Pembrolizumab and Lenvatinib in Patients With Advanced HCC Who Are Refractory to Atezolizumab and Bevacizumab Therapy

• ClinicalTrials.gov Identifier: NCT05101629
• Recruitment Status: Recruiting
• First Posted: November 1, 2021
• Last Update Posted: May 18, 2022
• Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Collaborators: Medizinische Hochschule Hannover, Germany, Prof. Dr. Arndt Vogel; Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Study Description

Brief Summary:

Patients with advanced HCC, refractory to atezolizumab and bevacizumab /IO-based therapy will be treated with pembrolizumab and lenvatinib. Efficacy of the combination therapy will be assessed by objective reponse rate, progression free survival, overal survival, safety/tolerability.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma	Drug: Pembrolizumab; Drug: Lenvatinib Capsules	Phase 2

Detailed Description:

This is a multicenter, single arm, open-label phase II trial investigating the clinical activity of a second-line therapy with the anti-PD-1 antibody pembrolizumab (200 mg IV, q3w) and the multiple receptor tyrosine kinase inhibitor (TKI) lenvatinib (8 mg for BW < 60 kg / 12 mg for BW ≥ 60 kg p.o. QD) in advanced HCC patients who are refractory to atezolizumab and bevacizumab/ IO-based therapy.

The primary objective is to assess the efficacy by objective response rate (ORR) according to RECIST 1.1 criteria.

Secondary objectives are to determine efficacy in terms of progression free survival (PFS), overall survival (OS) as well as safety and toxicity (acc. to NCI-CTC V5.0).

In addition, tissue and serum samples (optional) will be analyzed for molecular biomarkers predictive for ORR, PFS and OS.

32 patients will be enrolled in this trial.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase-II Open-label Study of Pembrolizumab and Lenvatinib in Patients With Advanced Stage Hepatocellular Carcinoma Who Are Refractory to Atezolizumab and Bevacizumab/ IO-based Therapy
• Actual Study Start Date: May 11, 2022
• Estimated Primary Completion Date: October 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Pembrolizumab Lenvatinib; Single arm with Pembrolizumab 200 mg over 30 minutes IV infusion on Day 1 every 3 weeks until disease progression or inacceptable toxicity or end of study treatment. Lenvatinib 8 mg for a body weight < 60 kg and 12 mg for a body weight ≥ 60 kg orally continuously once daily, starting on Day 1 of every 3 week cycle until disease progression or inacceptable toxicity or end of study treatment.

Drug: Pembrolizumab; Pembrolizumab 200 mg, IV, over 30 minutes every 3 weeks; Other Name: Keytruda; Drug: Lenvatinib Capsules; Lenvatinib 8 mg for BW < 60 kg / 12 mg for BW ≥ 60 kg oral, once daily for 3 weeks; Other Name: Lenvima

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) according to RECIST 1.1 criteria [ Time Frame: up to 36 months ]
   ORR, defined as the percentage of patients with complete response (CR) or partial response (PR) according to RECIST 1.1.

Secondary Outcome Measures :

1. Progression free survival (PFS) [ Time Frame: up to 36 months ]
   PFS, defined as time from first dose of study treatment to date of first observed disease progression according to RECIST 1.1 or death from any cause.
2. Overall survival (OS) [ Time Frame: up to 36 months ]
   OS, defined as time from first dose of study treatment to the date of death of any cause.
3. Safety and toxicity [ Time Frame: First treatment until 90 days after end of treatment, up to 27 months ]
   Adverse events will be recorded and graded according to NCI-CTC V5.0. Occurrence of (Serious) Adverse Events at any time during the study. Description by nature (Primary System Organ Class and Preferred Term), severity and causal relationship to drug administration.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Arndt Vogel, Prof. Dr.; 0049 176 1 532 9590; Vogel.Arndt@mh-hannover.de

Contact: Luisa Wohn; 0049 69 7601 3958; wohn.luisa@ikf-khnw.de

Locations

Germany

Charité-Universitätsmedizin Berlin; Recruiting

Berlin, Germany, 13353

Contact: Raphael U. Mohr, Dr.

Medizinische Hochschule Hannover; Not yet recruiting

Hannover, Germany, 30625

Contact: Arndt Vogel, Prof. Dr.

Sponsors and Collaborators

Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Medizinische Hochschule Hannover, Germany, Prof. Dr. Arndt Vogel

Merck Sharp & Dohme LLC

Investigators

• Study Chair: Salah Al-Batran, Prof. Dr.; Institut für Klinische Krebsforschung IKF GmbH

More Information

• Responsible Party: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• ClinicalTrials.gov Identifier: NCT05101629
• Other Study ID Numbers: SOLARIS; 2021-000355-40 ( EudraCT Number ); AIO-HEP-0121/ass ( Other Identifier: AIO-Studien GmbH )
• First Posted: November 1, 2021
• Last Update Posted: May 18, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: No IPD will be shared.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest:

Hepatocellular Carcinoma; HCC

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pembrolizumab; Lenvatinib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action