Regorafenib and Nivolumab Combined Versus TACE in Intermediate-Stage HCC Beyond Up-to-7 (RENOTACE) (RENOTACE)

• ClinicalTrials.gov Identifier: NCT04777851
• Recruitment Status: Not yet recruiting
• First Posted: March 2, 2021
• Last Update Posted: December 9, 2021
• Sponsor: Translational Research in Oncology
• Collaborator: Bayer
• Information provided by (Responsible Party): Translational Research in Oncology

Study Description

Brief Summary:

RENOTACE is a phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of regorafenib and nivolumab (Rego-Nivo) versus transarterial chemoembolization (TACE) for the first-line treatment of hepatocellular carcinoma (HCC or liver cancer). Approximately 496 patients in around 80 clinical sites worldwide will be randomized to receive either:

• Investigational arm: Regorafenib in combination with nivolumab (rego-nivo)
• Control arm: Transarterial chemoembolization (TACE)

In both arms, patients will receive trial treatment until progressive disease, unacceptable toxicity, deterioration of patient's condition that warrants permanent trial treatment discontinuation or other treatment discontinuation criteria is met. After trial treatment discontinuation, subsequent treatment will be administered according to the Investigator's clinical judgment.

It is hypothesized that combining regorafenib and nivolumab, may be advantageous over standard treatment at an earlier HCC stage such as the intermediate-stage. This drug combination was tested previously in pre-treated metastatic gastric and colorectal cancer (Phase 1b, REGONIVO trial). The 80 mg regorafenib dose had a manageable safety profile and encouraging antitumor activity (objective tumor response 40 precent) in patients with heavily pretreated disease. Based on these promising results, the Rego-Nivo combination is being tested in a number of ongoing clinical trials.

RENOTACE will compare the efficacy and safety of the standard of care approach in patients with this stage (i.e. TACE) versus Rego-Nivo, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Although there are a number of trials comparing TACE with TACE in combination with systemic therapy, this will be the first trial comparing TACE with systemic therapy alone, an approach that could potentially represent a shift in the management of intermediate-stage HCC.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Hepatocellular	Drug: Regorafenib in combination with nivolumab; Procedure: Transarterial Chemoembolization (TACE)	Phase 3

Detailed Description:

RENOTACE is a phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of regorafenib and nivolumab (rego-nivo) versus transarterial chemoembolization (TACE) for the first-line treatment of intermediate-stage hepatocellular carcinoma (HCC) with beyond up-to-7 criteria. Approximately 496 patients (about 248 in each arm) in around 80 sites will be randomized in order to power the study efficiently to measure a clinically meaningful improvement for the primary endpoint, progression-free survival (PFS) according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) based on the Investigator´s assessment. To provide a balanced representation from the different regions involved in the trial, the number of patients enrolled in Asian countries will be capped at approximately 50 precent.

The trial will include patients who had been diagnosed with intermediate-stage HCC by biopsy, cytology or diagnostic imaging, such as dynamic computed tomography (CT) or magnetic resonance imaging (MRI), according to the criteria of the American Association for the Study of Liver Diseases (AASLD). Patients should have at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease not amenable to curative treatment but amenable to TACE (conventional TACE or drug-eluting bead TACE), and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1, Child-Pugh class A, and beyond up-to-seven criteria.

The trial will include the following phases:

• Screening
• Treatment
• Follow-up

Patients will be randomized in a 1:1 ratio using the following stratification factors:

• Geographic region (Asia versus non-Asia)
• ECOG PS (0 versus 1)
• Albumin-Bilirubin (ALBI) grade (1 versus 2)
• HCC etiology (viral hepatitis versus non-viral)

Randomized patients will receive either:

• Investigational arm: Regorafenib in combination with nivolumab
• Control arm: TACE

In both arms, patients will receive trial treatment (Rego-Nivo or TACE) until progressive disease per mRECIST, unacceptable toxicity, deterioration of patient's condition that warrants permanent trial treatment discontinuation or other treatment discontinuation criteria is met. After trial treatment discontinuation, subsequent HCC treatment will be administered according to the Investigator's clinical judgment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 496 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III, Multicenter, Randomized, Open-Label Trial to Evaluate Efficacy and Safety of Regorafenib in Combination With Nivolumab Versus TACE for First-Line Treatment of Intermediate-Stage HCC With Beyond Up-to-7 Criteria
• Estimated Study Start Date: August 2022
• Estimated Primary Completion Date: August 2025
• Estimated Study Completion Date: January 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Regorafenib + Nivolumab; Investigational arm: regorafenib at a dose of 90 mg orally once per day (on days 1 to 21 of a 28-day cycle), in combination with nivolumab 480 mg using 30-minutes intravenous infusion (on day 1 of a 28-day cycle, every 4 weeks).	Drug: Regorafenib in combination with nivolumab; Randomized patients will receive regorafenib at a dose of 90 mg per day by mouth on days 1 to 21 of a 28-day cycle, in combination with nivolumab 480 mg using a 30-minute intravenous infusion, starting on day 1 of a 28-day cycle, every 4 weeks.; Other Names: Stivarga (regorafenib); Opdivo (nivolumab)
Active Comparator: Transarterial Chemoembolization (TACE); Control arm: Patients will be treated with transarterial chemoembolization (TACE) "on-demand" according to the clinical site's standards, with the goal of controlling all known liver lesions. Either conventional TACE (cTACE) or drug-eluting bead transarterial chemoembolization (DEB-TACE) may be used (as long as it is consistently applied for all patients at a given clinical site).	Procedure: Transarterial Chemoembolization (TACE); Patients will be treated with transarterial chemoembolization (TACE) "on-demand" according to the clinical site's standards, with the goal of controlling all known liver lesions. Either conventional TACE (cTACE) or drug-eluting bead transarterial chemoembolization (DEB-TACE) may be used (as long as it is consistently applied for all patients at a given clinical site).; Other Names: Convention transarterial chemoembolization (cTACE); Drug-eluting bead transarterial chemoembolization (DEB-TACE)

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) Assessed by the Investigator as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [ Time Frame: up to 3.5 years ]
   PFS, defined as the time (in months) from the date of randomization until the date of progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed locally by the Investigator using mRECIST.

Secondary Outcome Measures :

1. Progression-free Survival (PFS) Assessed by the Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: up to 3.5 years ]
   PFS, defined as the time (in months) from the date of randomization until the date of progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed locally by the Investigator using RECIST 1.1.
2. Progression-free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1 [ Time Frame: up to 3.5 years ]
   PFS, defined as the time (in months) from the date of randomization until the date of PD or death due to any cause, whichever occurs first. PD will be assessed by BICR using, independently, mRECIST and RECIST 1.1.
3. Overall Survival (OS) of Intermediate-Stage HCC (Rego-Nivo versus TACE) [ Time Frame: up to 3.5 years ]
   OS, defined as the time (in months) from the date of randomization until the date of death due to any cause.
4. Overall Response Rate (ORR) Assessed by Investigator and Blinded Independent Central Review (BICR) as per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST Version 1.1 [ Time Frame: up to 3.5 years ]
   ORR, defined as the proportion of patients who have a complete response (CR) or partial response (PR) according to RECIST v.1.1 and mRECIST, based on the Investigator's and BICR assessment.
5. Time to unTACEable Progression (TTUP) [ Time Frame: up to 3.5 years ]

   To evaluate the two treatment arms (rego-nivo versus TACE) with respect to TTUP. TTUP, defined as the time (in months) from the date of randomization until any of the following criteria are met:

   • Factors related to liver function:

     • Decompensated cirrhosis (Child-Pugh class B score > 8), including jaundice, clinical hepatic encephalopathy, and refractory ascites and/or hepatorenal syndrome
     • Impaired portal-vein blood flow (portal-vein thrombus, hepatofugal blood flow)
     • ECOG PS ≥ 2 Note: transient post-TACE impairment of liver function of Child-Pugh class B score > 8, that return to pre-TACE values within 4 weeks of the TACE session will not qualify as TTUP.

   • Factors related to HCC:

     • Failure of the treated nodule to achieve Stable Disease (SD), PR or CR by mRECIST
     • Malignant portal vein thrombosis
     • Marcovascular invasion (MVI) or Extra-hepatic Spread (EHS)
6. Duration of Response (DOR) of Rego-Nivo Versus TACE [ Time Frame: up to 3.5 years ]
   To evaluate the two treatment arms (rego-nivo versus TACE) with respect to DOR. DOR, defined as the time (in months) from first documentation of response (PR or CR) to PD or death, based on Investigator's assessment or death from any cause, in patients who had a best overall response of CR or PR.
7. Number of Patients with Adverse Events as Assessed by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 5 [ Time Frame: up to 3.5 years ]
   The NCI-CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading scale is provided for each AE term with unique clinical descriptions of severity based on this general guideline: Grade 1 (mild) to 5 (death). AEs will be tabulated by treatment arm, system organ class, preferred term, severity, and relationship to treatment.
8. Change from Baseline in the Patient Reported Outcomes (PRO) in the Physical Functioning Sub-scale Score of the European Organization for Research and Treatment of Cancer's (EORTC) Core Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: up to 3.5 years ]
   To evaluate PRO for health-related Quality of Life (QoL) in the two treatment arms (rego-nivo versus TACE) as assessed by European Organization for Research and Treatment of Cancer's (EORTC) Core Quality of Life Questionnaire (EORTC QLQ-C30).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Signed and dated Patient Informed Consent Form (PICF)
• ≥ 18 years-old at the time of PICF signature
• Confirmed diagnosis of HCC

• Intermediate-stage HCC, defined as follows:

  • Multinodular HCC localized to the liver
  • No evidence of EH/MVI
  • Not amenable to curative treatment
  • Child-Pugh Class A
  • ECOG PS 0 or 1
  • ALBI grade 1 or 2
• Beyond up-to-seven criteria
• Disease amenable to TACE
• Measurable disease as per RECIST 1.1
• No prior therapy for HCC
• Adequate hematologic and organ function
• Willing and able to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures
• Women of childbearing potential (CBP) must have confirmed negative serum pregnancy test
• Use of highly-effective contraceptive methods in women of CBP and men

Exclusion Criteria:

• No measurable tumor of a diffuse infiltrative HCC type
• Fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes
• Clinically meaningful ascites
• Prior treatment with regorafenib or a checkpoint inhibitor or other form of immunotherapy
• Concurrent participation in another interventional clinical trial
• Active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids
• Requirement of systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications
• Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Clinically-significant uncontrolled cardiovascular conditions.
• Infection > Grade 2 NCI-CTCAE v5.0
• Evidence or history of bleeding diasthesis or any hemorrhage or bleeding event
• Non-healing wound, ulcer, or bone fracture
• Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization
• Patient has known history of human immunodeficiency virus infection
• Persistent proteinuria of NCI-CTCAE v5.0 Grade 3
• Known HIV infection
• Unresolved clinically-significant toxicity greater than NCI-CTCAE v5.0 Grade 1
• Patient has any other concurrent severe and/or uncontrolled medical condition, social situation, etc. that would, in the Investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol
• Pregnant or breast-feeding

Contacts and Locations

Contacts

Contact: Project Management; +33 1 58 10 08 81; 041@trioncology.org

Sponsors and Collaborators

Translational Research in Oncology

Bayer

Investigators

• Study Chair: Peter R Galle; University Medical Center, Mainz, Germany

More Information

• Responsible Party: Translational Research in Oncology
• ClinicalTrials.gov Identifier: NCT04777851
• Other Study ID Numbers: TRIO041; 2021-000631-30 ( EudraCT Number )
• First Posted: March 2, 2021
• Last Update Posted: December 9, 2021
• Last Verified: December 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Translational Research in Oncology:

Hepatocellular Carcinoma; Hepatoma; Liver Cancer, Adult; Liver Cell Carcinoma; Liver Cell Carcinoma, Adult

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action