Regorafenib Plus Pembrolizumab in First Line Systemic Treatment of HCC

ID: NCT03347292
Status: Not yet recruiting
Phase: Phase 1
Start Date: May 15, 2018
First Submitted: November 16, 2017
Last Updated: February 22, 2018
Results: N/A
Organization: Bayer
Sponsors & Collaborators: Bayer, Merck Sharp & Dohme Corp.
Location: Germany
Conditions: Carcinoma, Hepatocellular
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Study Description

Brief Summary

This study will determine if the combination of regorafenib and pembrolizumab is safe and tolerated in patients with advanced liver cancer. In addition, the study will explore the anti-tumor activity of this combination as well as potentially identifying blood and tissue biomarkers associated with disease activity, status or response. The study will also investigate how the drugs behave in your body

Detailed Description

Condition or disease Intervention/treatment Phase

Carcinoma, Hepatocellular

Drug: Regorafenib(Stivarga, BAY73-4506)
Other Names
Drug: Pembrolizumab
Other Names
Phase 1

Tracking Information

First Submitted DateNovember 16, 2017
Last Update Posted DateFebruary 22, 2018
Anticipated Start DateMay 15, 2018
Anticipated Completion DateOctober 15, 2020
Anticipated Primary Completion DateAugust 14, 2020
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Incidence of treatment-emergent adverse event(TEAEs) [Time Frame: Up to 30 days after last dose of study drug]

    The following will be provided: Individual listings of adverse events. The incidence of treatment-emergent adverse events and treatment-emergent drug-related adverse events summarized in frequency tables using worst CTCAE v4.03 grade. Laboratory data outside the reference range will be listed with abnormal values flagged. The incidence of laboratory data outside the reference range summarized in frequency tables.

  • Severity of TEAEs [Time Frame: Up to 30 days after last dose of study drug]

  • Dose Limiting Toxicities(DLTs) [Time Frame: Up to 42 days after first treatment administration]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Maximum Tolerated Dose (MTD) [Time Frame: After approximately 18 months]

    The MTD is defined as the highest dose that can be given so that toxicity probability is below the target toxicity PT =35%.

  • Progression-free survival (PFS) [Time Frame: After approximately 36 months]

  • Time to progression (TTP) [Time Frame: After approximately 36 months]

  • Overall survival (OS) [Time Frame: After approximately 36 months]

  • Overall response rate (ORR) [Time Frame: After approximately 36 months]

  • Disease control rate (DCR) [Time Frame: After approximately 36 months]

  • Duration of response (DOR) [Time Frame: After approximately 36 months]

  • Duration of stable disease [Time Frame: After approximately 36 months]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleRegorafenib Plus Pembrolizumab in First Line Systemic Treatment of HCC
Official TitleA Multicenter, Non-randomized, Open-label Dose Escalation Phase Ib Study of Regorafenib in Combination With Pembrolizumab in Patients With Advanced Hepatocellular Carcinoma (HCC) With no Prior Systemic Therapy
Brief Summary

This study will determine if the combination of regorafenib and pembrolizumab is safe and tolerated in patients with advanced liver cancer. In addition, the study will explore the anti-tumor activity of this combination as well as potentially identifying blood and tissue biomarkers associated with disease activity, status or response. The study will also investigate how the drugs behave in your body

Detailed Description

Study TypeInterventional
Study PhasePhase 1
Estimated Enrollment
40
Allocation
Non-Randomized
Interventional Model
Sequential Assignment
Masking
None (Open Label)
Primary Purpose
Treatment
Conditions
Carcinoma, Hepatocellular
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Regorafenib(Stivarga, BAY73-4506)

Regorafenib 80mg/120mg/160mg q.d., 3 weeks on / 1 week off + pembrolizumab 200mg i.v. every 3 weeks

Other Names
Drug: Pembrolizumab

200 mg i.v.(Intravenous(ly)) every 3 weeks (Q3W). This dose will not be escalated or deescalated and the dosing schedule will not be changed

Other Names
Study Groups/Cohorts
Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.

Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30 patients per cohort is reached.

Study Arms
Experimental Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
Drug : Regorafenib(Stivarga, BAY73-4506)
Regorafenib 80mg/120mg/160mg q.d., 3 weeks on / 1 week off + pembrolizumab 200mg i.v. every 3 weeks

Experimental Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
Drug : Pembrolizumab
200 mg i.v.(Intravenous(ly)) every 3 weeks (Q3W). This dose will not be escalated or deescalated and the dosing schedule will not be changed

Experimental Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30 patients per cohort is reached.
Drug : Pembrolizumab
200 mg i.v.(Intravenous(ly)) every 3 weeks (Q3W). This dose will not be escalated or deescalated and the dosing schedule will not be changed

Experimental Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30 patients per cohort is reached.
Drug : Regorafenib(Stivarga, BAY73-4506)
Regorafenib 80mg/120mg/160mg q.d., 3 weeks on / 1 week off + pembrolizumab 200mg i.v. every 3 weeks

Arm Intervention/Treatment
Experimental Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
Drug : Regorafenib(Stivarga, BAY73-4506)
Experimental Dose escalation
The regorafenib starting dose will be 120 mg q.d.(once daily) 3 weeks on / 1 week off in combination with the recommended dose of pembrolizumab (200 mg Q3W). Pembrolizumab dose will not be escalated or de-escalated.
Drug : Pembrolizumab
Experimental Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30 patients per cohort is reached.
Drug : Pembrolizumab
Experimental Dose expansion
Dose expansion cohorts will continue to be expanded until the sample size of 30 patients per cohort is reached.
Drug : Regorafenib(Stivarga, BAY73-4506)

Recruitment Information

Recruitment Status:Not yet recruiting
Enrollment40
Completion DateOctober 15, 2020
Eligibility Criteria: Inclusion Criteria:
- Male or female patients ≥ 18 years of age on day of signing informed consent.
- Histological or cytological confirmation of HCC (hepatocellular carcinoma) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis.
- Barcelona Clinic Liver Cancer (BCLC) stage B or C that cannot benefit from treatments of established efficacy such as resection, local ablation, chemoembolization.
- Liver function status Child-Pugh (CP) Class A. CP status should be calculated based on clinical findings and laboratory results during the screening period.
- Any local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed ≥ 4 weeks before first dose of study medication. Note: patients who received sole intrahepatic intra-arterial chemotherapy, without lipiodol or embolizing agents are not eligible.
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
- At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1) and no older than 28 days before start of the study treatment. 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.
- Life expectancy of at least 3 months.
- Adequate bone marrow and organ function as assessed by the laboratory tests performed within 7 days before of treatment initiation.
- For patients recruited in the expansion cohort only, provision of archival (block) or fresh tumor tissue samples at baseline is mandatory. If archival tumor tissue is not available, patients should be willing to undergo a biopsy for provision of fresh tumor samples

Exclusion Criteria:
- Prior systemic therapy for HCC; prior exposure to regorafenib.
- Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1), or cytotoxicT-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy for HCC.
- Previous treatment with live vaccine within 30 days of planned start of study drugs (seasonal flu vaccines that do not contain a live virus are permitted).
- Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years (i.e., with use of diseasemodifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drugs. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
- Known history of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies).
- Dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
- Patients with chronic HCV infection with less than 4 weeks between completion of HCV therapy and start of study drug. Note: patients with chronic infection with HCV who are untreated or noncuratively treated HCV are allowed on study.
- Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE Grade 2 dyspnea).
- Known history of metastatic brain or meningeal tumors.
- Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease,malabsorption, or CTCAE Grade ≥ 2 diarrhea of any etiology.
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
Germany

Administrative Information

NCT Number:NCT03347292
Other Study ID Numbers
19497
KN-743
2017-003202-40
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Bayer
Collaborators
Merck Sharp & Dohme Corp.
Investigators
Not Available