RATIONALE: Biological therapies such as VNP20009 use different ways to stimulate the immune system and stop cancer cells from growing. PURPOSE: Phase I trial to study the effectiveness of VNP20009 in treating patients who have advanced or metastatic solid tumors that have not responded to previous therapy.

Condition	Treatment or Intervention	Phase
unspecified adult solid tumor, protocol specific	Drug: cefixime  Drug: ceftriaxone  Drug: ciprofloxacin  Drug: co-trimoxazole  Drug: VNP20009	Phase I

Further Study Details: 

OBJECTIVES: I. Determine the maximum tolerated dose and safety of intratumoral live, genetically modified Salmonella typhimurium (VNP20009) in patients with refractory, superficial solid tumors. II. Determine the efficacy of VNP20009 in these patients.

PROTOCOL OUTLINE: This is a dose-escalation study. Patients receive intratumorally injected live, genetically modified Salmonella typhimurium (VNP20009) on day 0. The tumor is biopsied on day 14. Cohorts of 3-6 patients receive escalating doses of VNP20009 until the maximum tolerated dose (MTD) or the optimal biologic dose (OBD) is determined. The MTD is defined as the highest dose in which no more than 1 patient in a cohort of 6 experiences dose-limiting toxicity (DLT). The OBD is defined as the dose at which 3-6 patients of a cohort have greater than 10 million colony-forming units of VNP20009 per gram in the tumor biopsy. Prior to reaching the OBD, 2 to 3 additional patients may be entered at a previous dose level shown to be safe to undergo biopsy of the injected lesion between days 5 and 8. Patients are assessed for systemic tumor response 4-5 weeks after treatment. If the injected lesion is stable or responding, and non-injected lesions have not grown, patients may receive up to 2 additional courses of treatment. Patients receive one of the following antibiotic regimens upon evidence of progressive disease, DLT, or discontinuation from the study: First line: Ciprofloxacin IV or orally every 12 hours on day 1 then orally twice a day for 18 days Second line: Ceftriaxone IV on day 1 then cefixime orally for 16 days Third line: Co-trimoxazole orally twice a day for 21 days Patients are followed for an additional 4 weeks after initiation of antibiotic therapy.

PROJECTED ACCRUAL: A total of 12-40 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically proven advanced or metastatic solid tumors that have failed prior therapy and no other therapy is available
• At least 1 tumor mass of a size that makes intratumoral injection feasible and biopsy or fine needle aspiration possible
• Major surgery for cancer not required
• No lymphoma
• No concurrent brain metastases (previously treated brain metastases with no evidence of recurrence allowed)

--Prior/Concurrent Therapy--

• Biologic therapy: At least 6 months since any bone marrow transplantation; At least 4 weeks since prior biologic therapy and recovered; No other concurrent biologic therapy; No prior allogenic transplants
• Chemotherapy: At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) and recovered; No concurrent chemotherapy
• Endocrine therapy: At least 2 weeks since prior hormonal therapy; No concurrent steroids
• Radiotherapy: At least 4 weeks since prior radiotherapy and recovered; No concurrent radiotherapy
• Surgery: See Disease Characteristics; At least 2 weeks since prior surgery and recovered; No artificial implant (e.g., heart valves, prosthetic hips or knees); No prior splenectomy
• Other: No other concurrent antibiotics; No concurrent immunosuppressives; No concurrent medications that directly or indirectly suppress the immune system

--Patient Characteristics--

• Age: 18 and over
• Menopausal status: Not specified
• Performance status: Karnofsky 70-100% OR ECOG 0-1
• Life expectancy: At least 3 months
• Hematopoietic: Granulocyte count at least 1,500/mm3; Platelet count at least 100,000/mm3; Hematocrit at least 30% (transfusion allowed); No bleeding disorder
• Hepatic: Bilirubin no greater than 1.5 times upper limit of normal (ULN); ALT/AST no greater than 1.5 times ULN (no greater than 3 times ULN in the presence of liver metastases); Alkaline phosphatase no greater than 1.5 times ULN (no greater than 3 times ULN in the presence of liver metastases); PT and aPTT no greater than 1.5 times ULN; No end stage liver disease
• Renal: Creatinine no greater than 1.5 times ULN; No urinary tract stones; No end stage renal disease
• Cardiovascular: No known valvular disease or ischemic peripheral vascular disease; No clinically significant atherosclerotic disease or arterial aneurysm(s); No unstable angina; No active coronary artery disease requiring medication; No myocardial infarction within the past 6 months; No congenital heart failure or cardiac arrhythmia requiring medication
• Pulmonary: No severe oxygen-dependent chronic obstructive pulmonary disease
• Other: Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception; Permanent central venous catheters and other indwelling devices allowed if easily removed or replaced; No gallstones; No active infection; No Salmonella infection within past 6 months; No fever caused by tumor or unknown cause (daily temperature no greater than 38 degrees C); HIV negative; No immunodeficiency; No other life-threatening illness; No commercial food handler, day-care worker, or health-care worker who plans to continue employment during protocol treatment; No allergy to quinolone or cephalosporin antibiotics

Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States
Ohio
      Cleveland Clinic Taussig Cancer Center, Cleveland,  Ohio,  44195,  United States
Texas
      Mary Crowley Medical Research Center, Dallas,  Texas,  75246,  United States

Study chairs or principal investigators

Mario Sznol,  Study Chair,  Vion Pharmaceuticals   

Study ID Numbers:  CDR0000067446; VION-CLI-005; NCI-V99-1581
Record last reviewed:  February 2004
Last Updated:  October 13, 2004
Record first received:  January 28, 2000
ClinicalTrials.gov Identifier:  NCT00004216
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2005-04-08