AUTHOR=Verschuur Arnauld , Heng-Maillard Marie-Amélie , Dory-Lautrec Philippe , Truillet Romain , Jouve Elisabeth , Chastagner Pascal , Leblond Pierre , Aerts Isabelle , Honoré Stéphane , Entz-Werle Natasha , Sirvent Nicolas , Gentet Jean-Claude , Corradini Nadège , André Nicolas 

TITLE=Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00950

DOI=10.3389/fphar.2018.00950

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC has shown its efficacy in adult tumor types such as breast and ovarian cancer and has to some extent been studied in pediatrics.</p><p><bold>Objective:</bold> To assess the anti-tumor activity and toxicity of a four-drug metronomic regimen in relapsing/refractory pediatric brain tumors (BT) with progression-free survival (PFS) after two cycles as primary endpoint.</p><p><bold>Methods:</bold> Patients ≥4 to 25 years of age were included with progressing BT. Treatment consisted of an 8-week cycle of celecoxib, vinblastine, and cyclophosphamide alternating with methotrexate. Kepner and Chang two-steps model was used with 10 patients in the first stage. If stabilization was observed in ≥2 patients, 8 additional patients were recruited. Assessment was according WHO criteria with central radiology review.</p><p><bold>Results:</bold> Twenty-nine patients (27 evaluable) were included in two groups: ependymoma (group 1, <italic>N</italic> = 8), and miscellaneous BT (group 2): 3 medulloblastoma (MB), 5 high grade glioma (HGG), 11 low grade glioma (LGG), 2 other BT. After first stage, recruitment for ependymoma was closed [one patient had stable disease (SD) for 4 months]. Cohort 2 was opened for second stage since 1 HGG and 3 LGG patients had SD after two cycles. Recruitment was limited to LGG for the second stage and 2 partial responses (PR), 6 SD and 2 progressive disease (PD) were observed after two cycles. Of these patients with LGG, median age was 10 years, nine patients received vinblastine previously. Median number of cycles was 6.8 (range: 1–12). Treatment was interrupted in five patients for grade 3/4 toxicity.</p><p><bold>Conclusion:</bold> This regimen is active in patients with LGG, even if patients had previously received vinblastine. Toxicity is acceptable.</p><p><bold>Trial Registration:</bold> This study was registered under <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/" xmlns:xlink="http://www.w3.org/1999/xlink">clinicaltrials.gov</ext-link> – NCT01285817; EUDRACT nr: 2010-021792-81.</p>