Official Title: “A Phase I Study of Intravenous Irinotecan and Bortezomib in Children With Recurrent/Refractory High-Risk 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 Type: Interventional

Study Design: Treatment, Open Label, Single Group Assignment, Safety Study

Study Primary Completion Date: April 2010

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.

Intervention(s) in this Clinical Trial

• 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

Primary Measures

• Find the highest dose of IV irinotecan that can be given with bortezomib without causing severe side effects.
  • Time Frame: 1-3 years
    Safety Issue?: Yes

Secondary Measures

• To determine if the neuroblastoma tumors get smaller after treatment with irinotecan and bortezomib.
  • Time Frame: 1-2
    Safety Issue?: No
• To find out the side effects seen by giving this drug combination on this schedule at different dose levels.
  • Time Frame: 1-3 years
    Safety Issue?: Yes

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:
• 1. Measurable tumor on MRI or CT scan or X-ray (at least 20 mm in at least one dimension) or 2. MIBG scan with positive uptake at minimum of one site, or 3. 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 beta-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 B-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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 1 Year

Maximum Age for this Clinical Trial: 25 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Michigan Cancer Center

Overall Clinical Trial Officials and Contacts

Rajen Mody, MD Principal Investigator University of Michigan Cancer Center  

Overall Contact: Rajen Mody, MD 1-800-865-1125 

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00644696

Study ID Number: UMCC 2006.084

ClinicalTrials.gov Identifier: NCT00644696

Health Authority: United States: Food and Drug Administration