| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced stage hepatocellular carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced hepatocellular carcinoma |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073069 |
| E.1.2 | Term | Hepatic cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective of this study is to assess the efficacy by Objective response rate (ORR) according to RECIST 1.1 criteria of the combined treatment with pembrolizumab and lenvatinib |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives of this study are to assess the efficacy by progression free survival and by overall survival as well as to assess safety and toxicity of the combined treatment with pembrolizumab and lenvatinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
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, not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP)
OR
b.) A WOCBP who agrees to follow the contraceptive guidance 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 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 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 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.
|
|
| E.4 | Principal 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. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
4. Have an ongoing AE (≥Grade 2) from prior systemic anti-cancer therapy including investigational agents or use of an investigational device.
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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) – percentage of patients with complete response (CR) or partial response (PR) according to RECIST 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Progression free survival (PFS)
Overall survival (OS)
Safety and Toxcitiy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Database closure is defined as the end of the trial: Sites need to collect survival data of patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additonal monitoring visits may be neccessary). Therefore, database closure is considered the end of the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 36 |
| E.8.9.1 | In the Member State concerned days | |
Print
