Following a first report of this combination in 1995, the
combination of carboplatin (Paraplatin) administered at an area-under-curve
(AUC) dosing and 3-hour infusional paclitaxel (Taxol) rapidly became
the favored first-line regimen for the treatment of patients with
advanced or metastatic nonsmall-cell lung cancer (NSCLC).
Follow-up reports established its ease of administration, favorable
toxicity profile, and more recently, efficacy equivalent to other
established first-line combination regimens such as cisplatin
(Platinol, CDDP) and vinorelbine (Navelbine).[2-4] The low incidence
of severe neutropenia and near absence of severe thrombocytopenia
with the carboplatin (Paraplatin) and paclitaxel combination led to
the hypothesis that a third active agent could be added to this
regimen with the possibility of further therapeutic gains. This
hypothesis was supported further by the recent confirmation that the
combination of carboplatin and paclitaxel produces significantly less
severe toxicity than (1) cisplatin combined with either gemcitabine
(Gemzar), docetaxel (Taxotere), or 24-hour infusional paclitaxel in
patients with poor performance status NSCLC, or (2) cisplatin
combined with vinorelbine in patients with good performance status NSCLC.[4,6]
Irinotecan (Camptosar, CPT-11), a semisynthetic derivative of
camptothecin, is a novel topoisomerase-I inhibitor with significant
activity in NSCLC patients. Single-agent phase II trials in Japan and
the United States that used a weekly schedule of 100 mg/m²/week
or an every-3-week schedule of 250 to 350 mg/m² in patients who
had not previously received chemotherapy, reported response rates in
the range of 11% to 34%.[7-8] Dose-limiting toxicity in these studies
consisted primarily of diarrhea, which occurred 1 to 2 weeks
following the start of treatment and was moderate to severe (grade 3
to 4) in 10% to 20% of patients. Severe (grade 4) hematologic
toxicity occurred in less than 5% of patients and febrile neutropenia
was rare. Three phase II clinical trials investigating irinotecan in
combination with cisplatin have reported objective responses in the
range of 31% to 54%.[9-11]
Because of its activity in NSCLC as well as its unique mechanism of
action and favorable toxicity profile, we hypothesized that
irinotecan could be added to near-standard doses of the combination
of carboplatin and paclitaxel and that the potential pharmacodynamic
interactions of these agents might produce response and survival
rates that eventually could be superior to those associated with
carboplatin and paclitaxel alone. Therefore, in 1996, we initiated a
two-step phase I/II trial of the combination of irinotecan,
carboplatin, and paclitaxel. Our primary goal was to determine the
maximum tolerated dose (MTD) of irinotecan that could be combined
with fixed doses of carboplatin and paclitaxel in patients with stage
IIIB or IV NSCLC. The secondary objectives were to determine the
toxicity profile of this new combination and to obtain data regarding
its efficacy in this disease.
Patient Eligibility Criteria
Eligible patients included male or female patients over the age of 18
years with a histologic diagnosis of TNM stage IIIB or IV
nonsmall-cell lung cancer, Southwest Oncology Group (SWOG)
performance status of 0 to 2, and a life expectancy equal to or
greater than 3 months. Disease could be evaluable or objectively
measurable for the phase I portion of the study, but had to be
objectively measurable for the phase II portion. Adequate
hematologic, hepatic, and renal function were required. These were
defined by the following laboratory values measured within 7 days
prior to study registration: white blood cells (WBC) ³
3,500/mm³, absolute neutrophil count (ANC) ³
1,500/mm³, platelet count ³
100,000/mm³, serum bilirubin £
1.25 times the upper limit of normal (ULN), aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) < 3
times ULN, and calculated creatinine clearance (Cockroft method) ³
50 mL/minute. Patients with a previous history of brain metastases
from NSCLC were eligible if 3 or more weeks had elapsed since
completion of radiation therapy, and if they were neurologically
improved and stable.
Patients were not eligible for the study if they had a history of
seizures, other malignancy within the preceding 5 years (except for
adequately treated basal or squamous cell skin cancer and in situ
cervical cancer), or prior chemotherapy. Patients with significant
cardiovascular disease, serious active infection, uncontrolled
diabetes mellitus, peripheral neuropathy, or interstitial lung
disease were ineligible. Pregnant or lactating women were excluded,
and men or women of reproductive potential were required to use
effective contraceptive methods.
Within the 21-day period preceding treatment, all patients were
required to undergo a complete history and physical examination,
screening electrocardiogram, computed tomography (CT) or magnetic
resonance imaging (MRI) scan of the brain, radionuclide bone scan (if
clinically indicated), and objective measurement of measurable
disease lesions using appropriate scans or x-rays. Within 7 days of
starting treatment, a complete blood cell count with differential and
platelet count and complex metabolic panel were required for all
patients; female patients had to have a negative pregnancy test.
The trial was designed to follow a two-step plan. It began with a
phase I dose-seeking study with a starting dose of irinotecan at 40
mg/m² administered intravenously over 90 minutes on days 1 and 8
combined with carboplatin at an AUC of 6 (Calvert method) and
paclitaxel 225 mg/m² infused over 3 hours on day 1 (regimen A,
below). This regimen was to be recycled every 3 weeks and the dose of
irinotecan was to be escalated (80, 100, 120 mg/m², etc) in new
cohorts of patients until the maximum tolerated dose was achieved.
However, as detailed below, unexpectedly severe toxicity was observed
at the starting dose level, prompting a change in the treatment plan.
The amended treatment plan called for a starting dose of irinotecan
at 40 mg/m² IV over 90 minutes on day 1 only combined with
carboplatin at an AUC of 5 (Calvert method) and paclitaxel 175
mg/m² infused over 3 hours on day 1 every 3 weeks (regimen B,
below). The dose of irinotecan was to be escalated (80, 125, 175
mg/m², etc) in new cohorts of patients until the maximum
tolerated dose was determined.
After the phase I portion of this clinical trial was completed, the
phase II portion was conducted at the maximum tolerated dose level in
an additional 30 to 40 patients with objectively measurable disease
in order to more fully characterize its toxicity profile and to
obtain preliminary efficacy data.
For this study, dose-limiting toxicity (DLT) was defined as
first-course grade 4 diarrhea despite aggressive loperamide (Imodium)
therapy, any grade 4 thrombocytopenia or neutropenic fever, any grade
3 or 4 nonhematologic toxicity (except nausea, vomiting, or grade 3
diarrhea), or failure to sufficiently recover from toxicities by day
36 of the first course. The maximum tolerated dose was defined as the
dose level immediately preceding the dose where ³
2 of 6 patients (³ 33%) experienced
dose-limiting toxicities during the first course. The study plan
allowed selection and exploration of an intermediate dose level
between two preplanned dose levels. Standard definitions for complete
response (CR), partial response (PR), stable disease, and disease
progression were used in patients with objectively measurable
disease. Survival was calculated from the date of study entry.
Adverse events and hematologic toxicities were monitored at weekly
intervals or more frequently if clinically indicated. Tumor
assessments (in patients with objectively measurable or evaluable
disease) were obtained at baseline (prestudy) and after every other
course of treatment (every 6 weeks). Complete and partial responses
required confirmation 4 to 6 weeks following first documentation.
Thirty-three patients were enrolled in the phase I portion of the
study (including 6 for regimen A, and 27 for regimen B); 40
additional patients with objectively measurable disease were entered
into the phase II portion of the study. Table
1 summarizes their characteristics.
Of 33 patients entered into the phase I portion of this study, 32
received a total of 151 courses of treatment (one patient entered did
not receive treatment), and the 40 patients entered into the phase II
portion of this study received 198 courses of treatment at the time
of this analysis (several patients continued to receive treatment
after this analysis was performed). The total, median number, and
range of treatment courses administered at each dose level is
summarized in Table 2.
Among the patients entered into the phase I portion of this study, 33
are evaluable for toxicity, including 6 patients entered at the
starting dose level in regimen A, and 26 patients entered at the four
dose levels explored in regimen B. Of six patients entered at the
irinotecan starting dose level of 40 mg/m² days 1 and 8 (regimen
A), three experienced one or more dose-limiting toxicities including
one grade 4 diarrhea with febrile/septic neutropenia, two grade 4
neutropenia, and one grade 3 neuropathy. This unexpectedly severe
level of toxicity occurred despite the fact that the irinotecan dose
on day 8 was withheld in four of the six patients, thus, prompting a
change in the treatment plan.
The new treatment plan (regimen B) began with a starting dose of
irinotecan 40 mg/m² on day 1 only combined with a decrease in
the dose of carboplatin from an AUC of 6 to an AUC of 5 (Calvert
method) and a decrease in the dose of paclitaxel from 225 mg/m²
to 175 mg/m². At this new starting-dose level, only one of 10
patients experienced first-course dose-limiting toxicities consisting
of grade 4 neutropenia, diarrhea, and fever. Escalation of the
irinotecan dose to 80 mg/m² did not produce first-course grade 3
to 4 toxicities in five patients. At the 125 mg/m² dose level of
irinotecan, however, first-course dose-limiting toxicities occurred
in three of eight patients. Since no dose-limiting toxicities had
been observed at the preceding 80 mg/m² dose level, a 100
mg/m² dose level of irinotecan was explored in three patients.
The absence of first-course dose-limiting toxicities prompted us to
further explore this dose level in 40 patients with objectively
measurable disease during the phase II portion of the study. Phase I
first-course dose-limiting toxicities are summarized in Table
All 40 patients entered into the phase II portion of this study were
evaluable for toxicity. All the grade 3/4 hematologic and
nonhematologic toxicities observed in 198 treatment courses
administered to date to these 40 patients and the 151 treatment
courses administered to the 32 evaluable patients entered into the
phase I portion of the study are summarized in Table
4. Grade 4 neutropenia was the most common dose-limiting
toxicity, occurring in 14 of 40 patients (35%) in phase II and 13 of
32 patients (41%) in phase I. Neutropenic fever occurred in 12 (30%)
patients (10 with grade 4 neutropenia and two with grade 3
neutropenia) in phase II and in four (12.5%) patients (all four with
grade 4 neutropenia) in phase I. Grade 3/4 diarrhea was the most
common nonhematologic toxicity, occurring in five (12.5%) patients in
phase II and in six (18.5%) of the patients in phase I. Grade 3/4
thrombocytopenia, neuropathy, or asthenia each occurred in less than
10% of patients in both phases of the study. At least one episode of
grade 3 vomiting occurred sometime during treatment in 6 of 40 (15%)
patients in phase II, but in only 1 of 32 (3%) patients in phase I.
An objective response could be assessed in 31 of 33 patients in phase
I (one patient was not evaluable and one patient was without
objectively measurable disease) and in 33 of 40 patients in phase II
(2 patients were not evaluable for response and evaluation was
premature for 5 patients). Unconfirmed objective responses occurred
in 20 of 31 patients in phase I (a 64.5% overall response rate)
including 3 CRs and 17 PRs; 3 CRs and 10 PRs (42%) were confirmed.
Unconfirmed objective responses occurred in 20 of 33 patients in
phase II (a 60.6% overall response rate) including one CR and 19 PRs;
1 CR and 16 PRs (51%) were confirmed. Table
5 details tumor response according to baseline patient
characteristics. The median time to progression and median survival
in 32 patients in phase I was 7.1 months and 11.6 months,
respectively. The 1-year survival in this group was 46.9%.
The design of this two-step phase I/II trial was based on the
hypothesis that the relatively nonoverlapping toxicities of
irinotecan and the combination of carboplatin and paclitaxel would
allow us to add nearly full doses of the former to near standard
doses of the latter combination. In the phase I portion of this
trial, it appeared that the maximum tolerated dose of irinotecan that
could be incorporated into this regimen was 100 mg/m², but that
this required a reduction in the standard doses of carboplatin and
paclitaxel from an AUC of 6 to an AUC of 5 and from 225 mg/m² to
175 mg/m², respectively.
However, in the phase II portion of the trial, the toxicity of this
new triple combination was unacceptably severe. Of 40 patients with
advanced or metastatic nonsmall-cell lung cancer, 14 suffered
grade 3/4 neutropenia (35%) and 30% suffered febrile or septic
neutropenia. We are now exploring an additional reduction in the dose
of carboplatin to an AUC of 4 in the hopes of reducing the incidence
of severe hematologic toxicity to a lower and more acceptable level.
Despite the toxicity, the triple combination of irinotecan,
carboplatin, and paclitaxel appears to have a high level of activity
in NSCLC. Our preliminary data indicate an objective response rate
greater than 60% and median survival of approximately 1 year.
Although patient selection can often inflate therapeutic outcomes in
uncontrolled phase II clinical trials, this usually occurs when
trials are conducted at single institutions rather than the
multi-institutional setting in which this trial was conducted.
Nevertheless, a well-designed, prospectively randomized, clinical
trial comparing this triple combination to the double combination of
carboplatin and paclitaxel administered at standard doses would be
required before any definitive conclusions could be drawn regarding
the efficacy of this new regimen and such a trial appears to be warranted.
The efficacy and, even more, the toxicity of this triple combination
strongly suggests that there are significant pharmacokinetic and/or
pharmacodynamic interactions among these agents. It is notable that
the doses of irinotecan, carboplatin, and paclitaxel that we are
currently exploring represent reductions of 77%, 33%, and 22% from
standard doses of these agents on an every-3-week schedule. Any
favorable patient selection that would have inflated the response or
survival rates would have served to deflate toxicity, but toxicity
was clearly and unexpectedly severe. Therefore, these drug
interactions appear to be real and, if they occur at the
pharmacodynamic level, are extraordinary. Further investigation of
the pharmacokinetic and pharmacodynamic interactions of these
compounds is needed.
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