VXM01 Phase I Study in Patients With Metastatic Colorectal Cancer With Liver Metastasis

Study Overview
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Brief Summary
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Phase I study in patients with metastatic colorectal cancer with liver metastasis under second or third line therapy to examine safety, efficacy, and immune biomarkers after treatment with VXM01

Official Title
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VXM01 Phase I Study in Patients With Metastatic Colorectal Cancer With Liver Metastasis Under Second or Third Line Therapy to Examine Safety, Efficacy, and Immune Biomarkers After Treatment With VXM01

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: VXM01


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent, including liver metastasis biopsy, signed and dated Histologically or cytologically confirmed colorectal cancer, excluding primary tumors of appendiceal origin (participants are eligible to enroll irrespective of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status) Male or female patients who must be post-menopausal for at least 2 years or surgically sterile. Confirmed metastatic colorectal cancer (Stage IV) Presence of non-resectable liver metastasis Accessibility of liver metastasis appropriate for biopsy sampling Adequate coagulation parameters including platelet count ≥100,000/mm3 Absence of concomitant medication which could represent a contraindication for biopsy (e.g., anti-platelet drugs including aspirin, ticlopidine, clopidogrel, IIb/IIIa receptor antagonists, non-steroidal anti-inflammatory drugs [NSAIDs], and vitamin K antagonist anticoagulants) The participant has received first-line irinotecan- or oxaliplatin-based therapy without or in combination with a targeted antibody for metastatic disease and a) Experienced radiographic disease progression during first-line therapy, or b) Experienced radiographic disease progression ≤ 6 months after the last dose of first-line therapy, or c) Discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression ≤ 6 months after the last dose of first-line therapy Receipt of no more than 3 prior systemic therapy regimen for metastatic disease Measurable or non-measurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v. 1.1) Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy > 3 months Adequate renal, hepatic, and bone marrow function Leukocytes ≥4.0 x 109 / L Absolute neutrophil count (ANC) > 1,500/mm3 Platelet count ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dL (can be post-transfusion) International normalized ratio (INR) ≤ 1.5 Activated partial thromboplastin time (aPTT) ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN ALT and AST ≤ 2.5 times ULN Creatinine ≤ 2.0 mg/dL Proteinuria ≤ 1+ by urine dipstick OR ≤ 1 g by 24-hour urine collection Patients who are able to understand the nature and purpose of the study including possible risks, willing to comply with the requirements, and to provide their written informed consent to participate in the study Exclusion Criteria: Concomitant treatment with anti-angiogenic therapy before progression of disease Treatment in any other clinical trial within 30 days before screening. Gastric bypass Ileostoma Other anatomical change of the gastrointestinal tract, interfering with gastrointestinal passage, except colostoma or colon bypass Untreated CNS metastases. Participants with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation ending at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to randomization. No evidence of Grade greater than or equal to 1 CNS hemorrhage based on pretreatment Magnetic Resonance Imaging (MRI) or intravenous (IV) contrast CT scan Significant traumatic injury or surgery within the past 4 weeks Cerebrovascular accident, transient ischemic attack, or subarachnoid hemorrhage within the past 6 months Other malignancies within the past 5 years except for adequately treated carcinoma in situ of the cervix, and/or basal cell skin cancer, and/or early endometrial carcinoma Pre-existing sensory or motor neuropathy ≥ grade 2 History or evidence of CNS disease (e.g., uncontrolled seizures) by neurological examination unless adequately treated with standard medical therapy History or evidence of thrombotic or hemorrhagic disorders, including intracranial hemorrhage Uncontrolled hypertension (i.e., blood pressure > 160/100 mm Hg) Clinically significant cardiovascular disease, including any of the following: Myocardial infarction or unstable angina within the past 6 months New York Heart Association class III-IV congestive heart failure Poorly controlled cardiac arrhythmia despite medication, except rate controlled atrial fibrillation Peripheral vascular disease ≥ grade 3 (i.e., symptomatic and interfering with activities of daily living requiring repair or revision) Positive for anti-typhoid IgG/IgM antibodies according to the onsite test on Day 0 Hemoptysis within 6 months before randomization Esophageal varices Upper or lower gastrointestinal bleeding within 6 months before randomization Non-healing wound, incomplete wound healing, bone fracture or any history of gastrointestinal ulcers within three years before inclusion, or positive gastroscopy within 3 months before inclusion Gastrointestinal fistula Thrombolysis therapy within 4 weeks before randomization Presence of any acute or chronic systemic infection Major surgical procedures, or open biopsy within 4 weeks before randomization Chronic concurrent therapy within 2 weeks before and during the initial treatment period (Day 1 to Day 7): Corticosteroids (except steroids for adrenal failure or emesis prophylaxis up to 4 mg daily dose) or immunosuppressive agents Antibiotics Bevacizumab or any other anti-angiogenic treatment Known multi-drug resistant gram-negative bacteria History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the study results or render the patient at high risk for treatment complications Women of childbearing potential

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VXM01<br>VXM01 10E6 or 10E7 CFU | Drug: VXM01<br>* Oral immunotherapy targeting VEGFR2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability taking into account treatment-limiting toxicities (TLTs) | AEs listed together with information on onset, duration, severity, seriousness, relationship to the study drug, relationship to chemotherapy and to the underlying disease, outcome, and action taken. Frequency tables by System Organ Class and preferred term. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Response by Enzme Linked Immuno Spot (ELISpot) | Patient-individual VEGFR-2 specific T-cell responses determined by ELISpot using cryopreserved peripheral blood mononuclear cells (PBMC) | 18 months | 
| Immune biomarker by tumor tissue immunohistochemistry staining | Immune biomarker including T-cell infiltration, Treg, myeloid derived suppressor cells (MDSC) by tumor tissue immunohistochemistry staining | 66 days | 
| Tumor vasculature by tumor tissue immunohistochemistry staining |  | 66 days | 
| Serum biomarker Response by Enzyme Linked Immuno Sorbent Assay (ELISA) | Serum VEGF A and collagen IV measured by ELISA | 18 months | 
| Clinical Response including tumor staging according to the response criteria in solid tumors (RECIST) | Tumor staging according to the response criteria in solid tumors (RECIST) and investigation of the primary tumor and metastasis, e.g., determination of primary tumor size, number and size of metastasis. | 18 months | 
| Biodistribution and shedding of VXM01 | Bacterial vector tissue biodistribution, persistence, and shedding of viable Ty21a bacteria (VXM01) determined by cultivation of stool samples | 10 days |