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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00644696
Recruitment Status : Completed
First Posted : March 27, 2008
Last Update Posted : July 6, 2017
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
University of Michigan Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Irinotecan and Bortezomib Phase 1

Detailed Description:

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase One Study of Intravenous Irinotecan and Bortezomib in Children With Recurrent/Refractory High-Risk Neuroblastoma
Study Start Date : April 2008
Actual Primary Completion Date : July 2012
Actual Study Completion Date : July 2012

Arm Intervention/treatment
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
Other Names:
  • Velcade
  • Cefpodoxime
  • Cefixime

Primary Outcome Measures :
  1. Determine highest dose of IV irinotecan administered in conjunction with bortezomib without causing severe side effects. [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Measure the neuroblastoma tumors after treatment with irinotecan and bortezomib to determine whether there was a change in size. [ Time Frame: 24 months ]

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Ages Eligible for Study:   1 Year to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00644696

United States, Michigan
The University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan Cancer Center
Millennium Pharmaceuticals, Inc.
Principal Investigator: Rajen Mody, MD University of Michigan Cancer Center

Responsible Party: University of Michigan Cancer Center Identifier: NCT00644696     History of Changes
Other Study ID Numbers: UMCC 2006.084
HUM 7859 ( Other Identifier: University of Michigan Medical School IRB )
First Posted: March 27, 2008    Key Record Dates
Last Update Posted: July 6, 2017
Last Verified: July 2017

Keywords provided by University of Michigan Cancer Center:

Additional relevant MeSH terms:
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action