First In-Human Phase I Trial of NHS-IL12 in Subjects With Metastatic Solid Tumors

Inclusion Criteria

- IINCLUSION CRITERIA:

Inclusion Criteria Patients must meet the following criteria for participation:

- Patients must have histologically confirmed malignancy confirmed by the Laboratory of
Pathology, NCI, that is metastatic or unresectable locally advanced solid epithelial
or mesenchymal tumors.

- Patients must have completed or had disease progression on at least one prior line of
disease-appropriate therapy for metastatic disease, or not be a candidate for therapy
of proven efficacy for their disease due to an underlying physical condition.

- Patients may have disease that is measurable or non-measurable but evaluable disease
(e.g. present on bone scan). Patients with third space fluid (for example pleural
effusions) as only site of disease will not be eligible.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at study
entry.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of NHS-IL12 in patients < 18 years of age, children
are excluded from this study, but will be eligible for future pediatric trials.

- Patients must have normal organ and marrow function as defined below:

1. Hematological eligibility parameters (within 16 days of starting therapy):

- Absolute granulocyte count greater than or equal to 1,500/mcL

- Absolute lymphocyte count greater than or equal to 500/mcL

- Platelet count greater than or equal to 100,000/mcL

- hemoglobin greater than or equal to 9 g/dL

2. Adequate hepatic function defined by a

- total bilirubin level less than or equal to 1.5 times ULN or in patients
with Gilbert's syndrome, a total bilirubin less than or equal to 3.0, and

- aspartate aminotransferase (AST) and alanine-aminotransferase (ALT) levels
less than or equal to 2.5 times ULN or, for patients with documented
metastatic disease to the liver, AST and ALT levels less than or equal to 5
times ULN.

3. Adequate renal function defined by an estimated creatinine clearance greater
than 60 mL/min determined by 24-hour urine sampling or by the Cockcroft-Gault
formula:

Ccr = (140 - age) (weight, kg) (constant)/[72 times Crserum (mg/100 mL). The constant is 1
for men and 0.85 for women OR Ccr = (140 - age) (weight, kg) (constant)/Crserum (micro
mol/L). The constant is 1.23 for men and 1.04 for women.

CD4 lymphocyte count or other T lymphocyte subset count will not be used to determine
eligibility.

- Patients must agree to practice effective contraception (both male and female
subjects, if the risk of conception exists). The effects of NHS-IL12 on the
developing human fetus are unknown. For this reason, women of child-bearing potential
and men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study
participation, and for 30 days after the last dose. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately.

- A minimum of 4 weeks will be required from any prior therapy, including chemotherapy,
immunotherapy and/or radiation. In addition, recovery to Grade 1 or less from
reversible all reversible toxicities related to prior therapy is required at study
entry. Prior immune therapy (e.g. related vaccinia and fowlpox vaccines or
antigen-specific peptides) is allowed.

- Subject or Legally Authorized Representative (LAR) must sign a written informed
consent document.

EXCLUSION CRITERIA:

Patients with any of the following will not be eligible for participation in this study:

- Patients who are receiving any other investigational agents. Patients who require
concurrent anticancer treatment (chemotherapy, radiotherapy, immunotherapy, cytokine
therapy except erythropoietin) or concurrent systemic therapy with steroids or other
immunosuppressive agents.

- Patients who have previously received rIL-12

- Acquired immune defects such as HIV or innate immunodeficiency because this agent
requires an intact immune system. In addition, these patients are at increased risk
of lethal infections when treated with marrow-altering therapy.

- Systemic autoimmune disease (e.g., lupus erythematosus, rheumatoid arthritis,
Addison's disease, autoimmune disease associated with lymphoma).

- History of organ transplant.

- History of or active inflammatory bowel disease (e.g., Crohn's disease, ulcerative
colitis).

- Chronic infections (e.g., hepatitis B or C, tuberculosis).

- Known hypersensitivity or allergic reactions attributed to any compounds of similar
chemical or biologic composition to the study medication, such as recombinant IL-12
or other monoclonal antibodies

- History of brain metastases, unless the patient received brain irradiation at least 4
weeks prior to enrollment, and is stable, asymptomatic, and off steroids for at least
4 weeks prior to registration, because of the poor prognosis of patients with brain
metastases and because they often develop progressive neurologic dysfunction that
would confound the evaluation of neurologic and other adverse events.

- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke < 6 months prior to enrollment, myocardial infarction < 6 months
prior to enrollment, unstable angina, congestive heart failure (greater than or equal
to NYHA III) or serious cardiac arrhythmia requiring medication.

- Pulmonary disease which, in the opinion of the investigator, may impair the patient's
respiratory tolerance to moderate pulmonary fluid overload (e.g., interstitial lung
disease, severe chronic obstructive pulmonary disease).

- All conditions associated with significant necrosis of nontumor-bearing tissues:
esophageal or gastroduodenal ulcers < 6 months prior to enrollment, organ infarction
< 6 months prior to enrollment, or active ischemic bowel disease.

- Presence of medically significant third space fluid (symptomatic pericardial
effusion, ascites or pleural effusion requiring repetitive paracentesis).

- History of active alcohol or drug abuse.

- Any significant disease that, in the opinion of the investigator, may impair the
patient's tolerance of study treatment.

- Significant dementia, altered mental status, or any psychiatric condition that would
prohibit the understanding or rendering of informed consent.

- Pregnancy (absence to be confirmed by beta-human chorionic gonadotropin test) or
lactation.

- Pleural effusion as the only evidence of metastatic disease.

- Expansion Cohorts only

- Patients must have measurable disease, defined as at least one lesion that can
be accurately measured as greater than or equal to 5 times 5 mm.