Nivolumab Alone or in Combination with Relatlimab for the Treatment of Resectable Hepatocellular Carcinoma
This phase Ib trial studies nivolumab alone or in combination with relatlimab for the treatment of hepatocellular carcinoma that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as nivolumab and relatlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Inclusion Criteria
- NEOADJUVANT ELIGIBILITY CRITERIA: Technically resectable HCC * HCC may be diagnosed pathologically, or noninvasively by the American Association for the Study of Liver Diseases (AASLD) criteria or the Organ Procurement and Transplant Network (OPTN) Obligatory Diagnostic Criteria for Hepatocellular Carcinoma (HCC) * No extrahepatic spread, no nodal disease, and no bilateral left and right branch portal vein involvement
- NEOADJUVANT ELIGIBILITY CRITERIA: Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator
- NEOADJUVANT ELIGIBILITY CRITERIA: Age >= 18 years old on the day of consent
- NEOADJUVANT ELIGIBILITY CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status =< 1 or Karnofsky >= 80
- NEOADJUVANT ELIGIBILITY CRITERIA: White blood cell count >= 2,000/ uL
- NEOADJUVANT ELIGIBILITY CRITERIA: Absolute neutrophil count >= 1,500/uL
- NEOADJUVANT ELIGIBILITY CRITERIA: Platelets >= 100,000/uL
- NEOADJUVANT ELIGIBILITY CRITERIA: Hemoglobin >= 8.5 g/dL
- NEOADJUVANT ELIGIBILITY CRITERIA: Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- NEOADJUVANT ELIGIBILITY CRITERIA: Lipase =< 1.5 x ULN and no radiologic or clinical evidence of pancreatitis
- NEOADJUVANT ELIGIBILITY CRITERIA: Adequate future liver remnant, and adequate liver function, based upon meeting the following laboratory criteria: * Child-Pugh Score of A * Total bilirubin =< 2 mg/dL. For subjects with known Gilbert’s disease, bilirubin =< 3.0 mg/dL; * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN * Serum albumin >= 2.8 g/dL * Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test =< 1.5 x ULN
- NEOADJUVANT ELIGIBILITY CRITERIA: Patients with virally-associated or non-virally associated HCC are eligible for participation. Patients with chronic or acute hepatitis B virus (HBV) infection (as characterized by positive hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibodies [anti-HBcA] with detectable HBV deoxyribonucleic acid [DNA] [=<10 IU/ml]) must have disease controlled (HBV DNA < 500) prior to enrollment. Patients who test positive for anti-hepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml) do not require anti-viral therapy prior to enrollment, but HBV DNA levels should be monitored and antiviral therapy should be initiated if HBV DNA is detected (>= 10 IU/ml)
- NEOADJUVANT ELIGIBILITY CRITERIA: Left ventricular ejection fraction (LVEF) assessment with documented LVEF >= 50% by either transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) (TTE preferred) within 6 months from first study drug administration
- NEOADJUVANT ELIGIBILITY CRITERIA: Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test for the patient to be eligible for trial enrollment
- NEOADJUVANT ELIGIBILITY CRITERIA: WOCBP must be willing to use either two adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout the study, starting with visit 1 through 5 months after the last dose of study therapy. Approved contraceptive methods include, for example; intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives. Spermicides alone are not an acceptable method of contraception. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- NEOADJUVANT ELIGIBILITY CRITERIA: Male patients must agree to use an adequate method of contraception, or to abstain from heterosexual activity (complete abstinence), starting with the first dose of study drug through 7 months after the last dose of study therapy
- NEOADJUVANT ELIGIBILITY CRITERIA: Ability to understand and the willingness to sign a written informed consent document
- ADJUVANT ELIGIBILITY CRITERIA: Patients must have had surgical resection of primary tumor
- ADJUVANT ELIGIBILITY CRITERIA: ECOG performance status 0-1
- ADJUVANT ELIGIBILITY CRITERIA: White blood cell count >= 2,000/uL
- ADJUVANT ELIGIBILITY CRITERIA: Absolute neutrophil count >= 1,500/uL
- ADJUVANT ELIGIBILITY CRITERIA: Platelets >= 100,000/uL
- ADJUVANT ELIGIBILITY CRITERIA: Hemoglobin >= 8.5 g/dL
- ADJUVANT ELIGIBILITY CRITERIA: Serum creatinine =< 1.5 x ULN OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- ADJUVANT ELIGIBILITY CRITERIA: Lipase =< 1.5 x ULN and no radiologic or clinical evidence of pancreatitis
- ADJUVANT ELIGIBILITY CRITERIA: Adequate future liver remnant, and adequate liver function, based upon meeting the following laboratory criteria: * Child-Pugh Score of A * Total bilirubin =< 2 mg/dL. For subjects with known Gilbert’s disease, bilirubin =< 3.0 mg/dL; * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 × ULN * Serum albumin >= 2.8 g/dL * Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test =< 1.5 x ULN
- ADJUVANT ELIGIBILITY CRITERIA: Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test for the patient to be eligible for trial enrollment
- ADJUVANT ELIGIBILITY CRITERIA: WOCBP must be willing to use either two adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout the study, starting with visit 1 through 5 months after the last dose of study therapy. Approved contraceptive methods include, for example; intrauterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, female condoms with spermicide, or oral contraceptives. Spermicides alone are not an acceptable method of contraception. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
- ADJUVANT ELIGIBILITY CRITERIA: Male patients must agree to use an adequate method of contraception, or to abstain from heterosexual activity (complete abstinence), starting with the first dose of study drug through 7 months after the last dose of study therapy
- ADJUVANT ELIGIBILITY CRITERIA: Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria
- NEOADJUVANT EXCLUSION CRITERIA: Fibrolamellar carcinoma or mixed HCC
- NEOADJUVANT EXCLUSION CRITERIA: Receiving, or previously received, any systemic chemotherapy, or investigational agent for HCC * Note: Prior surgical resection with recurrence, or palliative local therapy (including trans-arterial chemoembolization [TACE], yttrium 90 [Y-90] resin microspheres, etc.) would not exclude trial participation, but must have been performed at least 30 days prior to enrollment and there must be an area of viable tumor on scans
- NEOADJUVANT EXCLUSION CRITERIA: Patients with a history of prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, or anti-Lag-3 antibodies
- NEOADJUVANT EXCLUSION CRITERIA: Has a known additional malignancy that is expected to require active treatment within two years, or is likely to be life-limiting in the opinion of the treating investigator. Superficial bladder cancer, non-melanoma skin cancers, or low grade prostate cancer not requiring therapy would not exclude participation in this trial
- NEOADJUVANT EXCLUSION CRITERIA: Has a known history of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)
- NEOADJUVANT EXCLUSION CRITERIA: Has active co-infection with HBV and hepatitis D virus (HDV)
- NEOADJUVANT EXCLUSION CRITERIA: Has a diagnosis of immunodeficiency, or is receiving systemic steroid therapy above physiologic replacement dose, or any other form of immunosuppressive therapy
- NEOADJUVANT EXCLUSION CRITERIA: Prior tissue or organ allograft or allogeneic bone marrow transplantation. Exceptions can be approved by the Investigational New Drug (IND) Sponsor if loss of the graft is not a clinical concern
- NEOADJUVANT EXCLUSION CRITERIA: Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- NEOADJUVANT EXCLUSION CRITERIA: Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent). Inhaled or topical steroids, and adrenal replacement steroid doses =< 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
- NEOADJUVANT EXCLUSION CRITERIA: Has a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
- NEOADJUVANT EXCLUSION CRITERIA: Uncontrolled intercurrent illness including, but not limited to: symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- NEOADJUVANT EXCLUSION CRITERIA: Uncontrolled or significant cardiovascular disease (i.e. cardiomyopathy, congestive heart failure with New York Heart Association (NYHA) functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion), including, but not limited to any of the following: * Myocardial infarction (MI) or stroke/transient ischemic attack within the 6 months prior to consent * Uncontrolled Angina within the 3 months prior to consent * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes) * Corrected QT interval (QTc) prolongation > 480 msec * Cardiovascular disease-related requirement for daily supplemental oxygen * History of two or more MIs OR two or more coronary revascularization procedures * Subjects with history of myocarditis, regardless of etiology.
- NEOADJUVANT EXCLUSION CRITERIA: Troponin T (TnT) or I (TnI) > 2 x ULN. Subjects with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subjects may undergo a cardiac evaluation and be considered for treatment, following a discussion with the IND Sponsor. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo cardiac evaluation and be considered for treatment, following discussion with the IND Sponsor
- NEOADJUVANT EXCLUSION CRITERIA: Moderate or severe ascites
- NEOADJUVANT EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to monoclonal antibodies or any component of the study treatment formulations
- NEOADJUVANT EXCLUSION CRITERIA: Pregnant or lactating females
- NEOADJUVANT EXCLUSION CRITERIA: WOCBP and men with female partners (WOCBP) who are not willing to use contraception
- NEOADJUVANT EXCLUSION CRITERIA: Subjects unable to undergo venipuncture and/or tolerate venous access
- NEOADJUVANT EXCLUSION CRITERIA: Any other sound medical, psychiatric, and/or social reason as determined by the investigator
- NEOADJUVANT EXCLUSION CRITERIA: Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
- ADJUVANT EXCLUSION CRITERIA: More than 90 days have elapsed since surgery
- ADJUVANT EXCLUSION CRITERIA: Patient was found to have unresectable or metastatic disease intraoperatively
- ADJUVANT EXCLUSION CRITERIA: Patients who develop local recurrence or disease progression at any point in the study
- ADJUVANT EXCLUSION CRITERIA: The patient has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of adjuvant study drug
- ADJUVANT EXCLUSION CRITERIA: History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- ADJUVANT EXCLUSION CRITERIA: History of allergic reaction to nivolumab
- ADJUVANT EXCLUSION CRITERIA: Troponin T (TnT) or I (TnI) > 2 x ULN. Subjects with TnT or TnI levels between > 1 to 2 x ULN will be permitted if repeat levels within 24 hours are =< 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subjects may undergo a cardiac evaluation and be considered for treatment, following a discussion with the IND Sponsor. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the subject may undergo cardiac evaluation and be considered for treatment, following discussion with the IND Sponsor
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04658147.
PRIMARY OBJECTIVE:
I. To characterize the feasibility of neoadjuvant nivolumab or nivolumab plus relatlimab in resectable hepatocellular carcinoma (HCC).
SECONDARY OBJECTIVES:
I. To characterize the safety of neoadjuvant and adjuvant nivolumab or nivolumab plus relatlimab, in resectable HCC.
II. To estimate the percentage of patients with resectable HCC who obtain an R0 resection at approximately 8-12 weeks following neoadjuvant nivolumab or nivolumab plus relatlimab.
III. To determine the percentage of evaluable patients who obtain a pathologic response (including pathologic complete response [pCR], or major pathologic responses [MPR]) at week 8-12 following neoadjuvant nivolumab or nivolumab plus relatlimab.
IV. To determine the objective response rate (ORR) at approximately week 8 in patients with resectable HCC treated with neoadjuvant nivolumab or nivolumab plus relatlimab.
V. To determine the median overall survival (OS), 12 month OS, 18 month OS, 3 year OS, and 5 year OS, of patients with resectable HCC treated with perioperative nivolumab or nivolumab plus relatlimab.
VI. To determine the median disease free survival (DFS), 12 month DFS, 18 month DFS, 3 year DFS, and 5 year DFS, of patients with resectable HCC treated with neoadjuvant nivolumab or nivolumab plus relatlimab.
EXPLORATORY OBJECTIVES:
I. To collect peripheral blood mononuclear cells (PBMC), plasma, and serum to identify potential therapeutic targets, biomarkers and predictors of response (PCR/MPR, ORR, OS, and DFS) and autoimmune toxicity.
Ia. Measure pre- and post-treatment changes in PBMCs including effector, helper, and regulatory T cells, NK cells, monocytes, and macrophages through cell phenotyping analysis and gene expression profiling.
Ib. Proteomic approaches will be used on pre- and post-treatment sera and plasma to identify targets and biomarkers of response or toxicity.
II. To explore the effects of therapy on tumor and tumor infiltrating immune cells, and to explore potential molecular determinants of response, progression, and disease stability.
Ia. To determine the receptor occupancy of relatlimab in tumor infiltrating lymphocytes and in the blood.
Ib. Immunohistochemistry (IHC) and/or gene expression profiling will be used to compare the nature of tumors and immune infiltrates for responders versus non-responders.
Ic. Next-generation sequencing of T cell receptor (TCR) genes may be used to compare the tumor infiltrating T cell repertoire in responders and non-responders.
Id. Up-regulation of immune inhibitory molecules (such as programmed death-ligand 1 [PD-L1]) will be evaluated in the pre- and post-treatment samples.
Ie. Proteomic approaches to quantify protein expression and activation of specific signaling pathways in tumors from responders versus non-responders.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatments repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within 60 days, patients undergo surgical resection. Within 90 days of surgical resection, patients with no evidence of recurrence/progression may receive adjuvant nivolumab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive nivolumab IV over 30 minutes and relatlimab IV over 30 minutes on day 1. Treatments repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within 60 days, patients undergo surgical resection. Within 90 days of surgical resection, patients with no evidence of recurrence/progression may receive adjuvant nivolumab IV over 30 minutes and adjuvant relatlimab IV over 30 minutes on day 1. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then every 3 months for 2 years, and every 6 months for 3 years or until study closure whichever comes first.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationJohns Hopkins University/Sidney Kimmel Cancer Center
Principal InvestigatorMark Yarchoan
- Primary IDJ20121
- Secondary IDsNCI-2021-04556, CRMS-76353, IRB00246739
- ClinicalTrials.gov IDNCT04658147