Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas

PRIMARY OBJECTIVES:

I. Determine the tolerability, and define and describe the toxicities of nivolumab
administered as a single agent in children with relapsed or refractory solid tumors at the
adult recommended dose of 3 mg/kg.

II. Determine if systemic nivolumab exposure in children is similar to the systemic exposure
in adults following a 3 mg/kg dose.

III. Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and
define and describe the toxicities of nivolumab plus ipilimumab administered to children with
relapsed or refractory solid tumors.

IV. Assess antitumor effects of nivolumab across selected childhood solid tumors in seven
expansion cohorts (Parts B1-B6, B8); neuroblastoma (2 cohorts: measurable disease,
metaiodobenzylguanidine [MIBG] positive only non-measurable disease), osteosarcoma,
rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

V. Assess antitumor effects of nivolumab in combination with ipilimumab across selected
childhood solid tumors in two dose combinations (Part D and Part E).

VI. Characterize the pharmacokinetics of nivolumab alone and in combination with ipilimumab,
including area under the curve (AUC), concentration maximum (Cmax), concentration minimum
(Cmin), using intensive sampling.

VII. Assess immunogenicity of nivolumab alone and in combination with ipilimumab by measuring
anti-drug antibody (ADA) levels.

SECONDARY OBJECTIVES:

I. Conduct exploratory studies of the phenotypic and functional effects of nivolumab (alone
and in combination with ipilimumab), as well as changes in antibodies to previously
vaccinated viruses, in serum samples.

II. Explore whether correlations exist between PD-L1 expression on tumor and antitumor
effects of nivolumab (alone and in combination with ipilimumab) in pediatric solid tumors and
to conduct exploratory studies of potential tumor associated biomarkers of response in tumor
tissue (at least five out of the following markers: NRAS, BRAF, MEK, KIT, PDGF, TP53, RB1 and
BRCA1, Akt phosphorylation, IL-17 or PD-L1).

III. Explore presence of tumor infiltrating lymphocytes and their association with antitumor
effects of nivolumab (alone and in combination with ipilimumab).

IV. Conduct exploratory studies of the effect of nivolumab (alone or in combination with
ipilimumab) on cytokine levels in serum samples.

V. For Part E, determine tumor mutational burden of diagnostic specimens using FoundationOne
testing to explore immune- related gene expression or mutation and its association with
antitumor response to nivolumab in combination with ipilimumab.

OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study.

PART A (COMPLETED): Patients with recurrent or refractory solid tumors receive nivolumab
intravenously (IV) over 60 minutes on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

PART B (COMPLETED): Patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing
sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or melanoma receive nivolumab as in Part A.

PART C (COMPLETED):

INDUCTION: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on
day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE: Patients receive nivolumab IV as in Part A. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.

PART D (COMPLETED):

INDUCTION: Patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma,
Hodgkin lymphoma, non-Hodgkin lymphoma, or melanoma receive nivolumab IV and ipilimumab IV as
in Part C. Treatment repeats every 21 days for 4 courses in the absence of disease
progression or unacceptable toxicity.

MAINTENANCE: Patients receive nivolumab IV over 60 minutes on days 1 and 15. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity.

PART E: Participants receive nivolumab IV over 60 minutes on day 1 and ipilimumab IV over 90
minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of
disease progression or unacceptable toxicity. Participants then receive nivolumab IV over 60
minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up at approximately 100 days,
every 6 months for up to 24 months, and then annually for up to 60 months.

Inclusion Criteria:

- Parts A & C: patients must be >= 12 months and < 18 years of age at the time of study
enrollment

- Parts B1-B6, B8, D1-D6, E3, E4: patients must be >= 12 months and =< 30 years of age
at the time of study enrollment

- Part B7: patients must be >= 12 months and < 18 years of age at the time of study
enrollment

- Patients must have had histologic verification of malignancy at original diagnosis or
relapse

- Parts A & C: patients with recurrent or refractory solid tumors, without central
nervous system (CNS) tumors or known CNS metastases, are eligible; note: CNS
imaging for patients without a known history of CNS disease is only required if
clinically indicated

- Part B1: patients with relapsed or refractory neuroblastoma

- Part B2: patients with relapsed or refractory osteosarcoma

- Part B3: patients with relapsed or refractory rhabdomyosarcoma

- Part B4: patients with relapsed or refractory Ewing sarcoma or peripheral
primitive neuroectodermal tumor (PNET)

- Part B5: patients with relapsed or refractory Hodgkin lymphoma

- Part B6: patients with relapsed or refractory non-Hodgkin lymphoma

- Part B7: patients with unresectable melanoma or metastatic melanoma or relapsed
melanoma or refractory melanoma

- Part B8: Patients with relapsed or refractory neuroblastoma (MIBG evaluable
disease without Response Evaluation Criteria in Solid Tumors [RECIST] measurable
lesion)

- Once the dose-escalation portion of Part A is completed, cohorts that are open
concurrently for eligible patients (including Parts B and C and potential
pharmacokinetic [PK] expansion cohorts) may be selected at the treating
physician's discretion pending slot availability; in the event a disease group
cohort in Part B is completed after the initial stage of Simon's optimal
two-stage design, for selected disease cohorts, a corresponding cohort in the
same disease group for select disease types will be open in Part D:

- Part D1: Patients with relapsed or refractory neuroblastoma

- Part D2: Patients with relapsed or refractory osteosarcoma

- Part D3: Patients with relapsed or refractory rhabdomyosarcoma

- Part D4: Patients with relapsed or refractory Ewing sarcoma or peripheral PNET

- Part D5: Patients with relapsed or refractory non-Hodgkin lymphoma

- Part D6: Patients with relapsed or refractory neuroblastoma (MIBG evaluable
disease without RECIST measurable lesion)

- Part E3: Patients with relapsed or refractory rhabdomyosarcoma

- Part E4: Patients with relapsed or refractory Ewing sarcoma or peripheral PNET

- Parts A & C: patients must have either measurable or evaluable disease

- Parts B, D & E: patients must have measurable disease for Parts B1-B6, D1-D5, E3 and
E4; melanoma patients in Part B7 must have either measurable or evaluable disease;
neuroblastoma patients in Parts B8 and D6 must be evaluable for MIBG response without
evidence of RECIST measurable lesions

- Patient's current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life

- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 60 for patients =< 16
years of age; patients who are unable to walk because of paralysis, but who are up in
a wheelchair, will be considered ambulatory for the purpose of assessing the
performance score

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment; if after the required timeframe, the
defined eligibility criteria are met, e.g. blood count criteria, the patient is
considered to have recovered adequately

- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive

- At least 21 days after the last dose of cytotoxic or myelosuppressive
chemotherapy (42 days if prior nitrosourea)

- Hematopoietic growth factors: At least 14 days after the last dose of a
long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth
factor; for agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur; the duration of this interval must be discussed with
the study chair

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil count [ANC] counts): At least 7 days
after the last dose of agent

- Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1

- External beam radiation therapy (XRT)/external beam irradiation including
protons: >= 14 days after local XRT; >= 150 days after total body irradiation
(TBI), craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if
other substantial bone marrow (BM) radiation.

- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days
must have elapsed since systemically administered radiopharmaceutical therapy

- Stem cell infusion (with or without TBI):

- Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
cell infusion including donor lymphocyte infusion (DLI) or boost infusion:
>= 100 days after infusion, no evidence of graft versus host disease (GVHD)
and no requirement for immunosuppression

- Autologous stem cell infusion including boost infusion: >= 42 days

- Cellular therapy: >= 42 days must have elapsed since the completion of any type
of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic
cells, etc.)

- Patients must not have received prior exposure to nivolumab; for patients
enrolled in parts C, D and E, patients must not have received prior nivolumab or
ipilimumab

- For patients with solid tumors without known bone marrow involvement:

- Peripheral absolute neutrophil count (ANC) >= 750/mm^3

- Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)

- Patients with known bone marrow metastatic disease will be eligible for study provided
they meet the blood counts above (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; at least 5 of every cohort of 6 patients with a
solid tumor must be evaluable for hematologic toxicity, for Parts A and C; if
dose-limiting hematologic toxicity is observed on either Part A or C, all subsequent
patients enrolled must be evaluable for hematologic toxicity on that Part

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- Age 1 to < 2 years: maximum serum creatinine (mg/dL) 0.6 for males and females

- Age 2 to < 6 years: 0.8 for males and females

- Age 6 to < 10 years: 1 for males and females

- Age 10 to < 13 years: 1.2 for males and females

- Age 13 to < 16 years: 1.5 for males and 1.4 for females

- Age >= 16 years: 1.7 for males and 1.4 for females

- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

- No evidence of dyspnea at rest, no exercise intolerance due to pulmonary
insufficiency, and a pulse oximetry > 92% while breathing room air

- Serum lipase =< ULN at baseline; patients with glucose intolerance should be on a
stable regimen and be monitored

- All patients and/or their parents or legally authorized representatives must sign a
written informed consent; assent, when appropriate, will be obtained according to
institutional guidelines

- Tissue blocks or slides must be sent for all patients; if tissue blocks or slides are
unavailable, the study chair must be notified prior to enrollment

Exclusion Criteria:

- Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
must be obtained in girls who are post-menarchal; women of childbearing potential
(WOCBP) receiving nivolumab will be instructed 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 be instructed to adhere to contraception for a period
of 7 months after the last dose of nivolumab

- Patients requiring daily systemic corticosteroids are not eligible; patients must not
have received systemic corticosteroids within 7 days prior to enrollment; if used to
modify immune adverse events related to prior therapy, >= 14 days must have elapsed
since last dose of corticosteroid; Note: use of topical or inhaled corticosteroids
will not render a patient ineligible

- Patients who are currently receiving another investigational drug are not eligible

- Patients who are currently receiving other anti-cancer agents are not eligible

- Patients with CNS tumors or known CNS metastases will be excluded from this trial;
patients with a history of CNS metastases that have been previously treated may enroll
if sequential imaging shows not evidence for active disease; patients with extra axial
disease (e.g. skull [bone] metastasis that do not invade the dura) may enroll if there
is no evidence for CNS edema associated with the lesion

- Patients with a history of any grade autoimmune disorder are not eligible;
asymptomatic laboratory abnormalities (e.g. antinuclear antibody [ANA], rheumatoid
factor, altered thyroid function studies) will not render a patient ineligible in the
absence of a diagnosis of an autoimmune disorder

- Patients with >= grade 2 hypothyroidism due to history of autoimmunity are not
eligible; note: hypothyroidism due to previous irradiation on thyroidectomy will not
impact eligibility

- Patients who have an uncontrolled infection are not eligible

- Patients with a history of congestive heart failure (CHF) or are at risk because of
underlying cardiovascular disease or exposure to cardiotoxic drugs must have adequate
cardiac function as clinically indicated:

- Corrected QT interval (QTC) =< 480 msec

- Shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by
gated radionuclide study

- Patients with known human immunodeficiency virus (HIV) or hepatitis B or C are
excluded

- Patients who have received prior solid organ transplantation are not eligible

- 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

- Patients who have received prior anti-PD1 directed therapy (monoclonal antibody [mAb]
or small molecule) are not eligible

- Parts C, D, and E: patients who have received prior ipilimumab are not eligible