Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium

Memphis, TN, United States

Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium

Memphis, TN, United States
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Pollack I.F.,Childrens Hospital of Pittsburgh | Stewart C.F.,St Jude Childrens Research Hospital | Kocak M.,Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium | Poussaint T.Y.,Childrens Hospital Boston | And 6 more authors.
Neuro-Oncology | Year: 2011

This phase II study was designed to assess the safety and efficacy of gefitinib given with and following radiation therapy in children newly diagnosed with a poor prognosis brainstem glioma. Eligible patients were those with a previously untreated nondisseminated diffuse intrinsic brainstem glioma. Histological confirmation was not required, provided patients had a characteristic clinical history and MRI findings. Treatment consisted of gefitinib, administered orally, 250 mg/m2/day, during standard external beam radiotherapy, continuing for up to 13 monthly courses in the absence of disease progression or unacceptable toxicity. Toxicities, particularly intratumoral hemorrhage, were monitored. Pharmacokinetics and investigational imaging studies were performed in consenting patients. Forty-three eligible patients were included in the study. Therapy was well tolerated; only 4 patientswerewithdrawn from the study for dose-limiting toxicity after receiving therapy for 6, 9, 17, and 24 weeks. The 12- and 24-month progression-free survival rates were 20.9±5.6 % and 9.3±4%, respectively. Overall survival rates were 56.4±7.6% and 19.6± 5.9%, respectively, which appear nominally superior to other contemporaneous Pediatric Brain Tumor Consortium trials. Three patients remain progressionfree survivors with ≥ 36 months follow-up. The observation that a subset of children with this generally fatal tumor experienced long-term progression-free survival, coupled with recent observations regarding the molecular features of brainstem gliomas, raises the possibility that prospective molecular characterization may allow enrichment of treatment responders and improvement in outcome results in future studies of biologically targeted agents. © The Author(s) 2011.

Warren K.E.,U.S. National Cancer Institute | Gururangan S.,Duke University | Geyer J.R.,Seattle Childrens Hospital | McLendon R.E.,Duke University | And 10 more authors.
Journal of Neuro-Oncology | Year: 2012

To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O 6-benzylguanine (O6BG) and temozolomide ® (TMZ). Patients received O6BG 120 mg/m 2/d IV followed by TMZ 75 mg/m 2/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or longterm SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG. © 2011 Springer Science+Business Media, LLC. (outside the USA).

Gururangan S.,Duke University | Fangusaro J.,Childrens Memorial Hospital | Young Poussaint T.,Childrens Hospital Boston | Onar-Thomas A.,Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium | And 9 more authors.
Neuro-Oncology | Year: 2012

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion-weighted and T1 dynamic contrast enhanced permeability imaging and tumor immunohistochemistry for vascular endothelial growth factor (VEGF)-A and-B, hypoxia inducible factor-2α, VEGF receptor (R)-2, and carbonic anhydrase (CA)-9. Thirteen evaluable patients received a median of 3 courses (range, 2-12) of BVZ CPT-11. No sustained response was observed in any patient. Median time to progression in 10 patients was 2.2 months (range, 1.9-6.3). Two patients had stable disease for 10 months and 12 months, respectively. Six-month PFS was 25.7 (SE 11.1). Grades I-III toxicities related to BVZ treatment included fatigue in 4 patients, systemic hypertension in 2, epistaxis in 1, headache in 1, and avascular necrosis of bone in 1. Although there was a decrease in the mean diffusion ratio following 2 doses of BVZ, it did not correlate with PFS. BVZ CPT-11 was well tolerated but had minimal efficacy in cases of recurrent EPN. © 2012 The Author(s).

Geyer J.R.,Seattle Childrens Hospital | Stewart C.F.,St Jude Childrens Research Hospital | Kocak M.,Operations and Biostatistics Center for the Pediatric Brain Tumor Consortium | Broniscer A.,St Jude Childrens Research Hospital | And 10 more authors.
European Journal of Cancer | Year: 2010

Purpose: To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ≤21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG. Patients and methods: Three strata were identified: stratum 1A - BSG; stratum IB - incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II - incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m 2/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients. Results: Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m2/d, 1 of 10 at 250 mg/m2/d and 3 of 12 at 375 mg/m2/d. Subsequently a second patient at 250 mg/m2/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples. Conclusion: This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m2/d was selected for the phase II trial. © 2010 Elsevier Ltd. All rights reserved.

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