Overview

This is a multicentre randomised 3-arm phase II clinical trial in patients with resectable Hepatocellular Carcinoma (HCC). Sixty patients will be randomized 1:1:1 to 6 weeks of pre-operative therapy with: pembrolizumab, lenvatinib or the combination of pembrolizumab and lenvatinib followed by up to 12 months treatment with post-operative pembrolizumab. The aim of the study is to compare the efficacy of pembrolizumab combined with lenvatinib with that of pembrolizumab and lenvatinib alone in terms of major pathological response in patients with resectable HCC. Major pathological response will be defined by the proportion of patients with less than 10% viable tumour at resection.

Eligibility

Inclusion Criteria:

1. Have a diagnosis of Hepatocellular Carcinoma (HCC) confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible). Radiological confirmation of diagnosis is provided by the study site and defined by the presence of a liver mass of at least 1 cm and exhibiting arterial hypervascularity with washout in the portal venous phase seen in a tri-phasic magnetic resonance imaging (MRI).
2. At least one measurable disease based on RECIST 1.1.
3. Low risk of surgical morbidity and mortality from liver surgery as defined by the following criteria:
   • Single tumour
   • No requirement for vascular resection
   • Expected residual liver volume 40%
   • Minor (up to 3 segments) or major resection (up to 5 segments)

             If non-cirrhotic based on history, imaging, liver function +/- uninvolved liver
             biopsy):
             • Single tumour any size
             If cirrhotic
               -  Single tumour ≤ 5cm
               -  Major resection (up to 5 segments) only with good liver function as defined
                  locally by:
                    -  Normal Bilirubin and
                    -  No varices on pre-operative computerised tomography (CT)
                    -  Wedge pressure < 10mmHg or
                    -  Biopsy of uninvolved liver showing mild cirrhosis (Ashak grading)
          4. Child-Pugh A liver disease
          5. International normalised ratio (INR) ≤1.4
          6. ECOG Performance status 0 or 1
          7. Adequate haematological function as defined by:
               -  Haemoglobin (Hb) > 90g/l
               -  Neutrophil Count > 1.5 x 109/l
               -  Platelets > 75 x 109/l
          8. Adequate renal function with GFR >40ml/min using a validated creatinine clearance
             calculation (e.g. Cockcroft-Gault or Wright formula)
          9. Adequate liver function as defined by:
               -  Aminotransferase (ALT) or aspartate aminotransferase (AST) < 5.0 x ULN
               -  Albumin >32g/l
               -  Amylase and lipase ≤ 1.5 x ULN
         10. Patients with past or ongoing hepatitis C virus (HCV) infection will be eligible for
             the study. The treated patients must have completed their treatment at least 1 month
             prior to starting
         11. Patients with controlled hepatitis B will be eligible as long as they meet the
             following criteria:
               -  Antiviral therapy for hepatitis B virus (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 drug.
                  Patients on active HBV therapy with viral loads under 500 IU/mL should stay on
                  the same therapy throughout study treatment.
               -  Patients who are positive for anti-hepatitis B core antibody (HBc), negative for
                  hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis
                  B surface antibody (HBs), and who have an HBV viral load under 500 IU/mL, do not
                  require HBV anti-viral prophylaxis
         12. 18 years of age or over
         13. Predicted life expectancy of > 3 months
         14. Patients must have given written informed consent
         15. Patients must have the ability to swallow oral medication
        Exclusion Criteria:
          1. Has received any systemic chemotherapy, including anti-VEGF therapy, or any systemic
             investigational anticancer agents for advanced/unresectable HCC.
          2. Has received local therapy including trans arterial embolic, chemo- or radiotherapy,
             external beam radiotherapy or ablative therapy to the measurable lesion to be
             resected.
          3. 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 (e.g.,
             CTLA-4, OX-40, or CD137).
          4. Oesophageal or gastric variceal bleeding within the last 6 months.
          5. Has received a live vaccine within 30 days prior to registration (seasonal flu
             vaccines that do not contain live virus are permitted). Administration of killed
             vaccines is allowed.
          6. Active autoimmune disease that has required systemic treatment (i.e., with use of
             disease-modifying agents, corticosteroids or immunosuppressive drugs) in past 2 years
             except
               -  Vitiligo
               -  Psoriasis
               -  Autoimmune-related hyperthyroidism
               -  Autoimmune-related hypothyroidism who are in remission or on a stable dose of
                  thyroid-replacement hormone replacement therapy (e.g., thyroxine, insulin, or
                  physiologic corticosteroid replacement therapy for adrenal or pituitary
                  insufficiency) is not considered a form of systemic treatment and is allowed.
          7. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
             steroids or has current pneumonitis/interstitial lung disease.
          8. A diagnosis of immunodeficiency or is receiving systemic steroid therapy (>10mg daily
             prednisolone equivalent) or any other form of immunosuppressive therapy within 7 days
             prior to treatment.
          9. Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years. Note: Patients 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.
         10. Has clinically apparent ascites on physical examination that is not controlled with
             medication. Note: ascites detectable on imaging studies only are allowed.
         11. Uncontrolled blood pressure (Systolic BP)>150 mmHg or diastolic BP >90 mmHg) in spite
             of an optimised regimen of anti-hypertensive medication.
         12. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Patients on
             rifaximin or lactulose to control their hepatic encephalopathy are not allowed.
         13. Has medical contraindications that preclude all forms of contrast enhanced imaging
             (tri-phasic CT or MRI).
         14. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition
             that might affect the absorption of lenvatinib.
         15. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
         16. Clinically significant haemoptysis from any source or tumour bleeding within 2 weeks
             prior to start of treatment.
         17. Electrolyte abnormalities that have not been corrected.
         18. Significant cardiovascular impairment within 12 months of start of treatment such as
             history of congestive heart failure greater than New York Heart Association (NYHA)
             Class II, unstable angina, myocardial infarction or stroke within 6 months of start of
             treatment, or cardiac arrhythmia requiring medical treatment at screening.
         19. Prolongation of QTc interval to > 480 ms.
         20. Left ventricular ejection fraction (LVEF) below the institutional normal range as
             determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).
         21. Patients who are at risk for severe haemorrhage, bleeding or thrombotic disorders, or
             are receiving factor X inhibitors or anticoagulants that require therapeutic INR
             monitoring e.g. warfarin or similar agents. The degree of tumour invasion/infiltration
             of major blood vessels should be considered because of the potential risk of severe
             haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy.
         22. Patients having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine
             collection for quantitative assessment indicates that the urine protein is <1 g/24
             hours.
         23. Patients who have not recovered adequately from any toxicity from other anti- cancer
             treatment regimens and/or complications from major surgery prior to starting therapy.
         24. Has had major surgery to the liver prior to start of treatment. Note: If patient
             received any major surgery, they must have recovered adequately from the toxicity
             and/or complications from the intervention prior to starting study treatment.
         25. Has had a minor surgery (i.e., simple excision) within 7 days prior to start of
             treatment (Cycle 1 Day 1).
         26. Has a serious non-healing wound, ulcer, or bone fracture.
         27. History of human immunodeficiency virus (HIV) infection.
         28. Has an active infection requiring systemic therapy, with the exception of HBV, HCV.
         29. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or lenvatinib and/or any of
             their excipients.
         30. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection
             (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
         31. Has dual active HBV infection and hepatitis D virus (HDV) at the study entry.
         32. Has a known history of active tuberculosis (Bacillus tuberculosis).
         33. Has a known psychiatric or substance abuse disorder that would interfere with the
             patient's ability to cooperate with the requirements of the study.
         34. 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 the first dose of
             study intervention. Note: Patients who have entered the follow-up phase of an
             investigational study may participate as long as it has been 4 weeks after the last
             dose of the previous investigational agent.
         35. Has had an allogenic tissue/solid organ transplant.
         36. Women who are pregnant or breast feeding.
         37. Must be willing to use effective contraception during study and for 120 days after the
             last dose.
         38. 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.