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

Nathan J. Robison from Mark Kieran’s group in Boston just published a report of a phase II 5 drug regimen built upon the pioneer "4 drug regimen" published 8 years ago. The article is entitled "A phase II trial of a multi-agent oral anti-angiogenic (metronomic) regimen in children with recurrent or progressive cancer" was designed to evaluate the efficacy of a “5-drug” oral regimen in children with recurrent or progressive cancer.

One hundred one patients, ≤21 years old with recurrent or progressive tumors 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 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.Several angiogenesis markers were assessed.

Treatment was generally well tolerated and most common toxicities were hematologic.

Twenty-four (25%) patients completed 27 weeks therapy without progression, including LGG: 7 (58%), ependymoma: 7 (37%). These two groups seems to be the most sensitive to the metronomic regimen in line with previous reports. Besides, long term staibilzation or repsonses were seen in HGG: 1, medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%).

Response Rate and Clinical benefit rates were 13%, and 50%. Interestingly, baseline serum thrombospondin-1 levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).

The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata.