Clinical Trials /

Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers

NCT03785210

Description:

Background: A most common liver cancer in adults is hepatocellular carcinoma. Other kinds of liver cancer happen when colorectal or pancreatic cancer spreads to the liver. Researchers want to study if a combination of drugs helps people with these cancers. The drugs are nivolumab, tadalafil, and vancomycin. Objective: To investigate if nivolumab given with tadalafil and vancomycin causes liver cancer to shrink. Eligibility: Adults ages 18 years and older with hepatocellular carcinoma or metastases to the liver from colorectal or pancreatic cancer for which standard treatment has not worked Design: Participants will be screened with: Medical and cancer history Review of symptoms and ability to perform normal activities Physical exam Heart test. Some participants may meet with a cardiologist and/or have another heart test. Scan of the chest, abdomen, and pelvis Blood and urine tests Tumor sample review. This can be from a previous procedure. Participants will receive the study drugs in 4-week cycles. In each cycle participants will: Get nivolumab through a small plastic tube in the arm on Day 1. Take tadalafil by mouth 1 time every day. Take vancomycin by mouth 4 times a day. They will take it every day for weeks 1 3, then not take it for week 4. Complete a medicine diary of dates, times, missed doses and symptoms. Throughout the study, participants will repeat screening tests and will give stool samples or rectal swabs. After their last cycle, participants will have 3 follow-up visits over 3 months. Then they will be contacted every 6 months by phone or email and asked about their general well-being. ...

Related Conditions:
  • Colorectal Carcinoma
  • Hepatocellular Carcinoma
  • Pancreatic Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers
  • Official Title: Phase II Study of Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in Patients With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers

Clinical Trial IDs

  • ORG STUDY ID: 190033
  • SECONDARY ID: 19-C-0033
  • NCT ID: NCT03785210

Conditions

  • Heptocellular Carcinoma
  • Heptocellular Cancer
  • Metastatic Pancreatic Cancer
  • Metastatic Colorectal Cancer
  • Liver Metastasis

Interventions

DrugSynonymsArms
nivolumab1/ Arm 1
tadalafil1/ Arm 1
oral vancomycin1/ Arm 1

Purpose

Background: A most common liver cancer in adults is hepatocellular carcinoma. Other kinds of liver cancer happen when colorectal or pancreatic cancer spreads to the liver. Researchers want to study if a combination of drugs helps people with these cancers. The drugs are nivolumab, tadalafil, and vancomycin. Objective: To investigate if nivolumab given with tadalafil and vancomycin causes liver cancer to shrink. Eligibility: Adults ages 18 years and older with hepatocellular carcinoma or metastases to the liver from colorectal or pancreatic cancer for which standard treatment has not worked Design: Participants will be screened with: Medical and cancer history Review of symptoms and ability to perform normal activities Physical exam Heart test. Some participants may meet with a cardiologist and/or have another heart test. Scan of the chest, abdomen, and pelvis Blood and urine tests Tumor sample review. This can be from a previous procedure. Participants will receive the study drugs in 4-week cycles. In each cycle participants will: Get nivolumab through a small plastic tube in the arm on Day 1. Take tadalafil by mouth 1 time every day. Take vancomycin by mouth 4 times a day. They will take it every day for weeks 1 3, then not take it for week 4. Complete a medicine diary of dates, times, missed doses and symptoms. Throughout the study, participants will repeat screening tests and will give stool samples or rectal swabs. After their last cycle, participants will have 3 follow-up visits over 3 months. Then they will be contacted every 6 months by phone or email and asked about their general well-being. ...

Detailed Description

      Background:

        -  Current treatment options for patients with liver cancers, including hepatocellular
           carcinoma(HCC) and advanced liver cancers are limited and take no account of the known
           biological and genetic heterogeneity in these diseases. Median survival for advanced
           disease remains poor at approximately 1 year.

        -  Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody that is specific
           for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface
           membrane receptor. Nivolumab has been approved by FDA for the treatment of HCC and other
           solid tumors.

        -  Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor which have been approved by the
           FDA for the treatment of pulmonary arterial hypertension, benign prostatic hyperplasia
           and erectile dysfunction, with a relative safe clinical profile. PDE5 inhibitors have
           been examined in multiple malignancies and cancer cell lines for their direct anticancer
           activities, for their

      efficacy as chemo-sensitizers and for cancer chemoprevention.

        -  Oral vancomycin is antibiotic that has effect on altering gut commensal bacteria
           subsequently inducing a liver-selective anti-tumor effect.

        -  The aim of the study is to evaluate whether the immunomodulatory effect induced by PDE5
           inhibitor and oral vancomycin can be enhanced by immune checkpoint inhibition in
           advanced liver cancer.

      Objective:

      -To determine the Best Overall Response (BOR) according to Response Evaluation Criteria
      (RECIST 1.1) to combined treatment of nivolumab, oral vancomycin and tadalafil in patients
      with refractory primary HCC or liver dominant metastatic cancer from colorectal cancer (CRC)
      or pancreatic adenocarcinoma (PDAC).

      Eligibility:

        -  Histologically confirmed, hepatocellular carcinoma (HCC) Or

        -  Histologically confirmed carcinoma highly suggestive of a diagnosis of HCC Or

        -  Histologically confirmed advanced colorectal or pancreatic malignancy with liver
           involvement as dominant site of metastasis

        -  Measurable lesion, accessible for biopsy.

        -  Age greater than or equal to 18 years

        -  ECOG less than or equal to 1

        -  Acceptable renal, bone marrow and liver function.

        -  Willingness to undergo two mandatory tumor biopsies.

      Design:

        -  The proposed study is a phase II study of combined nivolumab, oral vancomycin and
           tadalafil treatment in patients with HCC or liver dominant metastatic cancer from
           colorectal or pancreatic cancers.

        -  Treatment will be delivered in cycles consisting of 4 weeks (+/- 3 days) until
           progression or unacceptable toxicity.

        -  Patients will be seen in Clinical Center on monthly basis with disease status evaluation
           every

           8 (+/-1) weeks after start of study therapy.
    

Trial Arms

NameTypeDescriptionInterventions
1/ Arm 1ExperimentalNivolumab, tadalafil and oral vancomycin
  • nivolumab
  • tadalafil
  • oral vancomycin

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have

               -  histopathological confirmation of HCC by the NCI Laboratory of Pathology (Cohort
                  1) OR

               -  histopathological confirmation of carcinoma by the NCI Laboratory of Pathology in
                  the setting of clinical and radiological characteristics which, together with the
                  pathology, are highly suggestive of a diagnosis of HCC (Cohort 1) OR

               -  histopathological confirmation of advanced colorectal or pancreatic malignancy by
                  the NCI Laboratory of Pathology with liver involvement as dominant site of
                  metastasis (Per multidiscipline tumor board review and approval) (Cohort 2).

          -  Patients must have disease that is not amenable to potentially curative resection,
             transplantation or ablation.

          -  Patients must have progressed on, been intolerant to, or refused prior
             sorafenib/lenvatinib therapy (Cohort 1 only).

          -  Subjects must have progressed on or after standard systemic chemotherapy (at least one
             line of chemotherapy for patients with liver metastasis from PDAC, at least two lines
             of chemotherapy for patients with liver metastasis from CRC) (Cohort 2 only).

          -  Patients must have evaluable or measurable disease per RECIST 1.1

          -  Patients must have lesion accessible for biopsy and be willing to undergo pre- and
             posttreatment biopsies.

          -  ECOG performance status of 0 to 1

          -  If liver cirrhosis is present, patient must have a Child-Pugh score less than or equal
             to 7

          -  Active chronic HBV infected subjects must be on antivirals and have HBV DNA <100IU/mL.
             HCV infected subjects can be enrolled with close HCV RNA level monitoring.

          -  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 tadalafil and
             vancomycin in patients less than 18 years of age, children are excluded from this
             study, but will be eligible for future pediatric trials

          -  Adequate hematological function defined by:

               -  white blood cell (WBC) count greater than or equal to 3 (SqrRoot) 10^9/L

               -  absolute neutrophil count (ANC) greater than or equal to 1.5 (SqrRoot) 10^9/L,

               -  lymphocyte count greater than or equal to 0.5 (SqrRoot) 10^9/L,

               -  platelet count greater than or equal to 120 (SqrRoot) 10^9/L, and

               -  Hgb greater than or equal to 9 g/ dL (more than 48 hours post-completion of blood
                  transfusion)

          -  Adequate hepatic function defined by:

               -  a total bilirubin level less than or equal to 1.5 (SqrRoot) ULN,

               -  an AST level <5(SqrRoot) ULN,

               -  an ALT level <5 (SqrRoot) ULN.

          -  Adequate renal function defined by:

               -  Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m^2 by 24
                  hours urine collection or as predicted by the Cockcroft-Gault formula:

               -  CrCl = (140 age (y)) x (weight in kg) x (0.85, if female) x1.73 m^2/72 x Serum
                  Creatinine (mg/dL) x pt. s BSA (m^2) Or

          -  The effects of nivolumab on the developing human fetus are unknown. For this reason,
             women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) 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 drug. 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.

          -  Patients with a history of cardiovascular disease may be enrolled per cardiology
             consultation and approval with echocardiogram and 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.

        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.

          -  Therapy with antibiotics within 3 days prior to enrollment.

          -  Therapy with nitrates, alpha-blockers, or cytochrome P450 (CYP3A4) inhibitors within
             7- days prior to enrollment and for whom stopping is unsafe and/or a safe substitute
             is not medically recommended. Use of PDE5 inhibitors such as vardenafil (Levitra ),
             tadalafil (Cialis ), and sildenafil citrate (Viagra ) less than or equal to 15-days
             prior to enrollment.

          -  The patient must not be currently on a corticosteroid dose greater than physiologic
             replacement dosing defined as 10 mg of cortisone per day or its equivalent.

          -  For PDAC patients with liver metastases, primary PDAC has not been resected (unless
             the primary is in the tail of the pancreas).

          -  Patients with known brain metastases will be excluded from this clinical trial because
             of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  Have signs of liver failure, e.g. clinical 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 CIDP, myasthenia gravis;
             systemic autoimmune disease such as 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.

          -  Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
             organizing pneumonia) or evidence of active pneumonitis on screening chest 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 that would limit compliance with
             study requirements.

          -  Patients with myocardial infarction or myocarditis within 12 months prior to
             enrollment.

          -  History of severe or unstable cerebrovascular disease.

          -  Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg)

          -  Stroke within 6 months prior to enrollment.

          -  HIV-positive patients are excluded because HIV causes complicated immune deficiency
             and study treatment can possess more risks for these patients.

          -  Have had prior transplant of any kind.

          -  Have ascites.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to nivolumab, tadalafil or vancomycin.

          -  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 s potential for
             teratogenic or abortifacient effects is unknown. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with nivolumab, breastfeeding should be discontinued if the mother is treated
             with nivolumab
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best Overall Response (BOR)
Time Frame:every 2 months
Safety Issue:
Description:Changes in tumor size and occurrence of metastases

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Anticancer Activities
  • Altering Gut Commensual Bacteria
  • Immunodulatory Effect
  • Checkpoint Inhibition

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