Trial of Nivolumab Following Partially Human Leukocyte Antigen (HLA) Mismatched BMT in Children & Adults With Sarcoma

High risk, recurrent, or refractory solid tumors in pediatric, adolescent and young adult
(AYA) patients have an extremely poor prognosis despite current intensive treatment regimens.
Johns Hopkins piloted an allogeneic bone marrow transplant (alloBMT) platform using a reduced
intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for
this population of pediatric and AYA solid tumor patients.With this strategy, investigators
demonstrated that RIC haploBMT with post-transplant cyclophosphamide (PTCy) is feasible and
has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus,
this approach serves as a platform for post-transplant strategies to prevent relapse and
optimize progression free survival. In this trial, the central hypothesis is that the
efficacy of alloBMT for high risk solid tumors can be improved by developing methods to
augment donor T cell responses against antigens selectively or uniquely expressed by tumor
tissue.

Investigators aim to demonstrated that Programmed death-ligand 1 (PD-1) blockade with
nivolumab will be safe and well tolerated after RIC haplo BMT, initially in a relapsed
population (Part A) and ultimately when given pre-emptively (Part B).

Inclusion Criteria:

1. Patients must be ≥ 12 months and ≤ 40 years of age at the time of study enrollment.

2. Patients with histologically confirmed sarcomas with an estimated <10% chance of long
term survival.

3. Performance Level: Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 60 for
patients ≤16 years of age.

4. Patients must be post RIC haploidentical BMT.

5. Patients must have fully recovered from the acute toxic effects of prior BMT.

6. Palliative (limited-field) radiation therapy is permitted, but only for pain control
to sites of bone disease present at baseline and only if all of the following criteria
are met:

1. Repeat imaging (mandatory) demonstrates no new sites of bone metastases.

2. The lesion being considered for palliative radiation is not a target lesion.

3. The case is discussed with the BMS medical monitor, and the medical monitor
agrees that the conditions required to receive palliative radiation are met.

7. For Part A, patients must have evidence of disease progression or relapse based on
standard restaging scans (RECIST criteria) and/or biopsy.

8. Subjects must consent to allow for a baseline tumor biopsy from a tumor site that is
NOT the only site of measurable disease. If a biopsy is not feasible, then archival
tumor material must be made available.

9. Organ Function Requirements:

I. Adequate Hematologic Parameters:

1. For patients with solid tumors without known bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) ≥ 750/mm3

- Platelet count ≥ 50,000/mm3

2. Patients with known bone marrow metastatic disease will be eligible for study without
the above criteria. They may receive transfusions provided they are not known to be
refractory to red cell or platelet transfusions. These patients will not be evaluable
for hematologic toxicity.

II. Adequate Renal Function Defined as:

1. Creatinine clearance or radioisotope Glomerular filtration rate (GFR) ≥ 70ml/min/1.73
m2 or

2. A serum creatinine based on age/gender as follows:

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

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

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

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

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

- Age ≥ 16 years, Male: 1.7 and Female 1.4

III. Adequate Liver Function Defined as:

1. Bilirubin (sum of conjugated + unconjugated) ≤1.5 x upper limit of normal (ULN) for
age

2. Serum glutamic pyruvic transaminase (SGPT) (ALT) ≤110 U/L. For the purpose of this
study, the ULN for SGPT is 45 U/L.

Exclusion Criteria:

1. GVHD: any history of Stage 4 skin GVHD or Stage 3 gut/liver GVHD (a.k.a. overall Grade
III/IV GVHD) or any severe chronic GVHD. Any person with ≤ Grade II GVHD must be off
systemic immunosuppressive therapy for at least 2 weeks prior to receiving Nivolumab
therapy.

2. Inhaled or topical steroids and adrenal replacement steroid doses are permitted in the
absence of active auto- or allo-immune disease

3. BMT-related toxicities: patients who developed idiopathic pneumonia syndrome (IPS) or
veno-occlusive hepatic disease (VOD) must be off systemic immunosuppression and/or
defibrotide for at least 14 days to be eligible.

4. Infection: Patients who have an uncontrolled infection, including history of
hepatitis.

5. Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.

6. Has active, known or suspected autoimmune disease. Subjects with vitiligo, type I
diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement, or conditions not expected to recur in the absence of
an external trigger are permitted to enroll.

7. Subjects with brain metastasis are excluded from this study. Subjects with brain
metastases are eligible if these have been treated and there is no magnetic resonance
imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete
and within 28 days prior to first dose of study drug administration.

8. Treatment with any chemotherapy, radiation therapy, biologics for cancer, or
investigational therapy within 28 days of first administration of study treatment
(subjects with prior cytotoxic or investigational products < 4 weeks prior to
treatment might be eligible after discussion between investigator and sponsor, if
toxicities from the prior treatment have been resolved to Common Terminology Criteria
for Adverse Events (CTCAE) grade 1 level).

9. Physical and Laboratory Test Findings:

1. Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBV sAg)
test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid
(RNA) or HCV antibody test indicating acute or chronic infection.

2. Subjects must not be dependent on continuous supplemental oxygen use.

10. Allergies and Adverse Drug Reaction

1. History of allergy to study drug components.

2. History of severe hypersensitivity reaction to any monoclonal antibody.

11. Pregnancy or Breast Feeding: Women of childbearing potential (WOCBP) must agree to
follow instructions for method(s) of contraception for the duration of study treatment
with nivolumab and 5 months after the last dose of study treatment {i.e., 30 days
(duration of ovulatory cycle) plus the time required for the investigational drug to
undergo approximately five half-lives. Males who are sexually active with WOCBP must
agree to follow instructions for method(s) of contraception for the duration of study
treatment with nivolumab and 7 months after the last dose of study treatment {i.e., 90
days (duration of sperm turnover) plus the time required for the investigational drug
to undergo approximately five half-lives.