Nivolumab With DC Vaccines for Recurrent Brain Tumors

This two-arm randomized trial will evaluate the safety of nivolumab in combination with DC
vaccinations for the treatment of bevacizumab-naïve subjects with first or second recurrent,
resectable World Health Organization (WHO) Grade III and IV malignant gliomas (MGs). Up to 66
patients will be enrolled and treated with the goal of accruing 30 patients (15 per arm) that
will receive nivolumab and at least 3 vaccines. After enrollment, leukapheresis will be done
for generation of DC vaccines and immunologic monitoring. All subjects will undergo standard
of care tetanus booster vaccination with 0.5 mL of Td (tetanus and diphtheria toxoids
adsorbed) intramuscularly (I.M.) into the deltoid muscle to ensure adequate immunity to the
tetanus antigen. Subjects will initially return every 2 weeks and receive approximately 3
infusions of nivolumab 3 mg/kg IV while the DC vaccines are being prepared from the initial
leukapheresis and will then be randomized 1:1 to one of 2 arms (Group I: nivolumab only
pre-surgery; Group II: nivolumab with DC vaccines pre-surgery). Patients who are unable to
tolerate nivolumab will be withdrawn from the study and replaced. Patients whose DCs or
Peripheral Blood Lymphocytes (PBLs) fail to meet release criteria will continue to receive
nivolumab only and will not undergo repeat leukapheresis. For patients whose leukapheresis
yields less than 4 vaccines, a repeat leukapheresis may be obtained a minimum of 2 weeks from
the previous leukapheresis (and may be repeated as needed) if stable. Peripheral blood will
be drawn for immune monitoring prior to treatment with the 4th cycle of nivolumab (first
post-randomization infusion of nivolumab).

Group I Treatment Plan (Nivolumab Only Pre-Surgery) After randomization, patients in Group I
will receive nivolumab 3 mg/kg IV every 2 weeks x approximately 8 weeks. The subject will
then undergo surgical resection of tumor within approximately 1-3 weeks. Approximately 2-4
weeks later, leukapheresis is repeated for generation of DC vaccines and immunologic
monitoring. Approximately 1 day to 2 weeks after leukapheresis, the subject will resume
nivolumab 3mg/kg IV every two weeks with DC vaccine administration intradermally (i.d.) for a
total of 3 vaccines. At the time of the third DC vaccine, patients will receive vaccine site
pre-conditioning. A single dose of Td toxoid (1 flocculation unit (Lf) in 0.4 milliliters
(mL) of saline) will be administered to a single side of the groin i.d. (as described above
for all vaccine administrations 12-24 hours prior to the third DC vaccine, which is always
given bilaterally at the groin site. At the vaccine #3 visit, prior to vaccine # 3
administration, erythema and induration measurements will be taken of pre-conditioning site.
Group I subjects will then receive monthly DC vaccine administrations intradermally for 5
months or until progression (whichever comes first).Total vaccines to be administered will be
8 post-surgery unless subject is removed. Nivolumab will continue until progression. At the
clinic visit following the last vaccine (#8), subjects will have peripheral blood drawn for
immune monitoring prior to infusion of nivolumab.

Group II Treatment Plan (Nivolumab with DC Vaccines Pre-Surgery) After randomization,
patients in Group II will receive the fourth cycle of nivolumab then receive nivolumab 3
mg/kg IV along with DC vaccines intradermally every 2 weeks x approximately 6 weeks for a
total of 3 vaccines. At the time of the third DC vaccine, patients will receive vaccine site
pre-conditioning. A single dose of Td toxoid (1 Lf in 0.4 mL of saline) will be administered
to a single side of the groin i.d. 12-24 hours before the third DC vaccine, which is always
given bilaterally at the groin site. At the vaccine #3 visit, prior to vaccine #3
administration, erythema and induration measurements will be taken of pre-conditioning
site.The subject will then undergo surgical resection of tumor within approximately 1-3
weeks. Approximately 2-4 weeks later, leukapheresis is repeated for generation of DC vaccines
and immunologic monitoring. Approximately 1 day to 2 weeks after leukapheresis, the subject
will resume nivolumab 3mg/kg IV every two weeks. When DC vaccines have completed processing
and are available for administration, monthly DC vaccine administrations as described above
will be administered for 5 months or until progression (whichever comes first). Total
vaccines to be administered will be 8 (3 pre- and 5 post-surgery) unless subject is removed.
Nivolumab will continue until progression. At the clinic visit following the last vaccine
(#8), subjects will have peripheral blood drawn for immune monitoring prior to infusion of
nivolumab.

Inclusion Criteria:

- Age 18-80 years of age

- First or second recurrence of MG (WHO Grade III or IV glioma or astrocytoma) in
surgically accessible areas with prior histologic diagnosis of MG

- Bevacizumab-naïve - no prior exposure to Bevacizumab

- Karnofsky Performance Status (KPS) of ≥ 70%

- Radiation Therapy (RT) with ≥ 45 Gray (Gy) tumor dose, completed ≥ 8 weeks prior to
study entry

- Laboratory values must meet the following criteria:

1. White Blood Count (WBC) ≥ 2000/microliters (uL)

2. Neutrophils ≥ 1500/uL

3. Platelets ≥ 100x103/uL

4. Hemoglobin ≥ 9.0 g/dL

5. Serum creatinine ≤ 1.5x the upper limit of normal (ULN) or creatinine clearance
(CrCl)≥ 40 mL/min (using the Cockcroft-Gault formula) c. Female CrCl = (140 - age
in years) x weight in kg x 0.85 /72 x serum creatinine in mg/dL d. Male CrCl =
(140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL

6. Aspartate Aminotransferase (AST) ≤ 3x ULN

7. Alanine Aminotransferase (ALT) ≤ 3x ULN

8. Bilirubin≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have total
bilirubin < 3.0 mg/dL)

9. Subjects must have resting baseline O2 saturation by pulse oximetry of ≥ 92% at
rest.

- Patients of child bearing potential or with partners of child-bearing potential must
practice recommended contraceptive methods to prevent pregnancy during treatment and
for 5 months after the last dose of nivolumab for women, 7 months after the last dose
of nivolumab for men, and for 6 months after the last dose of bevacizumab for subjects
receiving bevacizumab.

Exclusion Criteria:

- Contrast-enhancing tumor component crossing the midline, multi-focal tumor, or tumor
dissemination (subependymal or leptomeningeal)

- Clinically significant increased intracranial pressure (e.g., impending herniation),
uncontrolled seizures, or requirement for immediate palliative treatment

- Pregnant or need to breast feed during the study period (Negative human chorionic
gonadotropin (β-HCG) test required), or unable to maintain use of contraception while
on study and for 31 weeks after the last dose of nivolumab

- Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness

- Known immunosuppressive disease, autoimmune disease or human immunodeficiency virus
infection, Hepatitis B or Hepatitis C

- Known allergy or hypersensitivity to tetanus, or any other tetanus or diphtheria
toxoid-containing vaccine, or any component of this vaccine (i.e., aluminum phosphate,
formaldehyde)

- Known severe (Grade 3 or 4) infusion-related allergy or hypersensitivity to any
monoclonal antibody

- Previous radiation therapy with anything other than standard radiation therapy (such
as previous stereotactic radiosurgery) or previous treatment with an immune checkpoint
inhibitor (i.e., nivolumab, pembrolizumab, ipilimumab)

- Unstable or severe intercurrent medical conditions such as severe heart (New York
Association Class 3 or 4) or lung (FEV1 < 50%) disease, uncontrolled diabetes mellitus

- Corticosteroid use > 4 mg/day at time of consent

- Prior inguinal lymph node dissection.