Phase I Study of Ipilimumab (Anti-CTLA-4) in Children and Adolescents With Treatment-Resistant Cancer

Background:

Solid tumors represent approximately one fourth of cancer diagnoses in children. Despite
intensive regimens, patients with metastatic or recurrent solid tumors have unsatisfactory
survival rates. Therefore new therapies are needed to improve outcomes.

Accumulating preclinical and clinical evidence supports the use of biologic approaches to
heighten antitumor immunity in order to improve the effectiveness of immune based therapy.
Both directly activating immune based therapies such as cytokines and tumor vaccines as well
as therapies which disrupt negative counterregulatory signals such as those mediated by
CTLA-4:B7 may enhance existent antitumor immune responses.

Antibodies directed against CTLA-4 potently augment immune responses in animal models and
anti-CTLA-4 antibodies have demonstrated antitumor effects in a variety of preclinical tumor
models.

Phase I and phase II studies using ipilimumab have been performed in adults with a variety of
tumor types. Clinical responses have been observed in renal cell carcinoma, melanoma, and
prostate cancer. No trials have yet been performed to evaluate ipilimumab in children with
malignancy.

Objectives:

To determine the tolerance and toxicity profile of ipilimumab at a range of doses up to, but
not exceeding, the highest dose tolerated in adults, in patients less than or equal to 21
years of age with refractory solid tumors.

To assess the pharmacokinetics of ipilimumab administered intravenously in patients less than
or equal to 21 years of age with advanced and/or refractory solid tumors.

Eligibility:

Patients must be 1-21 years of age at the time of enrollment with solid malignant tumors
refractory to standard therapy.

Design:

A Phase I dose finding study with 4 planned dose levels.

Three patients will be enrolled at each dose level with an expanded cohort of 12 at the
highest or maximum torlerated dose with intent to include 6 patients < 12 years.

Re-induction with 4 infusions of ipilimumab at the assigned dose followed by another
maintenance phase is possible for subjects who have progressed during maintenance therapy.

- INCLUSION CRITERIA:

AGE: Patients must be greater than or equal to 1 years and less than or equal to 21 years
of age.

DIAGNOSIS: Histologically confirmed solid tumors, which may include but are not limited to
rhabdomyosarcoma and other soft tissue sarcomas, Ewing s sarcoma family of tumors,
osteosarcoma, neuroblastoma, Wilm s tumor, Hodgkin's or non-Hodgkin's lymphoma. Patients
with melanoma are eligible. Patients with a previous history of CNS metastases are eligible
if the metastases have been treated with surgery and/or radiotherapy, are clinically stable
as evidenced by no requirements for corticosteroids, the patient has no evolving neurologic
deficits and no progression in residual brain abnormalities without specific therapy over 4
weeks.

MEASURABLE/EVALUABLE DISEASE: Patients must have measurable or evaluable tumors.

PRIOR THERAPY:

- The patient s cancer must have relapsed following or failed to respond to standard
therapy and/or the patient s current disease state must be one for which there is no
known curative therapy or therapy proven to prolong survival.

- Patients must have completed their last dose of irradiation, chemotherapy, monoclonal
antibody, or investigational therapy at least 4 weeks prior to enrollment. For
patients who have undergone autologous stem cell transplantation, at least 3 months
must have elapsed since transplant.

- Patients must have recovered from the toxic effects (to a grade 1 or less) of all
prior therapy prior to enrollment, with the exception of the following:

- Hematological toxicity: recovery to levels required below

- Low electrolyte levels (Such individuals should receive appropriate
supplementation)

- For patients on anticoagulant therapy or with pre-existing coagulation
abnormalities, PT, PTT must return to baseline.

- Liver function tests must resolve to values required below

- Grade 3 hypoalbuminemia

- Alopecia

- Sterility

PERFORMANCE STATUS: Patients greater than 10 years old must have a Karnofsky Score of
greater than or equal to 50 and children less than 10 years old must have a Lansky score of
greater than 50. Patients who are unable to walk because of paralysis or weakness, but who
are up in a wheelchair will be considered ambulatory for the purpose of calculating the
performance score.

HEMATOLOGIC FUNCTION: Patients must have adequate bone marrow function, defined as a
peripheral absolute granulocyte count of greater than or equal to 1000/microL, hemoglobin
greater than or equal to 8 gm/dl, and a platelet count greater than or equal to
50,000/microL (may be corrected with transfusions).

HEPATIC FUNCTION: Aspartate transaminase (AST) and alanine transaminase (ALT), less than or
equal to 2.5-fold the upper limit of normal (ULN). Normal total bilirubin.

RENAL FUNCTION: Patients must have normal age-adjusted serum creatinine (see table below)
OR a creatinine clearance greater than or equal to 70 mL/min/1.73 m(2).

MAXIMUM SERUM CREATININE LEVEL FOR AGE:

- For children whose age is less than or equal to 5 years, 0.8 mg/dL

- For children whose age is greater than 5 but less than or equal to 10, 1.0 mg/dL

- For children whose age is greater than 10 but less than or equal to 15, 1.2 mg/dL

- For children whose age is greater than 15, 1.5 mg/dL

INFECTIOUS DISEASE:

-A patient with viral hepatitis (HBV, HCV) or human immunodeficiency virus (HIV) will be
excluded from trial to limit confounding variables in the assessment of the potential
hepatic toxicity of ipilimumab and uncertain impact of ipilimumab administration on viral
replication. Serology will not be required unless infection is clinically suspected. A
positive hepatitis B titer does not exclude a patient if immunization has been performed
and if there is no history of disease.

INFORMED CONSENT: All patients or their legal guardians (if the patient is less than 18
years old) must sign a document of informed consent (Pediatric Oncology Branch, NCI
screening protocol for NIH patients) prior to performing studies to determine patient
eligibility. After confirmation of eligibility, all patients or their legal guardians must
voluntarily sign the IRB approved protocol specific informed consent to document their
understanding of the investigational nature, the risks of this study and their willingness
to receive the therapy and undergo the research studies involved including pharmacokinetic
studies. The consent must be signed before any protocol related studies are performed (This
does not include routine laboratory tests or imaging studies required to establish
eligibility). When appropriate, pediatric patients will be included in all discussions in
order to obtain verbal assent.

DURABLE POWER OF ATTORNEY (DPA): Patients who are greater than or equal to 18 years of age
will be offered the opportunity to assign a DPA so that another person can make decisions
about their medical care if they become incapacitated or cognitively impaired.

BIRTH CONTROL: Patients of childbearing or child-fathering potential must be willing to use
a medically acceptable form of birth control which includes abstinence, while they are
being treated on this study and for 60 days following the last dose. Females of
childbearing potential must have a negative pregnancy test within 14 days prior to
initiation of study therapy and prior to each additional dose of ipilimumab.

EXCLUSION CRITERIA:

- Primary brain tumors

- Clinically significant unrelated systemic illness, such as serious infections or organ
dysfunction, which in the judgment of the Principal or Associate Investigators would
compromise the patient s ability to tolerate the agents in this trial or are likely to
interfere with the study procedures or results. This includes but is not limited to:

- Critically-ill or medically unstable patients

- Patients with active infection or other significant systemic illness

- Patients with active diarrhea

- Patients with active eye inflammation, uveitis

- Presence of a symptomatic pleural effusion

- Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm
disturbance

- History of malignant hyperthermia

- Concurrent or history of autoimmune disease excluding stable asthma

- Positive direct Coombs testing or history of hemolytic anemia

- Patients with a history of ongoing or intermittent bowel obstruction

- Concurrent radiation

- Patients with a history of allogeneic bone marrow transplantation.

- Untreated CNS metastases will render the patient ineligible however patients with a
previous history of CNS metastases are eligible if: the metastases have been treated
with surgery and/or radiotherapy, are clinically stable as evidenced by no
requirements for corticosteroids, the patient has no evolving neurologic deficits and
no progression in residual brain abnormalities without specific therapy are eligible
one week post radiation or radiosurgery. Patients with asymptomatic subcentemeric CNS
lesions will be eligible for trial if no immediate radiation or surgery.

- Patients with a history of previous therapy with ipilimumab will be excluded from
study participation.

- Treatment with any of the following immunomodulatory agents within 14 days prior to
study entry:

--Systemic corticosteroid therapy

---Erythropoeitin

- Retinoic acid

- Fenretinide

- Interferons or interleukins

- Cytokine-fusion proteins

- Growth hormone

- IVIG

- Treatment with myeloid growth factors (GM-CSF or G-CSF) within 72 hours prior to study
entry.

- Patients with autoimmune disease, including autoimmune hemolytic anemia, ulcerative
and hemorrhagic colitis, endocrine disorders (e.g., thyroiditis, hyperthyroidism,
hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal insufficiency),

sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome.

- Pregnant or breastfeeding females are excluded because ipilimumab may be harmful to
the developing fetus or nursing child.

- Concurrent administration of any other investigational agent.