Study of Irinotecan and Bortezomib in Children With Recurrent/Refractory Neuroblastoma
This Phase One pediatric trial seeks to take advantage of the susceptibility of neuroblastoma to proteasome inhibitors, proven in vitro, along with the proven in vitro synergy of bortezomib with irinotecan and the successful Phase I pediatric trials of bortezomib to create a treatment using these two drugs in combination to treat refractory/recurrent neuroblastoma in children and young adults 25 and under.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Intravenous Irinotecan and Bortezomib in Children With Recurrent/Refractory High-Risk Neuroblastoma|
- Determine highest dose of IV irinotecan administered in conjunction with bortezomib without causing severe side effects. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
- Measure the neuroblastoma tumors after treatment with irinotecan and bortezomib to determine whether there was a change in size. [ Time Frame: 24 months ] [ Designated as safety issue: No ]
|Study Start Date:||April 2008|
|Estimated Study Completion Date:||August 2016|
|Estimated Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: Irinotecan and Bortezomib
Irinotecan and Bortezomib will both be administered
Drug: Irinotecan and Bortezomib
Dose level-1a: IV Irinotecan 30 mg/m2/day, IV bortezomib 1.2mg/m2/day Dose level-1: IV Irinotecan 35 mg/m2/day, IV bortezomib 1.2mg/m2/day Dose level-2: IV Irinotecan 40 mg/m2/day, IV bortezomib 1.2mg/m2/day Dose level-3: IV Irinotecan 45 mg/m2/day, IV bortezomib 1.2mg/m2/day Dose level-4: IV Irinotecan 50 mg/m2/day, IV bortezomib 1.2mg/m2/day
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.
|United States, Michigan|
|The University of Michigan Comprehensive Cancer Center|
|Ann Arbor, Michigan, United States, 48109|
|Principal Investigator:||Rajen Mody, MD||University of Michigan Cancer Center|