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Conrad Notes
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CPT-11 IN CHILDHOOD SOLID TUMORS

F. Pein, MD, Institute Gustave Roussy, Villejuif, France, reported on a Phase I dose escalation study in children with refractory or relapsed solid tumors. The expected CPT-11 adverse reactions occurred after intravenous doses as high as 350 mg/msq. Additional pediatric studies are underway. (See prescribing information on irinotecan).

Background on CPT-11 This DNA-specific topoisomerase I inhibitor has regulatory approval for treating colorectal cancer resistant to 5-FU therapy. Approval covers doses as high as 350 mg/msq in Europe but lower in the US. The preclinical activity of CPT-11 in neuroblastoma and medulloblastoma xenografts (Br J Cancer 1996;74:537-545) prompted the Pharmacology Group of the French Society of Pediatric Oncology to undertake the present study.

Patient demography Ten male and 5 female children participated. The median age was 9.5 years (range, 10 mo to 17.5 y). All study patients had relapsed or were refractory to other therapy. Five children had brain tumors; the other types included 2 hepatoblastoma, 3 sarcoma, 2 malignant schwannoma, plus one each with Burkitt lymphoma, cavum epidermoid, or desmoplastic tumor. Histologic examination confirmed all of the diagnoses. Previous therapies ranged from 0 to 5 (median, 3).

CPT-11 treatment schedule Dosing with CPT-11 began at least 4 weeks after the last chemotherapy or at 6 weeks if nitrosourea had been included. Escalating doses of the drug were given at 200, 240, and 300 mg/msq by intravenous infusion (120 min) every 21 days to three children per group. Dosing cycles varied with the administered dose: 8 for 200 mg, 15 for 240 mg, and 5 for 300 mg. Six patients received 350 mg/msq for 14 cycles; this dose equals that approved in Europe for the treatment of colorectal cancer.

Atropine at 20 mcg/kg orally or subcutaneously provided control of cholinergic symptoms. For diarrhea, acetorphan 1.5 mcg/kg was given three times daily following the appearance of the first liquid stool.

Safety of CPT-11 in children Pein reported the overall toxicity of CPT-11 as:

No.
Pts.
Dose
(mg)

Cycles
No.
Rpts.

Adverse Reactions
3 200 8
1 grade 3 anemia
3 240 15
5 grade 1 delayed diarrhea
3 300 5
1 grade 3 neutropenia
6 350 14
3 grade 3 cholinergic
symptoms



7 grade 3 or 4 neutropenia



3 grade 3 nausea/vomiting



1 pain and abdominal cramps
without delayed diarrhea

Dose-limiting toxicity (DLT) had not been reached even with 350 mg/msq.

Therapeutic activity of CPT-11 Five patients resistant to other chemotherapy seemed to benefit from CPT-11 treatment. One brain-stem glioma patient experienced a "minor" response and four others showed some disease stability. The latter consisted of relatively slow-growing tumors: one patient each with ependymoma, sarcoma, astrocytoma and desmoplastic tumor. CPT-11 failed to help 10 other children: ependymoma, 2/3; hepatoblastoma, 2/2; sarcoma, 2/3; Burkitt lymphoma, 1/1; cavum epidermoid, 1/1; and malignant schwannoma, 2/2.

Investigator conclusions Pediatric DLT with CPT-11 is greater than 350 mg/msq. Preliminary pharmacokinetic data suggest that children and adults have similar patterns of absorption and metabolism. Additional study is needed to further define the pediatric DLT for CPT-11. The available data prompted initiating another study using the drug in children treated previously with cranio-spinal irradiation or high dose chemotherapy with stem cell support.

For professional correspondence, please contact Dr. Pein by E-mail at: ONCOPED@igr.fr

Eugene A. Conrad

Presented at The European Cancer Conference (ECCO 9), September 14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / December 1997
Send comments to: ConradNote@aol.com

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