Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1/PD-L1 Immune Checkpoint Inhibitors
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Pembrolizumab; Regorafenib (Stivarga, BAY73-4506)
Intervention description: Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).; Regorafenib to be given orally (p.o.) at a starting dose of 90 mg QD for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily is well tolerated the dose should be escalated to 120 mg starting after the first 4-week cycle of regorafenib.
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 95.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced or metastatic hepatocellular carcinoma (HCC); Liver cancer

Summary:

      Researchers are looking for a better way to treat people diagnosed with liver cancer which
      may have spread to nearby tissue and is unlikely to be cured or controlled with treatment
      (advanced metastatic hepatocellular carcinoma, HCC). Before a treatment can be approved for
      people to take, researchers do clinical trials to better understand its safety and how it
      works.

      In this trial, the researchers will learn more about the trial treatment, regorafenib, in a
      small number of participants. They will study the results when the trial treatment is taken
      with another cancer treatment called pembrolizumab.

      There will be 2 parts to this trial. The part 1 (pilot phase) will include about 52 men and
      women. The part 2 (expansion phase) will include about 67 men and women. All of the
      participants will have HCC and will be aged 18 years or older. All of the participants will
      have tried other treatments that did not help their HCC. These other treatments (PD-1/PD-L1
      Immune Checkpoint Inhibitors) are designed to work by stopping the activity of certain
      proteins in the immune system thought to play a role in HCC.

      During both parts of the trial, the participants will take regorafenib and receive
      pembrolizumab. In the pilot phase, there will be 2 groups of participants. The group that
      each participant joins will be based on the treatment they already received for their HCC.
      The researchers will review the results in each group to learn if regorafenib and
      pembrolizumab are helping one group of participants more than others. Outcome of this review
      will determine the population to be treated in the expansion phase.
    

Eligibility criteria:

        Inclusion Criteria:

          -  ≥ 18 years of age on the day of signing informed consent.

          -  Histological or cytological confirmation of HCC or non-invasive diagnosis of HCC as
             per American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic
             participants.

          -  Unresectable advanced HCC eligible for systemic therapy.

          -  Participants must have progressed after only one prior line of systemic immunotherapy
             treatment with an anti-PD-1/PD-L1 mAb administered either as monotherapy or in
             combination with other checkpoint inhibitors or other therapies. A wash out period of
             at least 28 days or 5 half-lives, whichever is shorter, must be completed for
             eligibility in this trial. PD-1/PD-L1 treatment progression is defined by meeting all
             of the following criteria:

               1. Has received at least 2 doses of an approved anti PD-1/PD-L1 mAb or received
                  PD-1/PD-L1 treatment for 8 weeks, whichever is longer.

               2. Has demonstrated disease progression after PD-1/PD-L1 treatment as defined by
                  RECIST 1.1. In the absence of rapid clinical progression, the initial evidence of
                  RECIST 1.1 disease progression is to be confirmed using iRECIST by a second
                  assessment no less than four weeks from the date of the first documented
                  progressive disease.

             i. This determination is made by the investigator. Once progressive disease is
             confirmed, the initial date of RECIST 1.1 progressive disease documentation will be
             considered that date of disease progression.

        ii. In cases of unequivocal clinical or radiological progression, disease progression
        confirmation may not be required after documented discussion and approval by the sponsor.

        c. Progressive disease has been documented within 12 weeks from the last dose of
        anti-PD-1/PD-L1 mAb.

        - Participants who receive anti-PD-1 therapy as adjuvant treatment following complete
        resection of liver cancer and have disease recurrence (unresectable locoregional disease or
        distant metastases) are eligible if they progressed while on active treatment or within 6
        months of stopping anti-PD-1 therapy. This will be considered the first line of systemic
        therapy.

        For these participants, the following applies:

          1. a second assessment to confirm disease progression beyond recurrence is not required;
             and

          2. they must have received at least 2 prior doses of anti-PD-1/PD-L1 mAb.

               -  Barcelona Clinic Liver Cancer (BCLC) stage B or C.

               -  Liver function status should be Child-Pugh (CP) Class A within 7 days prior to
                  the first dose of study intervention. CP status should be calculated based on
                  clinical findings and laboratory results during the screening period.

               -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
                  within 7 days prior to the first dose of study intervention.

               -  At least one measurable lesion by CT scan or MRI according to RECIST 1.1. Tumor
                  lesions situated in a previously irradiated area, or in an area subjected to
                  other loco-regional therapy, may be considered measurable if there has been
                  demonstrated progression in the lesion.

               -  Participants with controlled (treated) hepatitis B virus (HBV) infection will be
                  allowed 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 intervention.

                    -  Participants on active HBV therapy with viral loads under 500 IU/ml should
                       stay on the same therapy throughout study treatment.

                    -  Participants who are anti-HBc (+), negative for HBsAg, negative for
                       anti-HBs, and have an HBV viral load under 500 IU/mL that do not require HBV
                       antiviral prophylaxis.

               -  Provision of recent tumor tissue (as defined below) is mandatory at screening.
                  Exceptions will be accepted for participants with no recent baseline tumor
                  tissues after documented discussion and approval by the sponsor.

                    -  Tumor tissue obtained within 180 days of enrollment and after the last dose
                       of most recent anti-cancer therapy.

                    -  Or a new biopsy.

        Exclusion Criteria:

          -  Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes.

          -  Patients with disease that is suitable for local therapy administered with curative
             intent.

          -  Patients who experienced any Common Terminology Criteria for Adverse Events (CTCAE) ≥
             3 or any other immune- related toxicities that led to permanent discontinuation of
             treatment with immune checkpoint inhibitors in 1 L.

          -  Persistent proteinuria of CTCAE Grade 3 or higher.

          -  Diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy
             (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study
             interventions.

          -  Active autoimmune disease.

          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

          -  Any hemorrhage or bleeding event CTCAE Grade ≥ 3 within 28 days prior to the start of
             study medication.

          -  Patients with large esophageal varices at risk of bleeding that are not being treated
             with conventional medical intervention.

          -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
             within 6 months before the start of study medication.

          -  Ongoing infection CTCAE Grade > 2 requiring systemic therapy.

          -  Dual active HBV infection (HBsAg (+) and / or detectable HBV DNA) and HCV infection
             (anti-HCV Ab (+) and detectable HCV RNA) at study entry.

          -  Uncontrolled hypertension (systolic blood pressure ≥ 140 mmHg or diastolic pressure ≥
             90 mmHg) on more than 2 separate measurements despite optimal medical management.

          -  Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
             months).

          -  Myocardial infarction less than 6 months before start of study intervention.

          -  Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade ≥ 2
             dyspnea).

          -  Patients with previous malignancies (except non-melanoma skin cancers, and the
             following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or
             breast) are excluded unless a complete remission was achieved at least 3 years prior
             to study entry.

          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
             Participants with previously treated brain metastases may participate provided they
             are radiologically stable.

          -  Significant acute gastrointestinal disorders with diarrhea as a major symptom.

          -  Prior monotherapy treatment with any tyrosine kinase inhibitor in 1L.

          -  Prior treatment with regorafenib, in combination regimens with immune checkpoint
             inhibitors.

          -  Transfusion of blood products within 7 days prior to signing informed consent, or
             administration of colony stimulating factors within 4 weeks prior to signing informed
             consent.

          -  Previous assignment to treatment during this study.

          -  Previous (at least a minimum of 28 days, or 5 half-lives of an investigational drug
             before the start of study treatment, whichever is shorter) or concomitant
             participation in another clinical study with investigational medicinal product(s).