A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer

Nathan J. Robison, Federico Campigotto, Susan N. Chi, Peter E. Manley, Christopher D. Turner, Mary Ann Zimmerman, Christine A. Chordas, Annette M. Werger, Jeffrey C. Allen, Stewart Goldman, Joshua B. Rubin, Michael S. Isakoff, Wilbur J. Pan, Ziad A. Khatib, Melanie A. Comito, Anne E. Bendel, Jay B. Pietrantonio, Laura Kondrat, Shannon M. Hubbs, Donna S. NeubergMark W. Kieran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Background: Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a "5-drug" oral regimen in children with recurrent or progressive cancer. Procedure: Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed. Results: One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days-21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P=0.009). Conclusion: The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636-642.

Original languageEnglish (US)
Pages (from-to)636-642
Number of pages7
JournalPediatric Blood and Cancer
Volume61
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • Angiogenesis
  • Drug resistance
  • Pediatric oncology
  • Phase II clinical trials

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Fingerprint Dive into the research topics of 'A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer'. Together they form a unique fingerprint.

Cite this