Pediatric phase I trial and pharmacokinetic study of the platelet-derived growth factor (PDGF) receptor pathway inhibitor SU101
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To determine the maximum tolerated dose and the toxicity profile of the PDGF receptor pathway inhibitor SU101 in pediatric patients with refractory solid tumors, and to define the plasma pharmacokinetics of SU101 and its active metabolite SU0020 in children.
Patients between 3 and 21 years of age with CNS malignancy, neuroblastoma, or sarcoma refractory to standard therapy were eligible. The starting dose of SU101 was 230 mg/m2 per day administered as a 96-h continuous infusion every 21 days. Blood for pharmacokinetic analysis was obtained during the first cycle.
Entered into the trial were 27 patients, and 24 were fully evaluable for toxicity. Dose-limiting central nervous system toxicity was observed in two patients at the 440 mg/m2 per day dose level. Non-dose-limiting toxicities included nausea, vomiting, headache, fatigue, abdominal discomfort, diarrhea, pruritus, anorexia, constipation, and paresthesias. There were no complete or partial responses. One patient with rapidly progressive desmoplastic small round-cell tumor experienced symptomatic improvement and prolonged stable disease. Steady-state concentrations of SU101 were rapidly achieved and proportional to dose. The concentration of SU0020 was 100- to 1000-fold greater than that of SU101. The median clearance of SU0020 was 0.19 l/day per m2 and its terminal elimination half-life was 14 days.
SU101 administered on this schedule was generally well tolerated. The maximum tolerated dose of SU101 is 390 mg/m2 per day for 4 days repeated every 3 weeks. The neurotoxicity observed at the 440 mg/m2 per day dose level suggests that patients receiving repetitive cycles must be monitored closely, as SU0020 may accumulate over time.
KeywordsSignal transduction Pharmacokinetics Pediatric SU101 Leflunomide
- 1.Shawver LK, Schwartz DP, Mann E, Chen H, Tsai J, Chu L, Taylorson L, Longhi M, Meredith S, Germain L, Jacobs JS, Tang C, Ullrich A, Berens ME, Hersh E, McMahon G, Hirth KP, Powell TJ (1997) Inhibition of platelet-derived growth factor-mediated signal transduction and tumor growth by N-[4-(trifluoromethyl)-phenyl]5- methylisoxazole-4-carboxamide. Clin Cancer Res 3:1167–1177PubMedGoogle Scholar
- 3.Hermanson M, Funa K, Hartman M, Claesson-Welsh L, Heldin CH, Westermark B, Nister M (1992) Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loops. Cancer Res 52:3213–3219PubMedGoogle Scholar
- 7.Hermanson M, Funa K, Koopmann J, Maintz D, Waha A, Westermark B, Heldin CH, Wiestler OD, Louis DN, von Deimling A, Nister M (1996) Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomas. Cancer Res 56:164–171PubMedGoogle Scholar
- 8.Nister M, Libermann TA, Betsholtz C, Pettersson M, Claesson-Welsh L, Heldin CH, Schlessinger J, Westermark B (1988) Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res 48:3910–3918PubMedGoogle Scholar
- 10.Chung CK, Antoniades HN (1992) Expression of c-sis/platelet-derived growth factor B, insulin-like growth factor I, and transforming growth factor alpha messenger RNAs and their respective receptor messenger RNAs in primary human gastric carcinomas: in vivo studies with in situ hybridization and immunocytochemistry. Cancer Res 52:3453–3459PubMedGoogle Scholar
- 16.Maxwell M, Naber SP, Wolfe HJ, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN (1990) Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest 86:131–140PubMedGoogle Scholar
- 21.Eckhardt SG, Rizzo J, Sweeney KR, Cropp G, Baker SD, Kraynak MA, Kuhn JG, Villalona-Calero MA, Hammond L, Weiss G, Thurman A, Smith L, Drengler R, Eckardt JR, Moczygemba J, Hannah AL, Von Hoff DD, Rowinsky EK (1999) Phase I and pharmacologic study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors [see comments]. J Clin Oncol 17:1095–1104PubMedGoogle Scholar
- 22.VanUmmersen L, Ness E, Goldstein DJ, Disbrow G, Metlay G, Shawver L, Hannah AL, Marshall JL (1997) A phase I trial of SU101 in patients with solid tumors (meeting abstract). Proc ASCO p A740Google Scholar
- 23.Malkin MG, Mason WP, Lieberman FS, Hannah AL (1997) Phase I study of SU101, a novel signal transduction inhibitor, in recurrent malignant glioma (meeting abstract). Proc ASCO p A1371Google Scholar
- 24.Shapiro W, Ashby L, Obbens E, Isaacs J, Cropp G, DePaoli A, Hannah A (1999) A phase I/II study of SU101 in combination with carmustine (BCNU) in the treatment of patients newly diagnosed with malignant glioma (meeting abstract). Proc ASCO p A548Google Scholar
- 25.Malkin MG, Rosen L, Lopez AM, Mulay M, Cloughesy T, Hannah AL (1998) Phase 2 study of SU101, a PDGF-R signal transduction inhibitor, in recurrent malignant glioma (meeting abstract). Proc ASCO p A1504Google Scholar
- 26.Ko YJ, Small EJ, Kabbinavar F, Chachoua A, Taneja S, Reese D, DePaoli A, Hannah A, Balk SP, Bubley GJ (2001) A multi-institutional phase II study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. Clin Cancer Res 7:800–805PubMedGoogle Scholar
- 27.Ko YJ, Chachoua A, Small E, Reese D, Kabbinavar F, Taneja S, DePaoli A, Hannah A, Balk S, Bubley G (1999) Phase II study of SU101 in patients with PSA-positive prostate cancer (meeting abstract). Proc ASCO p A1220Google Scholar
- 28.Rosen L, Lopez AM, Mulay M, Chap L, Prager D, Pegram M, Rosen P, Hannah AL (1997) A phase I/II study of SU101 in patients with ovarian, prostate, and non-small cell lung cancers (meeting abstract). Proc ASCO p A739Google Scholar
- 29.Chap L, Chachoua A, Lopez A, DePaoli A, Hannah A (1999) A phase II study of SU101 in patients with advanced ovarian cancer (meeting abstract). Proc ASCO p A1437Google Scholar
- 30.Kabbinavar F, Hannah A, Rosen P, Sawyers C, Prager D, Baker C, DePaoli A, Cropp G (1999) Phase I trial of SU101 in combination with mitoxantrone in the treatment of patients with hormone refractory prostate cancer. Clin Cancer Res 5:3800SGoogle Scholar
- 31.Oda Y, Wehrmann B, Radig K, Walter H, Rose I, Neumann W, Roessner A (1995) Expression of growth factors and their receptors in human osteosarcomas. Immunohistochemical detection of epidermal growth factor, platelet-derived growth factor and their receptors: its correlation with proliferating activities and p53 expression. Gen Diagn Pathol 141:97–103PubMedGoogle Scholar
- 40.National Cancer Institute (1993) Guidelines for reporting adverse drug reactions. Cancer Therapy Evaluation Program Division of Cancer Treatment, Investigator’s Handbook. US Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, MD. Appendix XIIGoogle Scholar