A Phase I and Pharmacokinetic Study of Irinotecan Given As a 7-Day

Vol. 10, 1657–1663, March 1, 2004 Clinical Cancer Research 1657

A Phase I and Pharmacokinetic Study of Irinotecan Given as a 7-Day Continuous Infusion in Metastatic Colorectal Cancer Patients Pretreated with 5-Fluorouracil or Raltitrexed

Gianluca Masi,1 Alfredo Falcone,1 for activity, and we observed 3 (25%) partial responses, 2 Antonello Di Paolo,2 Giacomo Allegrini,1 (17%) minor responses, and 4 (33%) disease stabilizations. Romano Danesi,2 Cecilia Barbara,2 Conclusions: The administration of irinotecan as a 1 2 7-day continuous infusion every 21 days is feasible with Samanta Cupini, and Mario Del Tacca diarrhea being the dose-limiting toxicity; recommended 1Division of Medical Oncology, Department of Oncology, Civil 2 2 dose for Phase II studies is 20.0 mg/m /day. The comparison Hospital, Livorno, and Division of Pharmacology and of the present data with those obtained after a standard Chemotherapy, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy 30–90 min. i.v. infusion of irinotecan demonstrates that continuous infusion improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of ABSTRACT the active metabolite. Antitumor activity in pretreated met- Purpose: The purpose is to determine the plasma phar- astatic colorectal cancer patients is encouraging. macokinetics, the maximum-tolerable dose and to preliminary evaluate the antitumor activity of irinotecan admin- INTRODUCTION istered as a 7-day continuous infusion every 21 days in Irinotecan (CPT-11), a semisynthetic derivative of the nat- metastatic colorectal cancer patients pretreated with 5- ural alkaloid camptothecin, is a selective inhibitor of topoi- fluorouracil or raltitrexed. somerase I, a nuclear enzyme responsible for relaxation of Experimental Design: A total of 13 patients entered the supercoiled DNA during replication and transcription (1, 2). study. Three received irinotecan at 20 mg/m2/day (dose level Irinotecan has a broad spectrum of activity against solid I), 6 at 25 mg/m2/day (dose level II), and 4 at 22.5 mg/m2/day tumors; in particular, Phase III randomized studies in ad- (dose level III). In 8 patients, plasma levels of irinotecan and vanced colorectal cancer demonstrated improved survival its metabolites SN-38 and SN-38 glucuronide (SN-38glu) with irinotecan compared with best supportive care or 5- were measured by high-performance liquid chromatog- fluorouracil (5-FU) continuous infusion in patients pretreated raphy and main pharmacokinetic parameters, including with 5-FU (3, 4) and superior efficacy for the combination of steady-state concentration, area under the time-concentra- irinotecan/5-FU/leucovorin versus 5-FU/leucovorin in terms tion curve, and clearance, were calculated and normalized to of response rate, time to disease progression, and survival in the dose level of 22.5 mg/m2/day. chemotherapy-naõ¬ve patients (5, 6). Results: Dose-limiting toxicity was grade 3–4 diarrhea, In vivo irinotecan is enzymatically converted to its ac- which occurred in 4 of 6 patients at dose level II and in 2 of tive metabolite SN-38 by carboxyl-esterase (CE); SN-38 4 patients at dose level III. Therefore, we defined 22.5 mg/ forms reversible complexes with DNA/topoisomerase I that m2/day the maximum-tolerable dose and 20.0 mg/m2/day the generates single-strand breaks in the DNA. Then, cell death recommended dose for Phase II studies. Hematological tox- occurs when the DNA replication fork reaches the SN-38/ icity was rare. The pharmacokinetic data provided evidence DNA-topoisomerase I cleavable complexes, resulting in irre- that continuous infusion increased the metabolism of irino- versible double-strand breaks. This process may require sev- tecan to SN-38 with respect to standard 30/90-min adminis- eral hours or days to be completed, and although irinotecan tration. Indeed, the steady-state concentration of irinotecan, and SN-38 have terminal half-lives of ϳ6Ð13 and 12Ð24 h, -SN-38, and SN-38glu were 42.7 ؎ 25.2, 14.9 ؎ 1.9, and respectively, after a short i.v. infusion (7Ð9), a more pro nmol/liter, respectively, and the area under the longed exposure might enhance the formation of lethal strand 3.5 ؎ 31.7 time-concentration curves of irinotecan, SN-38, and SN- breaks and cytotoxicity because of the increasing number of .(38glu were 6.94 ؎ 0.41, 1.92 ؎ 0.30, and 4.23 ؎ 0.52 cells entering into the S phase of the mitotic cycle (10, 11 hx␮mol/liter, respectively. Twelve patients were evaluable Some in vitro and in vivo studies suggest that camptothecin derivatives bind topoisomerase I predominantly in actively transcribed genes (12) and that irinotecan is more effective when administered in prolonged infusion schedules in tumor- Received 12/23/02; revised 10/20/03; accepted 11/26/03. bearing mice (13, 14). Furthermore, longer infusions produce The costs of publication of this article were defrayed in part by the lower peak-plasma drug concentration, and this might over- payment of page charges. This article must therefore be hereby marked come the rate-limiting enzyme deacetylation of irinotecan to advertisement in accordance with 18 U.S.C. Section 1734 solely to SN-38 (15) allowing a more efficient drug activation. Clini- indicate this fact. Requests for reprints: Gianluca Masi, Division of Medical Oncology, cal studies did not confirm the improved activity of irinote- Civil Hospital, Viale Alfieri, 36, 57121 Livorno, Italy. Phone: 39-0586- can administered as protracted infusion observed in tumor- 223458; Fax: 39-0586-223457; E-mail: [email protected]. bearing mice, but in the clinical setting, this method of

administration of irinotecan was evaluated only in small tients recruited at the immediately lower dose level had com- Phase I studies, including heavily pretreated patients; there- pleted at least the first cycle (21 days). At least 3 new patients fore, a proper evaluation of antitumor activity of infusional were recruited for each dose level. Three additional patients (for irinotecan is lacking. a total of 6) were treated at a dose level if 1 of the first 3 patients Two Phase I and pharmacokinetic trials in adult patients exhibited DLT. The MTD was defined as the dose level asso- with solid tumors demonstrated that the administration of irino- ciated with the same DLT in at least 2 of 3Ð6 patients. DLT was tecan as a prolonged i.v. infusion (96 h and 14 days) is feasible defined as any National Cancer Institute-Common Toxicity Cri- with diarrhea being the dose-limiting toxicity (DLT) and with teria grade 3Ð4 nonhematological toxicity, except for alopecia promising antitumor activity, especially in colorectal cancer and vomiting, any grade 4 neutropenia lasting Ͼ 5 days, or patients. Pharmacokinetic analysis showed a greater SN-38/ associated with fever Ն 38¡C and any grade 4 thrombocytope- irinotecan area under the time-concentration curve (AUC) ratio nia occurring at any time during all of the treatment period. 2 (0.24 and 0.16, 96 h versus 14 days, respectively) compared After achieving the MTD at 25 mg/m /day, in consideration of 2 with the values observed after a 30Ð90 min infusion (approxi- the good tolerability of the starting dose of 20 mg/m /day, the mately 0.03Ð0.09) suggesting a more extensive metabolism of protocol was amended, and additional patients were treated at 2 irinotecan to SN-38 (16, 17). This observation may confirm the the intermediate dose of 22.5 mg/m /day. Therefore, the follow- 2 hypothesis of rate-limiting conversion of irinotecan to SN-38 ing dose levels were evaluated: 20 mg/m /day for 7 days (dose 2 and may explain, at least in part, the low dose-intensities achiev- level I); 25 mg/m /day for 7 days (dose level II); and 22.5 2 able with the continuous infusion schedules. mg/m /day for 7 days (dose level III). These findings demonstrate that protracted infusion are Treatment was administered every 3 weeks for a maximum associated to better irinotecan activation, but the schedules of nine cycles until evidence of disease progression, unaccept- evaluated in previous Phase I studies may be discommoding for able toxicity, or patient refusal. Treatment was delayed in case the patient and for the health care facilities. To evaluate a more one or more of the following were present on the day of drug 3 convenient schedule of irinotecan administration, we initiated a administration: neutrophils Ͻ 1,000/mm ; platelets Ͻ 100,000/ 3 Phase I study to define the maximum-tolerable dose (MTD) of mm ; and persistent diarrhea or stomatitis Ͼ grade 1. In case of irinotecan administered as a 7-day continuous infusion every 21 DLT, treatment was continued, after recovery, at the immedi- days, to determine the plasma pharmacokinetics of irinotecan, ately lower dose level or reduced by 25%. In case of life- SN-38 and SN-38 glucuronide (SN-38glu), and to preliminary threatening toxicities, treatment was discontinued or the dose evaluate the antitumor activity of this treatment in metastatic was reduced by 50%. colorectal cancer patients pretreated with 5-FU or raltitrexed. Neither antiemetic premedication nor prophylactic treatment with granulocyte colony-stimulating factor was routinely administered. In case of diarrhea, at the time of the first loose PATIENTS AND METHODS stool, patients were instructed to take 4 mg of loperamide Patients Selection. Main eligibility criteria included: followed by 2 mg every 2 h. Patients were allowed to stop taking histologically confirmed diagnosis of colorectal adenocarci- loperamide 12 h after the last episode of diarrhea. If diarrhea noma with metastatic disease, age Ͻ 75 years, Eastern Cooper- persisted for Ͼ 24 h despite loperamide treatment, patients were ative Oncology Group performance status Յ 2, measurable dis- treated with ciprofloxacin. If diarrhea persisted for Ͼ 48 h ease, leukocyte count Ն 3500/mm3, neutrophils count Ն 1500/ despite loperamide and ciprofloxacin treatment, patients were mm3, platelet count Ն 100,000/mm3, serum creatinine Յ 1.3 hospitalized for i.v. rehydration and treatment with octreotide. mg/dl, serum bilirubin Յ 1.5 mg/dl and aspartate aminotrans- Drug Administration. Irinotecan (Campto; Aventis ferase, alanine aminotransferase, and alkaline phosphatase Pharma, Italy) was supplied in 5-ml vials as a concentrated Յ 2.5 times normal values (Յ 5 times normal values if liver sterile solution, containing irinotecan 100 mg as the free base metastases were present), previous palliative chemotherapy with and sorbitol, lactic acid, and sterile water for injection. The 5-FUϩ/ϪLV or raltitrexed. Exclusion criteria were as follows: appropriate volume of irinotecan solution was transferred to a previous chemotherapy including irinotecan; symptomatic car- 100-ml pump reservoir. Final dilution to a total volume of 75 ml diac disease; myocardial infarction during the last 24 months; was made with 0.9% sodium chloride solution. The reservoir uncontrolled arrhythmia; active infections; inflammatory bowel was connected to a CADD-PLUS ambulatory infusion pump disease; and total colectomy. The study was approved by the (Deltec, Inc., St. Paul, MN) and infused for 7 days through an local Ethics Committee, and patients were informed of the implantable central venous catheter. In these conditions, irino- investigational nature of the trial and provided their written tecan is stable for extended periods of time (18). informed consent before registration onto the study. Assessability, Toxicity, and Response Criteria. Pre- Treatment and Dose Escalation. The starting dose of treatment evaluation included history and physical examination, irinotecan was 20 mg/m2/day given as a 7-day continuous performance status assessment, complete blood cell with differ- infusion (140 mg/m2 cumulative dose) repeated every 3 weeks. ential and platelet counts, complete blood profile, carcinoem- This dose represented 40% of the dose intensity achieved with bryonic antigen, urinalysis, electrocardiogram, chest X-ray or the recommended dose of 350 mg/m2 administered as a 30Ð90 computed tomography scan, abdominal computed tomography min infusion every 3 weeks and a similar dose intensity achiev- scan and/or magnetic resonance imaging, and any other appro- able with a 14 days continuous infusion (16). The dose was priate diagnostic procedure to evaluate metastatic sites. During escalated of 5 mg/m2/day in subsequent groups of patients up to treatment, a physical examination was performed every 3 determine MTD. Dose escalation was permitted only once pa- weeks, a complete blood cell count every week, and blood

profile and urine analysis every 3 weeks. Toxicities were mon- Table 1 Patient’s characteristics itored weekly and were scored according to standard National n Cancer Institute-Common Toxicity Criteria. Responses were Patients 13 assessed and evaluated every 9 weeks according to WHO cri- Male/Female 10/3 teria (19). For the evaluation of liver metastases, an abdominal Age, years computed tomography scan or magnetic resonance imaging was Median 60 Range 45Ð71 required. A chest X-ray and/or an abdominal sonogram or a computed tomography scan were repeated at least every 6 ECOG performance status 08 months if there was no evidence of lung or abdominal disease, 15 respectively. Primary Pharmacokinetics. Pharmacokinetic analysis of irinote- Colon 9 can and their metabolites, SN-38 and SN-38glu was performed Rectum 4 Previous surgery on primary tumor 13 in 8 patients receiving irinotecan at the doses of 20, 22.5, and 25 Number of metastatic sites 2 mg/m /day for 7 days. Blood was withdrawn from a peripheral Single 2 catheter placed in a vein of the forearm at baseline, 24, 72, 120, Multiple 11 and 168 h (end of infusion) and 30 min, and 1 and 2 h after the Sites of disease end of drug administration. Blood samples were centrifuged and Liver 12 Lung 6 plasma was stored at Ϫ20¡C until irinotecan and metabolite Abdomen 6 concentrations were determined by high-performance liquid Other 1 chromatography previously described with minor modifications Liver involvement Ͻ (20). To increase the lower limit of quantitation, 1 ml of plasma 25% 4 ␮ 25Ð50% 6 was used instead of 100 l. Plasma irinotecan and SN-38 were Ͼ50% 2 extracted from plasma with methanol containing 0.1% HCl 10 Previous chemotherapy N; the samples were centrifuged, and the clear supernatant was 5-FU/LV bolus 6 evaporated under nitrogen flow at 45¡C. The dried pellet was 5-FU c.i. 4 5-FU/LV bolus and 5-FU c.i. 1 reconstituted in methanol acidified with 0.1% HCl 10 N and Reltitrexed 2 ␮ ϫ eluted through a Bondapack C18 stationary phase (300 3.9 Previous radiotherapy 4 ␮ mm, 10 m; Waters, Milford, MA) by KH2PO4 0.1 M/acetoni- CEA, ng/ml trile (65:35, v/v) pH 4.0, containing 3 mM sodium heptansul- Median 19 fonate. The chromatographic system LC Module I Plus (Waters) Range (4.5Ð720) Courses administered 63 was equipped with a model 474 scanning fluorescence detector Courses/patient (excitation and emission wavelengths, 375 and 525 nm, respec- Median 5 tively). Data analysis was performed by the Millennium 2.1 Range 1Ð8 software (Waters). The SN-38glu plasma concentration was a ECOG, Eastern Cooperative Oncology Group; CEA, carcinoem- measured as described above after incubation of plasma samples bryonic antigen; c.i., continuous infusion; 5-FU, 5-fluorouracil; LV, with ␤-glucuronidase (1000 UI/100 ␮l of plasma) at 37¡C for leucovorin. 2 h before extraction. The difference between peak heights corresponding to SN-38 in ␤-glucuronidase-treated versus un- treated samples corresponded to the plasma levels of SN-38glu. The high-performance liquid chromatography method used Finally, the ratio between the AUC values of SN-38glu and SN-38 in the present study allowed a reproducible and sensitive meas- was calculated to obtain an indirect estimate of the activity of urement of plasma concentration of the drug and its metabolite. glucuronidation of the active metabolite SN-38. Coefficients of variation for irinotecan and SN-38 accounted for 7.8 and 12.5%, respectively, whereas lower limits of quantita- RESULTS tion were 1.36 and 0.41 nmol/liter, and the recovery was 87 and Patients and Toxicity. A total of 13 patients with met- 79% for irinotecan and SN-38, respectively. astatic colorectal adenocarcinoma entered the study. Patients Individual plasma concentrations of irinotecan, SN-38, and characteristics are listed in Table 1. All patients completed at SN-38glu were normalized to the dose of 22.5 mg/m2 and the AUC least one cycle of chemotherapy and were evaluable for toxicity. of irinotecan, SN-38, and SN-38glu from 0 to 170 h was calculated Overall, 63 courses of irinotecan therapy were administered by the log-linear trapezoidal method until the last sampling time. with a median of five cycles/patient (range, one to eight cycles).

Peak plasma concentration (Cmax) was obtained by visual inspec- One patient received only one cycle of chemotherapy because of tion of the concentration versus time profile of irinotecan and central venous catheter thrombosis, and he was subsequently

metabolites, whereas steady-state concentrations (Css) were calcu- treated with irinotecan 90-min infusion through a peripheral lated as mean values of plasma levels at 72, 120, and 168 h of vein of the forearm, whereas 2 patients received only two infusion. Finally, the clearance of irinotecan (Cl) was determined as courses of irinotecan treatment because of rapidly progressive

the infusion rate of the drug divided by its Css value (16). The disease. relative extent of metabolic conversion (REC) of irinotecan was The DLT was grade 3Ð4 delayed diarrhea. At the first dose 2 calculated as AUCSN-38/AUCCPT-11, whereas the drug metabolic level (20 mg/m /day), DLTs were not observed; therefore, sub- ϩ 2 ratio was obtained as (AUCSN-38 AUCSN-38glu)/AUCCPT-11 (16). sequent patients (6) were treated at 25.0 mg/m /day, and 1 case

of grade 4 diarrhea and 3 cases of grade 3 diarrhea occurred. Table 3 Overall maximum toxicity/patient (13 evaluable patients) Because of the absence of DLTs at the starting dose level and National Cancer Institute—Common 2 the high incidence of grade 3Ð4 diarrhea at 25.0 mg/m /day, 3 Toxicity Criteria grade (%) additional patients were treated at the intermediate dose level of Adverse event 1234 22.5 mg/m2/day to better define the MTD of irinotecan. At this dose level 1 patient experienced grade 3 delayed diarrhea, and n (%) n (%) n (%) n (%) Diarrhea 2 (15) 4 (31) 5 (38) 1 (8) we planned the enrollment of 3 additional patients at the same Nausea/vomiting 9 (69) 3 (23) 1 (8) 0 dose level, but after the recruitment of the fourth patient, we Asthenia 5 (38) 3 (23) 0 0 observed a second case of grade 3 diarrhea that occurred during Alopecia 2 (15) 2 (15) the third cycle. Therefore, we defined 22.5 mg/m2/day the MTD Cholinergic syndrome 0 0 0 0 and 20.0 mg/m2/day the recommended dose for Phase II studies. Thrombocytopenia 0 0 0 0 Neutropeniaa 2 (15) 4 (31) 1 (8) 0 Three additional patients initially treated at the irinotecan dose- a level of 25.0 and 22.5 mg/m2/day received, after dose reduction Febrile neutropenia: 0. for diarrhea, irinotecan at 20.0 mg/m2/day. At this dose, irinotecan was well tolerated thus confirming that the dose of 20.0 mg/m2/day administered as a 7-day continuous infusion every Table 4 Objective responses (12 evaluable patients) 21 days has a good toxicity profile and can be recommended for 2 additional studies. Table 2 summarizes the frequency and se- Irinotecan dose (mg/m /day) verity of DLTs/dose level. Overall 20.0 22.5 25.0 Delayed diarrhea developed 8Ð14 days after the start of irinotecan infusion and lasted for a median of 4 days (range, Response (WHO) n (%) nnn 1Ð24 days). Diarrhea generally responded to high-dose loper- Complete 0 amide, but 4 patients (five courses) needed additional treatment Partial 3 (25%) 3 Minor 2 (17%) 1 1 with ciprofloxacin and octreotide. No symptoms of cholinergic Stable 4 (33%) 2 2 syndrome (early onset diarrhea, flushing, or diaphoresis) were Progression 3 (25%) 1 2 observed. Grade 2 and 3 nausea and/or vomiting occurred, respectively, in 3 (23%) and 1 (8%) patients and responded well to standard antiemetics; on the contrary, grade 1 nausea occurred disease), 4 (33%) disease stabilizations, and 3 (25%) progres- in 69% of patients and was scarcely manageable with standard sions. All responses, except one minor response, were observed 2 treatment. Hematological toxicity was rare; one episode of grade at the dose level of 25.0 mg/m /day (Table 4). Responses lasted 3 neutropenia occurred, whereas no episodes of thrombocyto- a median of 6.0 months (range, 2.2Ð11.0 months). penia were observed, thus, granulocyte colony-stimulating fac- Pharmacokinetics. Main pharmacokinetic parameters of tor support was never required. Other observed toxicities were irinotecan and its metabolites are reported in Table 5, whereas grade 1Ð2 asthenia, occurring respectively in 5 (38%) and 3 the plasma profiles of irinotecan, SN-38, and SN-38glu are (23%) patients, and grade 1Ð2 alopecia in 4 (30%) patients shown in Fig. 1. Pharmacokinetic analysis demonstrated that the Ϯ (Table 3). Nine (14%) cycles were delayed of at least 1 week Css of irinotecan was 42.7 25.2 nmol/liter, whereas those of Ϯ Ϯ because of unresolved toxicities and 21 (33%) cycles and 7 SN-38 and SN-38glu were 14.88 1.85 and 31.72 3.47 (54%) patients required dose reductions because of diarrhea. nmol/liter, respectively. Moreover, the mean ratio of AUCSN-38 Ϯ Four patients were hospitalized because of diarrhea, but no toxic and AUCCPT-11 (REC) was 0.28 0.03, whereas irinotecan Ϯ 2 deaths occurred. clearance was 45.3 26.7 l/h/m . Finally, the drug metabolic Ϯ Antitumor Activity. Among the 12 patients evaluable ratio and the ratio of SN-38/SN-38glu were 0.88 0.07 and Ϯ for activity (1 patient not evaluable because of central venous 0.46 0.02, respectively. catheter thrombosis, and he was subsequently treated with irinotecan 90-min infusion through a peripheral vein of the fore- DISCUSSION arm), we observed 3 (25%) partial responses, 2 (17%) minor Irinotecan administered as a 30Ð90-min infusion has dem- responses (minor response was defined as 25Ð50% reduction in onstrated activity against a variety of solid tumors and has been approved in the majority of countries worldwide for the first and second line treatment of advanced colorectal cancer (21). De- velopment of strategies to enhance the efficacy of this drug is an Table 2 Dose levels and dose-limiting toxicities (DLTs) important issue. Irinotecan is a S-phase-specific agent, and given that only a fraction of cancer cells in a solid tumor are Dose Irinotecan dose No. of No. of level (mg/m2/day) patients DLTs Type of DLT actively synthesizing DNA at any given time, prolonged exposure could result in enhanced cytotoxicity of these drugs. Pre- I 20.0 3 ϩ 3a 0 None II 25.0 6 4 Grade 3Ð4 diarrhea clinical data in human tumor xenografts suggest that the activity III 22.5 4 2 Grade 3 diarrhea of topoisomerase I inhibitors is highly schedule-dependent and a Three additional patients initially treated at the II or III dose level protracted infusional schedules may be more effective (13, 14, of irinotecan received additional treatment at 20.0 mg/m2/day after dose 22, 23). Two Phase I and pharmacokinetic trials in adult patients reduction for diarrhea. with solid tumors demonstrated the feasibility and the activity of

Table 5 Plasma pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide normalized to the dose of 22.5 mg/m2/day. Data are mean Ϯ SD. Area under the Steady-state Peak plasma

time-concentration curve0Ð170 concentrations concentration Clearance hx␮mol/liter nmol/liter nmol/liter liter/h/m2 Irinotecan 7.03 Ϯ 0.47 42.7 Ϯ 25.2 60.5 Ϯ 21.3 45.3 Ϯ 26.7 SN-38 1.96 Ϯ 0.26 14.88 Ϯ 1.85 17.9 Ϯ 1.4 SN-38 glucuronide 4.35 Ϯ 0.50 31.72 Ϯ 3.47 43.9 Ϯ 0.4

(ϳ0.03Ð0.09), thus suggesting an extensive metabolism of irinotecan to SN-38 (14, 16, 17). These observations suggested that human carboxyl-esterase enzyme could be saturable, hence, the decrease in infusion rate could be associated to an augmented production of SN-38 (16). Data from the present study revealed a higher than a 4-fold increase in the REC with a 7-day continuous infusion versus the REC in patients treated at approximately the same cumulative dose of irinotecan (150 mg/m2) administered as a 60-min i.v. infusion (0.28 versus 0.073, respectively; Ref. 20). The increase in REC was mainly because of the increment in SN-38 AUC rather than to the reduction of irinotecan AUC. Indeed, the plasma concentration of the active metabolite at the end of infusion was less than one-third with respect to the maximal plasma concentration calculated after a 60-min infusion of irinotecan 150 mg/m2. It is conceivable that lower peak concentrations of SN-38 could also surmount problems related to saturable metabolic steps (i.e., glucuronidation) or to excretion Fig. 1 Plasma levels of irinotecan (CPT-11), SN-38, and SN-38 glu- processes (i.e., those regulated by cMOAT or P-gp) involved in curonide (SN-38glu) in 8 patients receiving irinotecan 20Ð25 mg/m2/ drug elimination, hence reducing systemic toxicity (16). Indeed, day for 7 days as continuous i.v. infusion. Plasma levels were normal- the slow rate of drug infusion facilitated irinotecan conversion ized to the dose of 22.5 mg/m2/day. Plasma concentrations of irinotecan and its metabolites after a 1-h infusion at the dose of 150 mg/m2 are into SN-38 and increased drug elimination, as demonstrated by reported for comparison (20). Symbols and bars, mean and SD, respec- the increase in REC and total body clearance of irinotecan (Cl) tively. with respect to previous studies (20). Interestingly, the comparison of the present results with those reported by Takimoto et al. (16) suggests that the increase in the rate of infusion and drug irinotecan administered as an i.v. infusion of 96 h or 14 days, dose is associated with a decrease in the metabolic ratio ϩ with main DLTs being diarrhea, nausea/vomiting, and throm- (AUCSN-38 AUCSN-38glu)/AUCCPT-11 and REC and increase in bocytopenia. An interesting finding in these studies was the SN-38/SN-38glu AUC ratio. Table 6 reports the SN-38 AUC markedly increased systemic exposure to SN-38, relative to the measured with short and prolonged infusion regimens and exposure to irinotecan, achieved with a protracted infusion shows that SN-38 AUC value after a 90-min infusion of irino- schedule. Indeed, it was observed that a higher SN-38/irinotecan tecan 150 mg/m2 was lower than that obtained after the admin- AUC ratio (0.24 and 0.16 for 96 h and 14 days, respectively) istration of irinotecan 22.5 mg/m2/day for 7 consecutive days compared with the values observed after a 30 or 90-min infusion (275 Ϯ 69 versus 1920 Ϯ 300 hxnmol/liter, respectively),

Table 6 Area under the time-concentration curve (AUC) of SN-38 after administration of irinotecan by short or prolonged infusions Dose intensity SN-38 AUC Dose regimen (mg/m2/week) (nmol/liter ϫ h) Reference Irinotecan administered as prolonged i.v. infusion 22.5 mg/m2/day ϫ 7 day every 3 wk 52.5 1920 Ϯ 300a 12.5 mg/m2/day ϫ 14 day every 3 wk 58.5 2500 Ϯ 1200a 16 12.5 mg/m2/day ϫ 4 day ϫ 2 wk every 3 wk 33.3 769 Ϯ 368a 15 Irinotecan administered as 1-h i.v. infusion 150 mg/m2 every 3 wk 50 275 Ϯ 69b 19 300 mg/m2 every 3 wk 100 484 Ϯ 132b 19 a Mean Ϯ SD. b Mean Ϯ SE.

despite the dose intensity being nearly equivalent (150 versus 2. O’Leary, J., and Muggia, F. M. Camptothecins: a review of their 157.5 mg/m2 every 3 weeks, respectively); hence, to obtain the development and schedules of administration. Eur. J. Cancer, 34: 1500Ð same AUC value of SN-38, the dose of irinotecan that could be 1508, 1998. administered would be too high and tolerated poorly. 3. Cunningham, D., Pyrhonen, S., James, R. D., Punt, C. J., Hickish, T. F., Heikkila, R., Johannesen, T. B., Starkhammar, H., Topham, C. A., With regard to treatment toxicity, we found that the Awad, L., Jacques, C., and Herait, P. Randomised trial of irinotecan plus administration of irinotecan as a 7-day continuous infusion supportive care versus supportive care alone after fluorouracil failure every 21 days is feasible with diarrhea being the DLT. The for patients with metastatic colorectal cancer. Lancet, 352: 1413Ð MTD is 22.5 mg/m2/day, and the recommended dose for 1418, 1998. additional evaluation is 20 mg/m2/day. The toxicity profile of 4. Rougier, P., Van Custem, E., Bajetta, E., Niederle, N., Possinger, K., Labianca, R., Navarro, M., Morant, R., Bleiberg, H., Wils, J., this prolonged infusion schedule seems to be different from Awad, L., Herait, P., and Jacques, C. Randomised trial of irinotecan that usually reported with short i.v. infusions; in particular, versus fluorouracil by continuous infusion after fluorouracil failure we observed a higher incidence of delayed diarrhea, but in patients with metastatic colorectal cancer. Lancet, 352: 1407Ð severe myelosuppression was uncommon, and cholinergic 1412, 1998. syndrome was absent. In the present study, we did not ob- 5. Douillard, J. Y., Cunningham, D., Roth, A. D., Navarro, M., James, R. D., Karasek, P., Jandik, P., Iveson, T., Carmichael, J., Alakl, M., serve significant correlations between irinotecan or SN-38 Gruia, G., Awad, L., and Rougier, P. Irinotecan combined with fluorou- pharmacokinetics and toxicity. With regard to antitumor ac- racil compared with fluorouracil alone as first-line treatment for meta- tivity, it was encouraging in 5-FU or raltitrexed-pretreated static colorectal cancer: a multicentre randomised trial. Lancet, 355: metastatic colorectal cancer patients. 1041Ð1047, 2000. In the present study, it has been observed an increase in 6. Saltz, L. B., Cox, J. V., Blanke, C., Rosen, L. S., Fehrenbacher, L., Moore, M. J., Maroun, J. A., Ackland, S. P., Locker, P. K., Pirotta, N., REC value with respect to that calculated after a 4-day contin- Elfring, G. L., and Miller, L. L. Irinotecan plus fluorouracil and leu- uous infusion or after shorter durations (i.e., 60 or 90 min). This covorin for metastatic colorectal cancer. N. Engl. J. Med., 343: 905Ð result supports an augmented conversion of irinotecan into 914, 2000. SN-38, whereas the 7-day infusion is consistent with a pro- 7. Gupta, E., Mick, R., Ramirez, J., Wang, X., Lestingi, T. M., Vokes, longed inhibition of topoisomerase-I enzyme. It is not clear the E. E., and Ratain, M. J. Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J. Clin. impact of such metabolic alterations on clinical activity of Oncol., 15: 1502Ð1510, 1997. irinotecan, but an important finding of all studies using infu- 8. Rivory, L. P., Haaz, M. C., Canal, P., Lokiec, F., Armand, J. P., and sional irinotecan is the different toxicity profile observed with Robert, J. Pharmacokinetic interrelationships of irinotecan (CPT-11) minimal hematological toxicity. This could make more feasible and its three major plasma metabolites in patients enrolled in Phase I/II the combination of irinotecan with myelosuppressive drugs such trials. Clin. Cancer Res., 3: 1261Ð1266, 1997. 9. Sparreboom, A., de Jonge, M. J. A., de Bruijn, P., Brouwer, E., as cisplatin or taxanes, and the irinotecan/cisplatin or irinotecan/ Nooter, K., Loos, W. J., van Alphen, R. J., Mathijssen, R. H., Stoter, G., taxanes combination are actives regimens in several tumors such and Verweij, J. Irinotecan (CPT-11) metabolism and disposition in as lung cancer and gastric cancer. cancer patients. Clin. Cancer Res., 4: 2747Ð2754, 1998. In conclusion, prolonged administration seems to be a 10. Ryan, A. J., Squires, S., Strutt, H. L., and Johnson, R. T. Campto- promising method of delivering irinotecan. Although total ad- thecin cytotoxicity in mammalian cells is associated with the induction ministered doses were ϳ50Ð60% lower than those administered of persistent double strand breaks in replicating DNA. Nucleic Acids Res., 19: 3295Ð3300, 1991. with a standard 30Ð90 min infusion, biological activity was seen 11. Gerrits, C. J., de Jonge, M. J., Schellens, J. H., Stoter, G., and in terms of both toxicity and antitumor effect. The lack of severe Verweij, J. Topoisomerase I inhibitors: the relevance of prolonged myelosuppression on this infusion schedule may offer an op- exposure for present clinical development. Br. J. Cancer, 76: 952Ð portunity to combine irinotecan with more myelosuppressive 962, 1997. chemotherapeutic agents. Severe diarrhea is the most important 12. Zhang, H., Wang, J. C., and Liu, L. F. Involvement of DNA toxicity observed in this study, and new strategies to decrease its topoisomerase I in transcription of human ribosomal RNA genes. Proc. Natl. Acad. Sci. USA, 85: 1060Ð1064, 1988. incidence are needed. Preliminary results of Govindarajan et al. 13. Houghton, P. J., Cheshire, P. J., Hallman, J. D., II, Lutz, L., (24, 25) indicate a reduced incidence of gastrointestinal toxic Friedman, H. S., Danks, M. K., and Houghton, J. A. Efficacy of effects of irinotecan by the concomitant use of thalidomide, and topoisomerase I inhibitors, topotecan and irinotecan, administered we are conducting a clinical and pharmacokinetic trial to con- at low dose levels in protracted schedules to mice bearing xenografts firm these findings. The optimization of such combinations of human tumors. Cancer Chemother. Pharmacol., 36: 393Ð 403, requires careful evaluation in future trials. 1995. 14. Furuta, T., and Yokokura, T. Effect of administration schedules on the antitumor activity of CPT-11, a camptothecin derivative. Jpn. J. ACKNOWLEDGMENTS Cancer Chemother., 17: 121Ð130, 1990. 15. Rivory, L. P., Bowles, M. R., Robert, J., and Pond, S. M. Conver- We thank Michele Andreuccetti for data analysis and technical sion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxy- assistance camptothecin (SN-38), by human liver carboxylesterase. Biochem. Pharmacol., 52: 1103Ð1111, 1996. 16. Takimoto, C. H., Morrison, G., Harold, N., Quinn, M., Monahan, B. P., REFERENCES Band, R. A., Cottrell, J., Guemei, A., Llorens, V., Hehman, H., Ismail, 1. Takimoto, C. H., and Arbuck, S. G. The camptothecins. In: B. A. A. S., Flemming, D., Gosky, D. M., Hirota, H., Berger, S. J., Berger, N. A., Chabner, and D. L. Longo (eds.), Cancer Chemotherapy and Biotherapy Chen, A. P., Shapiro, J. D., Arbuck, S. G., Wright, J., Hamilton, J. M., (Ed. 2), pp. 463Ð484. Philadelphia: Lippincott-Raven, 1996. Allegra, C. J., and Grem, J. L. Phase I and pharmacologic study of

irinotecan administered as a 96-hour infusion weekly to adult cancer pa- 21. Vanhoefer, U., Harstrick, A., Achterrath, W., Cao, S., Seeber, S., tients. J. Clin. Oncol., 18: 659Ð667, 2000. and Rustum, Y. M. Irinotecan in the treatment of colorectal cancer: 17. Herben, V. M. M., Schellens, J. H. M., Swart, M., Gruia, G., clinical overview. J. Clin. Oncol., 19: 1501Ð1518, 2001. Vernillet, L., Beijnen, J. H., and ten Bokkel Huinink, W. W. Phase I and 22. Houghton, P. J., Cheshire, P. J., Hallman, J. C., Bissery, M. C., pharmacokinetic study of irinotecan administered as a low-dose, con- Mathieu-Boue, A., and Houghton, J. A. Therapeutic efficacy of the tinuous intravenous infusion over 14 days in patients with malignant topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)- solid tumors. J. Clin. Oncol., 17: 1897Ð1905, 1999. carbonyloxy-camptothecin against human tumor xenografts: lack of 18. Li, W. Y., and Koda, R. T. Stability of irinotecan hydrochloride cross-resistance in vivo in tumors with acquired resistance to the topoi- in aqueous solutions. Am. J. Health Syst. Pharm., 59: 539Ð544, somerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin. 2002. Cancer Res., 53: 2823Ð2829, 1993. 19. Miller, A. B., Hoogstraten, B., Staquet, M., and Winkler, A. 23. Kawato, Y., Furuta, T., Aonuma, M., Yasuoka, M., Yokokura, T., Reporting results of cancer treatment. Cancer (Phila.), 47: 207Ð214, and Matsumoto, K. Antitumor activity of a camptothecin derivative, 1981. CPT-11, against human tumor xenografts in nude mice. Cancer 20. Falcone, A., Di Paolo, A., Masi, G., Allegrini, G., Danesi, Chemother. Pharmacol., 28: 192Ð198, 1991. R., Lencioni, M., Pfanner, E., Comis, S., Del Tacca, M., and Conte, 24. Govindarajan, R. Irinotecan and thalidomide in metastatic colorec- P. Sequence effect of irinotecan and 5-fluorouracil treatment tal cancer. Oncology (Basel), 14 (12 Suppl. 13): 29Ð32, 2000. on pharmacokinetics and toxicity in chemotherapy-naive meta- 25. Govindarajan, R., Heaton, K. M., Broadwater, R., Zeitlin, A., Lang, static colorectal cancer patients. J. Clin. Oncol., 19: 3456Ð3462, N. P., and Hauer-Jensen, M. Effect of thalidomide on gastrointestinal 2001. toxic effects of irinotecan. Lancet, 356: 566Ð567, 2000.

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Gianluca Masi, Alfredo Falcone, Antonello Di Paolo, et al.

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