NHS-IL12 for Solid Tumors

Background:

- Interleukin-12 (IL-12) is a proinflammatory cytokine produced by activated phagocytes
and dendritic cells (DCs) that plays a critical role in regulating the transition from
innate to adaptive immunity.

- IL-12 has shown some promising clinical activity in phase I trials, including
stabilization of disease in renal cancer patients with partial regression of a
metastatic lesion, but has not proceeded further in clinical development due to
toxicity.

- The NHS-IL12 concept is a strategy to reduce the toxicity associated with systemic
administration of recombinant human IL-12 by selectively targeting delivery to tumors.

The NHS-IL12 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the
H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded DNA.
Thus, NHS-IL12 targets delivery to regions of tumor necrosis where DNA has become exposed.

Objectives:

- To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of
NHS-IL12 administered subcutaneously every 4 weeks in patients with metastatic or
locally advanced solid epithelial or mesenchymal tumors.

- Secondary objectives include exploring the pharmacokinetics, immunogenicity and immune
response of subcutaneously administered NHS-IL12. Based on analysis of immune response,
in a preliminary fashion in two expansion cohorts after repeated treatments, the tumor
response (irRC) and progression free survival and overall survival will be described.

Eligibility:

- Adults with histologically or cytologically proven metastatic or locally advanced solid
epithelial or mesenchymal tumors, except unstable brain metastases, for which standard
curative or palliative measures do not exist or are no longer effective.

- Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.

- Patients with acquired immune defects, systemic autoimmune disease, history of organ
transplant, history of chronic infections, or history of active inflammatory bowel
disease will be excluded.

Design:

- With Amendment D, this is a phase I, open-label, dose-escalation study designed to
assess the safety, tolerability, PK, and biological and clinical activity of NHS-IL12.
Goals are to determine the MTD of every 4 week doses at a starting dose level of 2mcg/kg
of NHS IL12 and to define the biologically optimal treatment schedule.

- Patients will be enrolled in cohorts of 3 to 6 patients using a standard 3+3 approach
until MTD is reached.

- The trial will include a planned schedule-optimization amendment with up to 12 patients
at each of the 2 dose levels that are of greater biologic interest (MTD and dose below
MTD), which will be submitted as soon as a clear biological response (changes in
circulating cytokine levels) is measured in at least 3 patients at a given dose level.

- With a maximum accrual ceiling of 78 participants, this study will be completed within
2-3 years, enrolling up to 2 participants per month.

- INCLUSION CRITERIA:

Inclusion Criteria Patients must meet the following criteria for participation:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable locally advanced solid tumors.

- Patients must have completed or had disease progression on at least one prior line of
disease-appropriate therapy for unresectable locally advanced or 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, rising tumor markers, non-measurable by RECIST but visible
on CT 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 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 concurrent anticancer treatment
(chemotherapy, radiotherapy, immunotherapy, cytokine therapy except erythropoietin) at
the time of enrollment except for disease specific appropriate hormonal therapies
(e.g., ADT for prostate cancer, anti-estrogen for breast cancer, somatostatin analogue
for neuroendocrine cancer)

- Concurrent use of systemic steroids (within 10 days of enrollment) will be excluded,
except for physiologic doses of systemic steroid replacement or local (topical, nasal,
or inhaled) steroid use. Limited doses of systemic steroids (e.g., in patients with
exacerations of reactive airway disease) must have completed at least 10 days prior to
enrollment. Steroid use to prevent IV contrast allergic reaction or anaphylaxis in
patients who have known contrast allergies is allowed at any time prior to enrollment.

- 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

- Known hypersensitivity to methotrexate

- History of brain metastases 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.