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© 2000 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of Irinotecan and Docetaxel in Patients With Advanced Solid Tumors: Preliminary Evidence of Clinical ActivityFrom the Department of Oncology, Mayo Clinic and Foundation, Rochester, MN, and Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois, Chicago, IL. Address reprint requests to Alex A. Adjei, MD, PhD, Division of Medical Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; email adjei.alex{at}mayo.edu
PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m2, 160/65 mg/m2, 200/65 mg/m2, and 200/75 mg/m2) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non–small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m2 and docetaxel 65 mg/m2.
DOCETAXEL IS THE second taxane to be introduced into clinical practice. It is a semi-synthetic compound derived from the needles of Taxus baccata L, the European yew. Docetaxel exerts its cytotoxicity through binding to ß-tubulin, promoting the polymerization, and inhibiting the disassembly of microtubules.1 This causes cell arrest in mitosis, leading to cell death. In comparative studies, docetaxel has been found to be 1.3- to 12-fold more active in vitro than paclitaxel. These findings have been explained by the higher achievable intracellular concentrations, the higher affinity for microtubules, and the slower cellular efflux of docetaxel compared with paclitaxel.2 Both docetaxel and paclitaxel bind to microtubules with a stoichiometry of one molecule per  /ß tubulin dimer. Docetaxel shortens the lag time for initiation of polymerization and enhances the rate of tubulin polymerization to form microtubules. Approximately 1,000 patients with several different tumor types have been treated in Europe and North America in phase II trials using 100 mg/m2 of docetaxel administered as a 1-hour infusion every 3 weeks. Antitumor activity has been observed in breast, lung (both small-cell and non–small-cell), head and neck, ovarian, and gastric cancers.3-6 Docetaxel is hydroxylated by cytochrome P450 3A (CYP3A) isoforms to metabolites that display limited cytotoxicity in vitro.7 Docetaxel is characterized by a low hepatic extraction ratio, and as such, its disposition may be susceptible to changes in intrinsic metabolic clearance after administration of CYP3A substrates.7 Camptothecin is a plant alkaloid obtained from the Camptotheca acuminata tree. This drug was tested for antitumor activity and abandoned in the 1960s because of severe and unpredictable hemorrhagic cystitis, myelosuppression, nausea, and vomiting. Irinotecan (CPT-11) is a semi-synthetic, water-soluble analog of camptothecin, which has greater in vivo and in vitro activity and less severe and more predictable toxicity. Irinotecan is prodrug-like and converted in vivo by hepatic microsomal carboxylesterases to an active metabolite, SN-38, and by CYP3A4 to an inactive metabolite, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin.8 Cytotoxicity depends on the inhibition of the eukaryotic nuclear enzyme DNA topoisomerase I (Topo I). This enzyme is critical for DNA replication and transcription. It causes transient breaks in a single strand of DNA by forming a transient DNA-enzyme cleavable complex. These breaks release the torsional strain caused by synthesis of a new strand of DNA or RNA around a double helix. The camptothecins target this DNA Topo I complex, preventing the relegation of the nicked DNA strand. This inhibition results in intracellular accumulation of drug-stabilized Topo I-DNA cleavable complexes, arrest of DNA replication, and subsequent cell death.9 The Topo I inhibition by irinotecan is accounted for by the intracellular concentrations of SN-38, which is about 1,000 times more potent than the parent drug. The presence of an intact lactone ring in camptothecin and related compounds, including irinotecan, enhances antineoplastic activity. The lactone functional group undergoes a pH-dependent hydrolytic ring opening to the relatively inactive hydroxy acid form, with the closed-ring form predominating at low pH.10 Several phase II trials have shown irinotecan to possess a wide spectrum of activity in human tumors. These include colorectal, breast, lung, ovarian, and gastric cancers.11,12 Combination studies of irinotecan and docetaxel are justified because of their striking single-agent activity in several solid tumors. In vitro combination studies with taxanes and Topo I inhibitors have yielded conflicting results. Chou et al13 demonstrated synergistic cytotoxicity of the combination of topotecan, a topoisomerase-directed agent, and paclitaxel, a taxane in a cultured human teratocarcinoma cell line. Kaufmann et al14, however, found this drug combination to be antagonistic in a human non–small-cell lung cancer (NSCLC) cell line. These interactions may vary depending on the cell type studied and sequence of drug administration. Clinical studies could help determine whether these in vitro studies have any predictive value. In addition, administration of irinotecan before docetaxel may alter the disposition of docetaxel because both are metabolized by CYP3A isoforms. Based on the above reasons and the fact that the drug administration sequence of docetaxel followed by irinotecan was under study, we evaluated the sequence of irinotecan followed by docetaxel. The principal goals of the present study were to: (1) determine the maximum-tolerated dose (MTD) of the combination of irinotecan and docetaxel; (2) determine the dose-limiting toxicity of this combination; (3) determine the recommended doses for subsequent phase II studies; (4) seek preliminary evidence of antitumor activity; and (5) determine if prior administration of irinotecan alters the disposition of docetaxel.
Patient Selection Patients with histologic or cytologic evidence of metastatic or locally advanced cancer for which there was no established curative or life-prolonging therapy were eligible for this study. Eligibility criteria also included age  18 years; Eastern Cooperative Oncology Group performance status  2; prior radiation to 25% of bone marrow completed at least 4 weeks before study enrollment; two prior chemotherapy regimens for metastatic disease; life expectancy of at least 12 weeks; and adequate bone marrow (platelets 100 x 109 cells/L, absolute neutrophil count 1.5 x 109 cells/L), hepatic (total bilirubin within normal limits, aspartate transaminase 2.0 times normal), and renal (serum creatinine 1.5 times the upper limit of normal) functions. Patients with clinically significant effusions and uncontrolled diabetes mellitus were excluded. Concomitant antiseizure medications were not allowed because they can induce cytochrome P450 enzymes, which play a role in the metabolism of docetaxel and irinotecan and could potentially lead to unpredictable toxicity.
Dosage and Administration Irinotecan was administered IV over 90 minutes and was followed immediately by docetaxel administered IV over 60 minutes. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m2, 160/65 mg/m2, 200/65 mg/m2, and 200/75 mg/m2) were studied. The dose escalation scheme was empiric. Starting doses were 50% of the recommended phase II doses of each drug.3,15 Individual drug escalations were alternated. At least three new patients were entered at each dose level. Dose escalation was not allowed in individual patients. Courses were repeated every 3 weeks. Patients were medicated with dexamethasone 8 mg orally twice a day for 3 days, starting a day before institution of chemotherapy. Antiemetic prophylaxis consisted of granisetron 1 mg IV before treatment and granisetron 1 mg orally every 12 hours for 24 hours administered after treatment.
Dose-Limiting Toxicities
Pretreatment and Follow-Up Studies
Pharmacokinetic Analyses Analyses were performed using a nonlinear mixed effects model and first-order maximum likelihood estimation in the non-linear mixed effect model (NONMEM) program (version 5).19 A three-compartment open pharmacokinetic model was fit to the data. In one analysis, pharmacokinetic parameter estimation was performed assuming no prior knowledge of the parameter distributions. In a separate analysis, distributions of the pharmacokinetic parameters were obtained from the analysis of Bruno et al17 using data from 547 individuals after a single IV infusion of 103 to 284 mg of docetaxel alone over 1 to 2 hours. For patients in this study, individual estimates of docetaxel clearance were obtained by posterior Bayesian estimation using the published population pharmacokinetic model and individual sample concentrations and dosing records.
The distribution of individual clearance estimates in this patient population was compared with the distribution for the published population that did not receive irinotecan. The distribution for docetaxel clearance was confirmed using a bootstrap analysis, in which 100 data sets of 18 individuals were selected by sampling, with replacement from the original data set. From the resulting distribution of bootstrap parameter estimates, an approximate 95% confidence interval (CI) for clearance was calculated using the equation:
where p(CL*) is the grand mean bootstrap clearance estimate, p(CL*b) is the mean bootstrap clearance estimate for the bth data set, and B is the number of bootstrap.20 Significance testing was performed to determine whether irinotecan dose influenced docetaxel clearance, as determined by the change in the -2 log-likelihood at a significance level of P < .05.19 In addition, individual estimates of docetaxel clearance at different irinotecan and docetaxel doses were compared by analysis of variance.
Eighteen patients (Table 1) received 85 assessable courses of therapy through four dose levels (Table 2). The median number of courses administered per patient was four (range, one to 15 courses). The median age of study participants was 60 years (range, 42 to 80 years). Patients were of good performance status, with no patients with an Eastern Cooperative Oncology Group performance status above 1. Three patients had received no prior chemotherapy, and five patients had received two prior chemotherapy regimens. Ten patients had received prior radiation therapy. The most common tumor types were NSCLC, colorectal cancer, and gastric cancer. Patients with a variety of other cancers, including pancreas, sarcoma, and mesothelioma, were also enrolled (Table 1).
Hematologic Toxicity Neutropenia was the principal dose-limiting toxicity of this drug combination. Tables 3 and 4 list the median and range for nadir absolute neutrophil counts and the grades of neutropenia. Two episodes of grade 4 neutropenia and fever requiring hospitalization for parenteral antibiotics occurred at dose level 4, and one episode occurred at dose level 3. However, there were no episodes of documented infections in the setting of grade 4 neutropenia. The severity and incidence of neutropenia, which typically occurred by day 10 (median) and resolved by day 17 (median), seemed to be dependent on dose. Prolonged (> 5 days) NCI CTC grade 4 neutropenia occurred in four of six patients at irinotecan doses of 200 mg/m2 and docetaxel doses of 75 mg/m2. This precluded dose escalation above this dose level. Likewise, prolonged grade 4 neutropenia occurred in three of six patients treated at dose level 3 (irinotecan 200 mg/m2; docetaxel 65 mg/m2). All patients treated at these two dose levels subsequently had their drug doses reduced to the level 2 doses. No dose-limiting toxicities occurred at this dose level. Thus, the recommended phase II dose is irinotecan 160 mg/m2 and docetaxel 65 mg/m2 (dose level 2).
Effects on platelets were modest. Platelet decreases below 100 x 109 cells/L occurred in only 15 out of 85 courses, or 5 out of 18 patients. Platelet decreases below 75 x 109 cells/L requiring platelet transfusion occurred in only one course of treatment. The effects on RBCs were likewise mild. Anemia requiring RBC transfusions did not occur.
Nonhematologic Toxicity Skin toxicity manifested as swelling and erythema localized to the limb receiving docetaxel infusions and was documented in four out of 18 patients or seven out of 85 courses of treatment. These reactions were unrelated to extravasation of drug and resolved by the next cycle of treatment with no serious sequelae. Cold compresses and oral corticosteroids were used for the more marked cases. All skin reactions were mild (CTC grade 1). The frequently encountered nonhematologic toxicities are listed in Tables 5 and 6.
Antitumor Activity Sixteen patients were assessable for antitumor activity. The two patients who were not assessable discontinued therapy after one cycle of therapy. The reason for discontinuation in both cases was hospitalization as a result of febrile neutropenia at the highest dose level tested (irinotecan 200mg/m2 and docetaxel 75 mg/m2). Five out of the 16 patients achieved confirmed PRs, which lasted for a median of 5 months. Three of these patients had previously treated NSCLC. One patient had received etoposide/cisplatin concomitantly with radiation therapy. On relapse, he received a combination of pyrazoloacridine and carboplatin before enrolling onto this study. The second patient had previously received paclitaxel/carboplatin, and the third patient had received etoposide/cisplatin followed by gemcitabine, with no objective response to either regimen. Of the remaining responding patients, one patient had abdominal leiomyosarcoma previously treated with ifosfamide, mesna, doxorubicin, and cisplatin, with no response. The other responding patient had previously untreated cholangiocarcinoma. A sixth patient with a parotid tumor had complete disappearance of disease in the head and neck region but was classified as having stable disease because the index lesion (lung nodule) was unchanged. One patient with bladder carcinoma had stable disease through 10 cycles of treatment but went off study because of fluid retention. Four patients progressed after two cycles of therapy, and seven patients had disease stability for at least four cycles of treatment.
Pharmacokinetics From the three-compartment model fit to the data (Fig 1), docetaxel clearance was estimated to be 43.3 L/h (95% CI, 38.2 to 48.4 L/h). As listed in Table 7, pharmacokinetic parameter estimates for docetaxel after irinotecan administration differed slightly from those obtained by Bruno et al17 for docetaxel administered alone.
In these analyses, both significance tests and analyses of variance showed no apparent relationship between irinotecan dose and docetaxel clearance. Similarly, there was no relationship between docetaxel dose and docetaxel clearance, suggesting linear pharmacokinetics in the dose range studied.
The recommended phase II dose on this schedule is irinotecan 160 mg/m2 and docetaxel 65 mg/m2. Couteau et al21 have completed a phase I study of this drug combination with administration of docetaxel followed by irinotecan. The dose-limiting toxicity in their study was neutropenia, which is in agreement with the current study. However, their recommended phase II dose, docetaxel 75 mg/m2 and irinotecan 250 mg/m2, is substantially higher than the recommended dose of the present study. The sequence of drug administration in this study (irinotecan followed by docetaxel) was opposite that of the Couteau study, but it is unclear whether this could have contributed significantly to the different MTDs. This is especially true because the two drugs were administered in rapid succession without any time intervals between administration. One possible explanation is that the definitions of dose-limiting toxicity and, thus, MTD could have been different, although this cannot be assessed because the Couteau study has only been published in abstract form. Likewise, there could be differences in the patient populations studied with regards to performance status and extent of prior therapy. Because both irinotecan and docetaxel are substrates for CYP3A, we hypothesized that when IV infusions of irinotecan and docetaxel are administered sequentially, competition for this enzyme could result in a decrease in docetaxel clearance. Our findings, however, indicate that sequential administration of irinotecan and docetaxel results in a clinically negligible but statistically significant increase (12.5%) in clearance compared with previous trials where docetaxel was administered alone. Several mechanisms could explain the small increase in clearance. One possibility is based on in vitro metabolism studies for docetaxel that suggest two mechanistic pathways for metabolism, a high affinity/low velocity pathway and a low affinity/high velocity pathway.22 Because the latter is not saturable in the range of 2 to100 µmol/L, inhibition of CYP3A4 by irinotecan may shift the metabolism of docetaxel to the low affinity enzyme resulting in an increased velocity and, therefore, an increased clearance. It is also possible that competitive inhibition of CYP3A isoforms by irinotecan results in increased metabolism by other enzymatic pathways. Oral dexamethasone (8 mg twice a day for 3 days) was started 24 hours before docetaxel as prophylaxis against fluid retention. Dexamethasone is a potent inducer of CYP3A that may potentially increase the clearance of docetaxel. Although a single dose of dexamethasone increased CYP3A1 and CYP3A2 expression in rats within 12 hours of treatment,23 it is unclear if a 24-hour pretreatment is enough time to allow for significant induction of CYP3A activity in humans. Moreover, the studies on which the population kinetic model of Bruno et al17 is based were diverse. Some patients used dexamethasone pretreatment, whereas others did not. This makes it impossible to clearly define the role of dexamethasone in increasing the docetaxel clearance in our study. In any case, at the doses of irinotecan used in this study, there does not seem to be a dose-dependent relationship for the apparent shift in metabolism. More importantly, the clinically negligible change in docetaxel clearance could be explained by the differences in liver function of the patients. Most patients had mild baseline liver function abnormalities. Neutropenia was the most common toxicity on this study. Neutropenia was present at all dose levels studied but was brief and reversible with no serious sequelae except at the two higher dose levels where febrile neutropenia occurred in 14% of treatment courses. Although the higher doses of this combination could be studied with growth factors, this more costly approach seems to be unnecessary in the setting of treatment for metastatic disease because antitumor activity was seen at all dose levels tested. In addition, patients who received more than six courses of therapy with minimal toxicities were treated at the two lower dose levels Thus, our recommended phase II dose would seem to be reasonable for patients with metastatic disease. If this combination were being investigated in the neoadjuvant setting where a few cycles of a combination with high response rates were used, then the use of growth factors to allow the administration of higher doses on schedule may be justified. Diarrhea, which was predicted to pose a major problem because of the known toxicity pattern of irinotecan, was frequent but manageable with early use of antidiarrheal therapy. Although this is a phase I study with relatively few patients, the antitumor activity seen is striking enough to warrant further evaluation of this combination in a number of tumor types. Evaluation of this combination for NSCLC and gastroesophageal cancer is currently under way in the North Central Cancer Treatment Group.
Supported in part by grants no. CA77112, CA15803, and RR00585 from the National Institutes of Health, Bethesda, MD. We thank Deb Sprau and Sue Steinmertz for data management, Michelle Daiss for protocol administration, Jill Piens for coordination of the pharmacokinetic studies, Emel Rahman for statistical programming, the General Clinical Research Center nursing staff for patient care and pharmacokinetic blood sampling, and Gail Prechel for expert secretarial assistance.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
