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

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ClinicalTrials.gov Identifier: NCT03222076
Recruitment Status : Recruiting
First Posted : July 19, 2017
Last Update Posted : October 21, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Resectable Hepatocellular Carcinoma Biological: Ipilimumab Biological: Nivolumab Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 28, 2017
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : September 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (nivolumab)
Patients 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.
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm B (ipilimumab, nivolumab)
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.
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm C (ipilimumab, nivolumab)
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.
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 5 years ]
    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 :
  1. Objective response rate [ Time Frame: Up to 5 years ]
    Descriptive statistics including with 90% confidence interval will be computed.

  2. Time to progression [ Time Frame: Up to 5 years ]
  3. Progression free survival (PFS) [ Time Frame: Up to 5 years ]
    The Kaplan-Meier method will be used to estimate probability of PFS for each treatment arm.

  4. Conversion rate to surgery (Arm C) [ Time Frame: Up to 5 years ]
    Will be estimated along with the 95% confidence interval.


Other Outcome Measures:
  1. Immune response [ Time Frame: Baseline up to 2 years ]
    Will be correlated to treatment response. Immune responses, such as infiltration of CD8+/CD4+ T cells and dendritic cells, and cytokine levels in blood, will be compared between pre-treatment and post-treatment via paired t-test and Wilcoxon signed rank test. The overall treatment response rate will be summarized descriptively by dose with the n, percentage, and 95% confidence intervals. Comparison of the response rates between two treatment arms will be made via Fisher's exact test. Association between the binary overall treatment response and immune responses will be assessed by two-sample t-test and Wilcoxon rank sum test.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03222076


Contacts
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Contact: Ahmed Kaseb, MD 713-792-2828 akaseb@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Ahmed O. Kaseb    713-792-2828      
Principal Investigator: Ahmed O. Kaseb         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ahmed O Kaseb M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03222076     History of Changes
Other Study ID Numbers: 2017-0097
NCI-2018-01106 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0097 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: July 19, 2017    Key Record Dates
Last Update Posted: October 21, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Nivolumab
Ipilimumab
Antibodies
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents