IL-2 Expressing, Attenuated Salmonella Typhimurium in Unresectable Hepatic Spread

Study Overview
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Brief Summary
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The working hypothesis is that oral administration of an attenuated strain of Salmonella typhimurium is safe and efficacious for patients with unresectable hepatic metastasis from a solid tumor cancer. The primary objective of the study is to determine the MTD of Salmonella typhimurium in the treatment.

Detailed Description
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This phase I study will be done to evaluate a dose escalation scheme of oral administration of an attenuated strain of Salmonella typhimurium expressing human interleukin-2 (IL-2) in patients with unresectable hepatic metastases from a solid tumor cancer. Standard Phase I dose escalation scheme will be used to determine the MTD of Salmonella Typhimurium. Six dose levels of Salmonella will be studied with a minimum of 3 patients enrolled in a dose level.

Official Title
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A Phase 1 Study of an IL-2 Expressing, Attenuated Salmonella Typhimurium in Patients With Unresectable Hepatic Spread From Any Non-Hematologic Primary

Conditions
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Cancer of the Liver, Liver Cancer, Hepatoma, Liver Neoplasms, Biliary Cancer

Intervention / Treatment
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* Biological: Salmonella typhimurium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic documentation of malignancy (any solid tumor type) that has spread to the liver and deemed unresectable, and for which no effective standard therapies are available. Patients with additional disease outside of the liver will be allowed. Patients may have received any number of other prior therapies; however at least 3 weeks must have passed since last dose of chemotherapy or radiotherapy (6 weeks for Nitrosoureas or Mitomycin C) prior to study entry. Must have recovered from all acute toxicities (defined per National Cancer Institute's Common Toxicity Criteria for Adverse Events 3.0 ≤ grade 1) associated with previous treatment. Eastern Cooperative Oncology Group (ECOG) performance status ≤2. Life expectancy of greater than 2 months as determined by the enrolling investigator Adequate organ function within 1 week of treatment start defined as: Adequate bone marrow reserve: leukocytes ≥ 3,000/μl, absolute neutrophil count (ANC) ≥ 1,500/μl, platelets ≥ 100,000/μl Hepatic: bilirubin ≤1.5 times institutional upper limit of normal (×ULN), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN Renal: serum creatinine ≤ 1.5 x ULN Women of child-bearing potential and sexually active men must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Exclusion Criteria: Unable to take oral drugs or clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: malabsorption syndrome, major resection of stomach or small bowel Receiving any other investigational agents Known central nervous system metastases Residing in a household or having close contact with pregnant women, young children (under the age of 1 year) or immune compromised persons Engaged in activities that might pose a risk for widespread dissemination of this organism, including, but not limited to; health care, child care, or food service. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations. Pregnant or breastfeeding. Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of prior to the start of treatment. Pregnancy testing is not required for post-menopausal or surgically sterilized women. Breast-feeding mothers will be asked to discontinue feeding infants prior to enrolling in the study. Known HIV infection, need for chronic steroids or other immunosuppressant drugs, or other medical conditions that in the investigator's opinion result in a significant degree of immunosuppression. Patients without identified HIV risk factors are not required to have HIV testing to be eligible. Known active hepatitis B or C infection Known HLA B27 Have permanent artificial implants (such as, but not limited to prosthetic valves and joints.) Any other condition which in the investigator's opinion renders the patient at high risk for overwhelming infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Salmonella typhimurium 10 to the 5th - Level 1<br>Patients will receive (a minimum of 3 patients) escalating doses of Salmonella typhimurium to achieve a maximum tolerated dose (MTD). | Biological: Salmonella typhimurium<br>* Attenuated Salmonella typhimurium (virulent strain x4550) will be given orally in escalating dose groups: Level 1 = 10^5, Level 2 = 10^6, Level 3 = 10^7, Level 4 = 10^8, Level 5 = 10^9, Level 6 = 10^10.<br>|
| Experimental: Salmonella typhimurium 10 to the 6th -- Level 2<br>Patients will receive (a minimum of 3 patients) escalating doses of Salmonella typhimurium to achieve a maximum tolerated dose (MTD). | Biological: Salmonella typhimurium<br>* Attenuated Salmonella typhimurium (virulent strain x4550) will be given orally in escalating dose groups: Level 1 = 10^5, Level 2 = 10^6, Level 3 = 10^7, Level 4 = 10^8, Level 5 = 10^9, Level 6 = 10^10.<br>|
| Experimental: Salmonella typhimurium 10 to the 7th -- Level 3<br>Patients will receive (a minimum of 3 patients) escalating doses of Salmonella typhimurium to achieve a maximum tolerated dose (MTD). | Biological: Salmonella typhimurium<br>* Attenuated Salmonella typhimurium (virulent strain x4550) will be given orally in escalating dose groups: Level 1 = 10^5, Level 2 = 10^6, Level 3 = 10^7, Level 4 = 10^8, Level 5 = 10^9, Level 6 = 10^10.<br>|
| Experimental: Salmonella typhimurium 10 to the 8th - Level 4<br>Patients will receive (a minimum of 3 patients) escalating doses of Salmonella typhimurium to achieve a maximum tolerated dose (MTD). | Biological: Salmonella typhimurium<br>* Attenuated Salmonella typhimurium (virulent strain x4550) will be given orally in escalating dose groups: Level 1 = 10^5, Level 2 = 10^6, Level 3 = 10^7, Level 4 = 10^8, Level 5 = 10^9, Level 6 = 10^10.<br>|
| Experimental: Salmonella typhimurium 10 to the 9th - Level 5<br>Patients will receive (a minimum of 3 patients) escalating doses of Salmonella typhimurium to achieve a maximum tolerated dose (MTD). | Biological: Salmonella typhimurium<br>* Attenuated Salmonella typhimurium (virulent strain x4550) will be given orally in escalating dose groups: Level 1 = 10^5, Level 2 = 10^6, Level 3 = 10^7, Level 4 = 10^8, Level 5 = 10^9, Level 6 = 10^10.<br>|
| Experimental: Salmonella typhimurium 10 to the 10th - Level 1<br>Patients will receive (a minimum of 3 patients) escalating doses of Salmonella typhimurium to achieve a maximum tolerated dose (MTD). | Biological: Salmonella typhimurium<br>* Attenuated Salmonella typhimurium (virulent strain x4550) will be given orally in escalating dose groups: Level 1 = 10^5, Level 2 = 10^6, Level 3 = 10^7, Level 4 = 10^8, Level 5 = 10^9, Level 6 = 10^10.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Events to Determine the Maximum Tolerated Dose (MTD) of Salmonella Typhimurium | Maximum tolerated dose will be determined by the number of patients with Dose limiting toxicity (DLT) at a given dose level. DLT is defined as treatment related: Sepsis (salmonella) syndrome, Grade 4 vomiting or diarrhea, Other grade 3 or greater toxicity. If > or = 2 patients at a dose level has a DLT, this level will be declared the MTD. | Up to 24 Weeks After Dose of Salmonella typhimurium | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response to Treatment | Evaluation is performed using Response Evaluation Criteria in Solid Tumors (RECIST). Each patient will be assigned one of the following categories: Complete response (CR) the disappearance of all target lesion; Partial response (PR) at least a 30% decrease; Progressive disease (PD) at least a 20% increase, or the appearance of one or more new lesions; Stable disease (SD) neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease; early death from malignant disease; unknown (insufficient evaluation to determine response status). | 8 Weeks After Treatment with Salmonella Typhimurium | 
| Peripheral Blood NK Cells Count | Patients receiving doses of 10^5 through 10^10 Colony forming units of Salmonella typhimurium had their peripheral blood flow cytometry performed to identify the NK (Natural killer) cells population (CD8-, CD4-, CD49b+) prior to administration and at 5 weeks post administration. The flow cytometry data below was gathered by gating on the lymphocyte population of cells in the patient's blood, as determined by FSC vs. SSC. The mean percentage of NK cells in sample's lymphocyte population is given. | Baseline and 5 Weeks After Dosing with Salmonella typhimurium | 
| Peripheral Blood T Cells Count | Patients receiving doses of 10^5 through 10^10 Colony forming units of Salmonella typhimurium had their peripheral blood flow cytometry performed to identify the NK (Natural killer) cells population (CD25+, FoxP3+) prior to administration and at 5 weeks post administration. The flow cytometry data below was gathered by gating on the lymphocyte population of cells in the patient's blood, as determined by FSC vs. SSC. The mean percentage of T cells in sample's lymphocyte population is given. | Baseline and 5 Weeks After Dosing with Salmonella typhimurium | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Salmonella typhimurium, unresectable hepatic cancer, attenuated Salmonella typhimurium, IL-2