Study of Irinotecan and Bortezomib in Children With Recurrent/Refractory Neuroblastoma

Study Overview
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Brief Summary
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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 One 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.

Detailed Description
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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 gene amplification (MYCN is also called V-Myc Myelocytomatosis Viral Related Oncogene, Neuroblastoma Derived). 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.

Official Title
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A Phase One Study of Intravenous Irinotecan and Bortezomib in Children With Recurrent/Refractory High-Risk Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: Irinotecan and Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No greater than 25 years of age when originally diagnosed. Histologic verification of condition. Has recurrent/progressive; or resistant/refractory neuroblastoma with at least ONE of the following: Measurable tumor on MRI or CT scan or X-ray (at least 20 mm in at least one dimension) or MIBG scan with positive uptake at minimum of one site, or Bone marrow with tumor cells seen on routine morphology (not by NSE staining only) of bilateral aspirate and/or biopsy on one bone marrow sample. Has Lansky or Karnofsky score of 60%, and a life expectancy of > 2 months. Has fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy. Has not received treatment with myelosuppressive agents within 3 weeks and with any biological therapy within 2 weeks of study entry. Has not received radiation for a minimum of four weeks prior to study entry at the site of any lesion that was biopsied to document study eligibility. Patient is 2 months post myeloablative therapy and autologous stem cell transplant. At least six weeks must have elapsed since treatment with therapeutic doses of MIBG. Patients who have previously received combination bortezomib and irinotecan are ineligible but can have received one of the drugs. Must not have received hematopoietic growth factors within 2 days of study entry. Cannot be receiving enzyme-inducing anticonvulsants (phenobarbital, phenytoin, carbamazepine). Concomitant radiotherapy to painful bone lesions will be allowed (excluding intestinal tract, spine or pelvis) but other non-radiated sites of measurable disease must be available to assess response to chemotherapy. Patient has adequate bone marrow function (defined). Patient has adequate renal function (defined). Patient has adequate liver function (defined). Post-menarchal females must have a negative pregnancy test measuring beta-human chorionic gonadotropin(HCG). All males and females must use effective contraception during study. Exclusion Criteria: Patient is status post-allogenic stem cell transplant. Patient has uncontrolled infection or active diarrhea defined as 2 or more stools per day greater than baseline. Presence of HIV, active hepatitis B, or active hepatitis C infection. Pregnancy, as determined by Beta-human chorionic gonadotropin(HCG)measurement. Grade 2 peripheral neuropathy within 14 days before enrollment. Myocardial infarction within 6 months prior to enrollment or various other indications of heart disease. (defined) Hypersensitivity to bortezomib, irinotecan, cefixime, boron or mannitol. Female subject is breast-feeding. Serious medical or psychiatric illness likely to interfere with participation. Patient has received other investigational drugs within 14 days before enrollment.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Irinotecan and Bortezomib<br>Irinotecan and Bortezomib will both be administered | Drug: Irinotecan and Bortezomib<br>* 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<br>* Other names: Cefixime;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine highest dose of IV irinotecan administered in conjunction with bortezomib without causing severe side effects. |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure the neuroblastoma tumors after treatment with irinotecan and bortezomib to determine whether there was a change in size. |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroblastoma, Irinotecan, Bortezomib