Bivalent Vaccine With Escalating Doses of the Immunological Adjuvant OPT-821, in Combination With Oral ß-glucan for High-Risk Neuroblastoma

• To determine the maximally tolerated dose of OPT-821 in a vaccine containing two antigens abundantly expressed on neuroblastoma. (PHASE I) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• To improve event-free survival (EFS) of patients who are in second (or later) complete/very good partial remission (CR/VGPR), i.e., have no evidence of NB by standard studies after having received salvage therapy for relapse. (PHASE II) [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
• To assess anti-NB activity of the bivalent vaccine plus oral β-glucan in patients who are enrolled with evidence of minimal residual disease (MRD) by molecular biological testing of bone marrow. (PHASE II) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• To obtain preliminary data on whether subcutaneous administration of the bivalent vaccine produces an immune response directed against the target antigens in patients with high-risk neuroblastoma. (PHASE I) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To obtain preliminary data on the anti-neuroblastoma activity of the bivalent vaccine plus oral β-glucan in patients, including measuring the molecular response in blood and bone marrow. (PHASE I) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To obtain data on the immune response directed against the target NB-associated antigens in patients as induced by the subcutaneous administration of the bivalent vaccine. (PHASE II) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To assess FcRIIa, FcRIIIa, CR3 and CD18 gene polymorphism of leukocytes (effector cells), with a view towards a possible association with outcome. (PHASE II) [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• To obtain preliminary data on whether subcutaneous administration of the trivalent vaccine produces an immune response directed against the target antigens in patients with high-risk neuroblastoma. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To obtain preliminary data on the anti-neuroblastoma activity of the trivalent vaccine plus oral β-glucan in patients, including measuring the molecular response in blood and bone marrow. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

The purpose of this study is to test the safety and what effects, good and/or bad, treatment with a vaccine against neuroblastoma has on the patient and the cancer. In the first part of this study we found the highest dose of the vaccine that did not have too many side effects. We are now trying to find out what effects the vaccine has when given at the same dose to all patients.

The main treatment in this protocol is a vaccine. It is called a " bivalent vaccine" which means it has 2 antigens. An antigen is a specific protein on the surface of a cell. The antigens are called GD2L and GD3L.

We want the vaccine to cause the patient's immune system to make antibodies against the antigens. Antibodies are made by the body to attack cancer (and to fight infections). If the patient can make antibodies against the 2 antigens in the vaccine, those antibodies might also attach to neuroblastoma cells because a lot of each antigen is on neuroblastoma (and very little on other parts of the body). Then, the attached antibodies would attract the patient's white blood cells to kill the neuroblastoma. This protocol also uses β-glucan which is a kind of sugar from yeast. β-glucan is taken by mouth and can help white blood cells kill cancer. The best way to get the body to make antibodies against the 3 antigens is to link each antigen to a protein called KLH (which stands for: keyhole limpet hemocyanin) and to mix them with a substance called QS-21. But it is hard to get enough QS-21 so we are using an identical substance called OPT-821, which we can get easily in large amounts for use in patients.

Inclusion Criteria:

• Diagnosis of neuroblastoma (NB) as defined by international criteria,[104] i.e., histopathology (confirmed by the MSKCC Department of Pathology) or bone marrow metastases plus high urine catecholamine levels.
• High-risk NB as defined by risk-related treatment guidelines and the International NB Staging System,[104] i.e., stage 4 with (any age) or without (>18 months old) MYCN amplification, MYCN-amplified stage 3 (unresectable; any age), MYCN-amplified stage 4S, or disease resistant to standard chemotherapy.
• Relapsed high-risk NB (as defined above) and now in second or subsequent remission. Remission is defined as complete (CR) or very good partial (VGPR)remission, according to the International Neuroblastoma Response Criteria.[104] Urine catecholamine levels are no longer taken into consideration when staging.

Patients can be considered as in VGPR with 1 or 2 MIBG (+) sites that were previously- irradiated.

• Absolute lymphocyte count > or = to 500/mcl and absolute neutrophil count > or = to 500/mcl.
• Creatinine ≤ 2.0 mg/dL
• ALT, AST and Alkaline Phosphatase ≤ 2.5 times the upper limit of normal
• Bilirubin ≤ 2.0 mg/dL
• Patients with less than grade 3 toxicities (using the CTCAE v3.0) related to cardiac, neurological, pulmonary or gastrointestinal function as determined by physical exam.
• Prior treatment with other immunotherapy, including antibodies, is allowed
• > or = to 3 weeks between completion of systemic therapy and 1st vaccination.
• Signed informed consent indicating awareness of the investigational nature of this program.

Exclusion Criteria:

• History of allergy to KLH, QS-21, OPT-821, or glucan.
• Active life-threatening infection.
• Inability to comply with protocol requirements.