E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Objective: To compare progression-free survival (PFS) per RECIST 1.1 assessed by a blinded central imaging vendor. 2. Objective: To compare OS between pembrolizumab plus BSC versus placebo plus BSC.
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E.2.2 | Secondary objectives of the trial |
1. Objective: To compare objective response rate (ORR) per RECIST 1.1 assessed by a blinded central imaging vendor. 2. Objective: To evaluate the duration of response (DOR), disease control rate (DCR) and time to progression (TTP), per RECIST 1.1 assessed by a blinded central imaging vendor. 3. Objective: Evaluate the safety and tolerability profile of pembrolizumab.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
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E.3 | Principal inclusion criteria |
Subjects must: provide informed consent, be > or = 18 years of age, have confirmed diagnosis of HCC, have a life expectancy greater than 3 months, 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, have measurable disease based on RECIST 1.1 as confirmed by central imaging vendor, have ECOG Performance Scale of 0 or 1, have documented objective radiographic progression after stopping treatment with sorafenib or else intolerance to sorafenib, subjects with chronic infection by HCV who are untreated are allowed on study and subjects with successful HCV treatment are allowed as long as 4 weeks have passed between completion of HCV therapy and start of study drug, demonstrate adequate organ function, have negative pregnancy test for females of child bearing potential prior to starting study and male and female subjects of childbearing potential must be willing to use an adequate method of contraception. |
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E.4 | Principal exclusion criteria |
The subject will be excluded from participating in the trial if the subject: 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., has received sorafenib within 14 days of first dose of study medication, has had esophageal or gastric variceal bleeding within the last 6 months, has clinically apparent ascites on physical examination, (ascites detectable on imaging studies only IS allowed), has portal vein invasion of HCC based on imaging, has had encephalopathy in the last 6 months, 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 required treatment in the past two years, 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, has received locoregional therapy to liver or major surgery to liver or other site within 6 weeks prior to the first dose of study drug, has a diagnosed additional malignancy within 5 years prior to first dose of study treatment with some exceptions, has radiographically detectable central nervous system (CNS) metastases and/or carcinomatous meningitis, has a known history of, or evidence of, interstitial lung disease or active non-infectious pneumonitis, has known psychiatric or substance abuse disorders, is pregnant or breastfeeding, has received prior immunotherapy or previously participated in Merck pembrolizumab clinical trials, has untreated active Hepatitis B, 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, with exception for killed virus vaccines used for seasonal influenza vaccines. |
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E.5 End points |
E.5.1 | Primary end point(s) |
PFS per RECIST 1.1 criteria as assessed by the blinded central imaging vendor and OS will be used as the primary endpoints. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim analysis to be performed when at least 231 PFS events and at least 168 OS events (62% of planned OS events) have been observed, estimated to be 16.4 months after study start. If PFS or OS are significant, ORR will be analyzed. Results will be reviewed by an external data monitoring committee.
Final efficacy analysis for OS (assuming not declared futile at the interim analysis); to be performed when at least 270 OS events have been observed, estimated to be 25 months after study start. Results will be reviewed by an external data monitoring committee. |
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E.5.2 | Secondary end point(s) |
1. Compare ORR per RECIST 1.1 assessed by a blinded central imaging vendor. 2. Evaluate DOR, DCR and TTP per RECIST 1.1 assessed by a blinded central imaging vendor.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
During interim analysis, if PFS or OS are significant, ORR will be analyzed. Final efficacy analysis for ORR; to be performed when at least 270 OS events have been observed, estimated to be 25 months after study start. Results will be reviewed by an external data monitoring committee. Analyses of the DCR, TTP, and DOR data will be performed at the time of the interim and final analysis of OS.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
Chile |
Colombia |
Denmark |
France |
Germany |
Hong Kong |
Hungary |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Norway |
Poland |
Puerto Rico |
Russian Federation |
Taiwan |
Thailand |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |