E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adjuvant treatment of HCC |
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E.1.1.1 | Medical condition in easily understood language |
This is a study in early HCC (liver cancer) to evaluate the safety and efficacy of pembrolizumab as adjuvant therapy |
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073071 |
E.1.2 | Term | Hepatocellular carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
1A) To compare Recurrence-Free Survival (RFS) 2) To compare Overall Survival (OS) |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate the safety and tolerability 2) To compare score change from baseline in global quality of life (QoL) using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global health status/QoL scale and EORTC QLQ-HCC18 3) To characterize health utilities using the EuroQoL-5 Dimension Questionnaire, 5-Level (EQ-5D-5L) health utility scores |
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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) 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 |
1. Has a diagnosis of HCC documented radiologically by AASLD criteria (participants undergoing ablation without a prior biopsy) and/or pathologically (participants undergoing ablation and not meeting AASLD criteria, and participants undergoing surgical resection); fibrolamellar,sarcomatoid and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible and:A. Has a complete radiological response after surgical resection (R0resection) and an intermediate risk (Stage I), high risk (Stage II, IIIA) or very high risk of recurrence (subtypes of Stage IIIB as described below) as per American Joint Committee on Cancer (AJCC) 8th edition with adaptations based on tumor characteristics as established by the pathology report - Intermediate risk of recurrence: solitary tumor ≥2 cm without microvascular invasion and not histologic grade 3 or 4 - High risk of recurrence: solitary tumor ≥2 with microvascular invasio same size and histologic grade 3 or 4, or multiple tumors regardless of microvascular invasion or histologic grade - Very high risk of recurrence: single tumor or multiple tumors of any size with macrovascular invasion. Stage IIIB tumor(s) with direct invasion of adjacent organs or with perforation of visceral peritoneum will not be eligible OR B. Has a complete adiological response after local ablation (only radiofrequency or microwave ablation are allowed) and intermediate, high risk of recurrence or very high-risk group - Intermediate risk of recurrence: Solitary tumor ≥2 cm and ≤3 cm - High risk of recurrence: 2-4 tumors, with all ≤3 cm or one solitary tumor >3 cm and ≤5 cm. - Very high-risk group: 2-4 tumors with at least one >3 cm and all ≤5 cm. 2. No more than 12 weeks must have elapsed between the date of the staging and the date of surgical resection or local ablation. 3. Has an eligibility scan (CT of the chest, triphasic CT scan or MRI of the abdomen, and CT or MRI of the pelvis) confirming complete radiological response ≥4 weeks after complete surgical resection or local ablation. Randomization needs to occur within 12 weeks of the date of surgical resection or local ablation 4. Has no radiologic evidence of disease prior to enrollment as per investigator assessment 5. Has an ECOG performance status of 0 or 1 within 7 days prior to C1D1 6. Has a Child-Pugh class A liver score (5 to 6 points) within 7 days prior to C1D1 7. Has AFP concentration lower than 400 ng/mL within 28 days prior to C1D1 (if there are several AFP values available within 28 days prior to C1D1, the closest AFP value to C1D1 should be below 400 ng/mL) 8. Has AFP concentration at initial diagnosis prior to resection or ablation available 9. Participant may have a past or ongoing HCV infection. Participants must have completed their treatment at least 1 month prior to C1D1 or have received at least 1 month of DAA HCV therapy with no DAA-related safety events and stable LFTs. For participants not on anti HCV therapy at the time of randomization, DAAs for treatment of HCV infection can be initiated per Investigator's discretion, if LFTs are stable after 3-6 months of study intervention upon sponsor consultation. 10. Participant may have controlled hepatitis B, as long as they meet the following criteria: - Antiviral therapy for HBV must be given for at least 4 weeks and HBV viral load must be less than 500 IU/mL prior to first dose of study intervention. Participants on active HBV therapy with viral loads under 500 IU/mL should stay on the same therapy throughout study intervention - However, participants who are anti-HBc (+), negative for HbsAg, and negative or positive for anti-HBs, and who have an HBV viral load under 500 IU/mL, do not require HBV anti-viral prophylaxis 11. Has recovered adequately from toxicity and/or complications from the local intervention (surgical resection or local ablation) prior to starting study intervention 12. Is male or female, at least 18 years of age at the time of signing the informed consent 13. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 14. Participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the study and agrees to RFS, DMFS, TTR and OS data collection until the study endpoints arereached. The participant may also provide consent/assent for future biomedical research; however, the participant may participate in the main study without participating in future biomedical research 15. All participants who undergo surgical resection will be required to submit a tumor tissue sample during Screening. Participants who undergo local ablation are encouraged to submit a tumor tissue sample during Screening if available. All participants are encouraged to submit surrounding non-tumor tissue during Screening if available 16. Has adequate organ function |
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E.4 | Principal exclusion criteria |
1. Has a known additional malignancy that is progressing or has required active antineoplastic treatment (including hormonal) or surgery within the past 3 years 2. Has had esophageal or gastric variceal bleeding within the last 6 months. All cirrhotic participants will be screened for esophageal varices with an upper endoscopy, unless such assessment has been performed in the past 12 months before C1D1. If varices are present,they should be treated according to institutional standards before starting study intervention 3. Has clinically apparent ascites on physical examination 4. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their hepatic encephalopathy regardless of when the diagnosis of hepatic encephalopathy occurred are not eligible 5. Has received local therapy to liver ablation other than with radiofrequency or microwave ablation (ie alcohol ablation, transcatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], local radiation/Stereotactic Body Radiation Therapy [SBRT] or radioembolization) 6. Has a history of (noninfectious) pneumonitis/interstitial lung that required steroids or has current pneumonitis/interstitial lung 7. Has an active infection requiring systemic therapy 8. Has dual active HBV infection (HbsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry 9. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority 10. Has a known active tuberculosis (TB; Bacillus tuberculosis) 11. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137) 12. Has received prior systemic anti-cancer therapy for HCC including investigational agents 13. Is receiving any of the following prohibited concomitant therapies: - Antineoplastic systemic chemotherapy or biological therapy - Immunotherapy not specified in this protocol - Investigational agents other than pembrolizumab - Received prior radiotherapy within 2 weeks of start of study intervention - Oncological surgical therapy - Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE that is suspected to have an immunologic etiology. Inhaled or topical steroids are allowed, and systemic steroids at doses ≤10 mg/day prednisone or equivalent are allowed. Exception: steroids may be used for premedication prior to imaging 14. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®, [Influenza Vaccine Live, AstraZeneca]) are live attenuated vaccines and are not allowed 15. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to C1D1 16. 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 C1D1 17. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients 18. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs) 19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator 20. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study 21. Has had an allogenic tissue/solid organ transplant |
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Recurrence-Free Survival (RFS) 2.Overall Survival (OS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.Up to ~4 years 2.Up to ~6 years |
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E.5.2 | Secondary end point(s) |
1.Percentage of participants who experience an adverse event (AE) 2.Percentage of participants who discontinue study treatment due to an AE 3.Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Overall Scores and Subscale Scores 4.Change from Baseline in EORTC QLQ-Hepatocellular Carcinoma Module (EORTC QLQ-HCC18) Scale Score 5.Change from Baseline in European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) Health Utility Score
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.Up to ~6 years 2.Up to ~1 year 3.Baseline, time of last patient reported outcome (PRO) assessment (up to ~7 years) 4.Baseline, time of last PRO assessment (up to ~7 years) 5.Baseline, time of last PRO assessment (up to ~7 years)
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | Yes |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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 |
Brazil |
Canada |
China |
Colombia |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Malaysia |
New Zealand |
Peru |
Taiwan |
Thailand |
United States |
Switzerland |
Russian Federation |
Turkey |
Ukraine |
Belgium |
Bulgaria |
Czechia |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
United Kingdom |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |
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 |