Abstract
Backround: Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. Patients and methods: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg·min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. Results: Forty-one patients, age 2–19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n=9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n=8), medulloblastoma/PNET (n=6) and low-grade glioma (n=2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. Conclusion: The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.
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References
Allen J, Walker R, Luks E et al (1987) Carboplatin and recurrent childhood brain tumors J Clin Oncol 5:459–463
Elliott PJ, Hayward NJ, Dean RL et al (1996) Intravenous RMP-7 selectively increases uptake of carboplatin into rat brain tumors Cancer Res 56:3998–4005
Ford J, Osborn C, Barton T et al (1998) A phase I study of intravenous RMP-7 with carboplatin in patients with progression of malignant glioma Eur J Cancer 34:1807–1811
Friedman H, Krischer P, Oakes W et al (1992) Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: a Pediatric Oncology Group randomized phase II study J Clin Oncol 10:249–256
Gaynon P, Ettinger L, Baum E et al (1990) Carboplatin in childhood brain tumors: a Children’s Cancer Study Group phase II trial Cancer 66:2465–2469
Gregor A, Lind M, Newman H et al (1999) Phase II studies of RMP-7 and carboplatin in the treatment of recurrent high grade glioma J Neurooncol 44:137–145
Inamura T, Nomura T, Bartus RT et al (1994) Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors J Neurosurg 81:752–758
Marina N, Rodman J, Shema S et al (1993) Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors J Clin Oncol 11:554–560
Matsukado K, Inamura T, Nakano S et al (1996) Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of bradykinin analog, RMP-7 Neurosurgery 39:125–133
Prados M, Schold S, Fine H et al (2003) A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma Neuro-Oncol 5:96–103
Rapoport SI, Robinson PJ (1986) Tight-junctional modification as the basis of osmotic opening of the blood-brain barrier Ann N Y Acad Sci 481:250–267
Raymond JJ, Robertson DM, Dinsdale HB (1986) Pharmacological modification of bradykinin induced breakdown of the blood-brain barrier Can J Physiol Pharmacol 13:214–220
Simon R, (1989) Optimal two-stage designs for phase II clinical trials Controlled Clin Trials 10:1–10
Warren KE, Patel MC, Aikin AA et al (2001) Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors Cancer Chemother Pharmacol. 48:275–282
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This research was supported in part by the Intramural Research Program of the NIH, NCI. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.html
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Warren, K., Jakacki, R., Widemann, B. et al. Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children’s Oncology Group. Cancer Chemother Pharmacol 58, 343–347 (2006). https://doi.org/10.1007/s00280-005-0172-7
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DOI: https://doi.org/10.1007/s00280-005-0172-7