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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4622-4627
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.11.6103
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Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study

Lisa R. Bomgaars, Mark Bernstein, Mark Krailo, Richard Kadota, Soma Das, Zhengjia Chen, Peter C. Adamson, Susan M. Blaney

From the Baylor College of Medicine, Houston, TX; IWK Health Centre, Halifax, Nova Scotia, Canada; Keck School of Medicine, University of Southern California, Los Angeles; Rady Children's Hospital, San Diego; Children's Oncology Group, Arcadia, CA; University of Chicago, Chicago, IL; and Children's Hospital of Philadelphia, Philadelphia, PA

Address reprint requests to Lisa Bomgaars, MD, Texas Children's Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; e-mail: lbomgaars{at}txccc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype.

Patients and Methods A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m2/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed.

Results Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean ± standard deviation IRN plasma clearance was 374 ± 148 mL/min/m2, with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed.

Conclusion IRN 50 mg/m2/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Irinotecan (IRN), a semisynthetic water-soluble analog of camptothecin, is a prodrug that undergoes de-esterification to the more potent topoisomerase I inhibitor, SN-38.1,2 It is approved for the treatment of metastatic colorectal cancer and preclinically has activity against a broad spectrum of pediatric cancers.3-6 Xenograft data suggest that the activity of IRN is schedule dependent, leading to protracted schedules of administration children.4,7,8 The primary dose-limiting toxicities reported in children, irrespective of schedule of administration, are diarrhea and myelosuppression.7-11

Both IRN and SN-38 undergo pH-dependent reversible hydrolysis from active lactone forms to relatively inactive carboxylate forms. SN-38 is glucuronidated, primarily by UGT1A1, to SN-38G, an inactive metabolite that is excreted in the bile and urine.12 IRN also undergoes oxidation via CYP3A4 and 3A5 to relatively inactive metabolites, APC and NPC.13-16 The GI toxicity of IRN has been correlated with SN-38G formation, and glucuronidation is protective.17 The promoter region of UGT1A1 contains a variable number of TA repeats, the number of which (five to eight) is inversely correlated with gene transcriptional efficiency.18,19 The six-repeat allele, UGT1A1*1, is the most common; the seven-repeat allele, UGT1A1*28, is the second most common. Adult patients homozygous for the UGT1A1*28 allele have been shown to have an increased SN38 area under the curve (AUC), decreased SN38G to SN38 AUC ratios, and an increased risk of developing neutropenia and possibly diarrhea.20-24

The 50 mg/m2/d for 5 days dose and schedule for this pediatric phase II solid tumor study was based on data from the Pediatric Oncology Group phase I IRN study.7 Secondary objectives were to evaluate further the toxicity, pharmacokinetics, and pharmacodynamics of IRN, including an evaluation of the correlation between UGT1A1 genotype, pharmacokinetic parameters, and toxicity.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Eligibility
Patients older than 1 year and younger than 22 years of age at the time of initial diagnosis with refractory or recurrent solid or CNS tumors were eligible. Other eligibility criteria included measurable disease documented by imaging studies; predicted life expectancy of ≥ 8 weeks; Karnofsky or Lansky performance status of ≥ 50%; adequate bone marrow function (absolute neutrophil count > 1,000/µL, platelets > 100,000/µL, hemoglobin > 8.0 gm/dL); bilirubin less than 1.5 mg/dL; ALT less than 5x the upper limit of normal; creatinine normal for age or glomerular filtration rate ≥ 70 mL/min/1.73 m2; no uncontrolled infection; no concurrent anticancer therapy; at least 3 weeks since prior chemotherapy; at least 8 weeks from radiotherapy of assessable lesions; and recovery from toxicity of prior therapy. Patients with brain tumors who were receiving dexamethasone were required to have received a stable or decreasing dose for at least 2 weeks before study entry. Patients were excluded if they were pregnant or lactating, had received more than two prior chemotherapy regimens, had previously received IRN, or were receiving anticonvulsants.

The protocol was reviewed by the institutional review boards at participating institutions. Informed consent and assent, when applicable, were obtained from all participants.

Drug Administration and Study Design
IRN was supplied by the Division of Cancer Treatment, National Cancer Institute (Bethesda, MD). IRN 50 mg/m2/d was administered as a 60-minute intravenous infusion daily for 5 days every 21 days. All patients were premedicated with ondansetron, with a recommendation to also premedicate with dexamethasone. The protocol contained standardized dosing instructions for the administration of atropine (for early-onset diarrhea) and loperamide (for diarrhea occurring 24 hours after IRN). For diarrhea occurring during an infusion, or in the several hours after the infusion, atropine 0.01 mg/kg (maximum, 0.4 mg) was administered intravenously. For late diarrhea, a weight-based dose of loperamide was administered every 2 hours during the day and every 4 hours at night, until resolution of symptoms. Subsequent courses were administered when the absolute neutrophil count was more than 1,000/µL and platelets were more than 100,000/µL. The IRN dose was reduced to 39 mg/m2 if there was more than 25 days between courses due to toxicity, with the exception of neutropenia, in which granulocyte colony-stimulating factor support was attempted before a dose reduction. Adverse events were graded using version 2.0 of the National Cancer Institute Common Toxicity Criteria.

Evaluation of Response
All eligible patients who received at least 5 days of IRN and whose disease was assessed at least once and response confirmed, or who died as a result of disease-related causes before the first disease assessment were considered assessable for response. Patients with radiographic response were required to have repeat imaging to confirm the response 3 to 6 weeks after the initial documentation. Imaging reports in responding patients were reviewed by the Study Chair to confirm reported responses. A complete response (CR) was defined as the complete resolution of all evidence of disease for at least 3 weeks. A partial response (PR) was defined as ≥ 50% reduction in the sum of the products of the maximum perpendicular diameters of all measurable lesions, no progression in any lesion, and no new lesions. A minor response (MR) was ≥ 25% and less than 50% reduction in all measurable lesions without progression in any lesion or new lesions. Stable disease was defined as a decrease in tumor size less than a MR but with no disease progression. Progressive disease (PD) was defined as a more than 25% increase in the measurable lesions or the appearance of new lesions. We considered a CR or PR to be evidence of the activity of IRN in a particular patient, and classified these patients as having a response for study analysis.

Pharmacokinetic Studies
Blood samples (3 mL) were collected on day 1 of therapy. Sampling in the initial 17 patients was performed at 0.25, 0.5, 1, 2, 4, 6, 8, and 10 to 12 hours after the IRN infusion. Limited pharmacokinetic sampling (1.5, 4.5, 6, and 24 hours) was performed in subsequent patients. Samples were centrifuged immediately to separate the plasma and frozen at –70°C until analysis. Total concentrations (lactone and carboxylate) of IRN, SN-38, APC, and SN-38G were determined using assays described previously.9,25 Sixty-four sample sets were assayed at Texas Children's Hospital (Houston, TX) and 19 sample sets were assayed by Pharmacia (Kalamazoo, MI). APC concentrations were not provided for the samples analyzed at Pharmacia.

Pharmacokinetic parameters were calculated using model-independent methods. The terminal rate constant was determined by linear regression through the time points on the terminal portion of the elimination curve. The AUC was derived using the trapezoidal method and extrapolated to infinity. IRN clearance was determined by dividing the dose by the AUC. The volume of distribution at steady-state (Vdss) was estimated using the following equation: Vdss = ([dose/mass x AUMC]/[AUC]2) – ([dose/mass x infusion duration]/2AUC) x 1,000. The relative extent of conversion (REC), the relative extent of glucuronidation (REG), and the relative extent of metabolism (REM) were estimated using the following respective molar ratios: AUCSN-38/AUCIRN, AUCSN-38G/AUCSN-38, and AUCAPC/AUCIRN. For pharmacokinetic analyses, levels below the lower limit of quantification were set as zero.

Pharmacogenetic Studies
Blood (5 mL) for UGT1A1 genotype analysis was obtained from consenting patients. The UGT1A1 TA indel polymorphism was genotyped by polymerase chain reaction, and sizing by capillary electrophoresis was performed as described previously26 at the University of Chicago Genetic Reference Services Laboratory (Chicago, IL). Alleles with 5, 6, and 7 TA repeats are reported as TAn and genotypes are assigned based on the number of TA repeats in each allele (ie, 6/6, 6/7, 7/7, 5/6).

Statistics
Study design. A response rate of 10% was below what we considered adequate for continued investigation, and a response rate of 30% was considered to be of sufficient activity to warrant additional development of IRN for that tumor type. Therefore, a study design was selected that had a high probability to both reject IRN as effective if the true response rate was 10% and accept IRN as effective if the true response rate was 30%.

A three-stage design, enrolling nine, eight, and eight patients, was used in each of the following disease strata: neuroblastoma, Ewing sarcoma or peripheral primitive neuroectodermal tumors (PNETs), osteosarcoma, rhabdomyosarcoma, medulloblastoma or cerebral PNETs, ependymoma, and brainstem tumor. In the first stage, if zero of nine responses were observed then IRN was considered ineffective and the stratum was closed. If ≥ four of nine responses were observed, enrollment onto the stratum was closed with the conclusion that IRN demonstrated sufficient efficacy for additional development. In the second stage, if ≤ one of 17 patients achieved a response, then IRN was considered ineffective and the stratum was closed, whereas if ≥ five of 17 patients demonstrated a response, enrollment to the stratum was closed with the conclusion that IRN was efficacious. In the third stage, if ≤ five of 25 patients demonstrated response, IRN was considered ineffective. Otherwise, the drug was considered to demonstrate sufficient activity for additional development. With this design, if the true response rate (CR or PR) is 10%, the probability IRN is considered active in a stratum is .042. If the true response rate was 30%, the probability IRN is considered active in a stratum is .8. Patients with other solid tumor diagnoses were eligible for enrollment, although evaluation of activity was not formally applied.

Toxicity analysis. Toxicity of at least grade 2 using the National Cancer Institute Common Toxicity Criteria that was possibly, probably, or likely related to IRN was considered when characterizing adverse events associated with the regimen. Each course was assessed specifically for the occurrence of grade 4 neutropenia, ≥ grade 3 diarrhea, and ≥ grade 3 thrombocytopenia. The relationship between adverse events and patient characteristics was evaluated for course 1 toxicity only using Fisher's exact test.

Pharmacokinetics and genotype analysis. The relationship between pharmacokinetic parameters and genotype was evaluated using linear regression. The natural logarithm of the relevant pharmacokinetic parameters was used in the analysis to remove the range restrictions on these characteristics. The following statistical model was fitted to the data:

Formula
where x1i was 1 if the patient was 6/7 and 0 otherwise; and x2i was 1 if the patient was 7/7 and 0 otherwise.

The test of the composite hypothesis β1 = β2 = 0 was used to test the hypothesis of no effect of genotype on pharmacokinetic characteristic.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
A total of 181 patients enrolled, of whom 10 were ineligible for the following reasons: abnormal liver function tests (n = 2), enrollment into a closed stratum (n = 3), lack of institutional review board approval (n = 1), no pregnancy test results (n = 2), uncontrolled infection at study entry (n = 1), and unstable corticosteroid dose at study entry (n = 1). Patient characteristics for the 171 eligible patients, who received a total of 678 courses of IRN (median, two courses; range, one to 30 courses), are listed in Table 1.


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  		Table 1. Patient Characteristics

 
Response
Ten patients were not assessable for response for the following reasons: enzyme-inducing anticonvulsant therapy was initiated in one patient during course 1 (one patient); no measurable disease (one patient); therapy discontinued because of toxicity (two patients); failure to confirm response (one patient); tumor biopsy performed after baseline imaging scans were obtained (one patient); receipt of only two doses of drug during course 1 (one patient); and patients came off study after course 1 without having a disease evaluation (three patients). Of 161 patients (94%) assessable for response (Table 2), one patient with hepatoblastoma had a CR (22 courses), four patients with medulloblastoma had PRs (16%; 95% CI, 5% to 37%; median, 12 courses; range, six to 21 courses), and one patient each with rhabdomyosarcoma (seven courses), neuroblastoma (seven courses), and germinoma (eight courses) had a PR, for an overall response rate of 5%. An additional 10 patients with medulloblastoma had either a minor response or stable disease, for a median of 4.5 courses (range, two to 27 courses). Review of response data for a reported PR in the Ewing/PNET stratum resulted in a response change to MR, and closure of enrollment to this stratum during the second stage.


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  		Table 2. Response Summary by Disease Category

 
Toxicity
IRN was generally well tolerated. Table 3 outlines the grade 2 or greater toxicities attributed to drug that were experienced in at least 2% of courses. Of the 678 courses of protocol therapy administered, 634 were considered assessable for hematologic toxicity (n = 151) and 672 were considered assessable for nonhematologic toxicity (n = 168). Neutropenia and diarrhea were the most frequently reported toxicities. Grade 4 neutropenia considered possibly, probably, or likely related to IRN was reported in 35 courses (5.6%), and was greater than 7 days duration in 10 courses (1.5%). Grade 3 or 4 thrombocytopenia considered possibly, probably, or likely related to IRN was reported in seven courses (1.1%), and was less than 7 days duration. Grade 3 or 4 diarrhea considered possibly, probably, or likely related to IRN was reported in 46 courses (6.9%).


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  		Table 3. Grade 2 or Greater Toxicities Attributed to Irinotecan That Were Observed in at Least 2% of Courses

 
Of the 135 patients who received at least two courses of therapy, only seven (5%) required a dose reduction; three for diarrhea, three for thrombocytopenia (grades 1 to 3) resulting in delay of subsequent courses; and one for diarrhea and thrombocytopenia. Seven patients assessable for hematologic toxicity received granulocyte colony-stimulating factor therapy: four for delay in therapy secondary to neutropenia and three for fever and neutropenia or infection.

Twenty-nine (17%) patients were hospitalized with symptoms of diarrhea; three tested positive for infectious etiologies and one did not take loperamide as prescribed. The median duration of hospitalization was 4 days (range, 1 to 14 days). Twenty-seven patients received atropine for the treatment of acute diarrhea or cramping after at least one dose of IRN. In general, atropine was not required for the entire 5-day course. In 21 patients who received two or more courses, only four patients required atropine in more than one course (number of courses, two to four).

Pharmacokinetics
Pharmacokinetic data for IRN and metabolites were available for 79 patients (median age, 10 years; range, 2 to 23 years). We observed wide interpatient variability in drug disposition (Table 4), with a 7- to 20-fold variation in irinotecan and metabolite AUC values. The median values for REC, REG, and REM were 0.05 (range, 0.01 to 0.25), 2.24 (range, 0.39 to 9.6), and 0.15 (range, 0.02 to 0.71), respectively. There was no association or trend between pharmacokinetic parameters and diarrhea or thrombocytopenia.


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  		Table 4. Pharmacokinetic Parameters for Irinotecan and Metabolites

 
Pharmacodynamics
There was a trend for patients with SN-38 AUCinf and Cmax values above the median to be at greater risk for grade 4 neutropenia. In addition, there was a trend for patients with SN-38 and SN-38G t1/2 greater than the median, REG values below the median, and REC values above the median to be more likely to develop grade 4 neutropenia.

Pharmacogenetics
UGT1A1 genotyping was performed in 60 patients. Allele frequencies of TA5, TA6, and TA7 were 0.01, 0.74, and 0.25 respectively. Genotype was not significantly related to risk for any of the key toxicities noted above (Table 5).


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  		Table 5. Toxicity in Relationship to Genotype

 
Twenty-two patients had both genotype and complete pharmacokinetic data available; one patient with 5/6, 14 patients with 6/6, and seven patients with 6/7 genotype (Table 6). No pharmacokinetic data were available for patients with the UGT1A1 7/7 genotype for comparison. There were no statistically significant correlations between IRN, SN-38, or SN-38G exposure across TA indel genotype (data not shown).


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  		Table 6. Pharmacokinetic Parameters for Irinotecan and Metabolites Based on Genotype

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
To our knowledge, this is the largest pediatric phase II study of IRN published to date, and includes the first single study pediatric data regarding UGT1A1 genotype and toxicity. IRN administered as a daily infusion for 5 days repeated every 21 days resulted in eight objective responses, for an overall response rate of 5%, which did not meet the study activity level of significance in any of the tumor strata evaluated. Patients with medulloblastoma had the highest response rate of 16% (95% CI, 15% to 37%), with an additional 10 of 24 (40%) of patients experiencing disease stabilization for a median of 4.5 courses. No antitumor activity was observed in patients with Ewing/PNET, osteosarcoma, Wilms' tumor, brainstem glioma, or ependymoma. In contrast, in a recently reported phase II study of 32 solid tumor patients who received IRN 20 mg/m2/dose daily for 5 days for 2 consecutive weeks repeated every 28 days, an overall response rate of 23% was achieved, with a 16% response rate in patients with rhabdomyosarcoma, and a 38% response rate in patients with PNET.27 Because xenograft data indicate IRN activity is highly schedule dependent, the higher response rates between these two studies may be related to the differences in dosing schedules. Alternatively, small patient numbers and differences in pre-IRN regimens may also explain some of the difference.

The dose and schedule of IRN evaluated in this study, which included explicit supportive care guidelines in the event of acute or delayed diarrhea, were well tolerated. With the exception of SN-38G half-life, there was no statistically significant association between pharmacokinetic parameters and toxicity.

As we noted in our initial phase I trial,10,28 there was a large degree of interpatient variability in drug disposition in pediatric patients. The mean IRN clearance in this pediatric population was 22.4 ± 8.8 L/h/m2, which is comparable to that reported by Vassal et al10 (20.7 ± 9.5 L/h/m2) in children receiving doses of 200 to 720 mg/m2 once every 3 weeks, but was slightly higher than that reported by Mugishima et al11 (14.53 L/h/m2) in children receiving doses of 80 to 200 mg/m2 daily for 3 days every 25 days. Our mean REC value, 6% (range, 1% to 25%) was slightly higher than that reported by Vassal (mean, 1.5%; range, 0.15% to 5.55%), but was lower than has been reported by Ma et al28 in children receiving a lower dose protracted schedule of IRN. It should be noted that the latter data were for lactone concentrations only and may not be comparable.

The IRN product label was amended recently to include a warning that individuals homozygous for the UGT1A1*28 allele are at increased risk for neutropenia. In contrast to adult data, we were unable to find a correlation between UGT1A1 genotype and neutropenia in children with refractory solid tumors. The relationship between the UGT1A1*28 genotype and diarrhea in adult studies is less clear, and an association between this genotype and toxicity was not identified in our patient population either. Limitations of our analyses, however, include the small number of patients identified with the 7/7 genotype and the low incidence of toxicity.

In conclusion, with the possible exception of medulloblastoma, IRN used as a single agent for the treatment of recurrent or refractory solid and CNS tumors did not show a noteworthy response rate using the dose and schedule in this study. Using this schedule, additional consideration should be given to the evaluation of IRN, particularly in combination with agents that are synergistic with IRN, in children with medulloblastoma.


   AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Lisa R. Bomgaars, Boehringer Ingelheim Research Funds: Lisa R. Bomgaars, Pharmacia & Upjohn; Susan M. Blaney, Pharmacia & Upjohn Testimony: N/A Other: N/A


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Lisa R. Bomgaars, Mark Bernstein, Richard Kadota, Susan M. Blaney

Provision of study materials or patients: Mark Bernstein

Collection and assembly of data: Lisa R. Bomgaars, Mark Krailo, Soma Das, Zhengjia Chen, Susan M. Blaney

Data analysis and interpretation: Lisa R. Bomgaars, Mark Bernstein, Mark Krailo, Zhengjia Chen, Peter C. Adamson, Susan M. Blaney

Manuscript writing: Lisa R. Bomgaars, Mark Bernstein, Mark Krailo, Peter C. Adamson, Susan M. Blaney

Final approval of manuscript: Lisa R. Bomgaars, Mark Bernstein, Richard Kadota, Zhengjia Chen, Peter C. Adamson, Susan M. Blaney


   NOTES
 
Supported by Children's Oncology Group (COG) Grant No. CA 98543. A complete listing of grant support for research conducted by CCG and Pediatric Oncology Group before initiation of the COG Grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
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Submitted March 19, 2007; accepted July 20, 2007.


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