Pembrolizumab With or Without Elbasvir/Grazoprevir and Ribavirin in Treating Patients With Advanced Refractory Liver Cancer
Pembrolizumab With or Without Elbasvir/Grazoprevir and Ribavirin in Treating Patients With Advanced Refractory Liver Cancer
This phase I/II clinical trial studies the side effects of pembrolizumab with or without
 elbasvir/grazoprevir and ribavirin and to see how well they work in treating patients with
 liver cancer that has spread to other places in the body and does not respond to previous
 treatment. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the
 body's immune system attack the cancer, and may interfere with the ability of tumor cells to
 grow and spread. Elbasvir/grazoprevir and ribavirin may stop the growth of tumor cells by
 blocking some of the enzymes needed for cell growth. Giving pembrolizumab in combination with
 elbasvir/grazoprevir and ribavirin may work better in treating patients with liver cancer
 than with pembrolizumab alone.
PRIMARY OBJECTIVES:

 I. To estimate the tolerability of intravenous (V) administration of pembrolizumab as
 second-line systemic therapy in subjects with advanced hepatocellular carcinoma. (Arm A and
 Arm B).

 II. To evaluate the efficacy of pembrolizumab in combination with elbasvir/grazoprevir
 (Zepatier) as assessed by the proportion of subjects with hepatitis C virus (HCV) GT1 or GT4
 achieving Sustained Virologic Response 12 weeks after the end of all HCV study therapy
 (SVR12), defined as HCV ribonucleic acid (RNA) below the lower limit of quantitation (LLOQ)
 (either target detected unquantifiable [TD(u)] or target not detected [TND]) 12 weeks after
 the end of all study therapy. (Arm B)

 SECONDARY OBJECTIVES:

 I. To estimate the objective response rate (ORR), per Response Evaluation Criteria in Solid
 Tumors (RECIST) 1.1 assessed by MD Anderson radiology.

 II. To estimate the duration of response (DOR), disease control rate (DCR), time to
 progression (TTP), and progression-free survival (PFS) per RECIST 1.1 assessed by MD Anderson
 Department of Diagnostic Imaging.

 III. To evaluate the safety of pembrolizumab in combination with Zepatier as assessed by the
 proportion of subjects with HCV GT1 or GT4 achieving SVR12 and SVR24, defined as HCV RNA
 below the LLOQ (either TD[u] or TND) 12 and 24 weeks after the end of all study therapy.

 EXPLORATORY OBJECTIVES:

 I. To estimate ORR, DOR, DCR, TTP, PFS and overall survival (OS) per immune response RECIST
 (irRECIST) as assessed by MD Anderson radiology.

 II. To explore the relationship between progression on sorafenib versus intolerance of
 sorafenib and response to pembrolizumab.

 III. To perform exploratory biomarker research to study the correlation between immunological
 and molecular changes in tumor tissues and peripheral blood with TTP, OS, and rate of adverse
 events (AEs).

 IV. To explore the association between PD-1 ligand (PD-L1) expression by immunohistochemistry
 (IHC), somatic gene expression profiling (GEP) and antitumor efficacy of pembrolizumab based
 on RECIST 1.1.

 V. To explore predictive biomarkers to study the correlation of independent effect of
 cirrhosis grade and severity of portal hypertension by magnetic resonance imaging (MRI)
 classification on OS.

 VI. To explore retrospective risk stratification of the degree of the underlying liver
 dysfunction by IGF score.

 To explore retrospective risk stratification of the degree of the underlying liver
 dysfunction by IGF-1 score. See section 2.1. VII. To assess whether pembrolizumab in
 combination with Zepatier affects the course of viral infections in subjects with underlying
 HCV GT1 or GT4. We hypothesize that pembrolizumab in combination with Zepatier will help to
 reduce viral loads in those with untreated HCV.

 VIIII. To evaluate the response of HCV GT1 and GT4 to treatment as assessed by sustained
 virologic response at 4 and 12 weeks after the end of 12 to 16 weeks of pembrolizumab in
 combination with Zepatier dosing. Sustained virologic response is defined as defined as HCV
 RNA below the LLOQ (either TD[u] or TND).

 IX. To evaluate the emergence of viral resistance-associated variants (RAVs) to pembrolizumab
 in combination with Zepatier in subjects with HCV GT1 or GT4 without RAVs as baseline .

 X. To evaluate the efficacy of pembrolizumab in combination with Zepatier as assessed by the
 proportion of subjects with HCV GT1 or GT4 achieving undetectable (TND) HCV RNA and HCV RNA
 below the LLOQ at Weeks 2, 4, 12 and Follow- Up Week 4 (SVR4), Week 12 (SVR12), and Week 24
 (SVR24).

 XI. To explore the relationship between genetic variation and subject response to the
 treatment(s) administered.

 OUTLINE: Patients are assigned to 1 of 2 arms.

 ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles
 repeat every 21 days for up to 35 cycles in the absence of disease progression or
 unacceptable toxicity.

 ARM B: Patients receive pembrolizumab as in arm A. Patients also receive elbasvir/grazoprevir
 orally (PO) once daily (QD) and ribavirin PO QD on days 1-28. Treatment continues for 12-16
 weeks in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30-90 days and then every 12
 weeks.
Inclusion Criteria:

 -  FOR ARM 1 AND 2: Subjects with advanced hepatocellular carcinoma (HCC) with no
 curative option; for Arm 2 subjects that are HCV-positive with genotype 1 or 4 virus
 infection will be enrolled

 -  Be willing and able to provide written informed consent for the trial; the subject may
 also provide consent for Future Biomedical Research (FBR); however, the subject may
 participate in the main trial without participating in FBR.

 -  Have histologically or cytologically documented 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; for subjects without cirrhosis histological confirmation is
 mandatory

 -  FOR ARM A AND B: Have Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC
 stage B disease not amenable to locoregional therapy or refractory to locoregional
 therapy, and not amenable to a curative treatment approach

 -  Have a Child-Pugh A liver score at screening or within 14 days of first dose of study
 drug

 -  Have a predicted life expectancy of greater than 3 months

 -  Have measurable disease based on RECIST 1.1 as confirmed by the blinded MD Anderson
 radiology; target lesions situated in a previously irradiated area are considered
 measurable if progression has been demonstrated in such lesions; Note: the same image
 acquisition and processing parameters should be used throughout the study for a given
 subject

 -  Have a performance status of 0 or 1 using the Eastern Cooperative Oncology Group
 (ECOG) performance scale within 7 days of first dose of study drug

 -  Have documented objective radiographic progression after stopping treatment with
 sorafenib or else intolerance to sorafenib; intolerance to sorafenib is defined as:
 Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 drug-related adverse
 event(s) which both a) persisted in spite of comprehensive supportive therapy
 according to institutional standards and b) persisted or recurred after sorafenib
 treatment interruption of at least 7 days and dose reduction by one dose level;
 patients treated on sorafenib as the last treatment may start pembrolizumab at least
 14 days after the last dose of sorafenib

 -  FOR ARM B: Subjects with chronic infection by HCV who are treated or untreated are
 allowed on study; subjects with a past or resolved hepatitis B virus (HBV) infection,
 defined as having a negative hepatitis B surface antigen (HBsAg) test and a positive
 total hepatitis B core antibody (HBcAb) test and negative HBV deoxyribonucleic acid
 (DNA) test at screening, are eligible for the study

 -  Have a negative urine or serum pregnancy test within 72 hours prior to receiving the
 first dose of study medication (cycle 1, day 1) (female subjects of childbearing
 potential); if the urine test is positive or cannot be confirmed as negative, a serum
 pregnancy test will be required

 -  Be willing to use an adequate method of contraception for the course of the study
 through 120 days (Arm A) or 180 days (Arm B) after the last dose of study medication
 (male and female subjects of childbearing potential; acceptable methods of
 contraception are as follows: A) single method (one of the following is acceptable):
 a) intrauterine device (IUD); b) vasectomy of a female subject's male partner; c)
 contraceptive rod implanted into the skin B) combination method (requires use of two
 of the following): a) diaphragm with spermicide (cannot be used in conjunction with
 cervical cap/spermicide); c) cervical cap with spermicide (nulliparous women only); d)
 contraceptive sponge (nulliparous women only); e) male condom or female condom (cannot
 be used together); f) hormonal contraceptive: oral contraceptive pill
 (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal
 contraceptive ring, or subcutaneous contraceptive injection; abstinence (relative to
 heterosexual activity) can be used as the sole method of contraception if it is
 consistently employed as the subject's preferred and usual lifestyle and if considered
 acceptable by local regulatory agencies and Ethical Review Committees
 (ERCs)/Institutional Review Boards (IRBs); periodic abstinence (e.g., calendar,
 ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not
 acceptable methods of contraception; if a contraceptive method listed above is
 restricted by local regulations/guidelines, then it does not qualify as an acceptable
 method of contraception for subjects participating at sites in this country/region

 -  Absolute neutrophil count >= 1200/uL performed within 7 days of treatment initiation

 -  Platelets >= 60,000/uL performed within 7 days of treatment initiation

 -  Hemoglobin >= 8 g/dL without transfusion or erythropoietin (EPO) dependency within 7
 days performed within 7 days of treatment initiation

 -  Creatinine OR measured or calculated creatinine clearance (glomerular filtration rate
 [GFR] can also be used in place of creatinine or creatinine clearance) =< 1.5 x upper
 limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x
 institutional ULN; Note: creatinine clearance should be calculated per institutional
 standard performed within 7 days of treatment initiation

 -  Total bilirubin =< 2 mg/dL, or direct bilirubin =< ULN for those with total bilirubin
 > 2 x ULN performed within 7 days of treatment initiation

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x
 ULN performed within 7 days of treatment initiation

 -  Albumin >= 3 g/dL performed within 7 days of treatment initiation

 -  International normalized ration (INR) or prothrombin time (PT) activated partial
 thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant
 therapy as long as PT or aPTT is within therapeutic range of intended use of
 anticoagulants performed within 7 days of treatment initiation

 -  FOR ARM B: Have a detectable GT1, GT4, or HCV viral load TD(q) based on the Roche
 COBAS AmpliPrep/COBAS TaqMan HCV Test, version (v)2.0 from a blood sample; HCV RNA
 (10,000 IU/mL in peripheral blood) at the time of screening have documented chronic
 HCV GT1, GT4 (with no evidence of mixed genotype) infection: a. Positive for anti-HCV
 antibody, HCV RNA, or any of the above HCV GTs at least 3 months before screening (HCV
 RNA and HCV GT must be confirmed by screening lab results) OR b. Positive for anti-HCV
 antibody or HCV RNA at the time of screening with a liver biopsy consistent with
 chronic HCV infection (or a liver biopsy performed before enrollment with evidence of
 chronic hepatitis C (CHC) disease, such as the presence of fibrosis) or a Fibroscan
 performed within 12 months of day 1 of this study with a result of > 12.5 kPa or a
 FibroSure (Fibrotest) performed during Screening with a score of > 0.75 and an
 aspartate aminotransferase (AST): platelet ratio index (APRI) of > 2

 -  FOR ARM B: Subjects must undergo at screening HCV GT1a testing for resistance
 polymorphism as per Zepatier labe

 -  FOR ARM B: Have liver disease staging assessment as follows: Cirrhosis is defined as
 any one of the following: a. A liver biopsy performed prior to day 1 of this study
 showing cirrhosis (F4) b. Fibroscan performed within 12 calendar months of day 1 of
 this study showing cirrhosis with result > 12.5 kPa [29] c. A FibroSure (Fibrotest)
 performed during screening with a score of > 0.75 and an AST: platelet ratio index
 (APRI) of > 2; absence of cirrhosis is defined as any one of the following: a. Liver
 biopsy performed within 24 months of day 1 of this study showing absence of cirrhosis
 b. Fibroscan performed within 12 months of Day 1 of this study with a result of =<
 12.5 kPa [29] c. A Fibrosure (Fibrotest) score of 0.48 and AST to Platelet Ratio Index
 (APRI) of =< 1 during Screening Fibroscan cut-off of 12.5 kPa has a positive
 predictive value of 90% and a sensitivity of 95% for >/= F3; based on box and whisker
 plot of interquartile distribution > 12.5 kPa will exclude the majority of subjects
 with metavir F3 fibrosis; in the absence of a definitive diagnosis of presence or
 absence of cirrhosis by the above criteria, a liver biopsy is required; liver biopsy
 results supersede the results obtained by Fibroscan or Fibrosure

 -  Subjecs in Arm B treated with ribavirin (RBV) must agree to double barrier birth
 control from day 1 to 6 months following last dose of study therapy or they are
 excluded from this trial

 Exclusion Criteria:

 -  Is currently participating and receiving study therapy or has participated in a study
 of an investigational agent and received study therapy, herbal/complementary oral or
 IV medicine, or used an investigation device within 4 weeks of the first dose of
 treatment; subjects must also have recovered from associated therapy (i.e., to grade
 =< 1 or baseline) and from adverse events due to any prior therapy

 -  Has had esophageal or gastric variceal bleeding within the last 6 months; all subjects
 will be screened for esophageal varices, unless such screening has been performed in
 the past 12 months before first dose of treatment; if varices are present, they should
 be treated according to institutional standards before starting study treatment

 -  Subjects with ALT > 5 x ULN at day 1 are not eligible for enrollment

 -  Subjects with total bilirubin > 2.0 mg/dL at day 1 are not eligible for enrollment

 -  Subjects with clinically apparent ascites or encephalopathy, or untreated varices are
 not eligible for enrollment

 -  Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac
 involvement of HCC based on imaging

 -  Has had encephalopathy in the last 6 months; subjects on rifaximin or lactulose to
 control their encephalopathy are not allowed

 -  Had a solid organ or hematologic transplant

 -  Had prior systemic therapy for HCC other than sorafenib, or intercurrent local therapy
 to the liver tumor between sorafenib and study drug

 -  Has active autoimmune disease that has required systemic treatment in 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

 -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
 other form of immunosuppressive therapy within 7 days prior to the first dose of trial
 treatment; the use of physiologic doses of corticosteroids may be approved after
 consultation with the sponsor

 -  Has received locoregional therapy to liver (transarterial chemoembolization [TACE],
 transarterial embolization [TAE], radiation, radioembolization, or ablation) or
 surgery to liver or other site within 6 weeks prior to the first dose of study drug;
 minor surgery must have occurred at least 7 days prior to the first dose of study
 treatment (cycle 1, day 1); subjects must have recovered adequately (i.e., grade =< 1
 or baseline) from the toxicity and/or complications from any intervention prior to
 starting therapy

 -  Has a known history of an additional malignancy, except if the participant has
 undergone potentially curative therapy with no evidence of that disease recurrence for
 5 years since initiation of that therapy

 -  Has radiographically detectable (even if asymptomatic and/or previously treated)
 central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by
 local site investigator and radiology review/CIV

 -  Has a history of (non-infectious) pneumonitis that required steroids or there is
 current pneumonitis

 -  Has an active infection requiring systemic therapy

 -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the trial, interfere with the subject's
 participation for the full duration of the trial, or is not in the best interest of
 the subject to participate, in the opinion of the treating investigator, including
 dialysis

 -  Has known psychiatric or substance abuse disorders that would interfere with
 cooperation with the requirements of the trial

 -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
 projected duration of the trial, starting with the screening visit through 120 days
 after the last dose of trial treatment

 -  Has received prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2
 agents, or if the subject has previously participated in Merck pembrolizumab clinical
 trials

 -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

 -  Has untreated active hepatitis B; Note: to qualify for enrollment, antiviral therapy
 for HBV must be given for at least 3 months prior to first dose of study drug, and HBV
 viral load must be less than 100 IU/mL prior to first dose of study drug; those on
 active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy
 throughout study treatment; those subjects who are anti-HBc (+) and negative for
 HBsAg, Anti-HBs, and HBV viral load do not require HBV prophylaxis, but need close
 monitoring for reactivation

 -  Subjects who have received therapy for HCV =< 4 weeks from the start of pembrolizumab;
 Note: those with untreated HCV and those who completed HCV therapy >= 4 weeks of study
 treatment start are eligible

 -  Has dual infection with HBV/HCV or other hepatitis combinations at study entry

 -  Has received a live vaccine within 30 days of planned start of study therapy (cycle 1,
 day 1); Note: the killed virus vaccines used for seasonal influenza vaccines for
 injection are allowed; however intranasal influenza vaccines (e.g., FluMist) are live
 attenuated vaccines and are not allowed

 -  Has received sorafenib within 14 days of first dose of study medication