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© 2000 American Society for Clinical Oncology Phase I Study of 3-Week Schedule of Irinotecan Combined With Cisplatin in Patients With Advanced Solid TumorsFrom the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands; and Rhône-Poulenc Rorer, Antony, France. Address reprint requests to M.J.A. de Jonge, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands.
PURPOSE: To assess the feasibility, pharmacokinetic interaction, and possible sequence-dependent effects of the irinotecan/cisplatin combination given every 3 weeks, and to assess the influence of additional granulocyte colony-stimulating factor (G-CSF) on the hematologic toxicity. PATIENTS AND METHODS: Patients who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of a 90-minute irinotecan infusion followed by a 3-hour cisplatin infusion on day 1, with cycles repeated once every 3 weeks. After the maximum-tolerated dose was determined, the sequence of administration was reversed. In a separate cohort of six patients, we assessed the effect of G-CSF on the experienced hematologic toxicity and dose-intensity. Irinotecan doses ranged from 175 to 300 mg/m2 and cisplatin doses ranged from 60 to 80 mg/m2. RESULTS: Fifty-two patients entered the study; one was not eligible, and two were not assessable for response. Twenty-five patients were pretreated, and 26 were not. Fifty-one patients received a total of 223 courses. The dose-limiting toxicity was a combination of neutropenic fever, diarrhea, and fatigue at a dose level combining irinotecan 300 mg/m2 with cisplatin 80 mg/m2. Neutropenia was common (grades 3 to 4, 68%). Irinotecan pharmacokinetics were linear over the dose range studied. No sequence-dependent side effects were observed. Tumor responses included three complete responses and eight partial responses. CONCLUSION: For phase II studies, we recommend irinotecan 260 mg/m2 combined with cisplatin 80 mg/m2 once every 3 weeks for chemotherapy-naive patients in good physical condition, and irinotecan 200 mg/m2 combined with cisplatin 80 mg/m2 for other patients.
IRINOTECAN (CPT-11, Campto; Rhône-Poulenc Rorer, Antony, France) is a water-soluble camptothecin analog. Camptothecin analogs are a family of anticancer agents with a unique mechanism of action that is based on the reversible inhibition of DNA topoisomerase I.1,2 Topoisomerase I inhibitors are of great clinical interest because of their important antitumor activity as single agents in a broad spectrum of tumor types.3 In addition, topoisomerase I inhibitors may also interfere with the processes involved in DNA repair4-6 and enhance cytotoxicity when combined with DNA-damaging agents. The different toxicity profiles of platinum derivatives and topoisomerase I inhibitors and the lack of cross-resistance further support the potential use of these agents in combination. In preclinical studies, the combination of irinotecan and cisplatin was shown to be synergistic in several human tumor cell lines and human xenograft tumor models.7-13 Until now, phase I studies on the combination of irinotecan and cisplatin focused on fractionated dose schedules for both agents.14-24 The dose-intensity of irinotecan that could be achieved in these schedules in combination with cisplatin varied from 25% to 60% of the single-agent dose. The higher dose-intensities were reached when irinotecan was combined with a single administration of cisplatin. Throughout these studies, the major dose-limiting toxicities (DLTs) were neutropenia and diarrhea. Other side effects were nausea and vomiting, alopecia, and mucositis. Major responses were observed with all treatment schedules in patients with non–small-cell lung cancer, small-cell lung cancer, gastric carcinoma, head and neck carcinoma, and cervical carcinoma.14-30 In Europe, the recommended schedule of administration of irinotecan as a single agent is every 3 weeks at the dose of 350 mg/m2. Although there is no consensus yet, there seems to be a tendency among physicians to favor this 3-week schedule, not because of a belief in higher activity but because of patient convenience. Randomized studies comparing the two schedules are presently ongoing. In the present report, we describe a phase I study on the combination of irinotecan and cisplatin. Both were administered intravenously once every 3 weeks.
Patient Selection Patients with a histologically or cytologically confirmed diagnosis of a malignant solid tumor refractory to standard forms of therapy were eligible. Other eligibility criteria included the following: age between 18 and 70 years; Eastern Cooperative Oncology Group performance status  1; no previous anticancer therapy for at least 4 weeks (6 weeks for nitrosoureas or mitomycin); no previous therapy with topoisomerase I inhibitors or platin derivatives; no treatment with more than one prior combination regimen or two single-agent regimens; no major surgery within 28 days before inclusion; and adequate hematopoietic (absolute neutrophil count  2.0 x 109/L and platelet count 100 x 109/L), renal (serum creatinine concentration 135 µmol/L or creatinine clearance 60 mL/min), and hepatic function (total serum bilirubin level 1.25 times the upper normal limit and serum AST and ALT levels 3.0 times the upper normal limits; in case of liver metastasis, total serum bilirubin level 1.5 times the upper normal limit and serum AST and ALT levels 5.0 times the upper normal limits). Specific exclusion criteria included unresolved bowel (sub)obstruction and chronic diarrhea or chronic colic disease and symptomatic peripheral neuropathy greater than grade 1 according to the National Cancer Institute common toxicity criteria (NCI-CTC). All patients gave written informed consent before they were entered onto the study.
Treatment and Dose Escalation
Before the infusion of the cytotoxic drugs, patients were prehydrated with an infusion of 1,000 mL of dextrose/saline given over 4 hours. In the first part of the study, irinotecan (diluted in 250 mL of 0.9% sodium chloride solution) was administered intravenously (IV) over 90 minutes on day 1. Subsequently, cisplatin (diluted in 250 mL of 3.0% saline) was given as a 3-hour IV infusion, followed by 2,000 mL of dextrose/saline infused over 8 hours. To avoid cisplatin-induced renal damage, another 1,000 mL of dextrose/saline, along with 20 mmol of KCl and 2 g of MgSO4 per liter, was infused over the next 8 hours. Before irinotecan was administered, patients received antiemetic therapy consisting of ondansetron 8 mg IV combined with dexamethasone 10 mg IV. In case of severe acute cholinergic symptoms, ie, acute diarrhea, 0.25 mg of atropine was administered subcutaneously. For irinotecan-induced delayed-type diarrhea, high-dose loperamide therapy was administered orally at a starting dose of 4 mg at the first episode of diarrhea followed by 2 mg every 2 hours for at least 12 hours. The patient was allowed to stop loperamide only after a 12-hour diarrhea-free interval. If the diarrhea persisted for more than 24 hours despite the recommended loperamide treatment, a 7-day prophylactic oral antibiotic therapy (ciprofloxacin 500 mg bid) was added because severe diarrhea is considered a risk factor for febrile neutropenia. At least three patients were to be entered at each dose level. If DLTs were seen in one of three patients, an additional three patients were to be entered at that dose level. The MTD was defined as one dose level below the dose that induced DLTs during the first course, which were defined as NCI-CTC grade 3 or 4 neutropenia complicated with fever, grade 4 thrombocytopenia, and/or nonhematologic toxicity grade 3 (grade 2 for renal toxicity and grade 4 for vomiting lasting longer than 3 days), excluding nausea, in three or more of six patients. Intrapatient dose escalation was not allowed. If a patient encountered DLT, the doses of irinotecan and cisplatin were decreased one dose level at retreatment. Treatment resumed when the neutrophil count had recovered to 2.0 x 109/L and the platelet count to 100 x 109/L. In the second part of the study, after the MTD was reached, the sequence of administration of irinotecan and cisplatin was reversed. Cisplatin was administered before irinotecan at the MTD to determine sequence-dependent side effects and/or pharmacokinetic interaction. The hydration and antiemetics were administered in the same way as in the first part of the study. If no DLT was encountered, the dose was escalated further. In the third part of the study, the effect of granulocyte colony-stimulating factor (G-CSF; lenograstim) 150 µg/m2/d subcutaneously (maximum dose, 263 µg/d) on the experienced hematologic toxicity was assessed in six patients at a dose level recommended for further studies. At the dose levels studied, the nadir of the neutrocytopenia occurred in the second and third week after treatment; therefore, it was questioned whether G-CSF given from day 3 to day 13 would be sufficient to prevent neutrocytopenia. To study the effect of the timing of G-CSF on the observed neutrocytopenia, G-CSF given from day 3 to 13 in the first cycle was compared with G-CSF given from day 6 to 16 in the second cycle in the same patient.
Treatment Assessment
Pharmacokinetic Studies Plasma samples were assayed for irinotecan and 7-ethyl-10-hydroxycamptothecin (SN-38), its active metabolite, according to a validated reversed-phase high-performance liquid chromatographic method previously reported in detail.31,32 The mean overall extraction efficiencies for irinotecan and SN-38 ranged between 83.0% and 99.1%. The percentage deviation from nominal values, and the inter- and intra-assay precision for each compound, was always less than 12%. The lower limit of quantitation of irinotecan and SN-38 (total drug forms) was 2 ng/mL. Non–protein-bound and total cisplatin concentrations in plasma were determined by atomic absorption spectrometry according to the method of Reed et al,33 with modifications as previously described.34,35 Individual plasma concentrations of irinotecan and SN-38 were fit to a three-compartment model using Siphar v4.0 (SIMED, Creteil, France), as described elsewhere.36 The area under the plasma concentration–time curve (AUC) was estimated by least-squares fitting using weighting of 1/y. Total body clearance of irinotecan was calculated by dividing the dose administered by the observed AUC. Kinetic profiles of cisplatin were similarly obtained using a one- or two-compartment linear model with extended least-squares regression analysis, as reported earlier.37
Fifty-two patients entered this study between May 1996 and September 1998. Patient characteristics are listed in Table 2. One patient was not eligible because of elevated liver enzyme levels at study entry; all other patients were assessable for toxicity, and 49 patients were assessable for response. The majority of the patients were either asymptomatic or had only mild symptoms. There were 18 female patients and 33 male patients. Twenty-five patients had received prior chemo- and/or radiotherapy. At the highest dose levels studied, patients were carefully selected for study entry and most of them were not pretreated. The most common tumor type was colorectal cancer. The total number of assessable courses was 223. The median number of courses per patient was four (range, one to 10).
No DLTs were observed at the first two dose levels (Table 3). DLTs were reported for the first cycle at the following dose levels: neutropenic fever (one patient) at dose level C; neutropenic fever and grade 4 diarrhea (one patient) and nephrotoxicity (creatinine grade 2, one patient) at dose level D; neutropenic fever (two patients) and grade 3 fatigue (one patient) at dose level F; grade 3 and 4 diarrhea (two patients) and neutropenic fever (one patient) at dose level G; and grade 3 diarrhea (one patient) and neutropenic fever (one patient) at dose level H.
Eleven patients required dose reductions after experiencing DLT. Once dose reduction had taken place, these patients were evaluated for toxicity at the lower dose level.
Hematologic Toxicity
Since nonhematologic toxicities prevailed at the recommended dose level for phase II studies, ie, irinotecan 260 mg/m2 combined with cisplatin 80 mg/m2, G-CSF was not added to this dose level. Instead, G-CSF was added to the irinotecan 200 mg/m2–cisplatin 80 mg/m2 dose level, at which dose level the principal toxicity is neutropenia, to measure the effect of G-CSF on the experienced hematologic toxicity and achieved dose-intensity in six patients. G-CSF caused a reduction in both the duration and grade of myelosuppression (Table 5), resulting in a relative dose-intensity of 100%. No difference was observed when G-CSF was given on days 3 to 13 or days 6 to 16 after the start of the treatment (results not shown).
Nonhematologic Toxicity Gastrointestinal toxicity, including nausea, vomiting, and diarrhea, was the most prominent nonhematologic adverse effect. Diarrhea was one of the DLTs of this combination regimen, but it was grade 3 or 4 in only 4% of all cycles. The incidence of diarrhea increased from 42% at the first dose level to 93% to 100% at the dose levels combining irinotecan 300 mg/m2 with cisplatin 60 to 80 mg/m2 (Fig 1). Grade 3 or 4 diarrhea was observed in eight (4%) of 193 courses and occurred despite the use of a high-dose loperamide regimen. Treatment consisted of supportive care with IV administration of fluids and electrolytes. Grade 1 or 2 diarrhea occurred in 61% of the cycles and was more protracted at the higher dose levels. The median day of onset of diarrhea (all grades) was day 8 (range, days 2 to 26), and recovery was observed by day 9 (range, days 3 to 27). Nine patients received prophylactic therapy with ciprofloxacin because of late diarrhea persisting for longer than 24 hours. No cumulative intestinal toxicity was observed.
Grade 3 nausea and grade 3 or 4 vomiting were observed in 36 (16%) of the cycles, but they were transient and were no cause for dose reduction or withdrawal. One patient treated at the dose level combining irinotecan 300 mg/m2 with cisplatin 80 mg/m2 experienced grade 3 fatigue during the first course. Grade 2 or 3 fatigue was observed in six of 22 courses at the dose levels involving irinotecan 300 mg/m2. Other side effects were mucositis (grade 1 to 2, 7%), acute cholinergic-like syndrome (15%), and alopecia (grade 2, 55%). In only 11 patients (22 cycles), the acute cholinergic-like syndrome required treatment with atropine (0.25 mg subcutaneously). In all cases, atropine sulfate prevented or reduced the symptoms. There was no evidence that severe hepatic or pulmonary toxicity in any of the patients was treatment-related, and there was no evidence that irinotecan potentiated the renal and neurologic toxicity of cisplatin. The sequence of drug administration did not have a major influence on the observed toxicity. No treatment-related deaths were observed.
Antitumor Activity
Pharmacokinetics
Phase II studies have shown that, apart from antitumor activity in colorectal cancer, irinotecan also has activity in non–small-cell and small-cell lung cancer, cervical, gastric and ovarian cancer, and lymphoma, tumor types in which cisplatin also exerts substantial activity. The different toxicity profiles and the lack of cross-resistance further support the use of these agents in combination. Preclinical studies demonstrated that combining irinotecan and its major active metabolite, SN-38, with platinum derivatives resulted in synergistic cytotoxicity in several human tumor cell lines and human xenograft tumor models. Previous phase I studies on the combination of irinotecan and cisplatin used various schedules of administration with an emphasis on fractionated dosing. In all studies, irinotecan preceded the infusion of cisplatin. However, preclinical data on drug interactions between topoisomerase I inhibitors and platinum derivatives seem to suggest a possible sequence-dependent effect. The potential importance of sequence dependence in the clinical setting has been investigated only for the combination of cisplatin and topotecan, revealing enhanced myelosuppression when cisplatin administration preceded topotecan. Pharmacokinetic data suggested that the differences in toxicity were due in part to lower topotecan clearance when cisplatin was given before topotecan.39 The phase I study described in this article was performed to assess the feasibility of combining cisplatin and irinotecan in a 3-week schedule, to determine the MTD and side effects of the combination, to investigate sequence-dependent effects, and to study the impact of G-CSF administration on the observed hematologic toxicity at the dose recommended for further studies. The DLT in this study was a combination of neutropenic fever, fatigue, and diarrhea at the dose level combining irinotecan 300 mg/m2 with cisplatin 80 mg/m2. Dose reduction of cisplatin to 60 mg/m2 also resulted in DLT. At all dose levels, grade 3 to 4 neutropenia was observed ranging from 44% of the cycles at the first dose level to 85% at the higher dose levels, with a median duration of the nadir of 7 days. The median time to neutrophil nadir was 18 days (range, 7 to 23 days) at all dose levels. Compared with the median time to neutrophil nadir of 8 days (range, 5 to 28 days) after treatment with single-agent irinotecan at a dose of 350 mg/m2 every 3 weeks,40 the nadir in our study was delayed. In regard to the high percentage of grade 3 and 4 neutropenia observed, the incidence of neutropenic fever was strikingly low. The concomitant occurrence of neutropenia and diarrhea, indicative of a damaged intestinal mucosa, seemed to predestine patients treated with single-agent irinotecan to the development of neutropenic fever. The delayed neutrophil nadir in our study reduced the period of overlapping neutropenia and diarrhea (Fig. 2) and might reduce patients’ risk of developing neutropenic fever. The hematologic toxicity was comparable to that observed in a phase II study combining irinotecan 60 mg/m2 on days 1, 8, and 15 with cisplatin 60 mg/m2 on day 1 every 28 days (grade 3 or 4 neutropenia, 77% of the cycles; grade 3 or 4 thrombocytopenia, 12%).27
Diarrhea was also considered a DLT. However, grade 3 or 4 diarrhea was observed in only 4% of the cycles, but in these instances, it occurred despite the vigorous administration of loperamide. In phase I studies combining the weekly administration of irinotecan with cisplatin, diarrhea was not dose-limiting. However, in a subsequent phase II study, Kudoh et al27 reported an incidence of diarrhea of 76% among patients, with grade 3 or 4 diarrhea occurring in 19%. Single-agent therapy with irinotecan at a dose of 350 mg/m2 once every 3 weeks is complicated by grade 3 or 4 diarrhea in 22% of cycles.40,41 The incidence of grade 3 and 4 diarrhea in our study compared favorably to these data. No relationship could be demonstrated between the occurrence of the delayed-onset diarrhea and the biliary index of SN-38 (data not shown).42 The sequence of drug administration had no apparent influence on severity and frequency of the observed side effects. Since the nonhematologic side effects dominated at the irinotecan 260 mg/m2–cisplatin 80 mg/m2 recommended dose level, it was not considered advantageous to add G-CSF to this dose level. However, since this dose level is only feasible in highly selected (WHO performance status 0), chemotherapy-naive patients, we expanded the number of patients treated at the irinotecan 200 mg/m2–cisplatin 80 mg/m2 dose level and studied the effect of additional G-CSF on the observed hematologic toxicity and achieved dose-intensity at that dose level. Considering the median time to neutrophil nadir of 18 days at all studied dose levels, it was unclear whether early administration of G-CSF on days 3 to 13 could adequately prevent neutropenia. To study the effect of the timing of G-CSF use on hematologic toxicity, each patient received G-CSF on days 3 to13 in the first course and on days 6 to 16 in the second course. G-CSF use resulted in a reduction of the grade and duration of the myelosuppression, enabling optimal administration of both agents without treatment delay. The timing of G-CSF use had no apparent influence on the reduction of the hematologic toxicity. In this study, at the recommended dose level (irinotecan 260 mg/m2 and cisplatin 80 mg/m2), the median doses of irinotecan and cisplatin given during all cycles were 84 mg/m2/wk and 27 mg/m2/wk, respectively; at the dose level combining irinotecan 200 mg/m2 and cisplatin 80 mg/m2, the median doses were 50 mg/m2/wk and 27 mg/m2/wk, respectively. This compares favorably to the reported planned dose-intensity in earlier phase I trials studying the fractionated administration of irinotecan in combination with cisplatin, taking into account the data on absence of prior chemotherapy and on the performance score of the patient population in those trials which seem similar compared to ours.15-24 In these studies, only the planned dose-intensity of irinotecan and cisplatin was reported, and it varied between 25 to 60 mg/m2/wk for irinotecan and 15 to 30 mg/m2/wk for cisplatin (Fig 3).
In the present study, irinotecan and SN-38, its active metabolite, demonstrated linear and dose-independent pharmacokinetics over the dose range studied that were comparable to single-agent data.43,44 Even though we did not study either agent alone, our data do suggest that there is no apparent interaction. This is in contrast with the results reported by Masuda et al,16 who described an unexpected increase in plasma SN-38 levels after only a slight increase in the irinotecan dose. Comparison of the metabolic ratio of the conversion of irinotecan to SN-38 was recently considered to be a reliable parameter for determining a pharmacokinetic interaction.43 However, a comparison of the metabolic ratio of combination therapy and single-agent therapy did not reveal any difference indicative of a pharmacokinetic interaction. Also, the pharmacokinetic data on cisplatin in our study were comparable to single-agent data. Reversing the administration sequence of irinotecan and cisplatin did not seem to have any influence on the pharmacokinetic data. To determine more precisely whether the sequence of drug administration has an impact on the pharmacokinetic or metabolic interaction between irinotecan and cisplatin, a study is currently being conducted in which patients are treated in a cross-over design with cisplatin given either before or after irinotecan. Antitumor responses to the combination of irinotecan and cisplatin were observed in a variety of tumor types. Remarkably, complete responses were achieved in a patient with small-cell carcinoma of the bladder and a patient with rectal basaloid cell carcinoma. In conclusion, in this phase I study on the combination of irinotecan and cisplatin administered once every 3 weeks, the DLT was a combination of neutropenic fever, diarrhea, and fatigue. The recommended doses for phase II studies are irinotecan 260 mg/m2 and cisplatin 80 mg/m2 in nonpretreated patients in good physical condition (WHO performance status 0). In other patients, an irinotecan dose of 200 mg/m2 combined with a cisplatin dose of 80 mg/m2 should be considered. Addition of G-CSF at this dose level substantially reduces the hematologic side effects and should be considered if one aims to optimize dose-intensity.
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TOP
ABSTRACT
INTRODUCTION
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