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

Sponsor

Bayer (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04696055

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Locations

Arm

39.3

Anticipated Duration (Months)

2.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: Pembrolizumab Drug: Regorafenib (Stivarga, BAY73-4506)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

95 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 3, 2021

Actual Primary Completion Date :

May 5, 2022

Anticipated Study Completion Date :

May 15, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regorafenib+Pembrolizumab Participants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy.	Drug: Pembrolizumab Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W). Other Names: 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.

Arm

Intervention/Treatment

Experimental: Regorafenib+Pembrolizumab

Participants with advanced hepatocellular carcinoma (HCC) progressed on 1L anti-PD-1/PD-L1 therapy.

Drug: Pembrolizumab

Pembrolizumab 400 mg to be administered as an intravenous (IV) infusion every 6 weeks (Q6W).

Other Names:

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 Measures

Primary Outcome Measures

Objective response rate (ORR) per RECIST 1.1a by central assessment [Approximately 21 months]
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

Duration of response (DOR) per RECIST 1.1 by central assessment [Approximately 45 months]
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
Objective response rate (ORR) per RECIST 1.1 by investigator assessment [Approximately 45 months]
Duration of response (DOR) per RECIST 1.1 by investigator assessment [Approximately 45 months]
Number of participants with adverse events (AEs) [Approximately 45 months]
Number of participants with serious adverse events (SAEs) [Approximately 45 months]
Number of participants with safety-relevant changes in clinical parameters [Approximately 45 months]
Number of participants with dose modification [Approximately 45 months]
Dose modification includes dose interruption, dose reduction, dose discontinuation.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

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.
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.

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.

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

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:

a second assessment to confirm disease progression beyond recurrence is not required; and
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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center	Tucson	Arizona	United States	85719
2	City of Hope National Medical Center	Duarte	California	United States	91010-3012
3	University of Southern California	Los Angeles	California	United States	90033
4	University of California Irvine Medical Center	Orange	California	United States	92868-3201
5	Medical Oncology Hematology Consultants, PA	Newark	Delaware	United States	19713
6	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
7	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612-9416
8	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
9	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
10	Hôpital Beaujon - Clichy	Clichy		France	92110
11	Center Hospitalier Michallon - Grenoble	La Tronche		France	38700
12	Hôpital Claude Huriez - Lille	Lille		France	59037
13	Hôpital de la Croix Rousse	Lyon		France	69004
14	Hôpital de la Timone - Marseille	Marseille		France	13005
15	Hôpital Saint-Eloi	Montpellier Cedex		France	34295
16	Centre François Magendie - Pessac	Pessac		France	33600
17	Centre Hospitalier Universitaire de Nancy	Vandoeuvre les Nancy		France	54500
18	Hôpital Paul Brousse - Villejuif	Villejuif		France	94800
19	Eberhard-Karls-Universität Tübingen	Tübingen	Baden-Württemberg	Germany	72076
20	Klinikum der Universität München Grosshadern	München	Bayern	Germany	81377
21	Heinrich-Heine-Universität Düsseldorf	Düsseldorf	Nordrhein-Westfalen	Germany	40225
22	Universitätsklinikum Köln	Köln	Nordrhein-Westfalen	Germany	50937
23	Universitätsmedizin der Johannes Gutenberg Universität Mainz	Mainz	Rheinland-Pfalz	Germany	55131
24	Rambam Health Corporation	Haifa		Israel	3109601
25	Clalit Health Services Rabin Medical Center-Beilinson Campus	Petah Tikva		Israel	4941492
26	Tel-Aviv Sourasky Medical Center	Tel Aviv		Israel	6423906
27	Istituto Clinico Humanitas - Humanitas Mirasole S.p.A.	Milano	Lombardia	Italy	20089
28	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano	Lombardia	Italy	20122
29	A.O.U. Pisana	Pisa	Toscana	Italy	56126
30	Istituto Oncologico Veneto IRCCS (IOV)	Padova	Veneto	Italy	35128
31	Chiba University Hospital	Chiba-shi	Chiba	Japan	260-8677
32	National Cancer Center Hospital East	Kashiwa-shi	Chiba	Japan	277-8577
33	Japanese Red Cross Society Musashino Red Cross Hospital	Musashino-shi	Tokyo	Japan	180-8610
34	Samsung Medical Center	Seoul		Korea, Republic of	06351
35	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
36	Asan Medical Center	Seoul		Korea, Republic of	138-736
37	Institut Català d'Oncologia Hospitalet	Hospitalet de Llobregat	Barcelona	Spain	08907
38	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain	08036
39	Hospital General Universitario Gregorio Marañón \| Digestivo	Madrid		Spain	28007