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Clinical Trials |
Divisions of Medical Oncology [H. C. P., R. M. G., C. E., J. R., P. A. B., A. A. A., S. A. A.] and Oncology Research [J. M. R.] and Section of Biostatistics [J. A. S., P. A. S.], Mayo Clinic, Rochester, Minnesota 55905 and Pharmacia & Upjohn Company, Peapack, New Jersey 07977 [L. J. S., G. E., L. L. M.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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= 0.60;
P = 0.001). A total of five responses (one complete
response and four partial responses) were observed in the cohort of 32
patients with previously treated metastatic colorectal carcinoma. In
conclusion, gastrointestinal toxicity and hematological toxicity were
the dose-limiting toxicities of CPT-11 when administered as a
90-min infusion every 3 weeks. In this trial, the recommended Phase
II starting dose for patients with no prior AP radiation therapy was
found to be 320 mg/m2; for patients with prior AP
radiation, the recommended Phase II starting dose was 290
mg/m2. This once-every-3-week schedule has been
incorporated into a Phase I trial of CPT-11 combined with
5-fluorouracil and leucovorin. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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Based on initial reports from Japan of CPT-11 activity in patients with 5-FU-refractory metastatic colon cancer, clinical trials were initiated in the United States and Europe (5, 6, 7) . Several Phase I trials have been performed with CPT-11 using different schedules. In the United States, the Phase I schedule that provided the background for pivotal Phase II trials was developed by Rothenberg et al. (6) . In this schedule, weekly treatments of CPT-11 were given for 4 weeks followed by a 2-week rest period. The MTD was 150 mg/m2, with DLTs of diarrhea and neutropenia. Another Phase I trial performed in the United States used an every-3-week schedule (7) . The MTD was 240 mg/m2 , with DLTs consisting of a constellation of nausea and vomiting, abdominal cramping, diarrhea, and myelosuppression. The early European Phase I trials of CPT-11 evaluated several different schedules (8, 9, 10) . Abigerges et al. (8) conducted a Phase I trial using an every-3-week schedule combined with intensive loperamide support to control diarrhea. The DLT was neutropenia at the highest dose level of 750 mg/m2, although the current recommended dose of CPT-11 in Europe is 350 mg/m2 given every 3 weeks. Merrouche et al. (11) have also performed a feasibility study using a high-dose loperamide regimen and CPT-11 doses of 500 and 600 mg/m2 every 3 weeks.
Because of the discrepant MTDs from these initial Phase I trials, we performed another Phase I trial of CPT-11 given once every 3 weeks. We also wanted to reexamine the toxicities of the drug with this schedule and perform a pharmacokinetic analysis to assess any pharmacodynamic relationship between CPT-11, its metabolites, and DLTs.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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18 years; (c) an ECOG performance status of 
2;
(d) a life expectancy of at least 12 weeks; (e)
no prior chemotherapy within the previous 4 weeks (6 weeks in patients
treated with mitomycin C or nitrosoureas) and recovery from any toxic
effects of prior treatment; (f) no more than two prior
chemotherapy regimens; (g) no prior treatment with CPT-11 or
other camptothecins; (h) no prior radiation therapy for at
least 6 weeks and measurable lesions present outside the radiation
field; (i) radiation therapy to 25% of bone marrow;
(j) adequate hematopoiesis (neutrophil count
1,500/mm3, platelet count
150,000/mm3, and hemoglobin level of 9.0 g/dl),
renal function (serum creatinine 2.0 mg/dl), and liver function
(aspartate aminotransferase 3x institutional upper limit of normal
or 5x institutional upper limit of normal if liver involved
with metastatic disease, and serum bilirubin within institutional upper
limit of normal); (k) no active or uncontrolled infection;
(l) absence of pregnancy or lactation; (m) no
known central nervous system metastases or carcinomatous meningitis;
(n) no interstitial pneumonia or extensive/symptomatic
interstitial fibrosis of the lung causing greater than or equal to
grade 2 dyspnea; and (o) no medical (uncontrolled high blood
pressure, unstable angina, active congestive heart failure, myocardial
infarction within the previous 6 months, or serious uncontrolled
cardiac arrhythmia) or psychiatric conditions that might place patients
at risk for participation in investigational treatment. All patients
gave written informed consent according to institutional and federal
guidelines before treatment. After six patients were treated on protocol, patients were divided into those with no prior AP radiation therapy and those with prior AP radiation therapy. Once the MTD was determined for those patients with no prior AP radiation, the dose level was decreased two dose levels, and additional patients with prior AP radiation were enrolled. Also, because of the significant myelosuppression seen in one patient with prior exposure to both nitrosourea and mitomycin C, additional patients treated previously with these drugs were excluded from study entry.
Treatment Plan
The starting dose of CPT-11 was 240 mg/m2,
with planned dose escalation to 290, 340, and 390
mg/m2 every 3 weeks. An intermediate dose level
of 320 mg/m2 was subsequently added to better
define the MTD after DLT was observed at the 340
mg/m2 dose level. A minimum of three patients
were enrolled at each dose level and observed for at least 3 weeks
before enrolling any patients at the next dose level. If DLT was
observed in one of the first three patients enrolled at a dose level,
three additional patients were enrolled at the same level. DLT in two
or more patients identified that level as the DLT dose level. The MTD
was defined as one level below the DLT dose level. After identification
of the MTD, additional patients were enrolled to more fully evaluate
the toxicities at MTD. DLT was defined as (a) grade 4
hematological toxicity lasting for 5 or more days, (b)
febrile neutropenia, (c) grade 4 diarrhea or vomiting that
occurred despite adequate supportive measures, and (d) any
other nonhematological toxicity of grade 3 intensity or higher. In
addition, patients who had treatment delayed for 2 weeks as a result of
toxicity related to CPT-11 were considered to have DLT. Intrapatient
dose escalation was not permitted on this study.
CPT-11 was supplied by Pharmacia & Upjohn (Peapack, NJ) in two forms, 2-ml vials containing 40 mg of drug and 5-ml vials containing 100 mg of drug. The appropriate dose, based on actual calculated body surface area, was mixed in 500 ml of 5% dextrose and infused through a free-flowing i.v. catheter over a 90-min period.
Pretreatment and Follow-Up Evaluations
Prestudy evaluations comprised a complete history and physical
examination including height and weight, ECOG performance score,
complete blood count, serum electrolytes and chemistries, tumor markers
(where appropriate), serum pregnancy test in women with childbearing
potential, chest X-ray, baseline tumor measurements, and an
electrocardiogram. Patients were seen by an oncologist before each
CPT-11 infusion. During off-treatment weeks, an experienced oncology
nurse made phone inquiries about toxicity. Complete blood counts were
performed weekly. Patients were evaluated before each treatment. Serum
electrolytes and serum chemistries, tumor markers, and indicator
lesions were measured every other cycle. Patients were continued on
therapy if they tolerated treatment and their disease did not progress.
Toxicities were graded according to the National Cancer Institute
Common Toxicity Criteria.
Concurrent Therapy
Loperamide (Imodium or Kaopectate 1-D) was given to patients at
the earliest signs of diarrhea that occurred more than 12 h after
the CPT-11 infusion. Loperamide was prescribed at a dose of 4 mg after
the first loose bowel movement and then at 2 mg every 2 h until
diarrhea resolved for at least 12 h. Patients were allowed to take
loperamide, 4 mg every 4 h, during the night. Atropine was also
given at doses of up to 1 mg i.v. for diarrhea or abdominal cramping
that occurred during or immediately after the CPT-11 infusion.
Dexamethasone and other antiemetics (ondansetron or granisetron) were
used as clinically indicated. Patients who were taking warfarin had
prothrombin time monitoring weekly during the trial due to previous
report of a possible interaction between CPT-11 and warfarin.
Pharmacokinetics
Sample Collection.
Blood samples (7 ml) were drawn via venipuncture or indwelling i.v.
cannula into heparincontaining tubes at the following times:
(a) before beginning the CPT-11 infusion; (b) 45
and 90 min after beginning the infusion; (c) 5, 10, 15, and
30 min after the end of the infusion; and (d) 1, 2, 4, 6, 8,
10, 12, 24, 32, and 48 h after the end of the infusion. Blood
samples were collected from the arm contralateral to the infusion line.
If a heparin lock was used, 1 ml of whole blood was withdrawn and
discarded before sample collection.
Collection tubes were immediately placed into a slurry of ice water. The plasma was separated by centrifugation of the samples at 1000–1200 x g for 20 min and then transferred into plastic tubes. The plasma specimens were stored at -30°C until assay, and the time of the storage was within the year supported by stability data for CPT-11 and SN-38.
Assay Methods.
Plasma specimens were assayed for concentrations of total CPT-11 and
SN-38 using validated, sensitive, and specific isocratic
high-performance liquid chromatography methods with fluorescence
detection (12)
. Briefly, each plasma specimen was mixed
with an IS (camptothecin) in acidified acetonitrile to precipitate
plasma proteins and incubated for 15 min at 40°C to convert the
analytes to their respective lactone forms. After the addition of
triethylamine buffer (pH 4.2), the sample was centrifuged, and the
supernatant was transferred to an amber vial for injection (40 µl)
onto the high-performance liquid chromatography system. Chromatographic
separation was achieved using a Zorbax-C8 column (MacMod) and a mobile
phase consisting of 28:72 (v/v) acetonitrile:0.025 M
triethylamine buffer (pH 4.2). The fluorescence detector was
operated at an excitation wavelength of 372 nm; CPT-11 and IS were
monitored at an emission wavelength of 425 nm, whereas SN-38 was
monitored at 535 nm. To determine the concentrations of SN-38G, a
separate portion of each plasma sample was hydrolyzed via the addition
of a ß-glucuronidase solution. The conversion reaction was terminated
by precipitating the proteins using an acidified acetonitrile solution
of the IS, and the remainder of the procedure was repeated. Plasma
concentrations of SN-38G were estimated as the increase in SN-38
concentration after incubation of plasma with ß-glucuronidase.
Calibration standard responses were linear over the range of 1.28–3840
ng/ml for CPT-11 (r2 0.998) and over the range
of 0.48–640 ng/ml for SN-38 (r2 0.999). The
lower limit of quantitation of CPT-11 (expressed as the free base) and
SN-38 (expressed as the monohydrate) was 1.28 and 0.48 ng/ml,
respectively. The mean assay precision, which was expressed as the
coefficient of variation of the estimated concentrations of quality
control standards, averaged 4.5%, 4.3%, and 6.9%, respectively, for
low (12.8 ng/ml), medium (160 ng/ml), and high (3200 ng/ml)
concentrations of CPT-11 and averaged 4.9%, 4.5%, and 3.2%,
respectively, for low (1.20 ng/ml), medium (12.0 ng/ml), and high (320
ng/ml) concentrations of SN-38. Assay accuracy, expressed as the ratio
(%) of the estimated:theoretical QC standard concentrations, averaged
96–99.1% for CPT-11 and 90–99% for SN-38.
Calculation of Pharmacokinetic Parameters.
Doses of CPT-11 administered in this trial were expressed as the
hydrated hydrochloride salt (CPT-11 hydrochloride trihydrate). For
pharmacokinetic analyses, CPT-11 concentrations were expressed in free
base units (Mr of the hydrochloride
trihydrate = 677.19; Mr of the
anhydrous free base = 586.69), and SN-38 concentrations were
expressed as monohydrate equivalents
(Mr of the monohydrate = 410.44;
Mr of anhydrous SN-38 =
392.42).
CPT-11, SN-38, and SN-38G plasma concentration data were analyzed by
noncompartmental methods (13)
. The actual times of the
initiation of drug infusion and blood sampling were recorded, and the
time interval relative to the start of drug infusion was used to
calculate the AUCs. The apparent terminal elimination rate constants
(
z) were determined by linear least-squares regression of
plasma-concentration time points that were determined to lie in the
terminal log-linear region of the plasma concentration-time profiles.
The apparent elimination half-life
(t1/2) was calculated as 0.693/z.
Cmax and
Tmax values were determined from
individual patient CPT-11, SN-38, and SN-38G concentration-time curves.
AUC0-T values were determined using the linear
trapezoidal rule from time 0 to the last sampling time at which
quantifiable drug concentrations were detected
(CT). Area under the CPT-11 plasma
concentration-time curves through infinite time
(AUC0-
) was calculated by adding
CT/z to AUC0–48. The CL
and apparent Vz of CPT-11 were
calculated as dose/AUC0- and CL/z,
respectively, where dose is the administered dose of CPT-11 expressed
in free base equivalents. A metabolite ratio, estimated as the ratio of
metabolite SN-38 AUC0-:CPT-11
AUC0-, was used as a measure of the relative
extent of the conversion of CPT-11 to SN-38.
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Statistical Considerations |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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Relationships between treatment-related toxicities and pharmacokinetic parameters (Cmax and AUC values) for CPT-11, SN-38, and SN-38G were assessed. Initial assessment included an examination of scatterplots and simple correlational statistics in an attempt to demonstrate potential relationships between toxicity parameters and either Cmax or AUC values for CPT-11, SN-38, and SN-38G. If relationships were observed, further modeling was performed to characterize these relationships. These efforts included ordinary least-squares linear and logistic regression models. Limited sampling models were explored relating serum concentration levels with AUC using a series of regression models. The results of these analyses are reported elsewhere (14) .
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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. The number of patients
enrolled at each dose level and their prior AP radiation status is
shown in Table 2
. A total of 174
assessable courses of CPT-11 were administered (median, 4 courses;
range, 1–18 courses).
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. For patients without prior AP therapy,
dose-limiting hematological toxicity (grade 4 neutropenia for 5 days
or febrile neutropenia) occurred in two patients treated with 340
mg/m2. Another patient at this dose level
experienced grade 4 neutropenia lasting <5 days. Thrombocytopenia was
mild and infrequent, except in one patient treated at a dose of 290
mg/m2 who had undergone extensive prior treatment
with mitomycin C and a nitrosourea. This patient experienced grade 4
myelosuppression (leukocytes, neutrophils, and platelets).
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Gastrointestinal Toxicity.
Several gastrointestinal toxicities encountered during the first cycle
are summarized in Table 4
. Dose-limiting
gastrointestinal toxicities were encountered in both groups of
patients. For those patients without prior AP radiotherapy, two
episodes of grade 4 diarrhea (including hemorrhagic colitis in one
patient) were reported at the 340 mg/m2 dose
level. Another patient without prior AP radiation therapy had grade 4
diarrhea at the 320 mg/m2 dose level, but this
patient did not use the intensive loperamide regimen to limit the
severity of symptoms. Significant grade 4 diarrhea was seen in two
patients with prior AP radiotherapy at both the 290 and 320
mg/m2 dose levels. The patient treated with 290
mg/m2 received diphenoxylate/atropine (Lomotil)
for supportive care because of loperamide intolerance.
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. Vomiting was considered dose
limiting in two patients without prior AP radiotherapy; one had started
therapy at a CPT-11 dose of 290 mg/m2, and one
was treated with 320 mg/m2 CPT-11. One patient
treated with 320 mg/m2 CPT-11 experienced grade 4
vomiting, which was felt to be due to small bowel obstruction from
progressive disease. For patients with prior AP radiation therapy, two
episodes of grade 4 vomiting were encountered at doses of both 290 and
320 mg/m2. The patient treated with 320
mg/m2 also experienced DLT neutropenia and grade
3 fatigue. Antiemetic measures included 5-hydroxytryptamine 3
receptor inhibitors and dexamethasone in
three of the four patients with DLT episodes.
Cholinergic Symptoms.
CPT-11 administration has been associated with transient
cholinergic symptoms that occur during or immediately after the drug
infusion (15)
. These symptoms include abdominal pain,
diaphoresis, early diarrhea, lacrimation, salivation, bradycardia,
hypotension, and visual changes. Patients reported several of these
symptoms, with abdominal pain being the most frequently described
symptom (see Table 5
). Most events were
mild (grade 2), although one patient at the 320
mg/m2 dose level had grade 4 early diarrhea that
resolved spontaneously without the use of atropine. Cholinergic
symptoms appeared to occur more frequently at higher dose levels. The
incidence of cholinergic symptoms ranged from 33% of patients at the
240 mg/m2 dose level to 83% of patients treated
at a starting dose of 340 mg/m2. Use of atropine
was effective in ameliorating these symptoms. No clinically significant
bradycardia or hypotension was noted during first cycle CPT-11
administration.
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. Maximum CPT-11 concentrations were
generally observed at the termination of the infusion, with subsequent
peak metabolite levels occurring approximately 1 h after the
90-min infusion. SN-38 peak concentrations were approximately 60-fold
lower than CPT-11 peak concentrations, and SN-38G peak concentrations
were approximately 20-fold lower than CPT-11 peak concentrations.
CPT-11, SN-38, and SN-38G pharmacokinetics were determined by
noncompartmental analysis (Table 6)
. Due
to the substantial interpatient variability in AUC values at each dose
level and the narrow dose range studied, a dose-proportional increase
in mean CPT-11 AUC values was not observed in this study (Fig. 2A)
. Similarly, there was
extensive interpatient variability in the plasma CL of CPT-11, but
these values were comparable to those reported previously and were
independent of dose (Fig. 3)
. Mean values
of t1/2Z, CL,
VZ, and
Vss for CPT-11 were 12.4 ±
1.8 h, 13.0 ± 3.8 liters/h/m2,
234 ± 83 liters/m2, and 123 ± 38
liters/m2, respectively.
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respectively). Peak plasma concentrations of SN-38 were found 2 h
after the beginning of the CPT-11 infusion, and the disappearance of
SN-38 was somewhat longer than that of CPT-11, with a
t1/2Z of 21.1 ± 7.3 h.
Plasma exposure to SN-38 was approximately 5% of that found for the
parent drug. A relationship between dose and SN-38 AUC was not
observed. A moderately strong relationship was seen between CPT-11 AUC
and SN-38 AUC (Pearson correlation coefficient = 0.43;
P = 0.01).
Peak plasma concentrations of SN-38G were found 2 h after the
beginning of the CPT-11 infusion, and the disappearance of SN-38G
paralleled that of CPT-11, with a
t1/2Z of 18.3 ± 5.3 h. The
plasma exposure to the inactive metabolite SN-38G was approximately
15% of that found for the parent drug. A relationship between dose and
SN-38G AUC was not observed (Fig. 2C)
. A relationship was
seen between CPT-11 AUC and SN-38G AUC (Pearson correlation
coefficient = 0.58; P = 0.001).
Further exploratory analysis was undertaken to evaluate the
relationships between several pharmacokinetic parameters and toxicity.
Results indicate significant correlations between CPT-11 AUC and
vomiting; between SN-38 AUC and nausea, vomiting, and neutropenia; and
between SN-38G and nausea and thrombocytopenia (Table 7)
. The relationship between SN-38 AUC
and neutropenia expressed as the percentage change from baseline (Fig. 4)
was also significant (Spearman
= 0.72; P = 0.001).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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Our patient population consisted mainly of patients with previously
treated metastatic colorectal carcinoma (Table 1)
. Most patients had
received two prior chemotherapy regimens. This Phase I study initially
treated patients at the previously reported MTD of 240
mg/m2. Two patients experienced grade 4 vomiting
at 290 mg/m2, but in one of these patients, this
toxicity was related to small bowel obstruction and was not treatment
related. One patient experienced grade 4 myelosuppression at 290
mg/m2; however, this patient received extensive
prior mitomycin C and nitrosourea. Given alternative explanations for
these toxicities, further dose escalation was pursued, and eligibility
for previous chemotherapy and radiotherapy was amended. At the next
dose level of 340 mg/m2, three of six patients
experienced DLT. This includes one patient who experienced simultaneous
neutropenic sepsis and grade 4 diarrhea. An intermediate dose of 320
mg/m2 was evaluated in eight patients. One
patient experienced grade 4 vomiting and diarrhea. Thus, the MTD for
patients without prior AP radiation was determined to be 320
mg/m2 administered every 3 weeks.
Patients with prior AP radiation were enrolled at 290
mg/m2. One episode of grade 4 diarrhea and
vomiting was noted in the seven patients treated at this dose level.
With subsequent dose escalation to 320 mg/m2, two
of five patients experienced DLT. This included one patient with grade
4 diarrhea and another patient with grade 4 vomiting and neutropenia
lasting for >5 days. The MTD of CPT-11 administered every 3 weeks was
290 mg/m2 for patients with prior AP radiation
therapy. This slightly lower MTD for patients with prior pelvic
radiation therapy is not unexpected, given the finding of an increased
incidence of grade 4 leukopenia in patients with prior pelvic
radiotherapy reported in a Phase II trial using the weekly schedule
(17)
. Despite intensive loperamide support, diarrhea
remained a DLT, along with other gastrointestinal toxicities including
nausea and vomiting. A constellation of gastrointestinal symptoms
including abdominal cramping limited dose escalation in the previous
United States Phase I trial (7)
. This CPT-11-induced side
effect of abdominal cramping was common in our patient population
(Table 5)
but was easily ameliorated by atropine as described in
previous trials (15
, 19)
.
Discrepancies between MTDs reported in Phase I trials may be due to several factors. Patient populations can differ, as can the definitions of MTD. In the current trial, one patient experienced DLT at 340 mg/m2 that consisted of hemorrhagic colitis. This toxicity has been reported previously in prior Phase I and II trials; however, it is not the typical dose-limiting diarrheal toxicity reported with CPT-11 treatment. Older age has also been associated with a greater risk of diarrhea (20 , 21) . In the current trial, all patients experiencing DLT at 340 mg/m2 were >65 years of age, suggesting a potential contribution of age in this small subset of our patients. CPT-11-induced toxicity may also be influenced by baseline bilirubin levels (22) . One patient with prior pelvic radiation therapy and an abnormal baseline bilirubin had DLT in the current trial. Different definitions of MTD may lead to discrepant results. Abigerges et al. (8) used a MTD defined as the dose level below that which causes greater than 50% grade 3 or 4 toxicity in the same category of toxicity. Our definition of MTD was based on the occurrence of grade 3 or 4 toxicity in only two of six patients (33%) at a given dose level, with no requirement for identical DLTs to be observed in these patients. Finally, differences in the MTD may be the result of pharmacogenetic differences between the patient populations enrolled in various Phase I studies for enzymes involved in CPT-11 metabolism. Two forms of carboxylesterase catalyze the conversion of CPT-11 to SN-38 (23) , but a polymorphism has not been identified for the high-affinity form that most likely catalyzes the conversion at concentrations found in vivo after a dose of CPT-11. A mutant allele of UDP-glucuronosyltransferase (UGT1A1*28), the enzyme that catalyzes the conversion of SN-38 to SN-38G, has reduced capacity for SN-38 glucuronidation (24) . The relationship between the mutant genotype and SN-38 AUC has not been defined in a large group of patients.
The pharmacokinetics of total CPT-11, its active metabolite SN-38, and the inactive glucuronide conjugate SN-38G were determined in all 34 patients treated on this study. The pharmacokinetics of CPT-11 and SN-38 lactones were not performed based on the correlation between lactone and total concentrations (25) . The half-life values for SN-38 and SN-38G were longer than the previously reported values; however, this likely reflects differences in the number of points used to calculate the terminal elimination half-life and a longer specimen collection period for the current study (6, 7, 8) . We did not detect a correlation between AUC and CPT-11 dose level as was reported in previous Phase I studies (7 , 8) . This is likely explained by the narrow dose range over which the AUC values were determined, as well as the substantial variability in CPT-11 pharmacokinetics among the patients enrolled in this study. Correlations were found between CPT-11 AUC values and metabolite (SN-38 and SN-38G) AUC values.
Systemic exposure to SN-38 has been associated with hematological
toxicity, and SN-38 biliary excretion has been associated with
gastrointestinal toxicity (26, 27, 28)
. We examined baseline
total bilirubin with regard to toxicity incidence, but we did not find
a strong correlation (data not shown). This could be related to the
small number of patients and the different starting dose levels in the
trial. Evaluation of the relationship between AUCs and toxicities in
this study did suggest several potential correlations (Table 7)
. The
strongest relationship was between SN-38 AUC and neutropenia, a finding
that is generally consistent with the critical role of SN-38 as the
active CPT-11 cytotoxic metabolite. Both CPT-11 and SN-38 AUCs were
significantly correlated with vomiting. However, because these
variables are correlated with each other, it is difficult to know
whether CPT-11, SN-38, or both CPT-11 and SN-38 were most
responsible for emesis. Correlations between CPT-11 or SN-38 exposure
and vomiting or diarrhea were less than those for neutropenia, which
may be due in part to the less precise quantitative nature of
assessment of these toxicities. Thrombocytopenia is not a prominent
finding with CPT-11 treatment and was only weakly associated with the
AUCs of its metabolites. Although correlations between CPT-11, SN-38,
and SN-38G AUC values and several toxicities were observed, there was
considerable overlap in AUCs for patients experiencing grade 0–4
toxicities. The variability in SN-38 exposure may be due to
pharmacogenetic variability in the carboxylesterase and
UDP-glucuronosyltransferase. Variation of as much as 33-fold has been
observed for human carboxylesterase (23)
. Similarly, a
50-fold variation in the SN-38G formation rate has been observed in
normal human liver microsomal preparations (29)
.
This variability is reflected in coefficients, which ranged from
0.33–0.60 (Table 7)
. Collectively, these results suggest that
identification of patients at risk of experiencing severe neutropenia,
vomiting, or diarrhea may not be predictable based solely on the
magnitude of pharmacokinetic parameter estimates with a high degree of
precision. Further evaluations in larger patient populations would be
required to confirm these findings.
Although antitumor activity was not the primary end point in this Phase I trial, several objective responses were recorded. We observed four partial responses and one complete response in the 32 patients with refractory colorectal carcinoma. The overall response rate in this subset of patients was 15% (95% confidence interval, 5.3–32.8%), which is very similar to previous Phase II results using a different schedule and different doses (16, 17, 18) .
Recent multicenter Phase III studies have demonstrated survival benefit as the result of CPT-11 therapy in patients with advanced colorectal carcinoma (30 , 31) . These Phase III trials used a starting dose of CPT-11 at 350 mg/m2 given every 3 weeks. For patients with poor performance status or age greater than 70 years, 300 mg/m2 was the recommended starting dose. Whereas our data support the use of this schedule, a starting dose of 350 mg/m2 could not be reached in this patient population with good performance status. The current study adds to the prior dosing recommendations by documenting that patients with prior AP radiation therapy appear to be at increased risk of toxicity. Based on the findings of this study, a lower starting dose (290–300 mg/m2) should be used in these patients. Because of the frequency of gastrointestinal side effects, routine use of supportive measures including atropine, dexamethasone, a 5-hydroxytryptamine 3 antagonist, and intensive loperamide are recommended in this palliative setting.
The every-3-week schedule has been the basis for a Phase I trial in which CPT-11 is combined with 5-FU and leucovorin (32) . This regimen involves the administration of CPT-11 on day 1 of each cycle; 5-FU and leucovorin are given on days 2–5 of each 3-week cycle. This sequence was derived from in vitro studies suggesting synergistic cytotoxicity with this sequence (33) . Further evaluation of this combination regimen in a Phase III trial for previously untreated advanced colorectal cancer is planned.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Pharmacia & Upjohn Company and NIH
Grant MO1-RR00585 
2 To whom requests for reprints should be
addressed, at Division of Medical Oncology, Mayo Clinic Cancer Center,
200 First Street SW, Rochester, MN 55905. Phone: (507) 284-4718; Fax:
(507) 284-1803.
3 The abbreviations used are: topo-I,
topoisomerase I; CPT-11, irinotecan; MTD, maximum tolerated dose; DLT,
dose-limiting toxicity; AP, abdominal/pelvic; 5-FU, 5-fluorouracil;
ECOG, Eastern Cooperative Oncology Group; IS, internal standard; AUC,
area under the concentration-time curves;
Cmax, peak plasma concentrations;
Tmax, the time at which
Cmax occurred; CL, clearance;
Vz, terminal phase volume of
distribution; Vss, steady-state
volume of distribution; t1/2Z,
terminal phase half-life.
Received 8/ 6/99; revised 3/ 1/00; accepted 3/ 6/00.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSStatistical ConsiderationsRESULTSDISCUSSIONREFERENCES |
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  G. Batist, K. A. Gelmon, K. N. Chi, W. H. Miller Jr., S. K.L. Chia, L. D. Mayer, C. E. Swenson, A. S. Janoff, and A. C. Louie Safety, Pharmacokinetics, and Efficacy of CPX-1 Liposome Injection in Patients with Advanced Solid Tumors Clin. Cancer Res., January 15, 2009; 15(2): 692 - 700. [Abstract] [Full Text] [PDF]
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E. K. Rowinsky, M. Beeram, L. A. Hammond, G. Schwartz, J. De Bono, B. Forouzesh, Q. Chu, J. E. Latz, S. Hong, W. John, et al. A Phase I and Pharmacokinetic Study of Pemetrexed Plus Irinotecan in Patients with Advanced Solid Malignancies Clin. Cancer Res., January 15, 2007; 13(2): 532 - 539. [Abstract] [Full Text] [PDF]
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L. J. Schaaf, L. A. Hammond, S. J. Tipping, R. M. Goldberg, R. Goel, J. G. Kuhn, L. L. Miller, L. D. Compton, L. A. Cisar, G. L. Elfring, et al. Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction. Clin. Cancer Res., June 15, 2006; 12(12): 3782 - 3791. [Abstract] [Full Text] [PDF]
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N. Masubuchi, R. D. May, and R. Atsumi A Predictive Model of Human Myelotoxicity Using Five Camptothecin Derivatives and the In vitro Colony-Forming Unit Granulocyte/Macrophage Assay Clin. Cancer Res., October 1, 2004; 10(19): 6722 - 6731. [Abstract] [Full Text] [PDF]
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E. A. Perez, D. W. Hillman, J. A. Mailliard, J. N. Ingle, J. M. Ryan, T. R. Fitch, K. M. Rowland, C. G. Kardinal, J. E. Krook, J. W. Kugler, et al. Randomized Phase II Study of Two Irinotecan Schedules for Patients With Metastatic Breast Cancer Refractory to an Anthracycline, a Taxane, or Both J. Clin. Oncol., July 15, 2004; 22(14): 2849 - 2855. [Abstract] [Full Text] [PDF]
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A. P. Venook, C. Enders Klein, G. Fleming, D. Hollis, C. G. Leichman, R. Hohl, J. Byrd, D. Budman, M. Villalona, J. Marshall, et al. A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863 Ann. Onc., December 1, 2003; 14(12): 1783 - 1790. [Abstract] [Full Text] [PDF]
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R. M. Goldberg, S. H. Kaufmann, P. Atherton, J. A. Sloan, A. A. Adjei, H. C. Pitot, S. R. Alberts, J. Rubin, L. L. Miller, and C. Erlichman A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin Ann. Onc., October 1, 2002; 13(10): 1674 - 1680. [Abstract] [Full Text] [PDF]
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R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]
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), and SN-38G (
) after a 90-min i.v. infusion of
320 mg/m2 CPT-11.
