VXM01 Phase I Study in Patients With Metastatic Colorectal Cancer With Liver Metastasis
Primary Purpose
Colorectal Cancer
Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
VXM01
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer
Eligibility Criteria
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
Sites / Locations
- National Center of Tumor Diseases
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
VXM01
Arm Description
VXM01 10E6 or 10E7 CFU
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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)
Immune biomarker by tumor tissue immunohistochemistry staining
Immune biomarker including T-cell infiltration, Treg, myeloid derived suppressor cells (MDSC) by tumor tissue immunohistochemistry staining
Tumor vasculature by tumor tissue immunohistochemistry staining
Serum biomarker Response by Enzyme Linked Immuno Sorbent Assay (ELISA)
Serum VEGF A and collagen IV measured by ELISA
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.
Biodistribution and shedding of VXM01
Bacterial vector tissue biodistribution, persistence, and shedding of viable Ty21a bacteria (VXM01) determined by cultivation of stool samples
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02718430
Brief Title
VXM01 Phase I Study in Patients With Metastatic Colorectal Cancer With Liver Metastasis
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
February 2016 (undefined)
Primary Completion Date
March 2018 (Actual)
Study Completion Date
March 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vaximm GmbH
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
VXM01
Arm Type
Experimental
Arm Description
VXM01 10E6 or 10E7 CFU
Intervention Type
Drug
Intervention Name(s)
VXM01
Intervention Description
Oral immunotherapy targeting VEGFR2
Primary Outcome Measure Information:
Title
Safety and tolerability taking into account treatment-limiting toxicities (TLTs)
Description
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.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Immune Response by Enzme Linked Immuno Spot (ELISpot)
Description
Patient-individual VEGFR-2 specific T-cell responses determined by ELISpot using cryopreserved peripheral blood mononuclear cells (PBMC)
Time Frame
18 months
Title
Immune biomarker by tumor tissue immunohistochemistry staining
Description
Immune biomarker including T-cell infiltration, Treg, myeloid derived suppressor cells (MDSC) by tumor tissue immunohistochemistry staining
Time Frame
66 days
Title
Tumor vasculature by tumor tissue immunohistochemistry staining
Time Frame
66 days
Title
Serum biomarker Response by Enzyme Linked Immuno Sorbent Assay (ELISA)
Description
Serum VEGF A and collagen IV measured by ELISA
Time Frame
18 months
Title
Clinical Response including tumor staging according to the response criteria in solid tumors (RECIST)
Description
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.
Time Frame
18 months
Title
Biodistribution and shedding of VXM01
Description
Bacterial vector tissue biodistribution, persistence, and shedding of viable Ty21a bacteria (VXM01) determined by cultivation of stool samples
Time Frame
10 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carsten Gruellich, MD
Organizational Affiliation
National Center of Tumor Diseases Heidelberg
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Center of Tumor Diseases
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
Yes
Learn more about this trial
VXM01 Phase I Study in Patients With Metastatic Colorectal Cancer With Liver Metastasis
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