A Phase I Trial of a Live, Genetically Modified Salmonella Typhimurium (VNP20009) for the Treatment of Cancer by Intravenous Administration

Inclusion Criteria

INCLUSION CRITERIA:

Only patients must have advanced and/or metastatic, histologically documented solid tumors
will be included.

Patients must have a solid tumor which is no longer considered responsive to available
conventional modalities or treatments (failed any known standard curative or palliative
therapy for that disease), or a previously untreated tumor for which no effective standard
treatment is available. Patients must have measurable or evaluable metastatic disease.

All patients must have at least one tumor mass suitable and easily accessible for
excisional biopsy or fine needle aspiration. The procedure must be able to be performed
with minimum morbidity and discomfort to the patient.

ECOG performance status of 0 or 1.

Patients must be 18 years of age or older.

Patients must have expected survival of at least 3 months.

Men and women of child-bearing potential (i.e., women who are premenopausal or not
surgically sterile), must use acceptable contraceptive methods (abstinence, intrauterine
device (IUD), oral contraceptive or double barrier device), and women must have a negative
serum or urine pregnancy test 1 week before beginning treatment on this trial. Nursing
patients are also excluded.

Must be able and willing to give written informed consent.

Must be able and willing to execute a durable power of attorney (DPA).

No treatment with cytotoxic agents, or treatment with biologic agents within 3 weeks prior
to treatment with VNP20009. Must have fully recovered from toxicities of any prior
treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities.

Patients must have the following clinical laboratory values: (a) Granulocyte count of
greater than or equal to 2,000/mm(3); (b) Platelets greater than or equal to
100,000/mm(3); (c) Serum creatinine less than or equal to 1.5 mg/dl; (d) Bilirubin less
than or equal to 1.6 mg/dl, ALT, AST less than or equal to 1.5 times the upper limit of
normal, alkaline phosphatase less than or equal to 1.5 times the upper limit of normal,
(ALT, AST, alkaline phosphatase less than or equal to 3 times the upper limit in presence
of liver metastases); (e) Prothrombin Time (PT) and activated partial thromboplastin time
(aPTT) less than or equal to 1.5 times the upper limit of normal; (f) Hematocrit greater
than or equal to 30% (may be corrected by transfusion); (g) Patients should have daily T
max less than or equal to 38.0 degrees C.

EXCLUSION CRITERIA:

Patients with any one of the following criteria will not be eligible for study
participation:

Diagnosis of lymphoma or other hematologic malignancy.

An artificial implant that cannot be removed (e.g., heart valves, prosthetic hips or
knees, or other devices) which could represent a nidus of infection.

Known history of valvular disease or severe arteriosclerosis. Patients with a significant
murmur on physical examination will undergo an echocardiogram to evaluate for valvular
disease.

Known clinically significant atherosclerotic disease, peripheral vascular disease, or
arterial aneurysm(s) or arterial or venous malformations. Patients in atrial fibrillation
will undergo an echocardiogram to rule out presence of thrombus, which would make them
ineligible.

An ultrasound will be performed pre-treatment in patients with intact gallbladders. No
patients with any evidence of cholelithiasis or obstruction, unless they are able to
undergo a simple cholecystectomy with minimal morbidity, in which case they would be
eligible once they have fully recovered to their baseline status.

All patients will be screened with an ultrasound of the kidneys. Patients with
urolithiasis will be excluded.

Active infection of any kind, including Hepatitis B or chronic viral hepatitis.

Documented Salmonella infections within 6 months.

Currently using antibiotics.

Patients with tumor fever, or fever of unknown origin or cause.

Any known bleeding disorder.

Patients must not have had a splenectomy or documented immunodeficiency such as HIV
infection. These patients are excluded because VNP2009 may be more toxic in severely
immunocompromised patients.

Patients on steroids, immunosuppressives, or any other medications that can directly or
indirectly suppress the immune system.

Presence of any other life-threatening illness, such as unstable angina, severe oxygen
dependent chronic obstructive pulmonary disease (COPD), end stage liver or renal disease.

Requirement immediate palliative treatment of any kind including surgery.

Presence of a known brain metastases. Patients with previously treated brain metastases
and no evidence of recurrence are eligible.

Unwilling and unable to follow protocol requirements.

Hypersensitivity (history of allergic reactions) to quinolone or cephalosporin antibodies.

Patients who have been vaccinated against Salmonella Typhii within the past 6 months.