Clinical Trials /

Nivolumab and Yttrium-90 in Treating Patients With Liver Cancer Undergoing Surgical Resection

NCT03812562

Description:

This early phase I trial studies how well nivolumab and yttrium-90 work in treating patients with liver cancer who are undergoing surgical resection. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radioactive drugs, such as yttrium-90, may carry radiation directly to tumor cells and not harm normal cells. Giving nivolumab and yttrium-90 may work better in treating patients with liver cancer.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Yttrium-90 in Treating Patients With Liver Cancer Undergoing Surgical Resection
  • Official Title: Pilot Study of Nivolumab in Combination With Therasphere (Yttrium-90) for Treatment of Hepatocellular Carcinoma (HCC) With Intent for Resection

Clinical Trial IDs

  • ORG STUDY ID: NU 18I03
  • SECONDARY ID: NU 18I03
  • SECONDARY ID: NCI-2018-03602
  • SECONDARY ID: P30CA060553
  • NCT ID: NCT03812562

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (yttrium Y 90 glass microspheres, nivolumab)

Purpose

This early phase I trial studies how well nivolumab and yttrium-90 work in treating patients with liver cancer who are undergoing surgical resection. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radioactive drugs, such as yttrium-90, may carry radiation directly to tumor cells and not harm normal cells. Giving nivolumab and yttrium-90 may work better in treating patients with liver cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the hepatocellular carcinoma (HCC) recurrence rate post-resection in patients
      intended to undergo resection post yttrium Y 90 glass microspheres (yttrium-90 [Y-90]) +
      nivolumab.

      SECONDARY OBJECTIVES:

      I. To investigate the safety and feasibility of radioembolization and nivolumab in patients
      with HCC with intent for resection.

      II. To assess the pattern of recurrence post-resection (time frame and location of
      recurrence).

      III. To evaluate efficacy in patients with HCC treated with Y90 + nivolumab using overall
      survival.

      IV. To evaluate the drop-out rate and incremental changes in future liver remnant (FLR).

      EXPLORATORY OBJECTIVES:

      I. To assess immune-related biomarkers from original tumor biopsy if available. II. To
      identify differences in immunological profiles among patients who go undergo resection versus
      those who do not undergo resection due to progression or failure to grow FLR to sufficient
      level. III. In patients with hepatitis C virus (HCV), will explore changes in immunological
      profile associated with direct acting anti-viral agents.

      OUTLINE:

      Patients receive standard of care yttrium Y 90 glass microspheres intravenously (IV). Within
      1-2 weeks of completing of yttrium-90 treatment, patients receive nivolumab IV over 30
      minutes on day 1. Treatment repeats every 2 weeks for up to 4 doses in the absence of disease
      progression or unacceptable toxicity. If imaging shows adequate FLR and at least stable
      disease, patients will undergo resection within 2 weeks after the last dose of nivolumab.
      Patients who do not complete resection due to feasibility and have progressed or have
      evidence of high-risk explant may continue to receive nivolumab IV every 2 weeks for up to 1
      year.

      After completion of study treatment, patients are followed up at 30 days and then
      periodically for up to 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (yttrium Y 90 glass microspheres, nivolumab)ExperimentalPatients receive standard of care yttrium Y 90 glass microspheres IV. Within 1-2 weeks of completing of yttrium-90 treatment, patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity. If imaging shows adequate FLR and at least stable disease, patients will undergo resection within 2 weeks after the last dose of nivolumab. Patients who do not complete resection due to feasibility and have progressed or have evidence of high-risk explant may continue to receive nivolumab IV every 2 weeks for up to 1 year.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a diagnosis of hepatocellular carcinoma (HCC) confirmed by American
             Association for Study of Liver Diseases (AASLD) guidelines with a Childs-Pugh score of
             A or B (but, =< Childs score B8)

          -  Patients must be eligible for resection based on preserved hepatic function and lack
             of clinically significant portal hypertension (HTN)

               -  NOTE: Patients with branch or lobar portal vein thrombosis (PVT) who are
                  otherwise a candidate for resection will be included

          -  Patients must have a pre-established need for Y90 therapy prior to resection for FLR
             growth and/or retraction of tumor away from major vessel to improve margins

          -  Patients must have measurable disease according to the standard Response Evaluation
             Criteria in Solid Tumors (RECIST) version 1.1

          -  Patients with chronic hepatitis B are eligible as long as they have evidence of
             ongoing viral replication (detectable hepatitis B surface antigen [HBsAg], hepatitis B
             e-antigen [HBeAg], or hepatitis B virus [HBV] deoxyribonucleic acid [DNA]). They must
             have HBV DNA viral load < 100 IU/mL at screening. In addition, they must be on
             antiviral therapy per regional standard of care guidelines prior to initiation of
             study therapy. If not on antiviral therapy at screening, then the subject must
             initiate treatment per regional standard of care guidelines at the time of consent.
             Both HBeAg positive and negative patients will be included

          -  Patients positive for hepatitis C are permitted at physician discretion

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Adequate organ and bone marrow functions:

          -  Leukocytes >= 2,000/mcL

          -  Absolute neutrophil count >= 1,500/uL

          -  Hemoglobin >= 9 g/dL; transfusion is permitted for eligibility, but should be >= 7
             days from registration

          -  Platelets >= 50,000/mcL

          -  Total bilirubin =< 2.5 x institutional upper limit of normal (ULN) (except patients
             with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x ULN

          -  Serum creatinine of =< 2.0 x ULN (upper limit of normal) or creatinine clearance >= 30
             mL/minute (using Cockcroft/Gault formula below):

               -  Female creatinine clearance (CrCl) = (140 - age in years) x weight in kg x 0.85/
                  72 x serum creatinine in mg/dL

               -  Male CrCl = (140 - age in years) x weight in kg x 1.00/ 72 x serum creatinine in
                  mg/dL

          -  Females of childbearing potential (FOCBP) must have a negative serum or urine
             pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
             gonadotropin [HCG]) =< 7 days prior to registration

               -  NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a
                  tubal ligation, or remaining celibate by choice) who meets the following
                  criteria:

                    -  Has not undergone a hysterectomy or bilateral oophorectomy

                    -  Has had menses at any time in the preceding 12 consecutive months (and
                       therefore has not been naturally postmenopausal for > 12 months)

               -  NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred
                  contraception for the subject

          -  FOCBP and men who are sexually active with FOCBP must agree to follow instructions for
             method(s) of contraception for the duration of treatment and the designated
             post-treatment period

          -  Ability to understand and the willingness to sign a written informed consent prior to
             registration on study

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy =< 28 days prior to registration
             are not eligible

          -  Patients who have had prior immunotherapy including interleukin-2 and immune
             checkpoint antagonist and/or agonists are not eligible

          -  Patients who have not recovered to their baseline, =< grade 1, or tolerable grade 2
             (as documented by the treating physician) from adverse events due to agents
             administered >= 28 days earlier are not eligible

          -  Patients who have received any other investigational agents =< 28 days prior to
             registration are not eligible

          -  Patients with a history of allergic reactions attributed to compounds of similar
             chemical or biologic composition to nivolumab or Y90 are not eligible

          -  Patients who have had prior treatment with an anti-PD1, anti-PD-L1, antiPD-L2,
             anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
             co-stimulation or immune checkpoint pathways are not eligible

          -  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 chronic prolonged systemic corticosteroids (defined as corticosteroid use of
             duration one month or greater), should be excluded. These include but are not limited
             to patients with a history of:

               -  Immune related neurologic disease

               -  Multiple sclerosis

               -  Autoimmune (demyelinating) neuropathy

               -  Pure red cell aplasia

               -  Guillain-Barre syndrome

               -  Myasthenia gravis

               -  Systemic autoimmune disease such as systemic lupus erythematosus (SLE)

               -  Connective tissue diseases

               -  Scleroderma

               -  Inflammatory bowel disease (IBD)

               -  Crohn?s

               -  Ulcerative colitis

               -  Patients with a history of toxic epidermal necrolysis (TEN)

               -  Stevens-Johnson syndrome

               -  Anti-phospholipid syndrome

                    -  NOTE: Subjects with vitiligo, alopecia, type I diabetes mellitus, residual
                       hypothyroidism due to autoimmune condition only requiring hormone
                       replacement, psoriasis not requiring systemic treatment, or conditions not
                       expected to recur in the absence of an external trigger are permitted to
                       enroll

          -  Patients with any condition requiring systemic treatment with corticosteroids (> 10 mg
             daily prednisone equivalents) or other immunosuppressive medications =< 14 days prior
             to registration are not eligible

               -  NOTE: Inhaled steroids and adrenal replacement steroid doses > 10 mg daily
                  prednisone equivalents are permitted in the absence of active autoimmune disease.
                  A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g.,
                  contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
                  delayed-type hypersensitivity reaction caused by a contact allergen) is permitted

          -  Patients who have received live vaccine =< 28 days from registration are not eligible

               -  NOTE: Examples of live vaccines include, but are not limited to, the following:
                  measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus
                  Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines
                  for injection are generally killed virus vaccines and are allowed; however
                  intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and
                  are not allowed at any time during the study

          -  Patients with uncontrolled intercurrent illness including, but not limited to any of
             the following, are not eligible:

               -  Hypertension that is not controlled on medication

               -  Ongoing or active infection requiring systemic treatment

               -  Symptomatic congestive heart failure

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

               -  Any other illness or condition that the treating investigator feels would
                  interfere with study compliance or would compromise the patient?s safety or study
                  endpoints

          -  Female patients who are pregnant or nursing are not eligible

          -  Patients with new brain metastases are not eligible unless they have had treatment of
             lesions and are neurologically stable off steroids prior to registration

          -  Patients with another primary malignancy within 2 years of registration are not
             eligible with the following exceptions: adequately treated basal cell carcinoma,
             squamous cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of
             the uterine cervix, or any localized cancers that are deemed to be cured from
             investigator?s point of view

          -  Patients with known history of human immunodeficiency virus (HIV) or known acquired
             immunodeficiency syndrome (AIDS) are not eligible

          -  Prisoners or participants who are involuntarily incarcerated are not eligible

               -  NOTE: under certain specific circumstances a person who has been imprisoned may
                  be included as a participant. Strict conditions apply and Bristol-Myers Squibb
                  approval is required)

          -  Participants must not be compulsorily detained for treatment of either a psychiatric
             or physical (e.g., infectious disease) illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recurrence rate
Time Frame:Up to 3 years post-treatment
Safety Issue:
Description:This primary dichotomous endpoint will be summarized at each time point using a table of frequencies and counts.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Incidence of adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be tabulated and reviewed.
Measure:Overall survival (OS)
Time Frame:Up to 5 years post-treatment
Safety Issue:
Description:OS distributions will be estimated using the Kaplan Meier method, with estimates for the 25th percentile, median and 75th percentile for each time-to-event outcome. In addition, specific Kaplan-Meier estimates for survival at 1-year will be calculated, with Greenwood?s formula for variance used to calculate a 95% confidence interval (CI).
Measure:Overall increase in future liver remnant (FLR)
Time Frame:Up to 3 years post-treatment
Safety Issue:
Description:

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Northwestern University

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