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Clinical Cancer Research Vol. 12, 3774-3781, June 15, 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

Dose-Finding Phase I Clinical and Pharmacokinetic Study of Orally Administered Irinotecan in Patients with Advanced Solid Tumors

Isa E.L.M. Kuppens1, Eric Dansin3, Henk Boot1, Celine Feger4, Sylvia Assadourian4, Maria-Edith Bonneterre3, Jos H. Beijnen1,2,5, Jan H.M. Schellens1,5 and Jacques Bonneterre3

Authors' Affiliations: 1 Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute; 2 Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands; 3 Centre Oscar Lambret, Lille, France; 4 Department of Drug Innovation and Approval, Aventis Pharma, Antony Cedex, France; and 5 Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

Requests for reprints: Isa E.L.M. Kuppens, Department of Clinical Pharmacy and Toxicology, University Hospital Maastricht, Peter Debyelaan 25, 6229 HX Maastricht, the Netherlands. Phone: 31-43-387-7405; E-mail: isa_kuppens{at}hotmail.com.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study.

Experimental Design: Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m2 once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m2/d.

Results: The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m2/d for irinotecan single agent and 30/1,600 mg/m2/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively.

Conclusions: In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m2/d administered daily for 14 days every 3 weeks.

Irinotecan administered i.v. is registered for the treatment of patients with advanced colorectal carcinoma in combination with 5-fluorouracil/leucovorin and as monotherapy in patients who failed to respond to 5-fluorouracil (1–5). Furthermore, irinotecan has shown activity in esophageal (6, 7), gastric (8–13), small cell lung (14, 15), non–small cell lung (16), ovarian (17), and cervix (18) cancers.

In this study, irinotecan was combined with capecitabine. Capecitabine is a single agent registered for first line therapy of advanced colorectal cancer and for the treatment of patients with locally advanced metastatic breast cancer in combination with docetaxel or after failure of cytotoxic chemotherapy (19, 20). The combination of i.v. irinotecan and oral capecitabine has already proven to be active in metastatic colorectal cancer (21–23). In this study, both irinotecan and capecitabine were administered orally. Besides several advantages of oral administration in general (e.g., patient's preference, convenience, reduced hospital stay, and reduced cytotoxic exposure risk for health care workers), more specific advantages can be distinguished. Compared with i.v. administration, the metabolic ratio of total SN-38 (24, 25) to total irinotecan after oral administration is higher compared with short i.v. bolus irinotecan administration. Moreover, preclinical studies with topoisomerase I inhibitors showed an increased antitumor activity with protracted exposure at low concentrations (26–29). Based on these findings, phase I and II studies were undertaken with daily times five oral treatment and low-dose continuous infusion in cancer patients (30–34). To date, most of the few available clinical studies with oral irinotecan were designed to determine the feasibility of oral irinotecan administration and to establish the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). In our previous study, the advised future dose was 30 mg/m2/d for 14 days every 3 weeks (1). This was also found earlier by Sharma et al. (1, 35, 36). In both studies, the most commonly observed DLT was diarrhea. In both studies, the powder-filled capsule was used. In the present study, we used semisolid matrix capsules with the aim to determine the daily MTD and the DLT for the following administration schedules. Oral irinotecan was given over 14 days every 3 weeks (part I) and given concomitantly with capecitabine over 14 days every 3 weeks (part II). Furthermore, the aim was to establish the pharmacokinetic profile of irinotecan as single agent and of irinotecan combination treatment with capecitabine at the MTD (part I and in part II at the DLT level). In addition, the safety profile of these two oral treatments and any evidence of antitumor activity were documented.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patient population. Patients with pathologically proven locally advanced or metastatic solid tumors without available standard therapy or for whom irinotecan and/or capecitabine was considered adequate treatment were eligible for enrollment. Other inclusion criteria were patients ages ≥18 years, WHO performance status ≤2, and a life expectancy ≥3 months. The presence of measurable disease according to response evaluation criteria in solid tumors criteria was preferred but not required. Furthermore, biological values had to be adequate: bone marrow, absolute neutrophil count ≥2.0 x 109/L; platelets ≥100 x 109/L; hemoglobin ≥10 g/dL; adequate hepatic function defined as serum total bilirubin within the reference ranges; aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≤3x upper normal limit or ≤5x upper normal limit in case of liver metastases; serum creatinine ≤1.5 mg/dL (≤135 µmol/L) or a measured creatinine clearance ≥60 mL/min. Previous chemotherapy had to be discontinued for at least 4 weeks; in case of nitrosoureas or mitomycin C, chemotherapy had to be discontinued for at least 6 weeks. Patients should have recovered from toxicities from previous therapy to grade <2 (except alopecia), and patients had to be able to swallow normally, have a normal gastrointestinal absorption, and had to comply to intake of capsules according to treatment plan with scheduled visits and laboratory tests. Exclusion criteria included leukemia, prior high-dose chemotherapy with progenitor blood cells transplantation, symptomatic brain metastases or leptomeningeal involvement, concomitant severe infection or major organ failure, and chronic diarrhea. Furthermore, no concomitant treatment with cytochrome P450 3A inhibitors or inducers and no prior treatment with irinotecan, capecitabine, or 5-fluorouracil infusion were allowed, except for 5-fluorouracil bolus injection. Patients with known dihydropyrimidine dehydrogenase deficiency, surgery in the previous 4 weeks, prior extensive pelvic irradiation, and concurrent radiotherapy in case >25% of the bone marrow was involved in the irradiated field were excluded. In addition, pregnant or breast-feeding patients and patients with alcohol or drug addiction were excluded. The study was carried out with full ethical approval, and all patients were required to provide written informed consent before study enrollment.

Toxicity and response evaluation. Baseline evaluation before study entry included a complete medical history, a full physical examination, including WHO performance status, height, weight, body surface area, pulse, electrocardiogram, hematology, blood chemistry, and serum tumor markers, and evaluation of the extent of the tumor using appropriate radiographic imaging.

During the first cycle, hematologic evaluations were done twice weekly, cycles following thereafter once weekly (approximately on days 8 and 15 and weekly thereafter) each cycle. In case of grade 4 hematologic toxicity, a blood count was done twice weekly until recovery (to grade ≤3). Blood chemistries were done on days 8 and 15 of the first cycle and before dose every following cycle. Vital signs and serum markers were assessed every cycle. Every two courses, tumor assessment was done. Antitumor activity in patients with measurable disease was monitored according to the response evaluation criteria in solid tumors criteria (37). Adverse events were graded according to National Cancer Institute Common Toxicity Criteria (CTC) version 2.0 every week. At the off-treatment visit, all baseline evaluations were repeated, excluding general medical history, height, and body surface area. After the off-treatment visit, patients were followed monthly up to a maximum of 6 months for resolution of adverse events. Patients were instructed to take loperamide at the earliest sign of diarrhea (poorly formed or loose stool or increase in stool volume or liquidity) after intake of irinotecan. Patients were recommended to take 4 mg loperamide initially and then 2 mg every 2 hours until at least 12 hours after resolution of any problem with diarrhea and to take loperamide 4 mg every 4 hours at night. Prophylactic growth factors and anticholinergics were not allowed in the first cycle of irinotecan treatment. However, prophylactic administration of granulocyte colony-stimulating factor and therapeutic use in patients suffering with neutropenic complications was to be considered at the investigator's discretion.

Drug administration, dose escalation, and study design. Irinotecan (cpt-11 hydrochloride trihydrate, Pharmacia, Milan, Italy) was provided as semisolid matrix capsules containing 5, 20, or 50 mg of active drug substance. Capecitabine (5'-deoxy-5-fluorouridine, Hoffmann-La Roche, Basel, Switzerland) was provided as film-coated tablets containing 150 and 500 mg of active substance. In part I, irinotecan was administered orally, once daily for 14 consecutive days followed by 1 week of rest. Patients fasted for at least 4 hours before the daily oral dose and 1 hour following dosing before intake with a glass of water (~180 mL) at approximately the same time of day throughout treatment courses. The appropriate daily dose of irinotecan capsules was based on the actual calculated body surface area. The starting dose as a single agent was based on a previous study (1), in which powder-filled capsules were used. In part II of the study, irinotecan was administered as in part I, orally, once daily with capecitabine, orally twice daily at the end of a meal (breakfast and dinner) from days 1 to 14 every 3 weeks. The second daily dose of capecitabine was given at ~10 to 12 hours after the first dose of that day. The tablets were swallowed with a full glass of water. Time interval between the administration of irinotecan and capecitabine on days 1 to 14 was 2 hours. The starting doses of irinotecan and capecitabine in part II of the study were 20 mg/m2/d (280 mg/m2 per course) and 1,600 mg/m2/d, respectively. These doses were increased sequentially, and dose escalations in parts I and II were done according to the following guidelines. A minimum of three patients was treated at each dose level with minimally 1-week interval between the entry of the first patient and the next two patients. Before escalation to the next dose level, all three patients should have received at least one treatment cycle of 2 weeks and have received follow-up for toxicity for minimally 1 week. A DLT was defined as any of the following events during the first treatment cycle: grade 3 neutropenia before day 7 or grade 4 neutropenia >5 days during 14 days of treatment, febrile neutropenia, neutropenic infection (grades 3-4 neutropenia with documented infection), grade 4 thrombocytopenia, grades 3 to 4 diarrhea despite maximal intensive loperamide support, grade ≥2 nausea or grade ≥2 vomiting despite maximal oral antiemetic therapy or vomiting leading to discontinue the study treatment for 3 days, stomatitis grades 3 to 4, grade 3 palmar-plantar erythrodysesthesia, failure to complete the 14 days of full-dose irinotecan therapy, or any National Cancer Institute CTC grade 3 or 4 nonhematologic toxicity (except alopecia). In case of DLT, the treatment was discontinued until recovery of grade <1 and, if clinically indicated, resumed for the subsequent cycle at one dose level lower. If one of the first three patients experienced a DLT at a dose level, three additional patients were enrolled at this dose level. If no DLT was seen in any of the three additional patients, the dose was escalated in the next cohort. There were no intrapatient dose escalations. The MTD was defined as the dose at which two of three or two of six patients experienced DLT. The next lower dose level below the MTD was the recommended dose for phase II studies.

Patients could be retreated at a reduced dose level, depending on the adverse events in their current or any adverse events on the first day of the next cycle. Only when an adverse event was evaluated as not treatment related, the dose could be reescalated in the next cycle (if no toxicities >1 were observed, except for alopecia). No dose reductions within a treatment cycle were made. After assessment of the MTD of the combination, at least six patients were included at this dose level to ensure its feasibility. Treatment was continued until evidence of disease progression, unacceptable toxicity, or withdrawal of patient consent. Treatment of irinotecan and capecitabine was continued until evidence of disease progression, unacceptable toxicity, or withdrawal of patient consent.

Pharmacokinetics. The pharmacokinetic variables of irinotecan and metabolite SN-38 were determined in part I on days 1 and 14. Urine was also collected during the irinotecan dose escalation step on day 14. For irinotecan bioanalysis, venous blood samples (5 mL each) were collected into heparinized plastic tubes, immediately before and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, 18, and 24 hours after drug administration. Urine was collected immediately before drug administration and over the time intervals 0 to 10 and 10 to 24 hours after administration. After mixing, an aliquot of 10 mL of each fraction was stored for analysis. Blood samples were immediately chilled on ice and centrifuged. The plasma was stored at –20°C until analysis. The urine and plasma concentrations of total (lactone and open-ring form) of irinotecan and active metabolite SN-38 were quantified by a validated high-performance liquid chromatography method using solid-phase extraction and fluorescence detection (38). Pharmacokinetic analysis of the plasma concentration-time data obtained for the parent drug and metabolite was done by noncompartmental analysis using WinNonlin software version 4.1 (Pharsight Corp., Mountain View, CA). For each individual, the maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) were obtained directly from the experimental data. The elimination rate constant Kel was determined by log-linear regression analysis of the terminal phase of the plasma concentration versus time curve. The area under the concentration versus time curve (AUC{infty}) was estimated by the linear-logarithmic trapezoidal method up to the last measured data point with extrapolation to infinity using Kel (AUC{infty}). The metabolic ratio was defined as AUC{infty} of SN-38/AUC{infty} of irinotecan. Statistical analysis was done with Statistical Package for the Social Sciences for Windows version 11.0.

Dose-normalized AUC{infty} and Cmax values were calculated for comparison of patients treated at different dose levels. Urinary excretion was expressed as percentage of the irinotecan dose. The percentage of the administered dose recovered in the urine over 1 day was calculated as the amount excreted in the urine divided by the total administered dose times 100%.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Patient characteristics and dosing
A total of 42 patients with a median performance status of 1 (range, 0-2) were enrolled between May 2001 and August 2003. In part I of the study, 17 patients were included (11 females and 6 males) with a median age of 56 years (range, 23-75). The majority of patients had gastrointestinal cancer of varying origins. Fifteen patients had received prior chemotherapy, 9 patients prior radiation, and 9 patients prior surgery. The mean interval from diagnosis to study entry was 22.2 (range, 1.15-90.9 months) and 10.5 months (range, 0.6-59.1 months) in parts I and II of the study, respectively. The number of patients treated at each dose level and the number of cycles administered are summarized in Table 1 . The mean number of prior chemotherapy regimens for advanced disease was 2 (range, 1-6) in part I. In part II of the study, 25 patients were entered (15 females and 10 males) with a median age of 55.5 years (range, 47-75). All patients were assessable for toxicity, except for one patient who developed a thrombosis/emboli before receiving study medication. A total of 51 cycles were given in part I and 78 cycles in part II.


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  		Table 1. Dose escalation irinotecan monotherapy (part I) and combination of irinotecan and capecitabine (part II)

 
Safety results
Hematologic toxicity. No significant hematologic toxicity was observed for oral irinotecan when given as single agent. Only one patient had a CTC grade 2 absolute neutrophil count (≥1.0 x 109/L to <1.5 x 109/L) at 30 mg/m2/d. None of the 17 patients experienced a greater than grade 2 neutropenia during all treatment cycles. In the combination of irinotecan and capecitabine, one patient treated at the starting level of 20/1,600 mg/m2/d experienced an infection with neutropenia grade 3 for 6 days in cycle 2. No significant anemia and thrombocytopenia greater than grade 2 was encountered.

Nonhematologic toxicity. Nonhematologic CTC grades 1 and 2 adverse events that were frequently encountered were alopecia, fatigue, anorexia, headache, and abdominal pain and cramping (Table 2 ). Gastrointestinal toxicity, including vomiting and diarrhea, was dose limiting for the oral administration of irinotecan single agent and irinotecan combined with capecitabine. Table 3 lists the frequency and severity of diarrhea, nausea, and vomiting during treatment course 1 and for all other courses. The worst toxicities per patient are summarized. Grade 3 or 4 diarrhea was observed in 3 of 17 patients in 50 cycles in part I and in 7 of 25 patients in 78 cycles in part II. Grade 3 nausea and grades 3 to 4 vomiting were observed in one patient (in 50 cycles) in part I and in 2 patients (in 78 cycles) in part II. No cumulative intestinal toxicity was observed.


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  		Table 2. Toxicity other than gastrointestinal toxicity per CTC grade

 

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  		Table 3. Gastrointestinal toxicity per CTC grade

 
One DLT, which was diarrhea grade 3, was observed at 25 and 30 mg/m2/d irinotecan single agent. DLTs were observed in two patients in cycle 1 at the next higher dose level of 35 mg/m2/d. One patient suffered from grade 3 diarrhea and nausea and failed to complete treatment course 1. The other patient had grade 3 diarrhea and rash/desquamation. In part II, the first DLT was seen at 25/1,600 mg/m2/d of the combination regimen, which was grade 3 diarrhea. At the subsequent dose level of 30/1,600 mg/m2/d, no DLT was observed. At the dose level of 30/2,000 mg/m2/d, one patient suffered from an infection and diarrhea of both grade 3. As the gastrointestinal toxicity became more prominent and disabling without reaching formal DLT in other patients, this level was considered too high. Subsequently, the next lower dose level of 30/1,600 mg/m2/d was tested for feasibility. According to the dose escalation rules, the MTD was determined to be 30 mg/m2/d for the single agent irinotecan and 30/1,600 mg/m2/d for irinotecan combined with capecitabine. During the feasibility step at the recommended dose level of 30/1,600 mg/m2/d, one additional patient suffered from nausea grade 3. No treatment-related deaths were observed.

Pharmacokinetics
Figure 1 depicts the systemic exposure (AUC{infty}) of irinotecan and SN-38 on day 1 of a typical patient treated at the recommended dose of 30 mg/m2/d single agent. Pharmacokinetic variables at days 1 and 14 were determined for 17 patients in part I and for 2 patients in part II (Tables 4 and 5 ). Absorption was rapid, and maximal concentrations of irinotecan and SN-38 were achieved between 0 and 3 and 1.5 and 4 hours, respectively (median time after administration). Variability was high, and the coefficient of variation ranged between 16% and 54% for the AUC{infty} of irinotecan and between 8% and 114% for SN-38. No accumulation was observed, as no statistical difference between day 14 and day 1 was found for either AUC{infty} or Cmax (Table 4). The metabolic ratio (AUC{infty} SN-38/AUC{infty} irinotecan) during day 1 was 0.19 ± 0.11 (mean ± SD). The relationship between irinotecan dose and AUC{infty} for irinotecan and SN-38 is shown in Fig. 2 . The results of urinary excretion and renal clearance of irinotecan and SN-38 on days 1 and 14 are summarized in Table 5.


Figure 1
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  		Fig. 1. Typical pharmacokinetic profile of irinotecan and SN-38 of a patient treated at the recommended dose of 30 mg/m2.

 

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  		Table 4. Pharmacokinetic variables of irinotecan and SN-38 on days 1 and 14 after administration of irinotecan given over 14 days once daily every 3 weeks, part I in plasma

 

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  		Table 5. Urinary excretion of irinotecan and SN-38 on days 1 and 14 after administration of irinotecan given over 14 days once daily every 3 weeks, part I

 

Figure 2
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  		Fig. 2. A, individual area under the curve (AUC) values of irinotecan on days 1 and 14 in part I. B, individual area under the curve values of SN-38 on days 1 and 14 in part I.

 
Antitumor activity
A total of six patients were not assessable for formal tumor response. In part I, one patient was not evaluable because of nonmeasurable peritonitis carcinomatosa of the ovarian cancer. In part II, one patient was not evaluable for response because of early discontinuation of cycle 1 due to disease progression. One patient died before receiving the study medication, one patient had nonmeasurable ovarian/endometrioid adenocarcinoma, and two patients did not complete cycle 1 because of tumor pain grade 3. The mean number of cycles administered per patient was 3.0 (range, 1-12) for part I and 3.3 (range, 1-13) for part II.

In part I of the study, one partial response was documented in a 58-year-old female with breast cancer treated at 30 mg/m2/d. The response duration was 2 months. In part II, four patients developed partial responses. Two female patients, both ages 53, had a response duration of 2 and 4.5 months, respectively, while being treated with 20/1,600 and 25/1,600 mg/m2/d of irinotecan plus capecitabine. Another breast cancer patient, 47 years of age, developed a partial response of 5.5 months duration, whereas a patient of 63 years with a tumor of unknown primary showed a response duration of 5 months. Both patients were treated at 30/1,600 mg/m2/d. The mean time to progression for the patients in part I was 2.5 (range, 0.1-91.0 months) and 14.3 months (range, 0.5-59.9 months) in part II (Table 6 ).


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  		Table 6. Best response data across all dose levels

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this phase I study, we found that oral therapy with irinotecan given as single agent and coadministered with capecitabine is feasible. The recommended dose for irinotecan as single agent is 30 mg/m2/d daily for 14 days every 21 days and use of the semisolid matrix formulation. This confirms the results of our earlier study, in which we have tested another capsule formulation of irinotecan. Various schedules have been recommended for oral irinotecan administration (1, 39–42). In a once daily for 5 days every 3 weeks regimen, recommended dosages ranged from 50 to 80 mg/m2/d. Contrary to the findings with i.v. administration of irinotecan, myelosuppression was not dose limiting. In all studies investigating the oral formulation of irinotecan, the most commonly observed DLT was diarrhea and sometimes, also, vomiting occurred. In our study, we also found diarrhea to be dose limiting for irinotecan as single agent as well as in combination with capecitabine. Other toxicities were generally mild compared with i.v. administration and mostly did not exceed CTC grade 1 or 2. Phase I studies with prolonged schedules of irinotecan have suggested that alopecia and cholinergic syndrome are probably more closely related to peak concentrations of irinotecan and SN-38 than to total dose intensity. In concordance with these findings, in our study no patient suffered from cholinergic syndrome and alopecia was generally mild. Specific grade 3 or 4 toxicities contributed to capecitabine, such as hand-foot syndrome, were not encountered. Overall, the combination treatment was well tolerated. A dose of 30 mg/m2 irinotecan administered as single agent was feasible in combination with capecitabine. Capecitabine had to be applied at a lower dose when compared with the registered standard dose of two times 1,250 mg/m2/d as single agent. Of note, however, most patients in the United States cannot tolerate 1,250 mg b.i.d., although it is the registered standard dose, and in fact most patients are actually treated with a dose of 1,000 mg b.i.d. As capecitabine in this combination study could be administered at its clinically most often applied dose level of two times 1,000 mg/m2, a major pharmacokinetic and pharmacodynamic interaction is unlikely. In contrast, however, with our previous study, in which irinotecan was given as powder-filled capsules, irinotecan was administered as semisolid matrix capsules to improve the systemic exposure and decrease the high interpatient variability. We compared the pharmacokinetic variables of the current study with those obtained in our previous dose escalation study of irinotecan powder-filled capsule (1). Absorption was rapid, and also in this study a disappointingly large interpatient variability in the pharmacokinetic variables was observed at all doses. Dose proportionality with the AUC{infty} of irinotecan and SN-38 was difficult to assess because of the small numbers of patients per dose level and the high interpatient variability. The mean relative metabolic ratio of total SN-38 AUC{infty} to total irinotecan AUC{infty} was 0.19 ± 0.11 (mean ± SD), which is similar to previous studies using oral irinotecan and 5 to 10 times higher than after standard i.v. administration of irinotecan. The renal excretion of irinotecan and SN-38 reveals that both parent drug and its active metabolite are excreted in low amounts. This indicates that renal excretion is a minor pathway of elimination, which is in line with previous observations.

Currently, several other dose-finding studies are being done, in which irinotecan is combined with capecitabine in patients with advanced solid tumors (42–46).

In summary, the recommended dose for phase II studies was 30 mg/m2/d of irinotecan plus 1,600 mg/m2/d capecitabine daily for 14 days every 3 weeks. Irinotecan single agent and in combination with capecitabine was well tolerated with no major hematologic toxicity. The DLTs were diarrhea and vomiting. Additional phase II and III studies are required to establish the activity and efficacy of this oral combination in the treatment of cancer and see if the combination is any better than single-agent capecitabine.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The current address for I.E.L.M. Kuppens is Department of Clinical Pharmacy and Toxicology, University Hospital Maastricht, Maastricht, the Netherlands.

Irinotecan is currently developed by Pfizer, Inc.

Received 10/29/05; revised 2/15/06; accepted 4/20/06.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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