HGS-ETR2 to Treat Children With Solid Tumors

Background:

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

Members of the TNF ligand superfamily induce death in tumor cells through direct ligation of
death receptors and apoptosis induction.

TRAIL (TNF-related apoptosis inducing ligand) has specific anti-tumor activity against a wide
range of tumor cells without inducing death in normal cells. TRAIL-induced apoptosis has been
demonstrated in a wide variety of pediatric solid tumors, including Ewing's sarcoma,
osteosarcoma, neuroblastoma, and rhabdomyosarcoma.

HGS-ETR2 (Human Genome Sciences; human monoclonal antibody) is a fully human monoclonal
antibody that agonistically binds TRAIL receptor 2 and, like TRAIL itself, induces apoptosis
in a variety of malignant cell types with little effect on normal cells.

Limited caspase 8 expression is a primary factor in limiting to TRAIL mediated cell death in
some tumors; interferon gamma has been shown to be effective in increasing caspase-8
expression in tumors and in restoring sensitivity of tumors to TRAIL mediated cell death.

Objectives:

To determine the tolerance of the adult maximum tolerated dose and dose limiting toxicities
of lexatumumab in patients with refractory pediatric solid tumors.

To determine the MTD of lexatumumab in the presence of fixed dosing of interferon gamma 1b at
25 mcg/m(2) SC three times/week, which is less than the FDA approved dose.

To assess the pharmacokinetics of lexatumumab or lexatumumab in combination with interferon
gamma 1b in patients with pediatric malignant tumors refractory to standard therapy.

Eligibility:

Patients must be 1-30 years of age with solid malignant tumors refractory to standard
therapy.

Design:

A Phase I dose escalation study with 4 planned dose levels of lexatumumab starting at 30% of
the adult MTD and escalating up to 100% of the adult MTD, followed by a second dose
escalation using five lexatumumab dose levels in patients concomitantly receiving interferon
gamma 1b.

Three (expanded to six if DLT occurs) patients will be enrolled at each dose level of
lexatumumab until the adult MTD is reached and 6 patients will be enrolled at the adult MTD
dose. The MTD cohort of lexatumumab alone and combined regimen will be expanded to include 12
patients, which should include a minimum of 6 patients less than or equal to 12 years of age.
Once 6 patients greater than 12 years of age have completed lexatumumab alone, new patients
greater than 12 years of age will be enrolled in the combined regimen. Similarly, once 6
patients complete lexatumumab alone who are less than or equal to 12 years of age, new
patients less than or equal to 12 years of age will be enrolled in the combined regimen. A
final dose escalation of interferon gamma 1b will be performed with the maximum dose level of
lexatumumab, to a dose level wherein archival tissue demonstrated upregulation of caspase 8.

- INCLUSION CRITERIA:

AGE: Patients must be greater than or equal to 1 years and less than or equal to 30 years
of age in order to encompass a broad range of ages in children as well as to capture the
young adult population which is highly represented in many of these types of sarcomas being
studied.

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 primary or untreated metastatic CNS tumors or primary or metastatic hepatic tumors
will not be treated on this study.

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 the 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.

Patients must have completed their last dose of irradiation, chemotherapy, monoclonal
antibody, or investigational therapy at least 4 weeks prior to enrollment or their last
dose of nitrosurea (CCNU, BCNU) 6 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 of all prior therapy prior to
enrollment.

Patients must have been off colony stimulating factors (e.g. G-CSF, GM-CSF, Epo) for at
least 72 hours prior to enrollment.

Patients must have completed any biological therapy (including investigational therapies)
at least 7 days prior to study entry.

PERFORMANCE STATUS: Patients greater than 10 years old must have a Karnofsky Score of
greater than or equal to 50 and children less than or equal to 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/microliter,
hemoglobin greater than or equal to 8 gm/dl, and a transfusion independent platelet count
greater than or equal to 75,000/microliter.

Cardiac Function: Patients must have an ejection fraction of greater than 40% via MUGA or
Echo or a shortening fraction greater than 27% by Echo and must not have had a history of
congestive heart failure.

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

RENAL FUNCTION: Patients must have normal age-adjusted serum creatinine (see Table below)
OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).

Age Less than or equal to 5 with a max serum creatinine (mg/dl) of 0.8

Age less than 5 less than or equal to 10 with a max serum creatinine (mg/dl) of 1.0

Age less than 10 less than or equal to 15 with a max serum creatinine (mg/dl) of 1.2

Less than 15 with a max serum creatinine (mg/dl) of 1.5

INFORMED CONSENT: All patients or their legal guardians (if the patients is less than18
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

this study and their willingness to receive the therapy and to 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. Assent will be obtained
according to local IRB requirements.

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.

EXCLUSION CRITERIA:

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.

Patients with a history of allogeneic bone marrow transplantation. Patients who have
received autologous stem cell transplantation are eligible greater than 3 months after
completion of therapy if they meet other eligibility requirements.

Patients with hepatic tumors or metastases are excluded due to the potential for
hepatotoxicity with agents that target the TRAIL-R pathway. Patients with primary CNS
tumors will be excluded due to unknown penetration into the CNS.

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 change in residual
brain abnormalities without specific therapy over 6 weeks.

Pregnant or breastfeeding females are excluded because the risks of lexatumumab to the
developing fetus or nursing child are unknown.

Patients currently receiving other investigational agents.

History of any infection requiring hospitalization or parenteral antibiotics within 2 weeks
of study entry.

Co-existing medical illness that would place the subject at undue risk.

On immunosupressant therapy (with the exception of prednisone up to 10 mg/day, or
dexamethasone up to 4 mg/day), or with known human immunodeficiency virus (HIV) infection
or hepatitis B or C. Subjects with immune deficiency are excluded due to their increased
risk of life threatening toxicity when treated with anticancer agents.