Clinical Trials /

Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer

NCT03222076

Description:

This phase II trial studies the side effects and how well nivolumab with or with ipilimumab works in treating patients with liver cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer
  • Official Title: An Open-Label Preoperative Pilot Study Evaluating Nivolumab (Anti-PD-1 Antibody) Alone Versus Nivolumab Plus Ipilimumab (Anti-CTLA-4 Antibody) in Patients With Resectable and Potentially Resectable (HCC) (CA209-956)

Clinical Trial IDs

  • ORG STUDY ID: 2017-0097
  • SECONDARY ID: NCI-2018-01106
  • SECONDARY ID: 2017-0097
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03222076

Conditions

  • Hepatocellular Carcinoma
  • Resectable Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm B (ipilimumab, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm A (nivolumab)

Purpose

This phase II trial studies the side effects and how well nivolumab with or with ipilimumab works in treating patients with liver cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of therapy with nivolumab alone or nivolumab +
      ipilimumab in resectable hepatocellular carcinoma (HCC) in the context of presurgical
      therapy.

      II. To evaluate the safety and tolerability of therapy with nivolumab + ipilimumab in
      potentially resectable HCC in the context of pre-biopsy therapy.

      SECONDARY OBJECTIVES:

      I. To assess the efficacy of presurgical nivolumab alone or nivolumab + ipilimumab therapy in
      HCC by estimating the objective response rate (ORR) and time to progression (TTP) per
      Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 progression-free survival (PFS).

      II. To estimate the conversion rate to surgery for arm 3 potentially resectable patients.

      EXPLORATORY OBJECTIVES:

      I. To assess the immunological/biomarker changes in tumor tissues and peripheral blood in
      response to nivolumab alone or nivolumab + ipilimumab in HCC therapy (pre- versus [vs]
      post-treatment), and explore any potential association between these biomarker measures and
      antitumor response and immune-related response criteria (iRC) assessed by MD Anderson
      department of diagnostic imaging.

      OUTLINE: Patients with resectable tumors are randomized to 1 of 2 arms and patients with
      potentially resectable tumors are assigned to Arm C.

      ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment
      repeats every 2 weeks for up to 3 cycles in the absence of disease progression or
      unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks
      after surgery, patients continue nivolumab IV over 30 minutes every 4 weeks for up to 2 years
      in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive ipilimumab IV over 90 minutes on day 1 and nivolumab as Arm A.
      Treatment repeats every 2 weeks for up to 3 cycles for nivolumab in the absence of disease
      progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7.
      Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks
      and nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease
      progression or unacceptable toxicity.

      ARM C: Patients receive ipilimumab and nivolumab as in Arm B. Patients undergo post-treatment
      biopsy on day 1 of week 7, then receive ipilimumab IV over 90 minutes every 6 weeks and
      nivolumab IV over 30 minutes every 4 weeks for up to 3 additional cycles in the absence of
      disease progression or unacceptable toxicity. Beginning 4 weeks after surgery, patients
      receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4
      weeks up to 2 years in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 100 days, then every
      9 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (nivolumab)ExperimentalPatients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 2 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients continue nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
Arm B (ipilimumab, nivolumab)ExperimentalPatients receive ipilimumab IV over 90 minutes on day 1 and nivolumab as Arm A. Treatment repeats every 2 weeks for up to 3 cycles for nivolumab in the absence of disease progression or unacceptable toxicity. Patients undergo liver surgery on day 1 of week 7. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
Arm C (ipilimumab, nivolumab)ExperimentalPatients receive ipilimumab and nivolumab as in Arm B. Patients undergo post-treatment biopsy on day 1 of week 7, then receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks for up to 3 additional cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after surgery, patients receive ipilimumab IV over 90 minutes every 6 weeks and nivolumab IV over 30 minutes every 4 weeks up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must give written informed consent prior to initiation of therapy, in keeping
             with the policies of the institution. Patients with a history of major psychiatric
             illness must be judged able to fully understand the investigational nature of the
             study and the risks associated with the therapy

          -  Patients with histologically confirmed HCC (documentation of original biopsy for
             diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by
             American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic
             subjects is required (presence of arterial hypervascularity with venous washout). For
             subjects without cirrhosis, histological confirmation is mandatory. The determination
             of resectability status will ultimately lie in the clinical judgment of the surgical
             oncologist and medical oncologist involved in the care of the patient

          -  Patient must have measurable disease defined as a lesion that can be accurately
             measured in at least one dimension (longest diameter to be recorded) and measures >=
             15 mm with conventional techniques or >= 10 mm with more sensitive techniques such as
             magnetic resonance imaging (MRI) or spiral computed tomography (CT) scan

          -  Patient can have had prior treatment for HCC including prior surgery, radiation
             therapy, local-regional therapy (ablation or arterial directed therapies), and
             systemic therapy including sorafenib or chemotherapy (but not anti-PD-1 or anti-CTLA-4
             therapy)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1

          -  Absolute neutrophil count >= 1,500/·L (within 14 days of the first dose of study drug)

          -  Platelets >= 100,000/·L (within 14 days of the first dose of study drug)

          -  Hemoglobin (Hgb) > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen]
             to maintain or exceed this level) (within 14 days of the first dose of study drug)

          -  Total bilirubin =< 1.5 mg/dl (within 14 days of the first dose of study drug)

          -  Serum creatinine =< 1.5 times the upper limit of normal or estimated creatinine
             clearance (CrCL) > 40 mL/min (within 14 days of the first dose of study drug)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
             and/or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 5 X institutional upper limit of normal (within 14 days of the first dose of study
             drug)

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]) within 24 hours prior to the start of study drug

          -  Women must not be breastfeeding

          -  WOCBP must agree to follow instructions for method(s) of contraception from the time
             of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of
             study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post
             treatment completion

          -  Men who are sexually active with WOCBP must agree to follow instructions for method(s)
             of contraception for the duration of treatment with study drug (s) plus 5 half-lives
             of study drug (s) plus 90 days (duration of sperm turnover) for a total of 7 months
             post-treatment completion

          -  Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
             from contraceptive requirements. However, WOCBP must still undergo pregnancy testing

        Exclusion Criteria:

          -  Any other malignancy from which the patient has been disease-free for less than 2
             years, except for non-melanoma skin cancer, or in situ carcinoma of any site

          -  Patients who have organ allografts

          -  Patients who have had a major surgical procedure, open biopsy, or significant
             traumatic injury with poorly healed wound within 6 weeks prior to first dose of study
             drug; or anticipation of need for major surgical procedure during the course of the
             study (other than defined by protocol); or fine needle aspirations or core biopsies)
             within 7 days prior to first dose of study drug. NOTE: Patients will be allowed to
             start cycle 1 day 1 therapy after 24 hours from pre-treatment biopsy

          -  Autoimmune disease: Patients with a history of inflammatory bowel disease (including
             Crohn's disease and ulcerative colitis) are excluded from this study as are patients
             with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive
             sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
             Wegener's granulomatosis])

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS)

          -  Any underlying medical condition, which in the opinion of the Investigator, will make
             the administration of study drug hazardous or obscure the interpretation of adverse
             events, such as a condition associated with frequent diarrhea

          -  Patients who have had a history of acute diverticulitis, abdominal fistula,
             gastrointestinal perforation, intra-abdominal abscess, gastrointestinal (GI)
             obstruction, abdominal carcinomatosis which are known risks factors for bowel
             perforation, should be excluded from the study

          -  Patients who have a primary brain tumor (excluding meningiomas and other benign
             lesions), any brain metastases, leptomeningeal disease, seizure disorders not
             controlled with standard medical therapy, or history of stroke within the past year

          -  History of serious systemic disease, including myocardial infarction or unstable
             angina within the last 12 months, history of hypertensive crisis or hypertensive
             encephalopathy, uncontrolled hypertension (blood pressure of > 140/90 mmHg) at the
             time of enrollment, New York Heart Association (NYHA) grade II or greater congestive
             heart failure, unstable symptomatic arrhythmia requiring medication (patients with
             chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular
             tachycardia are eligible), significant vascular disease or symptomatic peripheral
             vascular disease

          -  Patients who have history of other diseases, 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 results of the study or render the subject at
             high risk from treatment complications

          -  Patients who are on high dose steroid (e.g. > 10 mg prednisone daily or equivalent) or
             other more potent immune suppression medications (e.g. infliximab)

          -  Patients who have had influenza, hepatitis, or other vaccines within a month prior to
             initiation of study drugs

          -  Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis
             within the past year

          -  Patients who have serious, non-healing wound, ulcer, or bone fracture

          -  Pregnancy (positive pregnancy test) or lactation

          -  Patients with prior orthotropic liver transplantation

          -  Patients with cirrhosis and severe synthetic liver dysfunction (Child Pugh B-C)

          -  Patients must not have received prior anticancer therapy with anti-CLTA-4 or anti-PD1
             for HCC. Patients receiving any concomitant systemic therapy for HCC are excluded

          -  Patients must not be scheduled to receive another experimental drug while on this
             study

          -  Patients who require ongoing anticoagulation will be excluded. Only aspirin will be
             permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted

          -  Patients must not require total parenteral nutrition with lipids

          -  Any patient who cannot be compliant with the appointments required in this protocol
             must not be enrolled in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Safety will be recorded through the incidence of adverse events, serious adverse events and specific laboratory abnormalities (worst grade) in each treatment arm.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 5 years
Safety Issue:
Description:Descriptive statistics including with 90% confidence interval will be computed.
Measure:Time to progression
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Progression free survival (PFS)
Time Frame:Up to 5 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate probability of PFS for each treatment arm.
Measure:Conversion rate to surgery (Arm C)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be estimated along with the 95% confidence interval.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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