| Eligibility |
Inclusion Criteria:
1. Histologically confirmed diagnosis of HCC.
2. Have a tumor, not eligible for resection or local ablation.
3. Have experienced disease progression under previous = 4 cycles/12 weeks first line
IO-based therapy.
4. Have a Child-Pugh Classification score = 6 for assessed liver function within 7 days
before allocation (Appendix 4)
5. Have at least one measurable site of disease based on RECIST 1.1 with spiral CT scan
or MRI. Lesions situated in a previously irradiated area are considered measurable if
progression has been demonstrated in such lesions.
6. Male/female* participants who are at least 18 years of age on the day of signing
informed consent will be enrolled in this study.
*There are no data that indicate special gender distribution. Therefore, patients will
be enrolled in the study gender-independently.
7. 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.
8. A male participant must agree to use a contraception as detailed in Appendix 3 of this
protocol during the treatment period and for at least 210 days after the last dose of
study treatment and refrain from donating sperm during this period.
9. The participant provides written informed consent for the trial.
10. Either pre-treatment tumor tissue available
- 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 15 unstained cut slides, newly cut slides should be submitted to
the IKF GmbH lab within 14 days from the date slides are cut.
OR tumor tissue is not available as e.g., patient has never undergone biopsy or tissue
depleted because of prior diagnostic testing
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.
12. Have a life expectancy of = 12 weeks.
13. Have adequate organ function as defined in the following table (Table 2). Specimens
must be collected within 7 days prior to the start of study intervention.
Table 2: Adequate Organ Function Laboratory Values System Laboratory Value
Hematological Absolute neutrophil count (ANC) = 1500/µL Platelets = 75000/µL
Hemoglobin = 8.0 g/dLa Renal Creatinine OR Measured or calculatedb creatinine
clearance (GFR can also be used in place of creatinine or CrCl) = 1.5 × ULN OR
= 40 mL/min for participant with creatinine levels > 1.5 × institutional ULN Hepatic
Total bilirubin = 2 mg/dL OR direct bilirubin = ULN for participants with total
bilirubin levels > 2 mg/dL AST (SGOT) and ALT (SGPT) = 5 × ULN Albumin = 3.0 g/dL
Pancreatic Amylase = 1.5 × ULN Lipase = 1.5 × 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 ALT (SGPT)=alanine
aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration
rate; ULN=upper limit of normal.
a Transfusion are permitted to meet criteria. b Creatinine clearance (CrCl) should be
calculated per institutional standard. Note: This table includes eligibility-defining
laboratory value requirements for treatment; laboratory value requirements should be
adapted according to local regulations and guidelines for the administration of
specific chemotherapies.
14. Participants with past or ongoing HCV infection will be eligible for the study. The
treated participants must have completed their treatment at least 1 month prior to
starting study intervention and HCV viral load must be below the limit of
quantification.
Participants with controlled hepatitis B will be eligible if 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 drug. Participants on active HBV
therapy with viral loads under 100 IU/mL should stay on the same therapy throughout
study intervention.
- Participants who are positive for anti-hepatitis B core antibody HBc, negative for
HBsAg, and negative or positive for anti-hepatitis B surface antibody (HBs), and who
have an HBV viral load under 100 IU/mL, do not require HBV antiviral prophylaxis.
- Has adequately controlled blood pressure with or without antihypertensive medications,
defined as BP = 150/90 mm Hg at Screening and no change in antihypertensive
medications within 1 week before Cycle 1 Day 1.
Exclusion Criteria:
1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
2. Have received prior therapy with any TKI.
3. 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 24 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.
4. Have an ongoing AE (=Grade 2) from prior systemic anti-cancer therapy including
investigational agents or use of an investigational device.
Note: 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 intervention.
5. Have received prior radiotherapy within 2 weeks of start of study intervention.
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-CNS disease.
6. Have received a live vaccine or live-attenuated vaccine within 30 days prior to the
first dose of study drug. Administration of killed vaccines is allowed.
7. Are currently participating in a study of an investigational agent or an
investigational device.
Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as they have recovered from all AEs due to previous therapies
to = Grade 1 or baseline. Participants with = Grade 2 neuropathy may be eligible.
8. Have a diagnosis of immunodeficiency or are 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.
9. Have a known additional malignancy that is progressing or has required active
treatment within the past 2 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.
10. Have 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.
11. Have severe hypersensitivity (= Grade 3) to lenvatinib, pembrolizumab and/or any of
its excipients.
12. Have a history of congestive heart failure NYHA > Class II, unstable angina,
myocardial infarction or stroke within 6 months of the first dose of study treatment,
or cardiac arrhythmia requiring medical treatment at Screening
13. Have bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.
Note: The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid
artery) should be considered because of the potential risk of severe hemorrhage
associated with tumor shrinkage/necrosis following lenvatinib therapy.
14. Have 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 (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment and is allowed.
15. Have a history of (non-infectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease.
16. Have an active infection requiring systemic therapy (exception: HBV infection - see
inclusion criteria).
17. Have a history of Human Immunodeficiency Virus (HIV) (mandatory testing for HIV during
screening is required).
18. Have 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.
19. Have known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
20. Are 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 study treatment.
21. Are unable to swallow orally administered medication or have gastrointestinal
disorders likely to interfere with absorption of the study medication.
22. Legal incapacity or limited legal capacity.
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