Pembrolizumab (MK-3475) in Hepatocellular Carcinoma

NCT02940496 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2016-0251NCI-2016-01983
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a Phase II study investigating single agent pembrolizumab (Keytruda®) as a second-line therapy for subjects with hepatocellular carcinoma (HCC) who either progressed on or after sorafenib or did not tolerate sorafenib.

Conditions

BCLC Stage B Hepatocellular Carcinoma; BCLC Stage C Hepatocellular Carcinoma; Hepatitis C Infection; Refractory Liver Carcinoma; Stage III Hepatocellular Carcinoma AJCC v7; Stage IIIA Hepatocellular Carcinoma AJCC v7; Stage IIIB Hepatocellular Carcinoma AJCC v7; Stage IIIC Hepatocellular Carcinoma AJCC v7; Stage IV Hepatocellular Carcinoma AJCC v7; Stage IVA Hepatocellular Carcinoma AJCC v7; Stage IVB Hepatocellular Carcinoma AJCC v7

Outcome Measures

Primary Outcomes (3)

• Correlation of HCC Stiffness to Overall Survival

  HCC stiffness was measured using magnetic resonance elastography (MRE) in kilopascals (kPa) and the change was compared with overall survival (OS). Analysis was performed using descriptive statistics and Spearman correlation (R); p-value \< 0.05 was considered statistically significant.

  up to 2 years

• Correlation of HCC Stiffness to Time To Disease Progression (TTP)

  HCC stiffness was measured using magnetic resonance elastography (MRE) in kilopascals (kPa) and the change was compared with time to disease progression (TTP). Analysis was performed using descriptive statistics and Spearman correlation (R); p-value \< 0.05 was considered statistically significant.

  up to 2 years

• Correlation of HCC Stiffness to the Number of Intratumoral CD3+ T Lymphocytes.

  HCC stiffness was measured using magnetic resonance elastography (MRE) in kilopascals (kPa) prior to treatment. Intratumoral CD3+ T lymphocytes count was also obtained through a biopsy prior to treatment and correlation was made between HCC stiffness and CD3+ T Lymphocyte count and the analysis was performed using descriptive statistics and Spearman correlation (R); p-value \< 0.05 was considered statistically significant.

  assessed prior to treatment at baseline

Study Arms (2)

Arm A (pembrolizumab)

EXPERIMENTAL

Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab

Arm B (pembrolizumab, elbasvir/grazoprevir, ribavirin)

EXPERIMENTAL

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

Drug: Elbasvir/Grazoprevir; Biological: Pembrolizumab; Drug: Ribavirin

Interventions

Elbasvir/Grazoprevir DRUG

Given PO

Also known as: Zepatier (BR); Elbasvir-Grazoprevir (SY); Grazoprevir/Elbasvir (SY); Grazoprevir-Elbasvir (SY); MK-8742/ MK-5172 (CN)

Arm B (pembrolizumab, elbasvir/grazoprevir, ribavirin)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm A (pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Arm A (pembrolizumab); Arm B (pembrolizumab, elbasvir/grazoprevir, ribavirin)

Ribavirin DRUG

Given PO

Also known as: 1-.beta.-D-Ribofuranosyl-1H-1,2, 4-triazole-3-carboxamide, Copegus, ICN 1229, ICN-1229, Rebetol, RIBA, RTCA, Viramide, Virazid, Virazole

Arm B (pembrolizumab, elbasvir/grazoprevir, ribavirin)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• M D Anderson Cancer Center

MeSH Terms

Conditions

Hepatitis C; Carcinoma, Hepatocellular

Interventions

elbasvir-grazoprevir drug combination; grazoprevir; elbasvir; pembrolizumab; Ribavirin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site

Intervention Hierarchy (Ancestors)

Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Ahmed Kaseb, MD
• Organization: MD Anderson Cancer Center

akaseb@mdanderson.org

(713) 792-2828

Study Officials

• Ahmed O Kaseb, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2016
• First Posted: October 21, 2016
• Study Start: December 9, 2016
• Primary Completion: August 9, 2023
• Study Completion: August 9, 2023
• Last Updated: July 15, 2025
• Results First Posted: July 15, 2025

Record last verified: 2025-07

Locations

US (1)