Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study

Gururangan, Sridharan; Fangusaro, Jason; Poussaint, Tina Young; McLendon, Roger E.; Onar‐Thomas, Arzu; Wu, Shengjie; Packer, Roger J.; Banerjee, Anu; Gilbertson, Richard J.; Fahey, Frederic H.; Vajapeyam, Sridhar; Jakacki, Regina I.; Gajjar, Amar; Goldman, Stewart; Pollack, Ian F.; Friedman, Henry S.; Boyett, James M.; Fouladi, Maryam; Kun, Larry E.

doi:10.1093/neuonc/not154

Cited by 140 publications

(118 citation statements)

References 31 publications

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“…Interpretation of stability in children with low-grade gliomas is problematic given the somewhat erratic growth course of these tumors and their potential slow rate of growth. Given the evidence now in two clinical trials an anti-angiogenesis drug (bevacizumab), was effective in halting growth and in some cases decreasing tumor size of low-grade gliomas with associated functional improvement, the results seen in this trial in children with low-grade gliomas is of interest [7, 15]. PTC299 is oral and easy to deliver and has a unique mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study

et al. 2014

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Background PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT) and characterize the pharmacokinetic profile of PTC299 in children with recurrent CNS tumors. Patients and Methods PTC299 was administered orally twice or three times daily, depending on the regimen. Four regimens were evaluated using the rolling 6 design, starting with 1.2 mg/kg/dose twice daily and escalating to 2 mg/kg/dose three times daily. Pharmacokinetic studies were performed during the first two courses. Results Twenty-seven children (14 male, median age 11.2, range 5.5–21 years) with recurrent brain tumors were treated; 21 were fully evaluable for toxicity assessment. Therapy was well-tolerated, and the only DLT was grade 3 hyponatremia. Grade three and grade four toxicities were uncommon in subsequent cycles. Median AUC0–Tlast values at the 2 mg/kg were similar to those observed in adults. The study was terminated while patients were being treated at the highest planned dose, due to hepatotoxicity encountered in the ongoing adult phase I studies. No complete or partial responses were observed. Two patients with low-grade gliomas were noted to have minor responses, and at the time of the study’s closure, 5 children with low-grade gliomas had been on therapy for 8 or more courses (range 8–16). Conclusion PTC299 was well-tolerated at the highest dose level tested (2 mg/kg/dose TID) in children with recurrent brain tumors and prolonged disease stabilization was seen in children with low-grade gliomas.

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Section: Discussionmentioning

confidence: 99%

Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study

et al. 2014

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“…In adults, dynamic contrast-enhanced (DCE) MR perfusion has been used to determine tumor grade [3][4][5] and to distinguish pseudoprogression from tumor recurrence, 6 thus affecting treatment. While dynamic susceptibility contrast perfusion and DCE-MR perfusion in adult brain tumors have been extensively studied in the literature, particularly for monitoring tumor antiangiogenesis treatments, 7-11 DCE-MR imaging studies in pediatric brain tumors have been scarce [12][13][14][15][16][17][18] and have not focused on tumor grading. Multiparametric methods to characterize and monitor brain tumors have also shown great promise.…”

Section: Abbreviationsmentioning

confidence: 99%

Automated Processing of Dynamic Contrast-Enhanced MRI: Correlation of Advanced Pharmacokinetic Metrics with Tumor Grade in Pediatric Brain Tumors

Vajapeyam¹,

Stamoulis

Ricci

et al. 2016

AJNR Am J Neuroradiol

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“…Therefore, this combination of enhanced irinotecan exposure may have appeal in other patient populations where irinotecan has proven beneficial, such as low grade glioma [35], Ewing Sarcoma [36, 37] and hepatoblastoma [38]. Gefitinib co-administration improved irinotecan exposure at lower irinotecan dosages without increased toxicity, which may allow for dose escalation of other active anti-cancer agents, such as temozolomide or vincristine.…”

Section: Discussionmentioning

confidence: 99%

Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

Brennan

Furman

Mao

et al. 2014

Cancer Chemother Pharmacol

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Purpose This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day). Results Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.

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Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas—a Pediatric Brain Tumor Consortium study

Abstract: The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.

Cited by 140 publications

References 31 publications

Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study

Phase I and pharmacokinetic trial of PTC299 in pediatric patients with refractory or recurrent central nervous system tumors: a PBTC study

Automated Processing of Dynamic Contrast-Enhanced MRI: Correlation of Advanced Pharmacokinetic Metrics with Tumor Grade in Pediatric Brain Tumors

Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

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