A phase 1 study of combination nivolumab and ipilimumab with irradiated GM-CSF secreting autologous neuroblastoma cell vaccine (GVAX) for relapsed or refractory neuroblastoma

This research clinical trial is studying the creation and administration of GVAX, an
irradiated GM-CSF secreting, autologous neuroblastoma cell vaccine (GVAX) in combination
with nivolumab and ipilimumab as a possible treatment for neuroblastoma.

The names of the study drugs involved in this study are:

- GVAX Vaccine, an immunotherapy developed from surgically removed tumor tissue

- Nivolumab

- Ipilimumab

Inclusion Criteria:

- Eligibility Criteria for neuroblastoma cell collection and vaccine manufacture

- Patients with histologically confirmed neuroblastoma, who meet the Children's
Oncology Group (COG) high-risk group assignment criteria

- Lansky/Karnofsky performance status ≥50% (see Appendix A)

- Participants must have clinical indication for surgical resection of their
neuroblastoma and undergo resection at Boston Children's Hospital

- Ability to understand and/or the willingness of their parent or legally
authorized representative to sign a written informed consent document.

- Eligibility Criteria to commence to receive study treatment with irradiated GM-CSF
secreting autologous tumor vaccine, nivolumab, and ipilimumab

- Histologically confirmed high-risk neuroblastoma based on COG assignment
criteria

- Residual disease at the end of standard therapy or relapsed neuroblastoma in
any disease state (including CR) by clinical criteria (histologic confirmation
of relapse or residual disease is not required).

- Age > 1 year of age

- Lansky/Karnofsky performance status ≥50% (see Appendix A)

- Prior Therapy - Patients must have fully recovered from the acute toxic effects
of all prior anti-cancer therapy and must meet the following minimal duration
from prior anti-cancer directed therapy prior to enrollment

- Myelosuppressive Chemotherapy: At least 21 days after the last dose of
myelosuppressive chemotherapy

- Small molecule biologic therapy: At least 7 days following the last dose
of a biologic agent.

- Monoclonal antibodies ≥ 7 days or 3 half-lives whichever is longer but no
longer than 30 days (with recovery of any associated toxicities)

- External beam irradiation: ≥ 14 days after small port XRT, ≥ 12 weeks
after large port radiation (≥ 50% of the marrow space) including total
body irradiation, craniospinal radiation, whole abdomen and whole lung
radiation

- 131I- MIBG therapy ≥ 6 weeks

- Autologous stem cell infusion following myeloablative therapy ≥ 6 weeks

- Any other investigational agents ≥ 14 days

- Organ function requirements

- Adequate bone marrow function defined as:

- ANC >/= 500/µL

- Hgb >8 (may not be transfused)

- Platelet count ≥30,000 (may not be transfused)

- Hepatic Function:

- Total bilirubin ≤ 1.5 x upper limit of normal for age

- ALT (SGPT) ≤ 3 x upper limit of normal (135 U/L) For the purpose of this
study, the ULN for ALT is 45 U/L

- Renal Function, a serum creatinine based on age/sex as follows:

- Maximum Serum Creatinine (mg/dL)

- Age 1 to <2 years Male: 0.6 Female: 0.6

- Age 2 to < 6 years Male:0.8 Female 0.8

- Age 6 to < 10 years Male:1 Female: 1

- Age 10 to < 13 years Male: 1.2 Female: 1.2

- Age 13 to < 16 years Male: 1.5 Female: 1.4

- Age ≥ 16 years Male: 1.7 Female: 1.4

- OR Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with
creatinine levels greater than the above age/sex maximum allowed values

- Adequate Pulmonary Function Defined as:

- No evidence of dyspnea at rest

- No exercise intolerance due to pulmonary insufficiency

- Pulse oximetry > 92% while breathing room air

- Adequate pancreatic function defined as

- Serum lipase

- No ≥ Grade 2 non-hematologic toxicity

- Absolute eosinophil count ≤ 5000/ul

- Negative B-HCG pregnancy test in females of childbearing potential. Must be
drawn or repeated within 24 hours prior to initial administration of study
drugs

- Women of childbearing potential (WOCBP) receiving nivolumab will be agree to
adhere to contraception for a period of 5 months after the last dose of
nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will
agree to adhere to contraception for a period of 7 months after the last dose
of nivolumab.

Exclusion Criteria:

- Participants who are receiving any other investigational agents.

- No systemic corticosteroid therapy, other than replacement therapy for adrenal
insufficiency or transfusion premedication. Participants who are receiving or have
received lympholytic steroid (>=40mg/m2 prednisone equivalent) therapy within 4
weeks of first anticipated vaccine administration are excluded, because high-dose
steroid therapy is expected to significantly limit the ability of the immune system
to respond to GVAX vaccination.

- Participants with known parenchymal brain metastases.

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to GM-CSF or DMSO.

- Participants with any form of primary immunodeficiency.

- Females who are pregnant are excluded from this study because GVAX is an
investigational biologic with the potential for teratogenic or abortifacient
effects. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with GVAX, breastfeeding should
be discontinued if the mother is treated with GVAX

- Uncontrolled intercurrent illness or serious uncontrolled medical disorder
including, but not limited to, ongoing or active infection, symptomatic congestive
heart failure, unstable angina pectoris, cardiac arrhythmia and/or pronounced
disturbances of the electrical conduction system of the heart or psychiatric
illness/social situations that would limit compliance with study requirements.

- Known HIV-positive participants on combination antiretroviral therapy are ineligible
because of the effect of GVAX vaccination on the disease course is unknown and
because the underlying disease is expected to limit the ability of the immune system
to respond to GVAX vaccination.

- Clinically relevant known active infection including active hepatitis B or C or any
other concurrent disease which in the judgment of the Investigator would make the
subject inappropriate for enrollment on this study

- History of a malignancy other than neuroblastoma with exception of the following
circumstances:

- Patients with a history of malignancy who have been adequately treated and have
been disease-free for at least 2 years are not excluded.

- Patients with adequately treated active non-invasive cancers (such as
non-melanomatous skin cancer or in-situ bladder, cervical and breast cancers)
are not excluded.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti PD L2 or anti-CTLA4
agent or with an agent directed to another stimulatory or co-inhibitory T-cell
receptor (e.g. OX 40, CD137).

- Has active autoimmune disease that has required systemic treatment in the past 12
months, or a documented history of clinically severe autoimmune disease, or a
syndrome that requires systemic steroids or immunosuppressive agents. Subjects with
vitiligo or resolved childhood asthma/atopy are exceptions. Intermittent use of
bronchodilators or local steroid injections are not excluded. Replacement therapy
(e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
treatment. Autoimmune diagnoses not listed must be approved by the protocol chair.

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.