VB-111 in Combination With Nivolumab in People With Metastatic Colorectal Cancer (mCRC)
Condition: Metastatic Colorectal Cancer; Colorectal Neoplasms; Colorectal Carcinoma; Colorectal Cancer With Hepatic Metastases; Colorectal Tumors
MeSH terms: Colorectal Neoplasms
Intervention: Vascular Biogenics (VB)-111; Nivolumab
Intervention description: 1E13 or 0.7E13 VP via intravenous (IV) infusion on Day 1 of cycle 1 and continue every 6 weeks; 240 mg of nivolumab via intravenous (IV) infusion on Day 1 of each cycle starting on cycle 2 and continue every 2 weeks
Intervention MeSH terms: Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Nonreplicating adenovirus; Antitumor Immunity; PD-1 inhibition; Immune Checkpoint Inhibition

Summary:

      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.

      ...
    

Eligibility criteria:

        -  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.