Combination Therapy of Interleukin-12 and Interleukin-2 to Treat Advanced Cancer

Background:

Renal cell cancer responds to treatment with a variety of antiangiogenic and immunomodulatory
drugs.

In the RENCA model of renal cell cancer the combination of IL-12 and pulse IL-2 cures 88-100%
of mice with established tumors.

The tumor regression observed in this model is due to both antiangiogenic and immunologic
effects.

Objective:

To define the maximum tolerated dose and dose-limiting toxicities of recombinant human IL-12
administered intravenously in combination with intermittent pulse recombinant human IL-2 in
adults with various advanced and/or refractory solid tumors.

To evaluate the pharmacokinetics of intravenous rhIL-12/pulse rhIL-2 administration in adults
with various advanced and/or refractory solid tumors.

To provide a preliminary assessment of the ability of rhIL-12/pulse rhIL-2 to modify
neovascularization and gene expression in the local tumor site, and to induce a measurable
antitumor effect in adults with various advanced and/or refractory solid tumors.

To evaluate the immunomodulatory activity of combined systemic administration of
rhIL-12/pulse rhIL-2.

Eligibility:

Patients with advanced solid tumors for whom a proven more effective therapy does not exist.
Patients with renal cell cancer will be required to have received sunitinib or sorefinib or
refused this option.

The patient must have normal organ function and a life expectancy of at least 12 Weeks.

Normal pulmonary function (as documented by PFTs), and for patients over the age of 50,
normal stress thallium testing.

No prior treatment with IL-12.

Design:

Phase I dose escalation with an expansion cohort of 10 patients treated at the maximum
tolerated dose.

Patients will be hospitalized for treatment. IL-2 will be given intravenously every 8 hours
on day 1 and this will be followed by intravenous administration of IL-12 every other day for
three doses on days 2, 4, and 6. After two days of rest the schedule will be repeated. Cycles
will be repeated every 36 days.

Tumor response will be evaluated after every treatment. Stable or responding patients will
continue treatment with evaluations after every cycle of treatment.

- INCLUSION CRITERIA:

Adult patients 18 years of age and older.

Pathologically or cytologically-proven diagnosis of non-hematologic malignancy, and the
presence of radiographically or clinically evaluable disease.

Patients with solid tumors including renal, breast, lung carcinomas, as well as sarcomas
for whom a proven more effective therapy does not exist. Patients with renal cell cancer
will have received sunitinib or sorefinib or refused this option.

Patients must not have received myelosuppressive chemotherapy, hormonal therapy,
radiotherapy or immunotherapy within four weeks of entry onto this protocol.

Estimated life expectancy of at least 12 weeks.

ECOG performance status of 0 or 1.

Patients must be free of acute infection or other significant systemic illness.

Negative serologic testing for hepatitis B will be required to limit confounding variables
in the assessment of the potential hepatic toxicity of this combination.

Negative serologic testing for human immunodeficiency virus (HIV) will be required given
the uncertain impact of rhIL-12 and/or rhIL-2 administration on viral replication, and the
potential alterations in immune responsiveness among patients concurrently infected with
HIV.

Adequate hepatic and renal function as evidence by:

Transaminases less than 2.5 times the upper limit or normal;

Total serum bilirubin less than 2.0 mg/dl;

Serum Cr less than 2.0 mg/dl or calculated creatinine clearance of greater than 60
ml/min/1.73M(2).

Adequate bone marrow function (without growth factor support) as evidence by:

Absolute Neutrophil count (ANC) greater than 1500 cells/mm(3);

Platelets greater than 100,000/mm(3).

For women of childbearing potential, a negative urine pregnancy test within 14 days prior
to initiation of study therapy is required. For patients of child-bearing potential,
contraceptive precautions must be maintained during study participation.

Normal pulmonary function (as documented by PFTs), and for patients over the age of 50,
normal stress thallium testing. Normal pulmonary function testing will be defined as DLCO
greater than 60% of predicted and FEVI greater than 70% of predicted.

EXCLUSION CRITERIA:

Critically-ill or medically unstable patients.

History or a presence of brain metastases.

History of coronary artery disease, angina or myocardial infarction.

Presence of clinically significant pleural effusion.

History of malignant hyperthermia are.

Concurrent or history of autoimmune disease.

History of congenital or acquired coagulation disorder.

Patients with a history of ongoing or intermittent bowel obstruction.

Women who are pregnant or lactating will be excluded.

Systemic corticosteroids, radiotherapy, chemotherapy, or other investigational agents
within 4 weeks prior to study entry.

Patients who have received any of the following agents with known immunomodulatory effects
within 4 weeks prior to study entry: G-CSF/GM-CSF, interferons or interleukins, growth
hormone, IVIG, retinoic acid.

Patients with a history of previous therapy with rhIL-12 will be excluded from study
participation. For patients with renal cell carcinoma, a history of therapy with rhIL-2
will not exclude patients from study participation.

Patients with concurrent administration of any other investigational agent.

Patients with hematologic malignancies including leukemia or lymphoma.

History of bone marrow or stem-cell transplantation.

Intercurrent radiation therapy patients will be allowed on study if in the opinion of the
principal investigator(s) its use is not necessitated by disease progression. For patients
with disease progression, radiation therapy will be administered as clinically indicated
and the patient will be withdrawn from study participation.