CLIN-PEDIATRICS CLINICAL RESEARCH
Authors: R. J. Packer, B. R. Rood, A. Onar-Thomas, S. Goldman, M. J. Fisher, C. Smith, J. Boyett, L. Kun, M. B. Nelson, P. Compton, P. Macey, S. Patel, E. Jacob, S. O'Neil, J. Finlay, R. Harper, G. Legault, A. Chhabra, J. C. Allen, S. J. Si, N. Flores, K. Haley, J. Malvar, J. Fangusaro, G. Dhall, R. Sposto, T. B. Davidson, J. L. Finlay, M. Krieger, J. L. Finlay, T. Zhou, D. C. Miller, J. R. Geyer, I. F. Pollack, A. Gajjar, B. H. Cohen, A. Nellan, J. C. Murray, J. Honeycutt, A. Gomez, H. Head, E. Braly, D. M. Puccetti, N. Patel, T. Kennedy, K. Bradley, S. Howard, S. Salamat, B. Iskandar, I. Slavc, A. Peyrl, M. Chocholous, M. Kieran, A. Azizi, T. Czech, K. Dieckmann, C. Haberler, Z. S. Sadighi, B. Ellezam, S. Khatua, J. Ater, A. Biswas, A. Kakkar, S. Goyal, S. Mallick, C. Sarkar, M. C. Sharma, P. K. Julka, G. K. Rath, T. Glass, D. D. Cochrane, S. R. Rassekh, K. Goddard, J. Hukin, C. E. Deopujari, Y. Khakoo, S. Hanmantgad, K. Forester, S. A. McDonald, K. De Braganca, K. Yohay, J. E. Wolff, R. Kwiecien, S. Rutkowski, T. Pietsch, A. Faldum, R.-D. Kortmann, C. Kramm, M. Fouladi, J. Olson, C. Stewart, M. Kocak, A. Onar-Thomas, L. Wagner, R. Packer, S. Goldman, S. Gururangan, S. Blaney, I. Pollack, C. Smith, T. Demuth, L. Kun, J. Boyett, R. Gilbertson, M. K. Powell, G. L. Klement, T. Roffidal, E. Fonkem, J. E. Wolff
Journal: Neuro-Oncology (2012)

BACKGROUND: PTC299 is a novel, orally bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level.METHODS: A phase I and pharmacokinetic study was performed in children between aged 3-21 years, inclusive, with recurrent brain tumors.PTC299 was given 2-3 times per day every day based on body weight.Six patients were enrolled at each dose level.Four dose levels were planned, beginning at 1.2 mg/kg/dose BID up to 2.0 mg/kg/dose TID; escalation was based on tolerability and mandatory pharmacokinetic data.RESULTS: A total of 28 patients (median age 11.6 years [range 5.5-21.1])were enrolled, with a wide variety of tumors including 8 low-grade gliomas, 9 high-grade gliomas, and 4 brainstem gliomas; 21 patients were evaluable for toxicity.One dose-limiting toxicity (DLT) possibly related to treatment (hyponatremia) was identified during the first course of treatment.Possibly related grade 3 toxic effects of hypernatremia (1), hypertension (1), and lethargy (1) were noted with prolonged use.Pharmacokinetic analysis in cycle 1 demonstrated the expected rise in drug concentrations with increasing doses.Concentrations at dose level three were similar to adult phase II levels.With prolonged use, some patients had drug accumulations without associated toxicity.Objective radiographic responses were not seen, but prolonged (greater than 6 months) stable disease was seen in 5 of 8 patients with low-grade gliomas, 2 of whom maintained disease control for more than 1 year.Four evaluable patients were entered at dose level 4, but the study was suspended pending evaluation of toxicity seen in the adult trials.CONCLUSIONS: PTC299 was well tolerated and prolonged disease control was seen in children with low-grade gliomas.Further study, possibly in combination with other agents, is reasonable, although the pharmacokinetic profile may be challenging, and the adult toxicity profile must be taken into account.