Hepatocellular Carcinoma
Conditions
Keywords
Advanced or metastatic hepatocellular carcinoma (HCC), Liver cancer
Brief 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.
Interventions
DRUGPembrolizumab
Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).
DRUGRegorafenib (Stivarga, BAY73-4506)
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.
Sponsors
Merck Sharp & Dohme LLC
Bayer
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment | Up to 15 months. Data up to 38 months are now available and are also reported for full transparency. | Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR per RECIST 1.1 by independent central assessment is reported). RECIST 1.1: response evaluation criteria in solid tumors version 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment | Up to 38 months | Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR by RECIST 1.1 investigator review is reported. RECIST 1.1: response evaluation criteria in solid tumors version 1.1 |
| Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment | Up to 38 months | Duration of response (DOR) for partial response (PR) and complete response (CR) was defined as the time from the first documented objective response of PR or CR, whichever noted earlier, to disease progression or death (if death occurs before progression was documented). DOR was defined for confirmed responders only, i.e., participants with a CR or PR. RECIST 1.1: response evaluation criteria in solid tumors version 1.1 |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to 38 months | An AE was considered as treatment-emergent (TEAE) if arising or worsening after start of first study intervention administration until 30 days after administration of any study intervention. In addition, any AEs qualifying as a serious adverse event (SAE) were collected for 90 days after the last dose of pembrolizumab, unless a new anti-cancer therapy had been initiated. |
| Number of Participants With Safety-relevant Changes in Clinical Parameters | Up to 38 months | Number of participants with clinically relevant trends observed in laboratory data, ECG data, or ECOG performance status is reported. |
| Percentage of Participants With Dose Modification | Up to 38 months | Dose modification included dose interruption, dose reduction, dose discontinuation. |
Countries
France, Germany, Israel, Italy, Japan, South Korea, Spain, United States
Participant flow
Recruitment details
The study was conducted between 03 February 2021 (first participant first visit) and 23 April 2024 (last participant last visit) at 39 centers in 8 countries.
Pre-assignment details
A total of 136 participants were screened, of whom 41 were screening failures. A total of 95 participants were assigned to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) Cohort 1 with participants after one systemic line of therapy consisting of atezolizumab plus bevacizumab treatment combination only.
Pembrolizumab 400 mg was administered as an intravenous (IV) infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib. | 68 |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) Cohort 2 with participants after one systemic line of therapy consisting of any PD-1/PD-L1 immune oncology (IO) containing first line treatment (excluding atezolizumab with or without bevacizumab) in monotherapy or combination regimens.
Pembrolizumab 400 mg was administered as an IV infusion every 6 weeks. Regorafenib was given orally at a starting dose of 90 mg once daily for 3 weeks of every 4 weeks (i.e., 3 weeks on, 1 week off). If the starting dose of 90 mg daily was well tolerated the dose was escalated to 120 mg starting after the first 4-week cycle of regorafenib. | 27 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 2 |
| Overall Study | Death | 4 | 0 |
| Overall Study | Other | 7 | 2 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Progressive Disease - Clinical Progression | 1 | 1 |
| Overall Study | Progressive Disease - Radiological Progression | 42 | 20 |
| Overall Study | Subject Decision | 1 | 2 |
Baseline characteristics
| Characteristic | Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Total | Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) |
|---|---|---|---|
| Age, Continuous | 70.9 Years STANDARD_DEVIATION 7.3 | 64.3 Years STANDARD_DEVIATION 12.4 | 61.7 Years STANDARD_DEVIATION 13.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 10 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 67 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 18 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 22 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 13 Participants | 9 Participants |
| Race (NIH/OMB) White | 20 Participants | 57 Participants | 37 Participants |
| Sex: Female, Male Female | 7 Participants | 22 Participants | 15 Participants |
| Sex: Female, Male Male | 20 Participants | 73 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 53 / 68 | 20 / 27 |
| other Total, other adverse events | 63 / 68 | 27 / 27 |
| serious Total, serious adverse events | 37 / 68 | 11 / 27 |
Outcome results
Primary
Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment
Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR per RECIST 1.1 by independent central assessment is reported). RECIST 1.1: response evaluation criteria in solid tumors version 1.1
Time frame: Up to 15 months. Data up to 38 months are now available and are also reported for full transparency.
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment | Up to 15 months (primary outcome as previously reported) | 5.9 Percentage of participants |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment | Up to 38 months (as of study completion) | 7.4 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment | Up to 15 months (primary outcome as previously reported) | 11.1 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Overall Response Rate (ORR) Per RECIST 1.1 by Central Assessment | Up to 38 months (as of study completion) | 14.8 Percentage of participants |
Secondary
Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment
Duration of response (DOR) for partial response (PR) and complete response (CR) was defined as the time from the first documented objective response of PR or CR, whichever noted earlier, to disease progression or death (if death occurs before progression was documented). DOR was defined for confirmed responders only, i.e., participants with a CR or PR. RECIST 1.1: response evaluation criteria in solid tumors version 1.1
Time frame: Up to 38 months
Population: Confirmed responders in Full Analysis Set (FAS)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment | Central assessment | 210 Days |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment | Investigator assessment | 431 Days |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment | Central assessment | 195 Days |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Duration of Response (DOR) Per RECIST 1.1 by Central Assessment and Investigator Assessment | Investigator assessment | 364 Days |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was considered as treatment-emergent (TEAE) if arising or worsening after start of first study intervention administration until 30 days after administration of any study intervention. In addition, any AEs qualifying as a serious adverse event (SAE) were collected for 90 days after the last dose of pembrolizumab, unless a new anti-cancer therapy had been initiated.
Time frame: Up to 38 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAE | 68 Participants |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 37 Participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any TEAE | 27 Participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 11 Participants |
Secondary
Number of Participants With Safety-relevant Changes in Clinical Parameters
Number of participants with clinically relevant trends observed in laboratory data, ECG data, or ECOG performance status is reported.
Time frame: Up to 38 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Number of Participants With Safety-relevant Changes in Clinical Parameters | 0 Participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Number of Participants With Safety-relevant Changes in Clinical Parameters | 0 Participants |
Secondary
Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment
Overall response rate (ORR) is defined as the percentage of participants with best overall response of confirmed complete response (CR) or partial response (PR). ORR by RECIST 1.1 investigator review is reported. RECIST 1.1: response evaluation criteria in solid tumors version 1.1
Time frame: Up to 38 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment | 7.4 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Overall Response Rate (ORR) Per RECIST 1.1 by Investigator Assessment | 18.5 Percentage of participants |
Secondary
Percentage of Participants With Dose Modification
Dose modification included dose interruption, dose reduction, dose discontinuation.
Time frame: Up to 38 months
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Percentage of Participants With Dose Modification | Regorafenib - drug withdrawal | 16.2 Percentage of participants |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Percentage of Participants With Dose Modification | Pembrolizumab - dose interruptions or delays | 14.7 Percentage of participants |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Percentage of Participants With Dose Modification | Regorafenib - dose reductions | 41.2 Percentage of participants |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Percentage of Participants With Dose Modification | Pembrolizumab - drug withdrawal | 4.4 Percentage of participants |
| Cohort 1 (Regorafenib + Pembrolizumab [1L: Atezolizumab + Bevacizumab]) | Percentage of Participants With Dose Modification | Regorafenib - drug interruptions or delays | 63.2 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Percentage of Participants With Dose Modification | Pembrolizumab - drug withdrawal | 11.1 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Percentage of Participants With Dose Modification | Regorafenib - drug interruptions or delays | 70.4 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Percentage of Participants With Dose Modification | Regorafenib - dose reductions | 63.0 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Percentage of Participants With Dose Modification | Pembrolizumab - dose interruptions or delays | 25.9 Percentage of participants |
| Cohort 2 (Regorafenib + Pembrolizumab [1L: Any Other IO Containing Treatment]) | Percentage of Participants With Dose Modification | Regorafenib - drug withdrawal | 25.9 Percentage of participants |