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. Author manuscript; available in PMC: 2009 Aug 5.
Published in final edited form as: J Neurooncol. 2008 Dec 10;92(2):165–175. doi: 10.1007/s11060-008-9749-4

Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results

Marta Santisteban 1,2, Jan C Buckner 1, Joel M Reid 1, Wenting Wu 1, Bernd W Scheithauer 1, Matthew M Ames 1, Sara J Felten 1, Daniel A Nikcevich 3, Martin Wiesenfeld 4, Kurt A Jaeckle 5, Evanthia Galanis 1,✉
PMCID: PMC2721337  NIHMSID: NIHMS130705  PMID: 19066728

Abstract

Purpose

The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment.

Methods

Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal.

Results

There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3–4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule.

Conclusions

Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.

Keywords: Enzyme-inducing antiepileptic drugs, Dexamethasone, Irinotecan, Pharmacokinetics, Recurrent gliomas

Introduction

Recurrent gliomas are associated with significant morbidity and mortality and most patients will eventually succumb to their disease [1]. Treatment options for recurrent disease are limited and with few exceptions have limited impact on duration and quality of the patients’ life [2, 3].

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin that is hydrolyzed after administration by carboxylesterases to its more active metabolite SN-38. The parent molecule is metabolized by cytochrome P450 3A4 to form the metabolite APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxy-campto-thecin) and SN-38 is conjugated with glucuronic acid by glucuronosyl transferase UGT1A1 to form SN-38 glucuronide (SN-38G). Irinotecan’s mechanism of action, i.e., inhibition of topoisomerase-I, a nuclear enzyme that plays a critical role in DNA replication and transcription [4, 5] differs from other chemotherapy agents employed in glioma treatment. In addition, its lipophilic nature and its low molecular weight result in excellent CNS penetration. Both single agent trials [6–12] and combination studies of CPT-11 with BCNU [13–15], temozolomide [16, 17], topoisomerase-II inhibitors [18] and celecoxib [19] in recurrent malignant gliomas have resulted in variable response rates varying from 7% to 21%. Recently, the addition of the antiangiogenic monoclonal antibody bevacizumab to CPT-11 has resulted in a 40–63% response rate with a 6-month progression free survival (PFS6) of 38–46% and acceptable toxicity [20–22] thus potentially opening new directions in recurrent glioma treatment. This wide variability of antitumor activity in response to irinotecan or irinotecan containing regimens could be explained on the basis of pharmacokinetic variations: first, a significant percentage of glioma patients receive concurrently anticonvulsants and corti-costeroids that induce hepatic enzymes involved in the metabolism or excretion of the CPT-11 [23]; furthermore the different administration schedules that have been employed could have affected the antitumor efficacy, since camptothecins are specific for the S-phase of the cell cycle [24].

The primary objective of this multicenter phase II trial was to evaluate the efficacy and toxicity of two different administration schedules of CPT-11 in recurrent glioma patients. Secondary goals include pharmacokinetic analysis of the impact of enzyme-inducing antiepileptic drugs (EIAEDs) and steroids and its association with toxicity and response to therapy.

Patients and methods

Eligibility criteria

Patients were eligible for inclusion in this study if they had a recurrent glioma with histologic confirmation at initial diagnosis and/or on recurrence to include astrocytoma, oligodendroglioma, mixed glioma, or gliosarcoma. Pathology material was reexamined at the time of study entry by the same neuropathologist (B.W.S.) to confirm histologic diagnosis. Patients had to be 18 years of age or older; have an Eastern Cooperative Group (ECOG) performance status (PS) of 0, 1 or 2; absolute neutrophil count and platelet count greater than 1,500/mm3 and 100,000/mm3 respectively, hemoglobin ≥ 9 g/dl, serum creatinine level ≤ 2 mg/dl, serum total bilirubin level ≤ 1.5 mg/dl and aspartate aminotransferase level less than 3 times the institutional upper normal limits. Patients had to be on a fixed dose of corticosteroids (or no corticosteroids) for at least 2 weeks prior to baseline scan. Up to one adjuvant chemotherapy regimen and one regimen for recurrent disease was allowed. At least 8 weeks should have elapsed from completion of RT, and at least 4 weeks from last chemotherapy administration (6 weeks for nitrosurea containing regimens). Exclusion criteria included prior use of CPT-11, topotecan or 9-aminocamptothecin. Other contraindications included pregnant or nursing women, uncontrolled infection, myocardial infarction within the previous 6 months, congestive heart failure requiring therapy, history of Gilbert’s syndrome and the presence of other active malignancy. The study was approved by the institutional review boards, and all patients signed an informed consent form prior to enrolment.

Treatment schedule

Patients received irinotecan according to one of two different schedules. The two schedules (A and B) opened sequentially to accrual. Patients in schedule A received irinotecan at a dose of 100 mg/m2 if they have had prior treatment with nitrosoureas or 125 mg/m2 (if no prior nitrosoureas) by 90-min intravenous infusion every week for 4 weeks with a two week rest period between courses. Patients in schedule B received irinotecan at a dose of either 250 mg/m2 (prior nitrosoureas) or 300 mg/m2 (no prior nitrosoureas) by 90 min intravenous infusion every 3 weeks. If dose limiting toxicities (DLTs) were encountered, irinotecan dose was decreased by 50 mg/m2 in subsequent cyles until toxicities decreased to grade 2 or lower. The following criteria met the study definition of DLT: grade 4 neutropenic fever, grade 4 non-hematologic toxicities and lack of recovery to baseline from previous toxicities. Grade 4 diarrhea, nausea and vomiting were considered dose-limiting if they occurred despite optimal supportive treatment. The irinotecan dose was decreased by 25 mg/m2 until toxicities decreased to grade ≤ 1, if patients experience ≥ grade 2 hematologic or non-hematologic toxicity. Grade 2/3 diarrhea, nausea and vomiting resulted in dose modification, only if they occurred despite optimal supportive treatment.

Treatment evaluation

Patients were assessed clinically and by imaging before every treatment, i.e., every 6 weeks for schedule A and every 3 weeks for schedule B. At each evaluation the patient’s objective status was defined as a function of the neurologic exam status and imaging results.

Response definition

Measurable disease was defined as a tumor visible on CT scan or MRI that could be easily measured by the products of perpendicular cross-sectional diameters. Evaluable disease was defined as tumor visible on CT scan or MRI but not amenable to bi-dimensional measurements because of tumor geometry. The MacDonald criteria for response assesment were employed to assess response in patients with measurable disease [25]. Complete response (CR) was defined as a total disappearance of all evidence of tumor with the patient no longer receiving corticosteroids. Partial response (PR) was defined as ≥50% reduction in the product of perpendicular diameters of contrast enhancing mass with no new lesions and the patient receiving stable or decreased corticosteroid dose. Progression was defined as ≥25% increase in the product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients with evaluable disease, regression was defined as unequivocal reduction in size of contrast enhancement or decrease in mass effect as determined by primary physician and quality control physicians and no new lesions, with the patient receiving stable or decreased steroid dose. Stable disease was defined as failure to qualify for CR, PR or tumor progression.

Pharmacokinetic analysis

Specimen collection

Blood samples (7 ml) were drawn via venipuncture or indwelling intravenous cannula into heparin-containing tubes from the arm contralateral to the infusion line at the following times: prior to the first irinotecan infusion; at the end of the infusion, and 1, 2, 4 and 24 h following the end of the infusion. If a heparin lock was used, 1 ml of whole blood was withdrawn and discarded prior to sample collection. Collection tubes were immediately placed into a slurry of ice water, the plasma was separated by centrifugation (1000–1200 × g for 20 min) and transferred into plastic tubes. The plasma specimens were stored at −70°C until assay for CPT-11 and SN-38, SN-38G and APC.

Specimen analysis

Plasma samples were assayed for CPT-11, SN-38 and APC using validated, sensitive and specific isocratic high-performance liquid chromatography methods. In brief, the plasma specimen was mixed with the internal standard camptothecin in acidified acetonitrile to precipitate plasma proteins, and incubated for 15 min at 40°C to convert the analytes to their respective lactones. After addition of tri-ethylamine buffer (pH 4.2), the sample was centrifuged and the supernatant was transferred to an amber vial for injection (40 μl) onto the HPLC system.

Chromatographic separation was achieved using a Zor-bax-C8 column (MacMod) and a mobile phase consisting of 28:72 (v/v) acetonitrile: 0.025 M TEA buffer (pH 4.2). The fluorescence detector was operated at an excitation wavelength of 372 nm; the CPT-11 was monitored at an emission wavelength of 425 nm; SN-38 was monitored at 535 nm.

CPT-11, APC and unconjugated SN-38 concentrations were determined by direct analysis of plasma. SN-38G concentrations were determined in a separate portion of each plasma sample in which SN-38G was hydrolyzed to SN-38 by incubation with β-glucuronidase. SN-38 concentrations determined following incubation of plasma with β-glucuronidase were labeled as “Total SN-38” (i.e., sum of unconjugated SN-38 and conjugated SN-38). Plasma concentrations of SN-38G were estimated as the difference between the Total SN-38 concentration and the SN-38 concentration.

Pharmacokinetic analysis

CPT-11, SN-38 and SN-38G plasma concentration data were analyzed by non-compartmental methods using the program WINNONLIN. The apparent terminal elimination rate constants (λz) were determined by linear least-squares regression through the 4 and 24 h plasma-concentration time points. The apparent elimination half-life (t1/2) was calculated as 0.693/λz Area under the plasma concentration–time curves (AUC0–24 h) were determined using the linear trapezoidal rule from time zero to the 24 h sample time. Area under the plasma concentration–time curves through infinite time (AUC0–∞) were calculated by adding CT/λz to AUC0–24 h. The CL of CPT-11 was calculated as dose/AUC0–∞, where dose is the administered dose of CPT-11 expressed in free base equivalents.

The pharmacokinetics for patients in cohort B were further compared to those from cancer patients treated on a previously completed phase I trial of irinotecan [26], who were not on EIAEDs. This phase I trial employed similar irinotecan regimens and pharmacokinetic assay methodology [26].

Statistical methods

The intervals to progression, treatment failure and death were calculated from the onset of treatment to the date of disease progression, treatment failure or death. Treatment failure was the occurrence of disease progression, appearance of unacceptable toxicity or refusal of the patient to continue treatment. The distributions of time to progression (TTP), time to treatment failure and time to death were estimated using the Kaplan-Meier method. The association of nominal risk factors with survivorship was assessed with log-rank tests. Duration of response for patients who responded to treatment was measured from the start of CPT-11 treatment to TTP. Multivariate analysis using Cox models was used to assess the importance of different prognostic variables in predicting response, TTP and OS. The two schedules were analyzed independently and no comparisons were made between each other.

Multivariate linear regression was used to explore the relationship between CPT-11, SN-38, SN-38G and APC AUC and CPT-11 clearance as dependent variables and age, gender, CPT-11 dose, use of steroids, use of any anticonvulsant, CBZ, DPH and PB as independent variables. Age was modeled as a continuous variable and the other independent variables were specified as indicator variables. The results shown are for forward stepwise regression modeling. Backward regression, models using the ranks of the dependent variables, and models using dose adjusted AUC provided consistent results.

Results

Patients

Sixty-four patients (32 per cohort) were enrolled in this trial by 15 NCCTG institutions. All patients were evaluable for toxicity, and all patients were included in the survival analysis. Thirty patients per cohort were evaluable for response. Table 1 lists demographic, histologic and prior treatment characteristics of these patients. The median age was 54.5 years for the whole population and the majority of tumors were pure astrocytomas. Fifty of the sixty-four of patients (78.1%) had received prior nitrosureas, 43 of the 64 patients (67.2%) were on steroids treatment and 52 of the 64 patients (81.3%) were on EIAEDs.

Table 1.

Baseline patient characteristics

Variable Schedule A (N = 32) n (%) Schedule B (N = 32) n (%) Total (N = 64) n (%)
Age
 Median 55.5 53.0 54.5
 Range 25–74 24–81 24–81
 Mean ± SD 52 ± 14.5 51 ± 15.5 51.5 ± 14.9
Gender
 Female 14 (43.8%) 10 (31.3%) 24 (37.5%)
 Male 18 (56.3%) 22 (68.8%) 40 (62.5%)
ECOG performance score
 0 4 (12.5%) 10 (31.3%) 14 (21.9%)
 1 18 (56.3%) 14 (43.8%) 32 (50.0%)
 2 10 (31.3%) 8 (25.0%) 18 (28.1%)
 3 0 0 0
 4 0 0 0
Steroids
 Yes 22 (68.8%) 21 (65.6%) 43 (67.2%)
 No 6 (18.8%) 11 (34.4%) 17 (26.6%)
 Missing 4 (12.5%) 0 4 (6.3%)
Anticonvulsants
 Yes 26 (81.3%) 26 (81.3%) 52 (81.3%)
 No 6 (18.8%) 6 (18.8%) 12 (18.8%)
Prior Nitrosoureas
 Yes 24 (75.0%) 26 (81.3%) 50 (78.1%)
 No 8 (25.0%) 6 (18.8%) 14 (21.9%)
Months since end of RT
 <6 5 (15.6%) 10 (31.3%) 15 (23.4%)
 6–12 11 (34.4%) 8 (25.0%) 19 (29.7%)
 >12 16 (50.0%) 14 (43.8%) 30 (46.9%)
Primary tumor resection
 None 0 0 0
 Biopsy 11 (34.4%) 9 (28.1%) 20 (31.3%)
 Subtotal 14 (43.8%) 14 (43.8%) 28 (43.8%)
 Total 7 (21.9%) 9 (28.1%) 16 (25.0%)
Histology
 Astrocytoma 22 (68.8%) 18 (56.3%) 40 (62.5%)
 Gliosarcoma 0 0 0
 Oligodendroglioma 4 (12.5%) 5 (15.6%) 9 (14.1%)
 Oligoastrocytoma 5 (15.6%) 8 (25.0%) 13 (20.3%)
 Unknown 1 (3.1%) 1 (3.1%) 2 (3.1%)
Grade
 1 0 0 0
 2 2 (6.3%) 6 (18.8%) 8 (12.5%)
 3 8 (25.0%) 6 (18.8%) 14 (21.9%)
 4 21 (65.6%) 19 (59.4%) 40 (62.5%)
 Unknown 1 (3.1%) 1 (3.1%) 2 (3.1%)
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Treatment delivery

Mean number of treatment cycles were 1.96 ± 2.42 (range 1–14) for schedule A and 3.71 ± 3.08 (range 1–12) for schedule B. Treatment discontinuation because of toxicity was similar in both groups (3.13%), 12.5% of the patients in schedule A refused continuing treatment, while only 3.13% of the patients refused to continue treatment on schedule B.

Response

The primary efficacy endpoint for this trial was confirmed objective response. This was similar in both arms: 2/32 patients (6.3%) in each cohort had partial responses. Of the responders one patient had an oligoastrocytoma, and three patients pure astrocytomas. Seven of 32 patients in cohort A and 25 of 32 patients in cohort B achieved stable disease as their best objective response (21.9% and 78.1% respectively, i.e., 32/64; 50% for the combined group). Twenty-one of the 32 patients (65.5%) in schedule A and 3 of the 32 patients (9.4%) in schedule B had progressive disease as their best objective responses (24/64; 37.5% for the combined group).

Toxicity

Most of the observed toxicity was mild (grade 1, 2). The incidence of grade 3 and 4 toxicity according to schedule is summarized in Table 2. The main toxicities were gastrointestinal and hematologic. The most common toxicity in schedule A was grade 3/4 thrombocytopenia (15.6%) followed by diarrhea (6.3%), infection, lethargy and transaminase elevation (3.1% each), nausea (34.4%) and leukopenia (21.9%). In schedule B the most common grade 3/4 toxicities were thrombocytopenia (22%) followed by nausea (9.4%), lethargy (9.4%), diarrhea (9.4%) and vomiting (6.3%).

Table 2.

Observed toxicity according to schedule

Schedule
 All
A (N = 32)
 B (N = 32)
N % N % N
Grade 3 heme 5 15.6 7 21.9 12
Grade 3 non-heme 4 12.5 11 34.4 15
Grade 4 non-heme 2 6.3 5 15.6 7
Grade 5 non-heme 1 3.1 1
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Progression-free survival and overall survival

At the time of this report, sixty-three patients (98.4%) have died (100% of the patients in cohort A and 96.9% in cohort B) and all patients had disease progression. Eight patients (12.5%) were progression-free at six months (2/32 in cohort A and 6/32 in cohort B). The median TTP in cohorts A and B were 1.6 and 1.9 months respectively. The median survival in cohorts A and B were 5.1 and 5.5 months. The one-year survival estimate was 19% both for cohorts A and B.

Pharmacokinetic analysis

The pharmacokinetics of CPT-11 and its metabolites were characterized in both patient cohorts in order to establish the impact of anticonvulsant usage for each schedule. Information regarding use of enzyme inducing anticonvulsants and dexamethasone is summarized in Table 3. Two approaches were employed to analyze the pharmacokinetic data. First, data were grouped according to treatment with dexamethasone and treatment with EIAEDs (Table 4). In this approach, patients treated with DPH, CBZ or PB that are all known to induce the p450 system were considered as a single group. Second, data were grouped according to treatment with individual anticonvulsants (Table 5). Patients treated with anticonvulsants that were not known to induce the p450 system were included with the group that received no anticonvulsants.

Table 3.

Baseline characteristics according to EIAEDsa and dexamethasone use

Anticonvulsant treatment
None CBZ DPH PB Total
Schedule A N 3 4 15 4 26
Median age (years) 62 47 46 47 55
Gender (M/F) 1/2 2/2 10/5 2/2 15/11
CPT–11 dose (100/125) 2/1 2/2 10/5 4/0 18/8
Steroids (Y/N) 2/1 3/1 12/3 3/1 20/6
Schedule B N 8 7 12 3 30
Median age (years) 52 44 54 43 50
Gender (M/F) 2/6 6/1 9/3 3/0 20/10
CPT-11 dose (250/300) 7/1 5/2 10/2 2/1 24/6
Steroids (Y/N) 7/1 3/4 8/4 1/2 19/11
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Abbreviations: CBZ carbamacepine, DPH phenytoin, PB Phenobarbital

a

Combinations of anticonvulsants were used in some patients

Table 4.

Effect of dexamethasone and EIAEDs on the pharmacokinetics of CPT-11 and its metabolites

Low CPT-11 dose (100/125 mg/m2)
 High CPT-11 dose (250/300 mg/m2)
None (n = 1) Dex alone (n = 3) EIAED alone n = 4) Dex + EIAED (n = 19) None (n = 3) Dex alone (n = 6) EIAED alone (n = 9) Dex + EIAED (n = 12)
CPT-11 Cmax 1010 2090 ± 1490 1180 ± 590 2160 ± 3270 2200 ± 610 2630 ± 670 1990 ± 688 2380 ± 1110
AUC 6710 7890 ± 2720 4930 ± 1380 5870 ± 4130 15,300 ± 5700 16,400 ± 3600 11,400 ± 4700 10,500 ± 3200
Cl 12.7 12.1 ± 2.5 20.8 ± 5.6 21.7 ± 10.5 15.3 ± 6.1 13.9 ± 3.9 21.6 ± 8.2 23.9 ± 6.6
t1/2 5.3 6.5 ± 0.9 5.0 ± 0.3 5.3 ± 0.7 5.4 ± 0.4 6.3 ± 0.9 5.1 ± 0.5 5.1 ± 0.7
APC Cmax 153 142 ± 110 127 ± 12 162 ± 101 401 ± 39 380 ± 113 359 ± 134 432 ± 100
AUC 1710 1860 ± 1610 1520 ± 297 1670 ± 1080 5010 ± 500 4720 ± 1580 4260 ± 1600 4610 ± 1740
t1/2 5.7 7.8 ± 2.1 5.5 ± 0.9 5.7 ± 0.9 6.0 ± 0.5 6.7 ± 2.3 6.0 ± 0.6 5.5 ± 1.1
SN-38 Cmax 21.6 17.4 ± 2.3 11.1 ± 2.8 12.1 ± 5.0 25.7 ± 24.7 39.4 ± 24.4 15.9 ± 6.4 16.6 ± 4.4
AUC 208 136 ± 34 85 ± 19 63 ± 33 232 ± 138 367 ± 218 150 ± 85 118 ± 44
t1/2 17.1 17.5 ± 4.0 10.4 ± 1.7 14.5 ± 12.1 12.1 ± 2.2 19.0 ± 5.8 11.7 ± 3.0 11.1 ± 3.3
SN-38G Cmax 34.4 64.5 ± 31.3 46.3 ± 14.1 57.7 ± 22.0 78.6 ± 30.4 137.3 ± 63.0 97.4 ± 18.0 90.9 ± 18.0
AUC 418 692 ± 367 377 ± 160 422 ± 216 828 ± 288 1558 ± 720 839 ± 240 658 ± 171
t1/2 13.5 16.6 ± 9.4 9.9 ± 2.8 9.1 ± 2.0 13.0 ± 1.4 14.6 ± 3.6 9.7 ± 1.5 9.8 ± 3.9
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Table 5.

Effect of individual EIAEDs on the pharmacokinetics of CPT-11 and its metabolites

Low CPT-11 dose (100/125 mg/m2)
 High CPT-11 dose (250/300 mg/m2)
None (n = 4) CBZ (n = 4) DPH (n = 16) PB (n = 3) None (n = 9) CBZ (n = 7) DPH (n = 12) PB (n = 2)
CPT-11 Cmax 1820 ± 1330 780 ± 450 2440 ± 3500 1190 ± 600 2490 ± 650 2780 ± 1340 1920 ± 590 2030 ± 280
AUC 7600 ± 2300 4000 ± 1840 6040 ± 4390 6190 ± 810 16,000 ± 4100 13,100 ± 5000 9100 ± 2200 13,500 ± 2500
Cl 12.2 ± 2.0 27.6 ± 10.7 21.4 ± 9.8 14.3 ± 2.0 14.3 ± 4.4 19.6 ± 7.2 26.0 ± 6.3 15.9 ± 2.9
t1/2 6.2 ± 0.9 4.9 ± 1.0 5.4 ± 0.6 5.0 ± 0.6 6.0 ± 0.9 4.8 ± 0.5 5.3 ± 0.6 5.1 ± 0.4
APC Cmax 145 ± 90 93 ± 43 154 ± 87 247 ± 120 387 ± 92 365 ± 99 408 ± 122 484 ± 193
AUC 1830 ± 1320 990 ± 590 1570 ± 860 2880 ± 1150 4820 ± 1280 4060 ± 1050 4490 ± 1890 5680 ± 2090
t1/2 7.3 ± 2.0 5.7 ± 0.9 5.7 ± 0.9 5.4 ± 0.2 6.5 ± 1.9 5.3 ± 0.5 5.8 ± 1.1 6.5 ± 1.1
SN-38 Cmax 18.4 ± 2.8 11.7 ± 3.5 11.9 ± 5.4 12.0 ± 0.9 34.9 ± 23.9 19.2 ± 5.6 14.6 ± 4.8 16.6 ± 1.6
AUC 154 ± 45 73 ± 38 60 ± 30 100 ± 14 322 ± 198 169 ± 86 106 ± 44 157 ± 2
t1/2 17.4 ± 3.3 9.4 ± 2.3 15.6 ± 13.1 10.5 ± 2.4 16.7 ± 5.8 10.4 ± 3.0 12.0 ± 3.4 10.8 ± 0.6
SN-38G Cmax 57.0 ± 29.7 49.7 ± 11.7 55.8 ± 24.0 63.7 ± 13.2 117.7 ± 59.8 97.7 ± 15.3 91.6 ± 20.0 91.8 ± 19.0
AUC 623 ± 330 330 ± 164 396 ± 201 622 ± 193 1310 ± 690 875 ± 248 631 ± 152 876 ± 127
t1/2 15.9 ± 7.8 8.6 ± 2.3 9.3 ± 2.0 10.2 ± 2.9 14.1 ± 3.0 8.7 ± 1.7 10.3 ± 3.8 9.8 ± 1.6
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CPT-11 plasma clearance for patients on schedule A varied over an 8-fold range (5.3–41.4 l/h/m2, Table 4). The CPT-11 clearance value in the single patient who received no concurrent treatment (12.7 l/h/m2) and the mean value in patients receiving concurrent treatment with dexamethasone alone (12.1 ± 2.5 l/h/m2) were similar to the mean value previously reported for a group of GI patients [27] who did not receive concurrent anticonvulsants and dexamethasone (13.0 ± 5.6 l/h/m2). CPT-11 clearance was 75% higher in those glioma patients who received EIAEDs with or without dexamethasone (21.6 ± 9.7 l/h/m2, Table 4). Exposure to the inactive CPT-11 metabolites APC and SN-38G were not substantially altered by dexamethasone and EIAEDs. SN-38 Cmax and AUC values for patients that received EIAEDs were significantly lower than the values for the patient that did not receive dexamethasone or EIAEDs (Table 4). Indeed, our results in dexamethasone plus EIAEDs patients in low-dose regimen (100–125 mg/m2) are very similar to the other prior phase II trial with PK analysis [6].

Because there are known differences in the enzyme induction pattern for individual anticonvulsants, effects of dexamethasone and each anticonvulsant on CPT-11 and metabolite PKs were evaluated. CPT-11 clearance was increased by DPH and CBZ, but the increase was not statistically significant (Table 5). When compared with values for patients that received no EIAEDs, APC Cmax and APC AUC values were higher in patients treated with PB, unchanged in patients treated with DPH, and lower in patients treated with CBZ. The difference in APC Cmax and AUC values between the PB and CBZ treatment groups was statistically significant. SN-38 AUC, but not SN-38 Cmax, significantly reduced by treatment with CBZ, DPH and PB. SN-38G Cmax were similar among the CBZ, DPH and PB treatment groups. SN-38G AUC values for patients who received CBZ or DPH were 40% lower than the values for patients who received PB or no EIAEDs.

CPT-11 plasma clearance for patients in cohort B varied over a 4-fold range (10.1–36.9 l/h/m2). The mean CPT-11 clearance values in patients who received no concurrent treatment (15.3 ± 6.1 l/h/m2) and the mean value in patients receiving concurrent treatment with dexamethasone alone (13.9 ± 3.9 l/h/m2) were similar to the mean value previously reported for patients in a phase I trial [26] who did not receive concurrent anticonvulsants and dexamethasone (13.0 ± 3.8 l/h/m2). CPT-11 clearance was 75% higher in those glioma patients who received EIAEDs with or without dexamethasone (22.9 ± 7.2 l/h/m2, Table 2). Dexamethasone and EIAEDs did not appear to substantially alter exposure to the inactive CPT-11 metabolite APC (Table 4). SN-38 and SN-38G Cmax and AUC values were highest in patients that received dexamethasone alone. This difference was statistically significant when compared with the other treatment groups.

The effect of each anticonvulsant on CPT-11 clearance, parent drug or metabolite exposure use was also evaluated (Table 5). CPT-11 clearance was increased by CBZ and DPH. The difference between the group that received no EIAEDs and the group that received DPH was statistically significant. APC exposure was not significantly altered by individual anticonvulsants, however, Cmax and AUC values were highest in patients treated with PB. SN-38 Cmax and AUC values were reduced by each of the anticonvulsants, and the difference for DPH was statistically significant. Similarly, SN-38G exposure was lower for patients in each anticonvulsant treatment group, but only DPH caused a statistically significant reduction of SN-38G exposure.

The effects of clinical and demographic covariates, prior nitrosoureas and anticonvulsants treatment on SN-38 AUC ?tul?> were evaluated by multivariate regression analysis (Table 6). The model for schedule A predicted that pretreatment bilirubin, steroids, CBZ, PB and DPH had a statistically significant effect on SN-38 AUC (R2 = 0.6952, P = 0.0001). Age, prior nitrosoureas CPT-11 dose [17] and gender had no effect on SN-38 AUC. The model for Cohort B predicted that CBZ and DPH had a statistically significant effect on SN-38 AUC (R2 = 0.3561, P = 0.0033). Age, prior nitrosoureas, CPT-11 dose, gender, pretreatment bilirubin, steroids, and PB had no effect on SN-38 AUC.

Table 6.

Multivariate regression models for SN-38 AUC0–24 h

Variable Cohort A
 Cohort B
Parameter estimate P Parameter estimate P
Intercept 126.9 0.0001 305.7 <0.0001
Steroids −31.2 0.0462 – –
Bilirubin 101.3 0.0298 – –
CBZ −78.5 0.0010 −137.0 0.0343
PB −52.3 0.0275 – –
DPH −78.3 0.0002 −200.1 0.0009
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Discussion

Development of effective treatment regimens for recurrent disease remains a significant challenge in the management of patients with malignant gliomas. Limited success in this setting can be due to limitations in drug delivery or to tumor resistance to standard cytotoxic therapies.

Following original observations demonstrating activity of CPT-11 in preclinical models [28, 29], a phase I trial determined that maximal tolerated dose (MTD) for patients with recurrent malignant gliomas treated on EIAEDs was 410 mg/m2/week, but as low as 115 mg/m2/week for patients not on EIAEDs [23].

In this phase II trial of CPT-11 in adult recurrent glioma patients, the objective response rate (RR) was very low (6.3%). Although the RR observed in this trial is consistent with rates reported in other studies (0–15%) [6–12] and the percentage of patients with SD was around 50%, time to progression (TTP) and survival was worse than previously reported: the median TTP was only 1.6 months for the weekly schedule and 1.9 months for the once every three weeks schedule. PFS at 6 months (PFS6) were 6% and 19% for schedules A and B respectively (13% for the whole group). Median OS were 5.1 and 5.5 months for schedules A and B respectively and 1-year survival was 19% for both groups, lower than OS in prior phase II trials. In other trials of weekly CPT–11 administration, median TTP was reported to be 3 to 7.3 months with a 56% PFS6, and median OS was 10.4–10.75 months [6, 10]. In trials employing the once every three weeks administration schedule, PFS6 was 0% [7], 0% [8], 26% [9] and 17.6% [12], median TTP was 0.75 months [7], 1.5 months [8] and 2.1 months [9], and median OS of was 4 months [7], 6 months [8] and 8.5 months [9]. Better results especially in some of the trials of weekly CPT-11 administration can be explained because of differences in eligibility criteria (78% of our patients had prior chemotherapy exposure) and the possible impact of EIAEDs on active drug metabolites.

Although weekly administration schedules appear to have a higher median TTP and median OS than intermittent high-dose schedules in prior phase II studies, no significant difference in outcome between the two schedules was observed in our study.

The most frequent dose-limiting toxicities of single agent CPT-11 in previous clinical trials using weekly or every-three-weeks schedules have been diarrhea and neutropenia [6, 8–10, 12]. In our trial no grade 3/4 neutropenia or leucopenia was observed. In contrast, five patients (15.6%) had grade 3/4 thrombocytopenia in schedule A and seven patients (21.9%) developed grade 3/4 thrombocytopenia in schedule B. This high-frequency of thrombocytopenia could be explained because of prior myelosuppressive treatments containing nitrosureas (75% in cohort A and 81.3% in cohort B), as compared to 48% [6] and 15% [8] in another phase II trials. Similarly to our results, Chamberlain et al observed an incidence of 23% of thrombocytopenia in a group of patients, 95% whom were pretreated with nitrosureas [7].

The interaction between CPT-11 and EIAEDs as a whole was reported in a phase II study of CPT-11 in glioma patients [30]. Increased CPT-11 clearance and reduced exposure to CPT-11, its active metabolite SN-38, and the inactive metabolites SN-38G and APC were associated with concurrent treatment with EIAEDs. Therefore, pharmacokinetic studies are extremely important with CPT-11: first, glioma patients often require dexamethasone to treat edema and P450 inducing anticonvulsants such as DPH, CBZ and PB for seizure management. These drugs are well known for producing drug interactions [31, 32] that are usually due to induction of drug metabolism enzymes. For example, each of the drugs induce CYP3A4-catalyzed inactivation of CPT-11 to APC. DPH, CBZ and PB induce UGT, which catalyzes the inactivation of SN-38 by glucuronidation. Dexamethasone induces carboxylesterases, which catalyzes the activation of SN-38. DPH and CBZ induce CYP2C9, which catalyzes the metabolism of DPH. Second, similar efficacy with decreased toxicity has been seen in the weekly schedule against the three week schedule in colorectal cancer patients treated with CPT-11 [27, 33]. Indeed, CPT-11 clearance in glioma patients who were not administered EIAEDs was similar to that found for other cancer patients administered similar doses and schedules of the drug [6, 33]. Although it is often not appropriate to compare pharmacokinetic data across studies performed at different times, CPT-11 analysis for each of these studies was performed in the same laboratory using identical methodology. Third, some interpatient pharmacogenetic differences could occur with regard to CPT-11 metabolism such as genetic polymorphisms in UGT and CYP2C9. They result in populations of patients that may be classified as slow or rapid metabolizers for these reactions.

While it is now possible to predict the qualitative nature of a metabolism-based drug interaction, it is much more difficult to predict the quantitative impact of the interaction due to the multiplicity of effects of each of these drugs. Since the metabolism phenotype of each anticonvulsant is different, we sought to evaluate the effect of individual drugs on CPT-11 pharmacokinetic by exploring relationships between treatment with individual anticonvulsants and exposure to CPT-11 and its metabolites in this phase II study. The effect of dexamethasone was difficult to establish in this group of patients. When data were grouped according to treatment with dexamethasone and treatment with EIAEDs, dexamethasone did not appear to affect AUC values of CPT-11 and its metabolites as might have been predicted by its known effect on carboxylesterase and CYP3A. CPT-11 AUC was higher for patients treated with dexamethasone, the increase in APC AUC was small and the lower SN-38 AUC was inconsistent with the recent observation that dexamethasone induces carboxylesterase. There may be several reasons for these observations. First, small and unbalanced groups were used to explore the effects of dexamethasone and anticonvulsants on CPT-11 pharmacokinetics, a problem often associated with performing such correlative studies in a chemotherapy treatment trial. Larger numbers of patients would be useful in assessing the role of individual anticonvulsants. Second, the administered dexamethasone doses were lower than those that induce CYP3A4 or carboxylesterase. The dose response relationship for enzyme induction by dexamethasone has not been established. Third, the peripheral edema, electrolyte imbalances and/or fat redistribution caused by dexamethasone may have a greater effect on the pharmacokinetics of concomitant medications than the induction or inhibition of metabolism.

Consistent with data from other clinical trials, CPT-11 pharmacokinetics in glioma patients were altered by EIA-EDs. However, this study further identified CPT-11 dose-dependent differential effects of individual anticonvulsants on CPT-11 pharmacokinetics. The magnitude and direction of the effect was dependent on the specific anticonvulsant. For example, large differences between APC AUC values were observed in cohort A patients administered lower doses of CPT-11, but not in cohort B patients administered higher doses of CPT-11 (Table 6). In contrast, such a difference was not observed when APC AUC data were grouped according to treatment with dexamethasone and EIAC (Table 4). As expected for CYP3A4 induction, PB increased APC AUC, and CBZ was associated with a 2-fold reduction in APC AUC.

All EIAEDs caused reduction of SN-38 AUC, with the greatest magnitude change produced by DPH. However, this reduction was not accompanied by a concomitant increase in SN-38G AUC that would be predicted by induction of UGT. Clearly, as suggested by the modest correlation coefficients, other factors contribute to the disposition of CPT-11 and its metabolites in glioma patients. As for dexamethasone, the difficulty in defining relationships between CPT-11 pharmacokinetics and anticonvulsant use might include small patient population, different anticonvulsant doses, dose response relationships, enzyme polymorphisms, and other disease-related factors.

Variability in the accessibility of the active form of the drug to the tumor could account for the modest RRs noted in these studies. Variations in schedule administration were small, since the AUC for SN-38 is only 3% of the AUC CPT-11 in patients in cohort A without concurrent dexamethasone and 1.5% in cohort B patients with same characteristics. No differences were shown in patients with concurrent dexamethasone in both cohorts. Four-fold decrease in SN-38:CPT-11 AUC ratio have been described in a clinical trial comparing a continuous low-dose i.v. infusion of CPT-11 over 14 days with short i.v. infusions, supporting the concept of the carboxylesterase activity and saturation [34]. This means that only a relatively small fraction of the dose is ultimately converted to the active metabolite of the drug.

Although combination of other chemotherapy agents with CPT-11 does not appear to increase its activity, the addition of bevacizumab to CPT-11 has significantly improved antitumor activity, including RRs, as well as PFS and OS [20–22]. Bevacizumab is a humanized monoclonal antibody that inhibits human VEGF, a key driving force of glioma angiogenesis [35]. Although the mechanism of this effect has not been completely elucidated, one hypothesis is that bevacizumab improves CPT-11 delivery because it decreases interstitial pressure and hypoxia resulting to tumor resistance to cytotoxic therapy. The clinical efficacy of the CPT-11/bevacizumab combination has resulted in increased use of irinotecan in the management of recurrent glioma patients.

In summary, the low response rate and survival outcome measures in our study, independently of CPT-11 administration, indicates low activity of single agent CPT-11 in the treatment of recurrent gliomas. Impact of EIAEDs as well as dexamethasone on CPT-11 pharmacokinetics appears to be decreased in the once-each-three weeks schedule, although this did not translate into outcome differences.

Acknowledgments

This study was supported by NCI grant CA25224 and Pharmacia & Upjohn. The authors would like to thank Paul Novotny and Stephen Cha from the Mayo Clinic Department of Biostatistics for their help with data analysis and Dr. Larry Schaaf from Ohio State for his help with sample analysis. They would also like to thank Mrs. Raquel Ostby for her help with manuscript preparation. This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-35269, CA-52352, CA-35195, CA-35101, CA-37417, CA-35415, CA-35448, CA-35103, CA-63849, CA-63848.

Additional participating institutions include: Missouri Valley Cancer Consortium, Omaha, NE 68131 (Gamini S. Soori, M.D.); Carle Cancer Center CCOP, Urbana, IL 61801 (Kendrith M. Rowland, Jr., M.D.); Medcenter One Health Systems, Bismarck, ND 58506 (Edward J. Wos, D.O. & John T. Reynolds, M.D.); Iowa Oncology Research Association CCOP, Des Moines, IA 50309–1014 (Roscoe F. Morton, M.D.); Meritcare Hospital CCOP, Fargo, ND 58122 (Preston D. Steen, M.D.); Toledo Community Hospital Oncology Program CCOP, Toledo, OH 43623 (Paul L. Schaefer, M.D.); Geisinger Clinic & Medical Center CCOP, Danville, PA 17822 (Albert M. Bernath, Jr., M.D.); Michigan Cancer Research Consortium, Ann Arbor, MI 48106 (Philip J. Stella, M.D.); Altru Health Systems, Grand Forks, ND 58201 (Todor Dentchev, M.D.), Siouxland Hematology-Oncology Associates, Sioux City, IA 51105 (Donald B. Wender, M.D.); Sioux Community Cancer Consortium, Sioux Falls, SD 57105 (Loren K. Tschetter, M.D.); CentraCare Clinic, St. Cloud, MN 56301 (Harold E. Windschitl, M.D.).

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