| Eligibility |
Inclusion Criteria:
1. Histologically confirmed diagnosis of HCC
2. Has a Child-Pugh Classification score = 6 for assessed liver function within 7 days
before allocation (Appendix 4: Child-Pugh Score)
3. Candidate for local ablation (via either RFA or MWA or brachytherapy or combination of
TACE with RFA, MWA or brachytherapy [ablation technique according to Investigator's
choice]), i.e.:
According to Investigator's assessment an R0 state can be obtained after a maximum of
two RFA/MWA interventions (initial ablation + one additional re-ablation at maximum).
4. Patients (including high risk patients) with: :
- Presence of = 5 tumor nodules with diameters = 7cm [longest axis] each OR
- Vascular infiltration
5. Has received no prior systemic therapy for HCC NOTE: Patients who have received prior
local therapy by transarterial chemoembolization (TACE) are not excluded if TACE has
been performed >8 weeks before study allocation.
6. Have measurable disease based on RECIST 1.1. Lesions situated in a previously treated
(e.g. irradiated or subject to TACE) area are considered measurable if vital tumor has
been demonstrated by contrast enhanced imaging in such lesions*.
7. Male/female participants who are at least 18 years of age on the day of signing
informed consent will be enrolled in this study.
8. A female participant is eligible to participate if she is not pregnant (see Appendix
3), not breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the
treatment period and for at least 120 days after the last dose of study
treatment.
A male participant with female partner of childbearing potential is eligible to
participate if he agrees to follow the contraceptive guidance in Appendix 3 during the
treatment period and for at least 120 days after the last dose of study treatment.
9. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
10. Have provided archival tumor tissue sample or newly obtained biopsy of a tumor lesion
not previously irradiated for mandatory pre-treatment evaluation (baseline).
- Newly obtained biopsies are preferred to archived tissue (archived specimen =6
months may be acceptable).
- Core or excisional biopsies mandatory (fine needle aspiration and bone metastasis
samples are not acceptable).
- Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
- If submitting unstained cut slides, newly cut slides should be submitted to the
central pathology lab within 14 days from the date slides are cut.
- Availability of baseline tumor biopsy samples has to be ensured by site before
first dose of study medication is administered.
- Specimens have to be sent to central pathology lab for accompanying research
project.
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the date of
allocation/randomization.
12. Have adequate organ function as defined in the following table. Specimens must be
collected within 7 days prior to the start of study treatment.
Adequate Organ Function Laboratory Values
Hematological
- Absolute neutrophil count (ANC) =1500/µL
- Platelets =100 000/µL
- Hemoglobin =9.0 g/dL or =5.6 mmol/L(a)
Renal
- Creatinine OR =1.5 × Upper Limit of Normal (ULN) OR Measured or calculated(b)
creatinine clearance (GFR can also be used in place of creatinine or CrCl) =30 mL/min
for participant with creatinine levels >1.5 × institutional ULN
Hepatic
- Total bilirubin =2.5 ×ULN OR direct bilirubin =ULN for participants with total
bilirubin levels >2.5 × ULN
- aspartate aminotransferase [AST (SGOT)] and alanine aminotransferase [ALT (SGPT)]
=5 × ULN
Coagulation
- International normalized ratio (INR) OR prothrombin time (PT) Activated partial
thromboplastin time (aPTT) =1.5 × ULN unless participant is receiving anticoagulant
therapy as long as PT or aPTT is within therapeutic range of intended use of
anticoagulants
13. If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
infection, meets the following criteria:
- Patients with HBV or HCV infection should be monitored for viral levels during
study participation.
- Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV
DNA should be managed per local treatment guidelines. Controlled (treated)
hepatitis B subjects will be allowed if they started treatment at the time point
of enrollment into the study by the latest and treatment is continued during
study participation.
- Patients with detectable HCV RNA are usually not treated for their HCV infection.
However, patients treated for HCV are considered suitable for inclusion if
antiviral therapy has been completed prior to first administration of study drug.
Exclusion Criteria:
1. Extrahepatic disease
2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
3. Presence of tumor thrombus involving main trunk of portal vein
4. Has at Screening and/or has had any prior history of Grade = 2 hepatic encephalopathy
5. Has at Screening pericardial effusion, uncontrollable pleural effusion, or clinically
significant ascites defined as meeting either of (a) detectable ascites on Screening
physical examination OR (b) has at Screening ascites requiring paracentesis
6. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation
(see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
Note: in the event that 72 hours have elapsed between the screening pregnancy test and
the first dose of study treatment, another pregnancy test (urine or serum) must be
performed and must be negative in order for subject to start receiving study
medication.
7. Has received prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1),
anti-Programmed death-ligand 1 (anti-PD-L1), or anti PD L2 agent or with an agent
directed to another stimulatory or co-inhibitory T-cell receptor (eg, Cytotoxic
T-lymphocyte-associated antigen 4 (CTLA-4), OX 40, CD137).
8. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks or at least 5 half-lives of the respective drug/IMP (whichever is
longer) prior to allocation.
Note: Participants must have recovered from all AEs due to previous therapies to
=Grade 1 or baseline. Participants with =Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting study
treatment.
9. Has received prior radiotherapy within 4 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (=2 weeks of radiotherapy) to non-central nervous system
(CNS) disease.
10. Has received a live vaccine within 4 weeks or for a period of at least 5 half-lives of
the respective drug/IMP (whichever is longer) before Screening and during Screening
for this trial prior to the first dose of study drug. 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 (e.g. FluMist®)
are live attenuated vaccines and are not allowed.
11. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks or for a period of at least
5 half-lives of the respective drug/IMP (whichever is longer) before Screening and
during Screening for this trial.
Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks or at least 5 half-lives of the
respective drug/IMP (whichever is longer) after the last dose of the previous
investigational agent.
12. 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 the first dose of study drug.
13. Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
excluded.
14. Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment.
15. Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients.
16. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
17. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
18. Has an active infection requiring systemic therapy (exception: HBV infection - see
inclusion criteria).
19. Has a history of Human Immunodeficiency Virus (HIV) (mandatory testing for HIV during
screening is required).
20. Has a known history of active tuberculosis(Bacillus Tuberculosis).
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating Investigator.
22. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
23. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
24. Legal incapacity or limited legal capacity.
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