Pembrolizumab (MK-3475) in Hepatocellular Carcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02940496
Recruitment Status : Active, not recruiting
First Posted : October 21, 2016
Last Update Posted : August 13, 2018
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn about the safety and tolerability of pembrolizumab when given to patients with advanced liver cancer.

This is an investigational study. Pembrolizumab is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work.

Up to 15 participants will be enrolled in this study. All will take part at MD Anderson.

Condition or disease Intervention/treatment Phase
Malignant Neoplasms of Digestive Organs Advanced Liver Cancer Drug: Pembrolizumab Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Pembrolizumab (MK-3475) in Subjects With Advanced Hepatocellular Carcinoma Who Progressed on or Were Intolerant to First-Line Systemic Therapy
Actual Study Start Date : December 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Pembrolizumab

Participants receive Pembrolizumab by vein over about 30 minutes on Day 1 of each 21-day cycle.

Participants may receive Pembrolizumab for up to 35 cycles (about 2 years).

Drug: Pembrolizumab
200 mg by vein every 3 weeks.
Other Names:
  • Keytruda
  • MK-3475
  • SCH-900475

Primary Outcome Measures :
  1. Predictive Biomarkers of Pembrolizumab as Second-Line After Sorafenib Systemic Monotherapy in Participants with Advanced Hepatocellular Carcinoma [ Time Frame: 9 weeks ]
    Analysis method based on binomial distribution (Clopper-Pearson method).

Secondary Outcome Measures :
  1. Objective Response Rate (ORR) of Pembrolizumab as Second-Line After Sorafenib Systemic Monotherapy in Participants with Advanced Hepatocellular Carcinoma [ Time Frame: 2 years ]
    ORR defined as the proportion of subjects who have a complete response (CR) or partial response (PR) using RECIST 1.1 and with confirmatory assessment as required per irRECIST at any time during the trial.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Male/female subjects with advanced HCC with no curative option will be enrolled in this trial.
  2. Be willing and able to provide written informed consent for the trial.
  3. Be =/>18 years of age on day of signing informed consent.
  4. Have histologically or cytologically documented 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. For subjects without cirrhosis histological confirmation is mandatory.
  5. 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.
  6. Have a Child-Pugh A liver score within 7 days of first dose of study drug.
  7. Have a predicted life expectancy of greater than 3 months.
  8. 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.
  9. 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.
  10. Have documented objective radiographic progression after stopping treatment with sorafenib or else intolerance to sorafenib. Intolerance to sorafenib is defined as: 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.
  11. Subjects with chronic infection by HCV who are treated or untreated are allowed on study. Subjects with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and negative HBV DNA test at screening, are eligible for the study. In addition, subjects with successful treatment (defined as sustained virologic response [SVR12] or SVR24) are allowed as long as 4 weeks have passed between completion of HCV therapy and start of study drug.
  12. 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.
  13. Be willing to use an adequate method of contraception for the course of the study through 120 days 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
  14. (Continuation of inclusion criteria #13) 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 ERCs/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.
  15. Demonstrate adequate organ function. All screening laboratory tests should be performed within 7 days of treatment initiation: a) Hematological - Absolute neutrophil count =/>1200/µL; Platelets =/> 60,000/µL; Hemoglobin =/> 8 g/dL without transfusion or EPO dependency within 7 days; b) Renal - Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or creatinine clearance) =/<1.5 × ULN OR =/>60 mL/min for subject with creatinine levels >1.5 × institutional ULN. Note: Creatinine clearance should be calculated per institutional standard; c) Hepatic - Total bilirubin =/<2 mg/dL, or direct bilirubin =/<ULN for those with total bilirubin >2×ULN; AST (SGOT) and ALT (SGPT) =/<5 × ULN ; Albumin =/>3 g/dL; d) Coagulation - INR or PT aPTT =/<1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Subjects with ALT >5x ULN at Day 1 are not eligible for enrollment.
  4. Subjects with Total Bilirubin >2.0 mg/dL at Day 1 are not eligible for enrollment
  5. Subjects with clinically apparent ascites or encephalopathy, or untreated varices are not eligible for enrollment
  6. Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging.
  7. Has had encephalopathy in the last 6 months. Subjects on rifaximin or lactulose to control their encephalopathy are not allowed.
  8. Had a solid organ or hematologic transplant.
  9. Had prior systemic therapy for HCC other than sorafenib, or intercurrent local therapy to the liver tumor between sorafenib and study drug.
  10. 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.
  11. 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.
  12. Has received locoregional therapy to liver (TACE, 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.
  13. Has a diagnosed additional malignancy within 3 years prior to first dose of study treatment with the exception of any curatively treated in-situ cancer.
  14. 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.
  15. Has a history of (non-infectious) pneumonitis that required steroids or there is current pneumonitis.
  16. Has an active infection requiring systemic therapy.
  17. 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.
  18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  19. 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.
  20. 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.
  21. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  22. 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.
  23. Subjects who have received therapy for HCV ≤ 4weeks from the start of pembrolizumab. Note: Those with untreated HCV and those who completed HCV therapy ≥4 weeks of study treatment start are eligible.
  24. Has dual infection with HBV/HCV or other hepatitis combinations at study entry.
  25. 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.
  26. Has received sorafenib within 14 days of first dose of study medication

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02940496

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Merck Sharp & Dohme Corp.
Principal Investigator: Ahmed Kaseb, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT02940496     History of Changes
Other Study ID Numbers: 2016-0251
NCI-2016-01935 ( Registry Identifier: NCI CTRP )
First Posted: October 21, 2016    Key Record Dates
Last Update Posted: August 13, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Malignant neoplasms of digestive organs
Advanced liver cancer
Advanced hepatocellular carcinoma

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Antineoplastic Agents