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

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.