A Phase II Study of Nivolumab + Ipilimumab in Advanced HCC Patients Who Have Progressed on First Line Atezolizumab + Bevacizumab

October 13, 2023 updated by: Academic and Community Cancer Research United
This phase II trial tests whether nivolumab and ipilimumab works to shrink tumors in patients with liver cancer that has spread to nearby tissue or lymph nodes (locally advanced), has spread to other places in the body (metastatic), or cannot be removed by surgery (unresectable). 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. Nivolumab and ipilimumab may be effective in killing tumor cells in patients with liver cancer.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVE:

I. To investigate the confirmed objective response rate (ORR) of nivolumab and ipilimumab in patients with hepatocellular carcinoma (HCC) who have progressed radiographically on atezolizumab/bevacizumab that necessitates change in treatment.

SECONDARY OBJECTIVES:

I. To determine the overall survival (OS) in hepatocellular carcinoma (HCC) patients treated with nivolumab and ipilimumab who have progressed radiographically on atezolizumab / bevacizumab that necessitates change in treatment.

II. To determine the progression free survival (PFS) in hepatocellular carcinoma (HCC) patients treated with nivolumab and ipilimumab who have progressed radiographically on atezolizumab/bevacizumab that necessitates change in treatment.

III. To determine the disease control rate in hepatocellular carcinoma (HCC) patients treated with nivolumab and ipilimumab who have progressed radiographically on atezolizumab/bevacizumab that necessitates change in treatment.

IV. To assess the frequency and severity of adverse events in hepatocellular carcinoma (HCC) patients treated with nivolumab and ipilimumab who have progressed radiographically on atezolizumab/bevacizumab that necessitates change in treatment.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 2 years from registration.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • Recruiting
        • University of Alabama- Birmingham
        • Principal Investigator:
          • Mehmet Akce, M.D.
        • Contact:
          • University of Alabama at Birmingham/O'Neal Comprehensive Cancer Center
          • Phone Number: 205-934-2992
    • Florida
      • Miami, Florida, United States, 33136
        • Recruiting
        • University of Miami Miller School of Medicine-Sylvester Cancer Center
        • Principal Investigator:
          • Lynn Feun
        • Contact:
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Not yet recruiting
        • Emory University Hospital/Winship Cancer Institute
        • Principal Investigator:
          • Maria Diab
        • Contact:
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Not yet recruiting
        • Mayo Clinic in Rochester
        • Principal Investigator:
          • Mehmet Akce
        • Contact:
    • New Jersey
      • New Brunswick, New Jersey, United States, 08903
        • Recruiting
        • Rutgers Cancer Institute of New Jersey
        • Contact:
        • Principal Investigator:
          • Sharon Li, M.D.
    • Tennessee
      • Nashville, Tennessee, United States, 37232

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age >= 18 years.
  • HCC diagnosis confirmed by histology/cytology or clinically by American Association for Study of Liver Diseases (AASLD) criteria in cirrhotic patients.
  • Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Locally advanced, metastatic, or unresectable disease.
  • Child Pugh class A.
  • Barcelona clinic liver cancer (BCLC) stage B (not amenable to liver directed therapy) or stage C.
  • Prior treatment with atezolizumab and bevacizumab combination with radiographic progression that necessitates change in treatment per treating physician. Patients with rapid progression on atezolizumab and bevacizumab (defined as patients who progressed radiographically in the first restaging scan that necessitates change in treatment) are excluded.
  • Washout period >= 4 weeks prior to registration is required since last atezolizumab and bevacizumab dose.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. (Form is available on the Academic and Community Cancer Research United [ACCRU] website).
  • Absolute neutrophil count (ANC) >= 1000/mm ^ 3 (obtained =< 28 days prior to registration).
  • Platelet count >= 60,000/mm^3 (obtained =< 28 days prior to registration).
  • Hemoglobin >= 8.5 g/dL (obtained =< 28 days prior to registration).
  • Total bilirubin =< 3 x upper limit of normal (ULN) (obtained =< 28 days prior to registration).
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 5 x ULN (obtained =< 28 days prior to registration).
  • International normalized ratio (INR) =< 2.3 or Prothrombin time (PT) =< 6 seconds above control OR if patient is receiving anticoagulant therapy and INR is within target range of therapy creatinine =< 1.5x ULN (obtained =< 28 days prior to registration).

  • Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only.

    • Note: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Provide informed written consent =< 28 days prior to registration.

  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).

    • Note: During the active monitoring phase of a study (i.e., active treatment), participants must be willing to return to the consenting institution for follow-up.
  • Willing to provide mandatory tissue specimens and blood specimens for correlative research purposes.

Exclusion Criteria:

  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown

    • Pregnant persons
    • Nursing persons
    • Persons of childbearing potential who are unwilling to employ adequate contraception.
  • Major surgery =< 4 weeks prior to registration.
  • Liver directed therapy (transarterial chemoembolization [TACE], Y-90, liver directed radiation) =< 28 days prior to registration. Prior liver directed therapy > 28 days prior to registration is allowed as long as patient has at least one measurable untreated lesion by RECIST v1.1.
  • Patients with rapid progression on atezolizumab and bevacizumab (who progressed radiographically in the first restaging scan that necessitates change in treatment) are excluded.
  • Prior treatment =< 4 weeks prior to registration with anti-CTLA-4 antibody for HCC.
  • Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.

  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.

    • Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.

  • Uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection excluding hepatitis C virus (HCV)
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Unstable cardiac arrhythmia
    • Psychiatric illness/social situations that would limit compliance with study requirements.
    • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients with chronic HBV infection as evidenced by detectable HBV surface antigen or HBV deoxyribonucleic acid (DNA) are eligible if on antiviral therapy and have HBV DNA < 100 IU/mL. Patients with active or resolved hepatitis C (HCV) infection as evidenced by detectable HCV ribonucleic acid (RNA) or antibody are eligible.
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 4 weeks prior to registration.
  • Other active malignancy =< 2 years prior to registration. Exceptions: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
  • History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
  • History of allogenic organ transplantation.

  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

    • Patients with vitiligo or alopecia
    • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    • Patients with celiac disease controlled by diet alone
  • History of leptomeningeal carcinomatosis.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

  • Current or prior use of immunosuppressive medication =< 14 days prior to registration. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication).
  • Receipt of live attenuated vaccine =< 30 days prior to registration; Note: Patients, if enrolled, should not receive live vaccine whilst on study treatment and up to 30 days after the last dose of study treatment.
  • Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
  • History of grade 3 or 4 immunotherapy related toxicity NCI CTCAE v5.0 due to prior regimen attributed to atezolizumab.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (nivolumab, ipilimumab)
Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
  • CMAB819
  • Nivolumab Biosimilar CMAB819
Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Confirmed objective response rate (ORR)
Time Frame: Up to 6 months
A confirmed response is defined to be either a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Disease status will be assessed using response evaluation criteria in solid tumors (RECIST) version (v.) 1.1 criteria. Overall Response Rate (ORR) is defined as the proportion of evaluable patients who achieve confirmed response (CR or PR) while on treatment. The final ORR point estimate and corresponding 95% confidence interval will be reported according to the method of Clopper-Pearson.
Up to 6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: Assessed up to 2 years
Overall survival (OS) is defined as the time from registration to death from any cause. OS will be estimated using the Kaplan-Meier method. Patients who are alive will be censored at the last follow-up date. The median OS and corresponding 95% confidence interval will be reported.
Assessed up to 2 years
Progression-free survival (PFS)
Time Frame: Assessed up to 2 years
Progression-free survival (PFS) is defined as the time from registration to the first disease progression or death from any cause, where disease progression is determined based on RECIST 1.1 criteria. PFS will be estimated using the Kaplan-Meier method. Patients who do not experience disease progression or death while on protocol will be censored at the last disease assessment date. The median PFS and corresponding 95% confidence interval will be reported.
Assessed up to 2 years
Disease control
Time Frame: Up to 2 years
Disease control is defined as achieving CR, PR, or maintaining SD for at least 6 months while on treatment. Objective status will be assessed using RECIST v. 1.1 criteria. Disease control rate will be calculated as the proportion of evaluable patients who achieve disease control. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper Pearson.
Up to 2 years
Incidence of adverse events
Time Frame: Up to 2 years
All patients who have initiated treatment will be considered evaluable for adverse event analyses. The rate of patients experiencing a grade 3+ adverse event will be reported using Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Academic and Community Cancer Research United

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Mehmet Akce, Academic and Community Cancer Research United

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 19, 2023

Primary Completion (Estimated)

January 31, 2024

Study Completion (Estimated)

January 31, 2027

Study Registration Dates

First Submitted

January 6, 2022

First Submitted That Met QC Criteria

January 6, 2022

First Posted (Actual)

January 20, 2022

Study Record Updates

Last Update Posted (Actual)

October 16, 2023

Last Update Submitted That Met QC Criteria

October 13, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACCRU-GI-2017 (Other Identifier: Academic and Community Cancer Research United)
  • P30CA015083 (U.S. NIH Grant/Contract)
  • NCI-2021-13335 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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