A Phase I Study of Intravenous Irinotecan and Bortezomib in Children With Recurrent/Refractory High-Risk Neuroblastoma
In spite of intensive treatment including high-dose chemotherapy with autologous peripheral
stem cell transplantation and radiation therapy, the long-term survival of patients with
high-risk neuroblastoma remains poor. Patients who experience a relapse of their disease or
fail to achieve complete remission fare even worse. More intense chemotherapy is not the
answer. The development of new drugs with different mechanisms of action are required.
Inhibitors of the proteasome have created a considerable interest in their use in cancer
chemotherapy, either as a single agent or in combination with other chemotherapeutic agents.
The precise mechanism of action for these class of drugs is unclear, however, inhibition of
I-kB degradation by VELCADE® (bortezomib) decreases NF-kB activity in neuroblastoma cell
lines as well as other systems.
Previous studies have reported the activity of Irinotecan, a strong Topoisomerase-I
inhibitor, against murine xenografts including those with high-risk features such as MYCN
amplification. Irinotecan has also been shown to be active against neuroblastoma xenografts
resistant to vincristine, melphalan, and topotecan, suggesting an alternative mechanism of
resistance to Irinotecan. In vitro synergy between bortezomib and Irinotecan has been
documented in pancreatic cancer by others and in neuroblastoma by our group.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine highest dose of IV irinotecan administered in conjunction with bortezomib without causing severe side effects.
Rajen Mody, MD
University of Michigan Cancer Center
United States: Food and Drug Administration
|The University of Michigan Comprehensive Cancer Center||Ann Arbor, Michigan 48109|