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

JRCT ID: jRCT2031200435

Registered date:23/03/2021

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: Hepatocellular Carcinoma
• Date of first enrollment: 19/04/2021
• Target sample size: 119
• Countries of recruitment: USA,Japan,France,Japan,Germany,Japan,Italy,Japan,Korea,Japan,Spain,Japan
• Study type: Interventional

Intervention(s)

Drug: Pembrolizumab
Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion
every 6 weeks (Q6W).
Other Name: Keytruda / MK-3475

Drug: Regorafenib (Stivarga, BAY73-4506)
Regorafenib will 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.

Outcome(s)

• Primary Outcome: Objective response rate (ORR) per RECIST 1.1a by central assessment [ Time Frame: Approximately 21 months ]

Secondary Outcome

1. Duration of response (DOR) per RECIST 1.1 by central assessment [ Time Frame: Approximately 45 months ]

2. Objective response rate (ORR) per RECIST 1.1 by investigator assessment [ Time Frame: Approximately 45 months ]

3. Duration of response (DOR) per RECIST 1.1 by investigator assessment [ Time Frame: Approximately 45 months ]

4. Number of participants with adverse events (AEs) [ Time Frame: Approximately 45 months ]

5. Number of participants with serious adverse events (SAEs) [ Time Frame: Approximately 45 months ]

6. Number of participants with safety-relevant changes in clinical parameters [ Time Frame: Approximately 45 months ]

7. Number of participants with dose modification [ Time Frame: Approximately 45 months ]

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. =>18 years of age on the day of signing informed consent
2. 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
3. Unresectable advanced HCC eligible for systemic therapy
4. 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:
a. Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb.
b. 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.
c. 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.
5. 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
6. Barcelona Clinic Liver Cancer (BCLC) stage B or C
7. 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.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
9. 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.
11. 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.
13. 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

Exclude criteria

2. Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes.
4. Patients with disease that is suitable for local therapy administered with curative intent.
5. 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.
6. Persistent proteinuria of CTCAE Grade 3 or higher.
7. 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.
8. Active autoimmune disease
9.History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14.Any hemorrhage or bleeding event CTCAE Grade >= 3 within 28 days prior to the start of study medication.
15. Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
16. 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.
19. Ongoing infection CTCAE Grade > 2 requiring systemic therapy.
20. Dual active HBV infection (HBsAg (+) and / or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
21. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg) on more than 2 separate measurements despite optimal
medical management.
23. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
24. Myocardial infarction less than 6 months before start of study intervention.
26. Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade >=2 dyspnea).
27. 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
28. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may
participate provided they are radiologically stable,
30. Significant acute gastrointestinal disorders with diarrhea as a major symptom
32. Prior monotherapy treatment with any tyrosine kinase inhibitor in 1L.
33. Prior treatment with regorafenib, in combination regimens with immune checkpoint inhibitors.
37. 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.
39. Previous assignment to treatment during this study.
40. 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).

Related Information

• Primary Sponsor: Tanigawa Takahiko
• Secondary Sponsor: Merck Sharp & Dohme Corp.
• Secondary ID(s): NCT04696055