VB-111 in Combination With Nivolumab in People With Metastatic Colorectal Cancer (mCRC)

Study Overview
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Brief Summary
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Background: Gastrointestinal cancer is one of the most common cancers worldwide. Researchers think an unmet need exists to understand and improve treatment options. They want to see if a combination of drugs can help people with metastatic colorectal cancer. Objective: To see if using a combination of Vascular Biogenics (VB)-111 and nivolumab is safe and will cause colorectal tumors to shrink. Eligibility: People ages 18 and older with microsatellite stable colorectal cancer that has spread to the liver Design: Participants must consent to sample collection protocol 11C0112. Participants will be screened with: Blood tests Scans Tumor samples. If these are not available, participants will have a biopsy. Before they start treatment and with every treatment cycle, participants will have: Physical exams Blood tests Heart tests Before they start treatment and every 4 cycles, participants will have computed tomography (CT) or magnetic resonance imaging (MRI) scans. For these, they will lie in a machine that takes pictures of the body. For the MRI, a soft padding or coil will be placed around their head. Participants will have biopsies before they start therapy. They will have them again after 2 6 weeks on study. On day 1 of 14-day cycles, participants will get one or both study drugs by vein. After they finish treatment, participants will have monthly visits for 3 months. They will have a physical exam and blood tests. If participants stop treatment for reasons other than their disease getting worse, they will have scans about every 8 weeks. This will continue until their disease gets worse. Participants will be contacted by phone or email every 6 months. This will continue for life. ...

Detailed Description
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Background: Immune based approaches in gastrointestinal (GI) cancers have unfortunately- with the notable exception of immune checkpoint inhibition in microsatellite instable (MSI-H) disease and gastric cancer-been largely unsuccessful. The reasons for this are unclear but no doubt relate to the fact that in advanced disease GI cancer appears to be less immunogenic, as evidenced by the lack of infiltrating lymphocytes with advancing T stage as well as an immunosuppressive tumor micro-environment. Vascular Biogenics (VB)-111 is an anti-angiogenic agent comprising of a nonreplicating E1 deleted adenovirus type 5 which contains a modified murine preproendothelin (PPE) promoter and Fas-chimera transgene VB-111 has been tested and shows promise in glioblastoma, ovarian and thyroid tumors Nivolumab is a human monoclonal antibody directed against programmed cell death protein 1 (PD-1). The aim of this study is to study the effects of VB-111 in colorectal cancer (CRC) and to evaluate whether the antitumor immunity induced by VB-111 therapy can be enhanced by PD-1 inhibition. Objectives: To determine the safety and tolerability of VB-111 in combination with nivolumab in patients with refractory, metastatic CRC To determine Best Overall Response (BOR) (partial response (PR) + complete response (CR)) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of combined treatment of VB-111 and nivolumab in patients with refractory, metastatic CRC. Eligibility: Histopathological confirmation of colorectal cancer metastatic to the liver Patients must have progressed on > 2 lines of standard of care chemotherapy for colorectal cancer or been intolerant of chemotherapy or refused prior chemotherapy. Patient's tumors must be documented to be microsatellite stable (MSS). Patients must have at least 1 focus of metastatic disease that is amenable to pre-and on-treatment biopsies and be willing to undergo this. All patients enrolled will be required to have measurable disease by RECIST v 1.1 criteria. Design: The proposed study is a phase II study of VB-111 in combination with immune checkpoint inhibition (nivolumab) in patients with metastatic CRC Treatment will be delivered in cycles consisting of 2 weeks with VB-111 given every 6 weeks and nivolumab given every 2-week until progression or unacceptable toxicity. Disease status evaluation will be done every 8 (+/- 1) weeks after the start of study therapy.

Official Title
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Phase II Trial of VB-111 in Combination With Nivolumab in Patients With Metastatic Colorectal Cancer (mCRC).

Conditions
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Metastatic Colorectal Cancer, Colorectal Neoplasms, Colorectal Carcinoma, Colorectal Cancer With Hepatic Metastases, Colorectal Tumors

Intervention / Treatment
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* Biological: Vascular Biogenics (VB)-111
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must have histopathological confirmation of colorectal cancer. Patients must have radiologically confirmed liver metastasis. Patients must: have progressed on > 2 lines of standard of care chemotherapy for colorectal cancer OR --been intolerant of standard of care chemotherapy for colorectal cancer OR refused prior standard of care chemotherapy for colorectal cancer. Patients who have a known Kirsten rat sarcoma (KRAS) wild type tumor must have progressed, been intolerant of or refused anti-epidermal growth factor receptor (EGFR) based treatment. Patient's tumors must be documented to be microsatellite stable (MSS). Patients must have at least 1 focus of metastatic disease that is amenable to pre- and on-treatment biopsies and be willing to undergo this. Ideally, the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigator's Patients must have measurable disease by RECIST v 1.1 criteria. Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of nivolumab in combination with Vascular Biogenics (VB)-111 in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Adequate hematological function defined by: white blood cell (WBC) count greater than or equal to 3x10(9)/L absolute neutrophil count (ANC) greater than or equal to 1.5x10(9)/L lymphocyte count greater than or equal to 0.5x10(9)/L platelet count greater than or equal to 100x10(9)/L Hemoglobin (Hgb) greater than or equal to 9 g/ dL (more than 48 hours post-completion of blood transfusion) Prothrombin time (PT) and Partial thromboplastin time (PTT) (seconds) < 1.2 x ULN. Patients who are anticoagulated do not need to meet criteria for PT and PTT International normalized ratio (INR) < 1.2 x ULN. Patients who are anticoagulated do not need to meet criteria for INR. Adequate hepatic function defined by: a total bilirubin level less than or equal to 1.5 x ULN, an Aspartate transaminase (AST) level less than or equal to 2.5xULN in the absence of hepatic metastasis; or less than or equal to 5 x ULN in the presence of hepatic metastases, an Alanine transferase (ALT) level less than or equal to 2.5xULN in the absence of hepatic metastasis; or less than or equal to 5 x ULN in the presence of hepatic metastases -Adequate renal function defined by: Creatinine OR Measured or calculated creatinine clearance (CrCl) (estimated glomerular filtration rate (eGFR) may also be used in place of CrCl) (A Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.): < 1.5x institution upper limit of normal OR greater than or equal to 50 mL/min/1.73 m(2) for participant with creatinine levels greater than or equal to 1.5 X institutional ULN The effects of nivolumab and VB-111 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation and up to 5 months (women) and 7 months (men) after the last dose of the nivolumab or 2 months after the last dose of VB-111 whichever is the longer time period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Troponin level in normal range at the time of enrollment. Patient must be able to understand and willing to sign a written informed consent document. Weight > 35kg Patients must be enrolled in tissue collection protocol 11C0112. EXCLUSION CRITERIA: Patients who have had standard-of-care anti-cancer therapy or therapy with investigational agents (e.g., chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies or other investigation agents), large field radiotherapy, or major surgery within 4 weeks prior to enrollment. Patients who have had anti-vascular endothelial growth factor (VEGF) therapy within 4 weeks prior to enrollment. Patients currently on a corticosteroid dose greater than physiologic replacement dosing defined as 10 mg of cortisone per day or its equivalent. Patients with known brain metastases because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with signs of liver failure, e.g., clinically significant ascites, encephalopathy, or variceal bleeding within 6 months prior to enrollment. Prior major liver resection: remnant liver <50% of the initial liver volume. Patients with a biliary stent can be included. Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome or Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), myasthenia gravis; systemic autoimmune disease such as Systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome. Such diseases should be excluded because of the risk of recurrence or exacerbation of disease. Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible. History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest computed tomography (CT) scan. 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 (within timeframes identified in the bullets below) that would limit compliance with study requirements. History of severe or unstable cerebrovascular disease. Pulse oximetry < 92% on room air Myocardial infarction within 6 months prior to enrollment History of myocarditis Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg) Stroke within 6 months prior to enrollment. Patients with proliferative and/or vascular retinopathy. Significant vascular disorders (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to enrollment. History of hemoptysis (> 1/2 teaspoon of bright red blood per episode) or active gastrointestinal (GI) bleeding within 6 months prior to enrollment. Evidence of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) History of abdominal fistula or gastrointestinal perforation within 6 months prior to enrollment. Human immunodeficiency virus (HIV)-positive patients are excluded because HIV causes complicated immune deficiency and study treatment can possess more risks for these patients. Prior autologous or allogenic hematopoietic stem cell transplant. Subjects with ascites. Patients with unhealed surgical wounds for more than 30 days. History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab or VB-111. History of severe hypersensitivity reaction to any monoclonal antibody. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years prior to enrollment. Pregnant women are excluded from this study because nivolumab and VB-111 potential for teratogenic or abortifacient effects are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and VB-111, breastfeeding should be discontinued if the mother is treated with nivolumab and/or and VB-111.

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: 1/Arm 1<br>Vascular Biogenics (VB)-111 and nivolumab | Biological: Vascular Biogenics (VB)-111<br>* 1E13 or 0.7E13 VP via intravenous (IV) infusion on Day 1 of cycle 1 and continue every 6 weeks<br>Drug: Nivolumab<br>* 240 mg of nivolumab via intravenous (IV) infusion on Day 1 of each cycle starting on cycle 2 and continue every 2 weeks<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 1, Grade 2, Grade 3, Grade 4, and/or Grade 5 Adverse Events That Are Possibly, Probably and/or Definitely Related to Drug | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event. | 90 days after treatment | 
| Best Overall Response (BOR) | Best overall response is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. | Follow up visits are planned to be performed at 60 (+/- 14 days) and 90 (+/- 14 days) days after treatment discontinuation to evaluate patient's safety, up to 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS) | Progression-free survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median PFS will be reported along with 95% confidence interval. PFS is defined as the time between the first day of treatment to the day of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. | The time between the first day of treatment to the day of disease progression, an average of 1.8 months. | 
| Median Overall Survival (OS) | Overall survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median OS will be reported along with 95% confidence intervals. Overall survival is the time between the first day of treatment to the day of death. | The time between the first day of treatment to the day of death, an average of 6.9 months. | 
| 6-month Progression-free Survival (PFS) | 6-month progression-free survival was assessed by the Kaplan-Meier technique with GraphPad Prism 9.3.1 for Windows (GraphPad, San Diego, CA) to calculate these values, and the median PFS will be reported along with 95% confidence interval. PFS is defined as the time between the first day of treatment to the day of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonreplicating adenovirus, Antitumor Immunity, PD-1 inhibition, Immune Checkpoint Inhibition