Phase II Open-Label Study of Pembrolizumab and Lenvatinib in Advanced Hepatocellular Carcinoma Refractory to Atezolizumab and Bevacizumab Therapy
- Trial ID
- 2024-515731-29-00
- Protocol
- SOLARIS
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of the combined treatment with pembrolizumab and lenvatinib in patients with advanced stage hepatocellular carcinoma who are refractory to atezolizumab and bevacizumab/IO-based therapy. This will be assessed by the Objective Response Rate (ORR) according to RECIST 1.1 criteria. The clinical relevance of this objective lies in determining the potential of this combination therapy to provide a measurable response in a patient population with limited treatment options.
Secondary objectives include assessing the efficacy of the treatment by progression-free survival and overall survival. Additionally, the study aims to evaluate the safety and toxicity of the combined treatment regimen. These secondary objectives are crucial for understanding the broader impact of the therapy on patient outcomes and its safety profile.
Participants
The clinical trial involves participants diagnosed with **advanced stage hepatocellular carcinoma**. The study population includes both male and female subjects, aged 18 years and older, with no specific gender distribution indicated. Participants are required to have a histologically confirmed diagnosis of hepatocellular carcinoma and must have at least one measurable site of disease. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and a life expectancy of at least 12 weeks. Adequate organ function is a prerequisite, and participants with controlled hepatitis B or past hepatitis C infection are eligible under certain conditions. The trial population was selected based on these criteria, and participants must provide written informed consent. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, but specific details regarding this aspect are not provided.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combined treatment regimen involving **pembrolizumab** and **lenvatinib** in patients with advanced stage hepatocellular carcinoma who have shown resistance to prior immunotherapy. This is a phase II, open-label study, with the primary objective being the assessment of the objective response rate (ORR) according to RECIST 1.1 criteria. The trial is expected to run from March 2022 to April 2025, with a maximum treatment period of 24 months for each participant. The study employs a non-randomized, open-label design, allowing for direct observation of treatment effects without the use of a placebo or control group.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis of hepatocellular carcinoma, measurable disease, and adequate organ function. Following the screening, participants will receive treatment with **pembrolizumab** via intravenous infusion and **lenvatinib** orally. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse effects. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is up to 24 months, contingent upon individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The study aims to provide valuable insights into the potential benefits of this combination therapy for patients with limited treatment options due to resistance to previous therapies.
Treatment
The clinical trial involves the administration of **pembrolizumab**, marketed under the name KEYTRUDA, which is provided as a 25 mg/mL **concentrate for solution for infusion**. This pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose of pembrolizumab is 200 mg, with a total maximum dose of 7000 mg over the course of the treatment period. The treatment is administered over a maximum period of 24 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The product is manufactured by Merck Sharp & Dohme B.V. and is authorized for use in the European Union under the marketing authorization number EU/1/15/1024/002.
In addition to pembrolizumab, the trial also includes the administration of **lenvatinib**, marketed as LENVIMA, which is provided in the form of 4 mg **hard capsules**. Lenvatinib is administered **orally** with a maximum daily dose of 12 mg and a total maximum dose of 420 mg over the treatment period. Similar to pembrolizumab, the treatment duration for lenvatinib is also capped at 24 months. Lenvatinib is a chemically synthesized compound, classified under the ATC code L01EX08. The product is manufactured by Eisai GmbH and holds the marketing authorization number EU/1/15/1002/001 in the European Union.
Both pembrolizumab and lenvatinib are utilized in this study to evaluate their combined efficacy in patients with advanced stage hepatocellular carcinoma who are refractory to atezolizumab and bevacizumab or other IO-based therapies. The study aims to assess the objective response rate according to RECIST 1.1 criteria. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen.
Efficacy
The efficacy of the clinical trial will be assessed primarily by evaluating the **Objective Response Rate (ORR)**, which is defined as the percentage of patients achieving a complete response (CR) or partial response (PR) according to RECIST 1.1 criteria. This assessment will be conducted in patients with advanced stage hepatocellular carcinoma who are refractory to atezolizumab and bevacizumab/IO-based therapy. The ORR will be determined through imaging techniques such as spiral CT scans or MRI to measure the size of the tumors.
Secondary endpoints for efficacy assessment include **Progression-Free Survival (PFS)** and **Overall Survival (OS)**. These parameters will provide additional insights into the duration of time patients remain free from disease progression and the overall survival time from the start of the treatment. Safety and toxicity will also be monitored as part of the secondary endpoints to ensure the treatment's safety profile is acceptable.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically confirmed diagnosis of HCC.
- Either pre-treatment tumor tissue available • Newly obtained biopsies are preferred to archived tissue. • 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
- 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.
- Have a life expectancy of ≥ 12 weeks.
- 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.
- 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.
- Have a tumor, not eligible for resection or local ablation.
- Have experienced disease progression under previous ≥ 4 cycles/12 weeks first line IO-based therapy.
- Have a Child-Pugh Classification score ≤ 6 for assessed liver function within 7 days before allocation (Appendix 4)
- 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.
- 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
- 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: a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b.) 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.
- 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.
- The participant provides written informed consent for the trial.
Exclusion Criteria
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
- 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.
- Have severe hypersensitivity (≥ Grade 3) to lenvatinib, pembrolizumab and/or any of its excipients.
- 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
- 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.
- 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.
- Have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Have an active infection requiring systemic therapy (exception: HBV infection – see inclusion criteria).
- Have a history of Human Immunodeficiency Virus (HIV) (mandatory testing for HIV during screening is required).
- 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.
- Have known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- Have received prior therapy with any TKI.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication.
- Legal incapacity or limited legal capacity.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 30 Mar 2022 | 32 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
LENVIMA 4 mg hard capsules | Test | HARD CAPSULES | ORAL | 12 | 24 | PRD2958373 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 24 | PRD4323105 |