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Hepatocellular CarcinomaPhase 2NCT03222076

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

A Phase 2 study testing Ipilimumab and Nivolumab in people with Hepatocellular Carcinoma and Resectable Hepatocellular Carcinoma, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ipilimumab and Nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteUnited States
Study dates
28 Sep 2017to 14 Sep 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • Target population
  • Patients with histologically confirmed HCC (Documentation of original biopsy for diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by 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 MRI or spiral CT scan.
  • Patient can have had prior treatment for HCC including prior surgery, radiation therapy, local-regional therapy (abalation or arterial directed therapies), and systemic therapy including sorafenib or chemotherapy (but not anti-PD-1 or anti-CTLA-4 therapy)
  • ECOG performance status ≤ 1.
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  • Within 14 days of the first dose of study drug, patients must have adequate organ and marrow function as defined below:
  • Absolute neutrophil count ≥ 1,500/μL
  • Platelets ≥100,000/μL
  • Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to maintain or exceed this level)
  • Total bilirubin ≤ 1.5 mg/dl
  • Serum creatinine ≤ 1.5 times the upper limit of normal or estimated CrCL >40mL/min.
  • AST (SGOT) and/or ALT (SGPT) ≤ 5 X institutional upper limit of normal Age and Sex
  • Men and women ≥ 18 years of age
  • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 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 as described in these sections.
  • Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% per year when used consistently and correctly.
  • At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below:
  • HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
  • Male condoms with spermicide
  • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner.
  • Nonhormonal IUDs, such as ParaGard
  • Tubal ligation
  • Vasectomy
  • Complete Abstinence* *Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Abstinence is only acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, profession of abstinence for entry into a clinical trial, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.
  • LESS EFFECTIVE METHODS OF CONTRACEPTION
  • Diaphragm with spermicide
  • Cervical cap with spermicide
  • Vaginal sponge
  • Male Condom without spermicide*
  • Progestin only pills by WOCBP subject or male subject's WOCBP partner
  • Female Condom* *A male and female condom must not be used together

Who cannot join

  • Any of the following criteria will disqualify the patient from participation:
  • Target Disease Exceptions
  • 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.
  • Medical History and Concurrent Disease
  • 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); 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.
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  • 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, 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).
  • Prohibited Therapies and/or Medications
  • 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.
  • Other Exclusion Criteria:
  • Any patients who cannot be compliant with the appointments required in this protocol must not be enrolled in this study.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

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 (HCC)

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.

Read the detailed description

Primary Objective:

--To evaluate the safety and tolerability of therapy with nivolumab alone or nivolumab + ipilimumab in resectable HCC in the context of presurgical therapy.

Note: Note: As of January 8, 2020, 30 patients have been enrolled and 27 patients have been randomized. The PI decided to stop enrollment since the study has reached its target enrollment of 30 patients

Secondary Objectives:

--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 RECIST 1.1 progression-free survival (PFS).

Exploratory Objectives:

--To assess the immunological/biomarker changes in tumor tissues and peripheral blood in response to nivolumab alone or nivolumab + ipilimumab in HCC therapy (pre- 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.

Being tested
Ipilimumab, Nivolumab
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IpilimumabBiological

    Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4

    Given IV

  • NivolumabBiological

    Also called BMS-936558, MDX-1106, NIVO, ONO-4538

    Given IV

Study groups in NCT03222076
Study groupRoleWhat they receive
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.
Receives: Biological: 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.
Receives: Biological: Ipilimumab; Biological: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Safety and Tolerability of Presurgical Nivolumab With or Without Ipilimumab, Defined as the Number of Participants With of Adverse Events.

    The frequency of adverse events, serious adverse events (grade ≥3), and laboratory abnormalities. 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.

    Measured: Up to 5 years

Secondary outcomes (3)

  1. Objective Response Rate

    Overall response rate, defined as the proportion of patients with a complete response or partial response after 6 weeks of therapy by RECIST 1.1 criteria divided by the number of randomly assigned patients.

    Measured: After 6 weeks of therapy, up to 5 years

  2. Time to Progression

    Time to progression defined as the time from the start of the study drug to the first documented tumor progression or recurrence of the tumor as determined by the investigator by RECIST 1.1 or immune-related response criteria.

    Measured: Up to 5 years

  3. Progression Free Survival (PFS)

    Progression free survival, defined as the time from the start of treatment to the date of progessive disease, recurrence, or death, whichever occurred first. The Kaplan-Meier method will be used to estimate probability of PFS for each treatment arm.

    Measured: Up to 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Jul 2017
  2. Study start28 Sep 2017
  3. Primary completion14 Sep 2022
  4. Study completion14 Sep 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03222076
Sponsor's protocol ID
2017-0097
Other IDs
NCI-2018-01106, 2017-0097
Status last verified
Jun 2023
First submitted
17 Jul 2017
Last updated
10 Jul 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Kaseb AO, Hasanov E, Cao HST, Xiao L, Vauthey JN, Lee SS, Yavuz BG, Mohamed YI, Qayyum A, Jindal S, Duan F, Basu S, Yadav SS, Nicholas C, Sun JJ, Singh Raghav KP, Rashid A, Carter K, Chun YS, Tzeng CD, Sakamuri D, Xu L, Sun R, Cristini V, Beretta L, Yao JC, Wolff RA, Allison JP, Sharma P. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022 Mar;7(3):208-218. doi: 10.1016/S2468-1253(21)00427-1. Epub 2022 Jan 20.

    PubMed 35065057

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ipilimumab and Nivolumab in people with Hepatocellular Carcinoma and Resectable Hepatocellular Carcinoma, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 35 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 10 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety and Tolerability of Presurgical Nivolumab With or Without Ipilimumab, Defined as the Number of Participants With of Adverse Events. (time frame: Up to 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03222076, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2023.

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