Clinical Trials /

Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1/PD-L1 Immune Checkpoint Inhibitors

NCT04696055

Description:

Researchers are looking for a better way to treat people suffering from 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.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Regorafenib Plus Pembrolizumab in Patients With Advanced or Spreading Liver Cancer Who Have Been Previously Treated With PD-1/PD-L1 Immune Checkpoint Inhibitors
  • Official Title: An Open-Label Study of Regorafenib in Combination With Pembrolizumab in Patients With Advanced or Metastatic Hepatocellular Carcinoma (HCC) After PD1/PD-L1 Immune Checkpoint Inhibitors

Clinical Trial IDs

  • ORG STUDY ID: 21469
  • SECONDARY ID: MK-3475-B70
  • SECONDARY ID: Keynote B70
  • SECONDARY ID: 2020-003555-16
  • NCT ID: NCT04696055

Conditions

  • Carcinoma, Hepatocellular

Interventions

DrugSynonymsArms
PembrolizumabKeytruda / MK-3475Regorafenib+Pembrolizumab
Regorafenib (Stivarga, BAY73-4506)Regorafenib+Pembrolizumab

Purpose

Researchers are looking for a better way to treat people suffering from 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.

Trial Arms

NameTypeDescriptionInterventions
Regorafenib+PembrolizumabExperimentalParticipants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy.
  • Pembrolizumab
  • Regorafenib (Stivarga, BAY73-4506)

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 had prior 1L immunotherapy treatment with a PD-1/PD-L1
             checkpoint inhibitor administered either as monotherapy or in combination with other
             therapies. This also includes patients receiving prior treatment with pembrolizumab as
             monotherapy or in combination. A wash out period of at least 28 days or 5 half-lives,
             whichever is shorter, must be completed for eligibility in this trial. In case of
             discontinuation due to progression, the following criteria are required in order to
             define PD-1/PD-L1 treatment progression:

               1. Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.

               2. Has demonstrated disease progression after PD-1/PD-L1 as defined by RECIST 1.1.
                  The initial evidence of PD is to be confirmed by a second assessment no less than
                  four weeks from the date of the first documented PD, in the absence of rapid
                  clinical progression.

                  In cases of unequivocal progression (clinical or radiological), PD confirmation
                  may not be required after documented discussion and approval by the sponsor.

               3. Progressive disease has been documented within 12 weeks from the last dose of
                  anti-PD-1/PD-L1 mAb.

             i. Progressive disease is determined according to iRECIST ii. This determination is
             made by the investigator. Once PD is confirmed, the initial date of PD documentation
             will be considered the date of disease progression.

          -  Participants who receive anti-PD-1 therapy as adjuvant treatment following complete
             resection of liver cancer and have disease recurrence (unresectable loco-regional
             disease or distant metastases) are eligible if they progressed while on active
             treatment or within 6 months of stopping anti-PD-1 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. 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.

               -  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
                       anti-viral 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 > 150 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) per RECIST 1.1a by central assessment
Time Frame:Approximately 21 months
Safety Issue:
Description:ORR is defined as the proportion of participants with best overall response of confirmed complete response (CR) or partial response (PR). RECIST: Response Evaluation Criteria in Solid Tumors

Secondary Outcome Measures

Measure:Duration of response (DOR) per RECIST 1.1 by central assessment
Time Frame:Approximately 45 months
Safety Issue:
Description:DOR is defined as the time (in days) from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death. RECIST: Response Evaluation Criteria in Solid Tumors
Measure:Objective response rate (ORR) per RECIST 1.1 by investigator assessment
Time Frame:Approximately 45 months
Safety Issue:
Description:
Measure:Duration of response (DOR) per RECIST 1.1 by investigator assessment
Time Frame:Approximately 45 months
Safety Issue:
Description:
Measure:Number of participants with adverse events (AEs)
Time Frame:Approximately 45 months
Safety Issue:
Description:
Measure:Number of participants with serious adverse events (SAEs)
Time Frame:Approximately 45 months
Safety Issue:
Description:
Measure:Number of participants with safety-relevant changes in clinical parameters
Time Frame:Approximately 45 months
Safety Issue:
Description:
Measure:Number of participants with dose modification
Time Frame:Approximately 45 months
Safety Issue:
Description:Dose modification includes dose interruption, dose reduction, dose discontinuation.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Bayer

Trial Keywords

  • Advanced or metastatic hepatocellular carcinoma (HCC)
  • Liver cancer

Last Updated

March 11, 2021