# A Population-Based Clinical Trial of Irinotecan and Carboplatin

Authors: Derick Lau; Minh Huynh; Jewel Johl
Journal: Journal of Oncology
 (2009)

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## Abstract

Purpose. Phase  I trials of anticancer drugs are commonly conducted using the method of modified Fibonacci. We have developed a population-based design for phase I trials of combining anticancer drugs such as irinotecan and carboplatin. Patients and Methods. Intrapatient dose escalation of irinotecan and carboplatin was performed according to a predetermined schema to reach individual dose-limiting toxicity (DLT) in 50 patients with solid tumors refractory to previous chemotherapy. The individual toxicity-limiting dose levels were analyzed for normal distribution using the method of Ryan-Joiner and subsequently used to determine a population-based maximum tolerated dose (pMTD). For comparison, a simulation study was performed using the method of modified Fibonacci. Results. The most common dose-limiting toxicities (DLTs) included neutropenia (58%), thrombocytopenia (16%), and diarrhea (8%). The frequency of individual toxicity-limiting dose levels of 50 patients approximated a normal distribution. The dose levels associated with individual limiting toxicities ranged from level 1 (irinotecan 100 mg/m2 and carboplatin AUC = 4 mg/mL x min) to level 8 (irinotecan 350 mg/m2 and carboplatin AUC = 6). The pMTD was determined to be dose level 3 (150 mg/m2 for irinotecan and AUC = 5 for carboplatin). In contrast, the MTD was determined to be dose level 4 (200 mg/m2 for irinotecan and AUC 5 for carboplatin) by modified-Fibonacci simulation. Conclusions. The population-based design of phase I trial allows optimization of dose intensity and derivation of a pMTD.  The pMTD has been applied in phase II trial of irinotecan and carboplatin in patients with small-cell lung cancer.


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## Body

## 1. Introduction

Phase I
clinical trials of new anticancer agents have been commonly conducted using the
method of modified Fibonacci [1]. In brief, 3 patients
are treated at a starting dose which is typically one tenth of the dose that is
lethal to 10% of animals defined in preclinical studies. If none of the 3
patients experiences DLT, then the next 3 patients will be treated at the next
higher dose. If DLT is observed,
additional patients will be treated at the same or lower dose level to
determine MTD according to a predetermined schema. The MTD is defined as the highest dose reached
for which the incidence of DLT occurs in less than 33% of the subjects. Typically, intrapatient dose escalation is
not allowed.There
are several shortcomings associated with the modified-Fibonacci design. It has long
been recognized that a substantial number of patients are likely to be treated
at subtherapeutic doses [2, 3]. This is
particularly true for drugs with potential anticancer activity. Since the primary purpose of phase I trials
is to determine DLT and MTD, the efficacy of the drug may not be evident for
certain tumor types as there are
only a small number of patients enrolled into the trial. Furthermore, the modified-Fibonacci design
does not take into account individual variations in therapeutic and toxicologic
responses due to genomic polymorphisms [4, 5]. In addition, since there is a limit of 3 subjects allowed for each
cohort, a waiting period of up to four weeks is commonly required before
enrollment of the next cohort of subjects. This latter requirement creates anxiety of waiting for eligible patients.Several
alternative phase I designs have been proposed which limit the number of
patients accrued at each dose level and accelerate the dose escalation process [1, 6]. There
has also been an increase in the number of clinical trials that include a
component of intrapatient dose escalation although no formal validation with
the modified-Fibonacci approach has been reported [7–9]. We have pioneered a population-based design
to maximize therapeutic efficacy, to provide preliminary efficacy information and
to allow derivation of a pMTD for subsequent phase II trials.Irinotecan and
cisplatin have been shown to have promising efficacy in patients with
small-cell lung cancer in phase III trial where irinotecan was given on a
weekly schedule [10]. We wished to
perform a population-based phase I trial of irinotecan, given every 3 weeks,
and carboplatin, a platinated anticancer drug which is generally better
tolerated than its
cisplatin analog.


## 2. Methods

### 2.1. Patients and Intrapatient Dose Escalation

Eligibility criteria
included patients with a diagnosis of advanced solid tumor not curable by
standard therapies; measurable disease; Zubrod performance status of 0–2; age>18
years; prior chemotherapy was allowed except irinotecan or carboplatin;
adequate hematologic (ANC >1500 and platelets >100 000/mL), hepatic
(total bilirubin and SGOT <2× upper limit of normal), and renal (serum
creatinine <1.5 mg/dl) functions. All
patients signed informed consent in accordance with guidelines of the institutional
review board.Intrapatient
dose-escalation schema is shown in Table1. This schema was extrapolated
from the results of a previous population-based phase I trial of irinotecan and
epirubicin in patients with solid tumors, in which the pMTD was determined to
be 100 mg/m2 for irinotecan and 50 mg/m2 for
epirubicin in previously chemotherapy-treated patients [11]. All patients were started at dose level 3, which
consisted of irinotecan, 150 mg/m2, infused intravenously over 90
minutes, and carboplatin, AUC 5 mg/mL × min, given as an intravenous bolus on
day 1. The carboplatin dose was
determined according to the Calvert formula [12] and a calculated creatinine
clearance [13]. Toxicity was graded according to the common toxicity criteria,
Version 2, of the National Cancer Institute (NCI). Treatment was repeated every 21 days and the
dose for subsequent cycle was escalated by one dose level as outlined in Table 1 if no grade III or IV toxicity was observed. For any grade IV neutropenia, grade III or IV thrombocytopenia, or grade
III or IV nonhematologic toxicity, the dose was decreased by one level as
outlined in Table 1. No prophylactic
growth factor was allowed. Patients
remained on treatment for at least 6 cycles, or until there was evidence of
disease progression, intolerable toxicity, or voluntary withdrawal.Table 1
Schema of dose levels for irinotecan and
carboplatin.
Dose levelIrinotecan (mg/m2)Carboplatin AUC1100421005315054200552505625067300683506In accordance to common practice, DLT was
defined as grade III or IV thrombocytopenia, grade IV neutropenia, or any grade
III or IV nonhematologic toxicity. Similar to the modified-Fibonacci method [1], the
pMTD was defined as the highest dose level that caused DLT in less than 33% of
the population studied (DLT33%). For each subject who did not reach DLT,
the dose level associated with DLT was assumed to be one level higher than the
last one the subject received prior to coming off the study.Responses
were evaluated after 3 cycles of treatment. Tumor measurement was performed
according to the NCI RECIST criteria [14].


### 2.2. Statistical Analysis

Based on the results of a previous population-based phase I trial of irinotecan
and epirubicin, the optimal number of subjects was estimated to be 25 to 50 for
reaching a Gaussian or normal distribution of individual toxicity-limiting dose
levels [11]. The computer program of
Ryan-Joiner test (Minitab Release 14, statistical software for Windows, Minitab
Inc., State College, Pa, USA) was employed to determine the normality of the
distribution of individual toxicity-limiting dose levels [15]. In the Ryan-Joiner analysis, a correlation
coefficient, r, was obtained to determine the degree of normality. The more closer was r to 1, the more normal was the distribution(1)r=∑Yibis2(n−1)∑bi2, where Yi was an individual toxicity-limiting
dose level, bi was the
probability percentage point of the normal distribution associated with the
individual dose level, s denoted the sample variance, and n was the sample
size.To
determine the pMTD, the mean(MDLT) and standard deviation (SDDLT)
of the 50 individual dose levels associated with DLT were calculated. The pMTD was the estimated highest dose level
that caused DLT in less than 33% of the subjects (DLT33%). Assuming that the individual DLT followed a
normal distribution, the 33% cutoff point was just below 17% to the left from
the mean. Therefore,  (2)DLT33%=MDLT−(SDDLT×Z17%),where Z17% is the
level of standard deviation to the left of the MDLT with a probability
of 17% under a normal distribution curve [16]. Thus, the pMTD would be one dose level lower than DLT33%.


### 2.3. Modified-Fibonacci Simulation

To compare the pMTD derived from the population-based approach
with the MTD that otherwise would have been obtained with the modified-Fibonacci
method, a simulation exercise was performed using the data from the current
study. The Fibonacci simulation would
also allow us to compare the number of subjects required using each
approach. The procedures for simulation were performed according
to the3+3 rule of modified Fibonacci [1] with the following assumptions. (1)
The first cohort of subjects started at dose level 3; (2) if a patient treated
at a particular dose level had
not experienced DLT, it was assumed that no DLT would have been
experienced at a lower starting dose; (3) if a patient had experienced DLT at a particular dose
level, it was assumed that this patient would have experienced DLT at a higher
dose level; (4) the MTD is defined as the highest dose reached for which the
incidence of DLT is less than 33% in the subjects [1].


## 2.1. Patients and Intrapatient Dose Escalation

Eligibility criteria
included patients with a diagnosis of advanced solid tumor not curable by
standard therapies; measurable disease; Zubrod performance status of 0–2; age>18
years; prior chemotherapy was allowed except irinotecan or carboplatin;
adequate hematologic (ANC >1500 and platelets >100 000/mL), hepatic
(total bilirubin and SGOT <2× upper limit of normal), and renal (serum
creatinine <1.5 mg/dl) functions. All
patients signed informed consent in accordance with guidelines of the institutional
review board.Intrapatient
dose-escalation schema is shown in Table1. This schema was extrapolated
from the results of a previous population-based phase I trial of irinotecan and
epirubicin in patients with solid tumors, in which the pMTD was determined to
be 100 mg/m2 for irinotecan and 50 mg/m2 for
epirubicin in previously chemotherapy-treated patients [11]. All patients were started at dose level 3, which
consisted of irinotecan, 150 mg/m2, infused intravenously over 90
minutes, and carboplatin, AUC 5 mg/mL × min, given as an intravenous bolus on
day 1. The carboplatin dose was
determined according to the Calvert formula [12] and a calculated creatinine
clearance [13]. Toxicity was graded according to the common toxicity criteria,
Version 2, of the National Cancer Institute (NCI). Treatment was repeated every 21 days and the
dose for subsequent cycle was escalated by one dose level as outlined in Table 1 if no grade III or IV toxicity was observed. For any grade IV neutropenia, grade III or IV thrombocytopenia, or grade
III or IV nonhematologic toxicity, the dose was decreased by one level as
outlined in Table 1. No prophylactic
growth factor was allowed. Patients
remained on treatment for at least 6 cycles, or until there was evidence of
disease progression, intolerable toxicity, or voluntary withdrawal.Table 1
Schema of dose levels for irinotecan and
carboplatin.
Dose levelIrinotecan (mg/m2)Carboplatin AUC1100421005315054200552505625067300683506In accordance to common practice, DLT was
defined as grade III or IV thrombocytopenia, grade IV neutropenia, or any grade
III or IV nonhematologic toxicity. Similar to the modified-Fibonacci method [1], the
pMTD was defined as the highest dose level that caused DLT in less than 33% of
the population studied (DLT33%). For each subject who did not reach DLT,
the dose level associated with DLT was assumed to be one level higher than the
last one the subject received prior to coming off the study.Responses
were evaluated after 3 cycles of treatment. Tumor measurement was performed
according to the NCI RECIST criteria [14].


## 2.2. Statistical Analysis

Based on the results of a previous population-based phase I trial of irinotecan
and epirubicin, the optimal number of subjects was estimated to be 25 to 50 for
reaching a Gaussian or normal distribution of individual toxicity-limiting dose
levels [11]. The computer program of
Ryan-Joiner test (Minitab Release 14, statistical software for Windows, Minitab
Inc., State College, Pa, USA) was employed to determine the normality of the
distribution of individual toxicity-limiting dose levels [15]. In the Ryan-Joiner analysis, a correlation
coefficient, r, was obtained to determine the degree of normality. The more closer was r to 1, the more normal was the distribution(1)r=∑Yibis2(n−1)∑bi2, where Yi was an individual toxicity-limiting
dose level, bi was the
probability percentage point of the normal distribution associated with the
individual dose level, s denoted the sample variance, and n was the sample
size.To
determine the pMTD, the mean(MDLT) and standard deviation (SDDLT)
of the 50 individual dose levels associated with DLT were calculated. The pMTD was the estimated highest dose level
that caused DLT in less than 33% of the subjects (DLT33%). Assuming that the individual DLT followed a
normal distribution, the 33% cutoff point was just below 17% to the left from
the mean. Therefore,  (2)DLT33%=MDLT−(SDDLT×Z17%),where Z17% is the
level of standard deviation to the left of the MDLT with a probability
of 17% under a normal distribution curve [16]. Thus, the pMTD would be one dose level lower than DLT33%.


## 2.3. Modified-Fibonacci Simulation

To compare the pMTD derived from the population-based approach
with the MTD that otherwise would have been obtained with the modified-Fibonacci
method, a simulation exercise was performed using the data from the current
study. The Fibonacci simulation would
also allow us to compare the number of subjects required using each
approach. The procedures for simulation were performed according
to the3+3 rule of modified Fibonacci [1] with the following assumptions. (1)
The first cohort of subjects started at dose level 3; (2) if a patient treated
at a particular dose level had
not experienced DLT, it was assumed that no DLT would have been
experienced at a lower starting dose; (3) if a patient had experienced DLT at a particular dose
level, it was assumed that this patient would have experienced DLT at a higher
dose level; (4) the MTD is defined as the highest dose reached for which the
incidence of DLT is less than 33% in the subjects [1].


## 3. Results

### 3.1. Patient Characteristics

A
total of 50 patients were enrolled from a single institution within a period of
24 months. Patient characteristics are
summarized in Table2. There were 27
male and 23 female patients. The median
age was 61 years with a range of 35–83 years. Forty-seven patients (94%) had a Zubrod
performance status of 0 or 1. All the
patients had previously received at least one regimen of chemotherapy and the
mean number of previous chemotherapy regimens was 1.6 (range 1 to 3). Forty-two percent of the patients had a diagnosis of nonsmall-cell lung
cancer, 20% with small-cell lung cancer, 20% with gastrointestinal cancer, 6%
with head/neck cancer, and 12% with a variety of solid cancers.Table 2
Patient characteristics.
Number of patients50Male/female27/23Age (yr)range35–83Median61Performance
status01213523Number of previous chemotherapies12522035Tumor
typesNonsmall-cell lung21Small-cell lung10Gastrointestinal10Head/neck3Miscellaneous6


### 3.2. Derivation of Population-Based MTD

Among the 50 patients enrolled, the median
number of cycles of irinotecan and
carboplatin, that had been delivered,
was three. Treatment was discontinued
before reaching DLT in 10 patients due to disease progression or voluntary
withdrawal. Dose escalation to DLT was
achieved in the remaining 40 patients. As shown in Table3, the most common grade III/IV toxicities or
dose-limiting toxicities were neutropenia in 58%, thrombocytopenia in 16%, diarrhea
in 8%, nausea/emesis in 8%, and asthenia in 4% of the patients.Table 3
Dose-limiting
grade III/IV toxicities (N = 50).
ToxicitiesNumber
of patients (%)Neutropenia29 (58)Thrombocytopenia8 (16)Diarrhea4 (8)Nausea/emesis4 (8)Asthenia2 (4)The
distribution of individual toxicity-limiting dose levels ranged from level 1 (100
mg/m2 of irinotecan and AUC 4 of carboplatin) to level 8 (irinotecan
350 mg/m2 and carboplatin AUC 6) as shown in Figure 1. The individual toxicity-limiting dose levels approximated
a normal distribution with a correlation coefficient, r, of 0.992, based on the
Ryan-Joiner analysis. The cumulative percentage
of subjects with increasing toxicity-limiting dose levels are shown in Figure 2. Assuming a normal distribution of the
toxicity-limiting dose levels, the DLT33% was calculated to be 3.9. By the definition that pMTD was one dose
level lower than that of DLT33%, the pMTD was thus 2.9 which
approximated 150 mg/m2 of irinotecan and AUC 5 of carboplatin.Figure 1
Distribution
of individual dose levels associated with dose-limiting toxicity (DLT) of irinotecan
and carboplatin (N = 50).Figure 2
Cumulative percent of patients experienced
dose-limiting toxicity (DLT) with increasing dose levels of irinotecan and
carboplatin (N = 50).Forty
of the 50 patients were assessable for responses. Ten patients were not assessable for response
due to early disease progression or withdrawal from the study before having
received 3 cycles of treatment. The best
responses by tumor type are shown in Table4. Of note, the response rate was 40% for small-cell lung cancer, 24% for
nonsmall-cell lung cancer, and 30% for gastrointestinal malignancies consisting
mainly of esophageal and gastric cancers. There was no apparent correlation between response rate and individual
MTD levels.Table 4
Tumor types and best response to treatment. PR: partial response; SD: stable
disease; PD: progressive disease; NA: not assessable.
Tumor typesNumber
of patientsTotalPRSDPDNANonsmall-cell lung215736Small-cell lung104321Gastrointestinal103322Head and neck30120Miscellaneous61311Total5013171010


### 3.3. Modified-Fibonacci Simulation

By
the Fibonacci simulation, an
MTD of dose level 4 (200 mg/m2 of irinotecan and AUC 5 of
carboplatin) was derived after simulation of 18 consecutive patients.Table5 outlines the features of the population-based approach versus the modified-Fibonacci
method.Table 5
Comparison of features of population based
versus modified-Fibonacci method in phase I trials.
FeaturesPopulation basedFibonacciNumber
of patients required~50~20Enrollment
of patientsContinuousCohorts of threeWaiting time between cohortsNoneRequiredEfficacy
optimizedYesNoPreliminary
efficacy dataYesYes/No


## 3.1. Patient Characteristics

A
total of 50 patients were enrolled from a single institution within a period of
24 months. Patient characteristics are
summarized in Table2. There were 27
male and 23 female patients. The median
age was 61 years with a range of 35–83 years. Forty-seven patients (94%) had a Zubrod
performance status of 0 or 1. All the
patients had previously received at least one regimen of chemotherapy and the
mean number of previous chemotherapy regimens was 1.6 (range 1 to 3). Forty-two percent of the patients had a diagnosis of nonsmall-cell lung
cancer, 20% with small-cell lung cancer, 20% with gastrointestinal cancer, 6%
with head/neck cancer, and 12% with a variety of solid cancers.Table 2
Patient characteristics.
Number of patients50Male/female27/23Age (yr)range35–83Median61Performance
status01213523Number of previous chemotherapies12522035Tumor
typesNonsmall-cell lung21Small-cell lung10Gastrointestinal10Head/neck3Miscellaneous6


## 3.2. Derivation of Population-Based MTD

Among the 50 patients enrolled, the median
number of cycles of irinotecan and
carboplatin, that had been delivered,
was three. Treatment was discontinued
before reaching DLT in 10 patients due to disease progression or voluntary
withdrawal. Dose escalation to DLT was
achieved in the remaining 40 patients. As shown in Table3, the most common grade III/IV toxicities or
dose-limiting toxicities were neutropenia in 58%, thrombocytopenia in 16%, diarrhea
in 8%, nausea/emesis in 8%, and asthenia in 4% of the patients.Table 3
Dose-limiting
grade III/IV toxicities (N = 50).
ToxicitiesNumber
of patients (%)Neutropenia29 (58)Thrombocytopenia8 (16)Diarrhea4 (8)Nausea/emesis4 (8)Asthenia2 (4)The
distribution of individual toxicity-limiting dose levels ranged from level 1 (100
mg/m2 of irinotecan and AUC 4 of carboplatin) to level 8 (irinotecan
350 mg/m2 and carboplatin AUC 6) as shown in Figure 1. The individual toxicity-limiting dose levels approximated
a normal distribution with a correlation coefficient, r, of 0.992, based on the
Ryan-Joiner analysis. The cumulative percentage
of subjects with increasing toxicity-limiting dose levels are shown in Figure 2. Assuming a normal distribution of the
toxicity-limiting dose levels, the DLT33% was calculated to be 3.9. By the definition that pMTD was one dose
level lower than that of DLT33%, the pMTD was thus 2.9 which
approximated 150 mg/m2 of irinotecan and AUC 5 of carboplatin.Figure 1
Distribution
of individual dose levels associated with dose-limiting toxicity (DLT) of irinotecan
and carboplatin (N = 50).Figure 2
Cumulative percent of patients experienced
dose-limiting toxicity (DLT) with increasing dose levels of irinotecan and
carboplatin (N = 50).Forty
of the 50 patients were assessable for responses. Ten patients were not assessable for response
due to early disease progression or withdrawal from the study before having
received 3 cycles of treatment. The best
responses by tumor type are shown in Table4. Of note, the response rate was 40% for small-cell lung cancer, 24% for
nonsmall-cell lung cancer, and 30% for gastrointestinal malignancies consisting
mainly of esophageal and gastric cancers. There was no apparent correlation between response rate and individual
MTD levels.Table 4
Tumor types and best response to treatment. PR: partial response; SD: stable
disease; PD: progressive disease; NA: not assessable.
Tumor typesNumber
of patientsTotalPRSDPDNANonsmall-cell lung215736Small-cell lung104321Gastrointestinal103322Head and neck30120Miscellaneous61311Total5013171010


## 3.3. Modified-Fibonacci Simulation

By
the Fibonacci simulation, an
MTD of dose level 4 (200 mg/m2 of irinotecan and AUC 5 of
carboplatin) was derived after simulation of 18 consecutive patients.Table5 outlines the features of the population-based approach versus the modified-Fibonacci
method.Table 5
Comparison of features of population based
versus modified-Fibonacci method in phase I trials.
FeaturesPopulation basedFibonacciNumber
of patients required~50~20Enrollment
of patientsContinuousCohorts of threeWaiting time between cohortsNoneRequiredEfficacy
optimizedYesNoPreliminary
efficacy dataYesYes/No


## 4. Discussion

In
this study, we have demonstrated the feasibility of applying a population-based
approach in conducting phase I trial and the derivation of a pMTD for
irinotecan and carboplatin for subsequent phase II trials.This
study clearly illustrated the phenomenon of population polymorphism in clinical
practice. We showed that the individual DLTs
occurred over a range of 8 dose levels. At dose level 1, the dose for irinotecan was 100 mg/m2 and
carboplatin was AUC of 4. At dose level 8, the corresponding doses were 350
mg/m2 and AUC of 6, respectively. It is quite remarkable to see that one patient could tolerate 3.5 times higher
of irinotecan and 1.5 times higher of carboplatin than another patient. This marked degree of interpatient dose
variation was most likely due to interpatient variability in pharmacogenomics. In this regard, irinotecan is a typical
example with individual variability in pharmacokinetics and toxicity. Following intravenous administration, irinotecan
is converted to an active metabolite, SN-38, which is subsequently deactivated
by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). It has been demonstrated that variability in
pharmacokinetics and toxicity of irinotecan correlates with polymorphisms of the
UGT1A1 promoter [17, 18]. In this study,
we did not monitor the pharmacokinetics of irinotecan or pharmacogenetics of
UGT1A1. Nevertheless, we believe that
the intrapatient dose-escalation scheme is appropriate for conducting phase I
trials with a drug such as irinotecan.Maximum tolerated doses of carboplatin and irinotecan
have been reported in previous phase I trials although irinotecan typically was
administered on a weekly schedule in these studies. Based on phase I trial on patients with
relapsed or refractory advanced malignancies as reported by Jones et al., the
MTD was irinotecan at 60 mg/m2 on days 1 and 8 in combination with
carboplatin at AUC 4.0 on day 1 for 28-day cycles [19]. In another phase 1 trial on subjects with
ovarian cancer previously treated with cisplatin-based chemotherapy, Yonemori
et al. reported that the MTD of the irinotecan/carboplatin combination was 60 mg/m2 on days 1, 8, and 15, and 5 mg mL/minute on day 1,
respectively, for 28-day cycles [20]. Undoubtedly, the delivery of the 3-week
regimen as reported in our study is more convenient and presumably less costly.In
phase I trials employing the modified-Fibonacci design, the
initial cohorts of subjects are commonly given subtherapeutic doses of an
anticancer drug. On the other hand,
some subjects in the subsequent cohorts may receive toxic doses as dose
escalation is based on the3+3 rule [1]. In the intrapatient dose-escalation design, each subject is started on a
low dose and is entitled to receive a higher dose as long as there is no
DLT. Thus, this latter approach tends to
minimize toxicity and maximize efficacy in each subject.In
traditional phase I trials, only 3 subjects can be enrolled at a dose level at
one time. Generally, they have to be
observed for a month before the next cohort of subjects can be enrolled at the
next dose level. This requirement
results in unnecessary waiting for potentially eligible patients and may
prolong the conduct of a study. With the
population-based method, subjects commonly can be enrolled continuously to a
study without a mandatory waiting period.There are potential disadvantages
associated with the population-based design. A patient may develop progressive disease or
leave the study for other reasons before subsequent dose escalation and
determination of DLT can be achieved. Dose
escalation in the same patient may result in cumulative toxicity and,
theoretically, an
MTD level lower than that obtained with the Fibonacci method. However, in our study, the DLTs were reached with
the 3 lowest dose levels in more than 50% of subjects. In addition, there were subjects who
tolerated more than 4 sequentially escalated doses without experiencing obvious
cumulative toxicity. These observations indicate
that the intolerance to treatment is intrinsic to each subject rather than due
to cumulative toxicity.With a
population-based approach, it is apparent that a larger number of subjects are required than that
for the modified-Fibonacci design. In
our study, we had enrolled 50 subjects to derive a pMTD. In comparison, only 18
subjects would have been needed with the Fibonacci simulation. With a limitation of the number of subjects,
it may yield a MTD not representative of a population. Based on the results of Ryan-Joiner analysis
and pMTDs, we estimated that 40 patients would have been adequate to obtain
similar results with the population-based approach. With a larger number of patients having a
variety of tumor types, however, it provides a better opportunity to evaluate
efficacy in a certain tumor type. For
example, in our study, we observed partial response in 4 of 10 patients with relapsed
small-cell lung cancer. This observation has led to phase II trial which
employed the pMTD of irinotecan (150 mg/m2) and carboplatin (AUC = 5) derived
in this study in patients with relapsed small-cell lung cancer [21].The
population-based design is open ended in regard to the number of patients to be
accrued and dose levels to be escalated. This design appears most appropriate for a combination of anticancer
drugs with proven single-agent anticancer activity and toxicity. It may not be
appropriate for anticancer drugs with low toxicity profiles such as the
molecular-targeting agents.We conclude that the population-based
design is a feasible approach for conducting phase I trials of anticancer
drugs. This approach allows derivation of a pMTD without causing obvious
cumulative toxicity.



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*Source: 458528-2009-04-23.xml*