-treat population (n=241) demonstrated no significant
difference in survival between patients treated with histamine
dihydrochloride/IL-2/interferon a2b (HDC/IL-2/IFN, red) or
dacarbazine (DTIC, blue) (P=0.94).
Annals of Oncology original article
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Although median survival was longer in the group receiving
HDC/IL-2/IFN [271 (216–330, 95% CI) days versus 231 (157–
291) days for the DTIC group], no statistically significant
differences were seen in the Kaplan-Meier estimates for the ITT
population (P=0.94, stratified log-rank test, Fig. 1).
Analysis comparing the Kaplan-Meier estimate of the
percentage of ITT patients alive in the two treatment groups
revealed a statistically significant higher survival rate at 6
months after randomization (P=0.028) in the group receiving
HDC/IL-2/IFN. However, this trend was not retained for later
time periods.
The ITT-LM population was prospectively identified as
a subset of the overall study population that would be
considered in the primary analysis of the study. Although
median survival was longer in the group receiving HDC/IL-2/
IFN [211 (175–272) days versus 154 (114–256) days for the
DTIC group], no statistically significant differences were seen
(P=0.70, Fig. 2).
The results of the multivariate regression analyses for the ITT
and ITT-LM populations are presented in Table 2. In the ITT
population, baseline performance status and serum LDH were
statistically significant predictors of survival. In the ITT-LM
population, only serum LDH was a statistically significant
predictor of survival. In neither the ITT nor ITT-LM
populations did the treatment effect vary according to LDH
level (LDH >ULN P=0.43, LDH £ULN P=0.47 for ITT;
LDH >ULN P=0.55 and for LDH £ULN P=0.90 for
ITT-LM).
Of the 241 patients in the ITT population, 235 (98%) had
either died or experienced disease progression at the time of
data cut-off. The difference between the Kaplan-Meier
estimates of duration of progression-free survival for the two
treatment groups showed a trend but was not statistically
significant; 92 (88–95) days versus 83 (76–87) days for HDC/
IL-2/IFN and DTIC, respectively, P=0.18).
In the ITT population, no statistically significant differences
were seen between the two treatment groups in best tumor
response (Table 3). Fifteen (13%) of the patients receiving
HDC/IL-2/IFN and 17 (15%) of the patients receiving DTIC
achieved a CR or PR. The duration of objective response in
the ITT population was longer for HDC/IL-2/IFN at 310
(178–NA) days than for DTIC [219 (171–290), P=0.44].
Striking differences in median survival were seen among
the participating countries (P=0.003, log-rank test, Table 4,
Fig. 3). Germany (median 482 days, P=0.001), Canada
(336 days, P=0.045) and Australia (230 days, P=0.045) all had
longer median survival than the United Kingdom (178 days).
In Canada, Sweden and the United Kingdom, the median
duration of survival was higher for the group receiving
HDC/IL-2/IFN; however, in Germany and Australia, the
median duration of survival was higher for the group
receiving DTIC, with large variances in the medians between
countries. Despite uniform entry criteria patients in different
countries were entered at different stages of their disease
Figure 2. Kaplan–Meier survival distribution curves for the intention-to-
treat population with liver metastases demonstrated no significant
difference in survival between patients treated with histamine
dihydrochloride/IL-2/interferon a2b (HDC/IL-2/IFN, red, n=60) or
dacarbazine (DTIC, blue, n=59) (P=0.70).
Table 2. Duration of survival: multivariate Cox proportional hazards model: intent-to-treat population
Covariate ITT ITT-LM
Hazard ratio 95% CI Pvalue
a
Hazard ratio 95% CI Pvalue
a
Treatment (HDC/IL-2/IFN versus DTIC) 0.95 0.71–1.28 0.7424 0.87 0.57–1.33 0.5213
Number of disease sites
2 versus 1 0.95 0.63–1.43 0.8001 0.97 0.50–1.90 0.9346
‡3 versus 1 1.58 0.90–2.79 0.1110 1.52 0.63–3.64 0.3481
Baseline WHO PS (0 vs. 1) 0.58 0.42–0.79 0.0005* 0.66 0.43–1.01 0.0576
Sex (male vs. female) 1.18 0.86–1.61 0.3003 1.38 0.90–2.12 0.1426
Serum LDH (‡ULN vs. <ULN) 2.53 1.82–3.52 <0.0001* 2.15 1.37–3.36 0.0008*
Site of metastatic disease
Lymph metastases (yes vs. no) 0.82 0.56–1.18 0.2808 1.04 0.59–1.82 0.9058
Lung metastases (yes vs. no) 1.04 0.71–1.51 0.8552 1.09 0.63–1.90 0.7603
Liver metastases (yes vs. no) 1.05 0.73–1.50 0.8049
Bone metastases (yes vs. no) 1.04 0.64–1.70 0.8648 1.01 0.50–2.01 0.9867
CI, confidence interval; DTIC, dacarbazine; HDC, histamine dihydrochloride; IL-2, interleukin-2; IFN, interferon a2b; ITT, intent-to-treat population; ITT-
LM, intent-to-treat liver metastases population; ULN, upper limit of normal; WHO PS, World Health Organization performance status.
a
From Wald chi-square test. Differences that reached statistical significance are marked with an asterisk(*).
original article Annals of Oncology
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(Table 4). Australia and Germany had significantly fewer
patients with elevated LDH than Sweden and Canada. Germany
also had significantly fewer patients with stage M1c than
Sweden and the United Kingdom. Performance status also
varied with Australia and Germany, despite the lowest
frequency of patients with elevated LDH and/or stage M1c,
having the highest frequency of patients considered to have
performance status 1.
In contrast to other phase 3 trials in melanoma we
permitted the entry of patients with ocular melanoma. In this
group of 37 patients median survival was longer for those
receiving HDC/IL-2/IFN [325 (174–611) days versus 220
(118–283) days for the DTIC group, P=0.14].
safety
The percentage of patients experiencing any AE was similar
between the two treatment groups (99% for the HDC/IL-2/IFN
group and 97% for the DTIC group), as was the percentage
of patients who died on study or within 28 days of the last
dose of study drug (10% for the HDC/IL-2/IFN group and 10%
for the DTIC group, all patients died from melanoma). Most
AE experienced by patients in both groups were mild or
moderate in severity. The percentage of patients who
discontinued because of an AE was also similar between the
two groups (23% for the HDC/IL-2/IFN group and 20% for
the DTIC group). Fatigue, lethargy, nausea and vomiting
were the most common AEs in the HDC/IL-2/IFN arm while
abdominal pain and hepatobiliary abnormalities were the
most common in the DTIC population (Table 5).
discussion
Stage IV melanoma patients have a poor prognosis and DTIC
remains the standard treatment despite no demonstrable
overall survival advantage. In this randomized study comparing
DTIC to an outpatient immunotherapy regimen, we did not
show statistically significant differences in terms of overall
survival, tumor response or duration of response. The duration
of response was 90 days longer in the combination group than
in the DTIC group, albeit this difference did not attain
statistical significance. The results for other secondary
endpoints were similar between groups.
The similarity in outcomes between the two treatment arms
may be explained by their being equally ineffective against
metastatic melanoma. However, a number of factors need to be
considered before coming to this conclusion. The survival
difference that this trial was powered to detect, at 50%, is very
large. A more modest advantage in favor of immunotherapy
may have been missed. At the time that this trial was conceived
Table 3. Tumor response: intent-to-treat population
Best tumor response DTIC,
N=122
HDC/IL-2/IFN,
N=119
n(%) n(%)
Complete remission 3 (3) 3 (3)
Partial remission 14 (12) 12 (10)
Stable disease 34 (29) 34 (29)
Progressive disease 65 (56) 69 (58)
DTIC, dacarbazine; HDC, histamine dihydrochloride; IL-2, interleukin-2;
IFN, interferon a2b; ITT, intent-to-treat population; N, number of patients
in specified treatment group; n, number of patients with specified response.
Table 4. Duration of survival, by country analyses: intent-to-treat population
Country
a
Elevated LDH (%) Stage M1c (%) WHO PS 1 (%) DTIC HDC/IL-2/IFN
NKaplan-Meier
estimate of
median duration
in days
b
(95% CI)
NKaplan-Meier
estimate of
median duration
in days
b
(95% CI)
Australia 38
c
70 55
h,i,j
32 239 (139–354) 34 216 (175–300)
Canada 52 74 26 11 318 (112–468) 12 353 (310–423)
Germany 25
d,e
65
f,g
40 28 540 (256–674) 24 459 (275–600)
Sweden 61 84 32 23 188 (129–343) 22 276 (167–611)
United Kingdom 44 82 30 26 125 (94–214) 25 208 (145–359)
CI, confidence interval; DTIC, dacarbazine; HDC, histamine dihydrochloride; IL-2, interleukin-2; IFN, interferon a2b; N, number of patients enrolled in
specified country; LDH, lactate dehydrogenase; ULN, upper limit of normal; Stage M1c, visceral metastases other than lung and/or LDH >ULN; WHO PS,
WHO performance status.
a
Israel is not included in these analyses because only four patients were enrolled at sites in that country.
b
Number of days from date of randomization to date of death (or to last date known to be alive).
c
P=0.012 vs. Sweden.
d
P=0.028 vs. Canada.
e
P=0.0004 vs. Sweden.
f
P=0.032 vs. Sweden.
g
P=0.048 vs. the United Kingdom.
h
P=0.015 vs. Canada.
i
P=0.016 vs. Sweden.
j
P=0.0071 vs. the United Kingdom.
Annals of Oncology original article
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the sample size was on a par with many melanoma phase
3 trials. The drop-out rate by the end of cycle 1 matched the
20% we anticipated in the trial design. However, the lower
percentage of patients in the immunotherapy arm able to go
beyond the first cycle of treatment may also have contributed to
an underestimate of its potential. In contrast, the treatment
duration of the similar HDC/IL-2/IFN regimen used in the
earlier single site phase II study was a median 5 months [14].
This was probably a reflection of the relative complexity of the
regimen, and of physicians’ unfamiliarity with it and the
attendant side-effects.
The dose of IL-2 administered in this study, 144 MIU/m
2
during a 12-week period, is lower than in the two randomized
studies where the combination of HDC and IL-2 showed
a survival benefit over IL-2 alone. In the previously mentioned
study in melanoma [12] 224 MIU/m
2
of IL-2 was given
during a 12-week period. In a phase 2 study in renal cell
carcinoma a flat dose of 540 MIU IL-2 was administered
during a 10-week period [15].
The large intercountry differences in median survival
observed for this relatively small cohort of 241 patients
complicates interpretation of the trial. It is clear that, despite
uniform entry criteria, patients in different countries were
entered at different stages of their disease, as shown by the
variations in proportions of patients with elevated LDH and/or
M1c disease between countries. This may reflect differing care
pathways, local predispositions towards particular types of
therapy or competing studies available only in some countries.
Whatever the reason, it highlights an important issue in the
design of clinical trials in melanoma. The need for studies with
several hundred patients means that international
collaborations will be the norm for future studies, and careful
attention will be required to ensure that baseline assumptions
with respect to outcome apply across trials. For example, we
assumed a 7-month median survival in our control arm, but
in Germany DTIC-treated patient survival, at 17.7 months, was
more than double that estimate.
This randomized, phase 3 study of combination
immunotherapy with HDC/IL-2/IFN for AJCC stage IV
malignant melanoma demonstrated similar efficacy with
regards to overall survival, tumor response rates, duration of
response and progression-free survival compared to DTIC.
The lack of statistical difference between the treatment
groups in overall survival may be explained by an
insufficient biological activity of the combination treatment
or, alternatively, by the study being insufficiently powered,
intercountry differences with respect to survival, the lower
percentage of patients in the HDC/IL-2/IFN group who
completed more than one cycle of therapy and by the
relatively low dosage of IL-2. Risk as measured by percentage
of patients who died, had a severe AE or discontinued
because of an AE was similar between the two groups.
Immunotherapy regimens may yet provide treatment
alternatives for patients with stage IV melanoma, but this
immunotherapeutic regimen did not improve upon the
response rate and overall survival seen with DTIC.
Figure 3. Kaplan–Meier survival distribution curves for patients among
participating countries demonstrated a significant difference in survival
between countries (P=0.003, log-rank test): Australia (blue, n=66),
Sweden (green, n=45), United Kingdom (UK, red, n=51), Germany
(black, n=52) and Canada (pink, n=23). Israel (n=4) excluded.
Table 5. Incidence of most common and most severe adverse events:
safety population
Toxicity [n(%)] DTIC, N=116 HDC/ IL-2/IFN, N=114
Grade 3 Grade 4 Grade 3 Grade 4
Patients with
at least one AE
42(36) 9(8) 68(60) 4(4)
Hematological
Anemia 1 (1) 1 (1) 2 (2) 1 (1)
Granulocytopenia 2 (2)
Neutropenia 2 (2) 1 (1)
Thrombocytopenia 1 (1) 1 (1)
Cardiac 0 0 0 0
Gastrointestinal 17 (15) 1 (1) 26 (23)
Abdominal pain 10 (9) 12 (10)
Bleeding 3 (3) 1 (1)
Nausea 5 (4) 10 (9)
Vomiting 2 (2) 12 (10)
General
Fatigue 1 (1) 16 (14)
Lethargy 11 (10)
Multiorgan failure 3 (3)
Hepatobiliary 7 (6) 3 (3) 2 (2)
Infections 1 (1) 1 (1) 4 (4)
Anorexia/cachexia 1 (1) 1 (1) 2 (2)
Musculoskeletal pain 7 (6) 7 (6)
Headache 1 (1) 7 (6)
Depression 2 (2)
Brain edema 1 (1)
Renal 1 (1) 1 (1)
Respiratory 5 (4) 3 (3)
Skin 3 (3) 3 (3)
Flushing 4 (4)
DTIC, dacarbazine; HDC, histamine dihydrochloride; IL-2, interleukin-2;
IFN, interferon a2b; N, total number of patients in specified treatment
group; AE, adverse event; n, number of patients with specified severe
adverse event.
original article Annals of Oncology
6|Middleton et al.
by guest on June 4, 2013http://annonc.oxfordjournals.org/Downloaded from
acknowledgements
We thank the other investigators participating in this study:
M. Millward, P. Hersey, I. Davis, G. Toner, M. Byrne, I. Olver,
J. Trotter, R. Kefford, D. Kotesak, D. Wyld, J. Mattsson,
U. Stierner, C. Ingvar, A. Ha
˚kansson, J. Hansson, C. Lindholm,
M. Rande
´n, JH. Svensson, G. Wagenius, M. Breivald,
T. Hamblin, P. Lorigan, C. Price, C. Garbe, EB Bro
¨cker,
H. Na
¨her, R. Kaufmann, D. Schadendorf, C. Peschel,
P. von den Driesch, W. Sterry, W. Tilgen, K. Belanger,
Y. Drolet, F. Patenaude, R. Rajan, M. Smylie, T. Peretz,
R. Weitzen and R. Isacson. We thank the people at Maxim
Pharmaceuticals, Covance, CroMedica Global Inc. and
Synteract who managed this clinical trial. Acknowledgment
of research support: EpiCept Corporation (former Maxim
Pharmaceuticals), San Diego, CA, USA.
Conflict of interest statement. Dr A. Hauschild has served as
consultant to Maxim Pharmaceuticals and Schering Plough
(less than $10,000) and research funding from Schering
Plough (less than $100,000). No stock ownership and others.
Dr S. Burdette-Radoux had research funding from Maxim
Pharmaceuticals (less than $100,000). Dr K. Gehlsen was
Clinical Senior Officer of Maxim Pharmaceuticals at time of
the study. Dr K. Hellstrand served as consultant to Maxim
Pharmaceuticals (less than $100,000) and had research
funding from Maxim Pharmaceuticals (more than $100,000).
Dr P. Naredi served as consultant to Maxim Pharmaceuticals
(less than $100,000) and had research funding from Maxim
Pharmaceuticals (less than $100,000). Dr M. Middleton served
as consultant to Maxim Pharmaceuticals (less than $10,000).
Dr D. Thomson, none declared; Dr R. Andersson, none
declared.
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