INCLUSION CRITERIA:
The subject must meet all of the following inclusion criteria for enrollment:
Histologically or cytologically documented malignant epithelial mesothelioma, adenocarcinoma of the pancreas, non-small-cell lung carcinoma (NSCLC) or carcinoma of the ovaries who have failed or who are not candidates for standard treatment. Patients who voluntarily decline standard therapy may also be considered for enrollment. Patients with ovarian adenocarcinoma are eligible only after failing 2nd line therapy unless they have previously and voluntarily declined therapy.
Age 18 years or older
ECOG performance score 0-1 or Karnofsky Performance Status (KPS) 80 % to 100 %.
Anticipated life expectancy greater than the duration required for a subject to complete the study.
Female subjects of childbearing potential must consent to use a medically acceptable method of highly effective contraception (oral hormonal contraceptive, condom plus spermicide, or hormone implants) throughout the study period and for 28 days after their final CRS-207 administration. A barrier method of contraception must be employed by all subjects (male and female), regardless of other methods.
Subject provides informed consent and is willing and able to comply with all study procedures
Adequate organ function defined as follows:
Hematologic
Platelets greater or equal to 100 times 10(9)/L
Hemoglobin greater or equal to 9.0g/dL
Total WBC count greater than or equal to 3.5 times 10(9)/L
ANC greater than or equal to 1.5 times 10(9)/L
Total lymphocyte count greater than or equal to 1.0 times 10(9)/L
CD4(+) count greater than or equal to 0.2 times 10(9)/L
PT/INR and PTT less than or equal to 1.3 times clinical laboratory ULN
Hepatic
Bilirubin less than or equal to 1.5 times clinical laboratory ULN
AST, ALT and alkaline phosphatase less than or equal to 2.5 times clinical laboratory ULN (less than or equal to 3.5 times clinical laboratory ULN is acceptable for patients with pancreatic adenocarcinoma)
GGT less than or equal to 5 times clinical laboratory ULN
Renal: Serum creatinine less than 1.5 times clinical laboratory ULN
EXCLUSION CRITERIA:
The subject must not have any of the following exclusion criteria:
Known metastases to central nervous system (CNS). Patients with primary pulmonary adenocarcinoma must have MRI or CT of CNS within the 28 days prior to study entry to assess possible CNS metastases.
History of listeriosis or vaccination with a listeria based vaccine
Known allergy to penicillin.
History of allergy/hypersensitivity to yeast or any other component of CRS-207 (e.g., glycerol).
Clinically significant heart disease (such as uncontrolled angina, myocardial infarction within 3 months, congestive heart failure of New York Heart Association III or IV)
Individuals with valvular heart disease who require antibiotic prophylaxis for prevention of endocarditis, consistent with the most recent AHA guidelines. Also excluded are patients who have cardiac conditions associated with high- or moderate-risk of endocarditis according to the previous version of guidance for prevention of bacterial endocaditis, including prosthetic cardiac valves (including bioprosthetic and homograft valves) previous bacterial endocarditis, congenital heart disease, surgically constructed systemic pulmonary shunts or conduits, acquired valvular dysfunction (e.g., rheumatic heart disease), hypertrophic cardiomypathy, mitral valve prolapse with valvular regurgitation and or thickened leaflets, arterial aneurysm.
O(2) saturation less than 92 percent on room air, as measured by pulse oximeter
Study subjects who have or are suspected to have compromised pulmonary function, based upon history and physical exam, are not eligible for study entry unless VC, DLco, and FEV(1) are documented greater than or equal to 60 percent of the predicted value.
Active, clinically significant autoimmune disease or history or autoimmune disease requiring systemic treatment.
Clinical laboratory results corresponding to Grade 3 or 4 CTCAE clinical metabolic/laboratory abnormalities.
Hepatic cirrhosis or clinically relevant ascites or individuals who have substantial risk of obstructive jaundice (e.g., by tumor mass compression of the hepatic hilum).
Artificial (prosthetic) joint or other artificial implant or devices that cannot easily be removed. Dental implants and breast implants are allowed if there is no history of infection of the implants and no clinically significant adverse events associated with the implants.
Know coagulation disorder or receiving anticoagulant medication.
Patients requiring regular transfusions more frequently than twice per month.
Blood transfusion within fourteen days of study entry, unless leuko-reduced and irradiated.
Any immunodeficiency disease or immune compromised state (e.g., use of immunosuppressive agents; chemotherapy or radiation therapy within 28 days prior to CRS-207 administration or planned within 28 days after CRS-207 administration).
Use of systemically active steroids for more than 2 days, within 28 days prior to CRS-207 administration or planned within the study period after CRS-207.
Individuals using greater than 325 mg/day of aspirin are excluded from the study (chronic daily use of aspirin less than or equal to 325 mg/day and heparin flushes for central lines are allowed).
Use of more than 2 grams per day of acetaminophen.
Systemic (IV, IM, SQ or PO) antibiotics within 14 days prior to CRS-207 administration.
Receipt of an investigational product within 28 days prior to CRS-207 administration or planned within the study period.
Symptomatic nephorolithiasis or cholelithiasis. Individuals with asymptomatic nephrolithiasis or cholelithiasis may be enrolled in the study, if approved by review with the Medical Monitor.
Received a bone marrow or stem cell transplant or a major organ allograft.
Major surgery or significant traumatic injury occurring within 28 days prior to CRS-207 administration or anticipated surgery or procedure requiring general anesthesia or deep sedation during study participation (including 28 days after last dose or CRS-207).
Unhealed surgical wounds.
Infection with HIV, HTLV-1, HCV, or HBV.
Lm isolation from fecal specimen at screening visit (Visit 1).
Intercurrent illness that is either life threatening or of clinical significance such that it might limit compliance with study requirements. Such illness might include, but are not limited to, ongoing or active infection, metabolic (e.g., diabetes) or neurologic disease, peripheral vascular disease, or psychiatric illness/social situations.
Thromboembolic events (VTE, MI, TIAA, stroke or angina) occurring with the past 6 months prior to study entry.
Subjects who, in the opinion of the investigator, do not have sufficient peripheral venous access to permit completion of study dosing and compliance with study phlebotomy regimen.
Subjects who, in the opinion of the investigator, should not participate in the study or may not be able or willing to follow the study schedule for any reason.
Female subjects who are pregnant or lactating. Female subjects of childbearing potential must have a negative serum beta-hCG test at study screening.
History of alcohol dependence or use of illicit drugs that could potentially interfere with adherence to study procedure or requirements (e.g., opioids, cocaine, amphetamines, hallucinogens, etc.)
Individuals who cannot avoid during the course of the study close contact with another individual known to be at high risk of listeriosis (e.g., newborn infant, pregnant female, etc.)
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 09/20/2008