Combination of Regorafenib and Nivolumab in Unresectable Hepatocellular Carcinoma

NCT04310709 | Completed Phase 2

• 1 other identifier: RENOBATE
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 3

Brief Summary

Regorafenib and nivolumab are proven effective agents for the management of unresectable hepatocellular carcinoma patients. As preclinical studies have suggested potential synergism between antiangiogenic agents and immune checkpoint inhibitors, regorafenib and nivolumab may have synergism in terms of efficacy. Herein, this study investigates the combination of regorafenib and nivolumab as first-line therapy in patients with unresectable hepatocellular carcinoma.

Conditions

Carcinoma, Hepatocellular; Hepatoma

Keywords

Hepatocellular carcinoma; Regorafenib; Nivolumab

Outcome Measures

Primary Outcomes (1)

• Response rate

  Proportion of patients with complete response/partial response graded by Response Criteria in Solid Tumor version 1.1

  6 months

Secondary Outcomes (3)

• Adverse events

  1 year

• Progression-free survival

  1 year

• Overall survival

  1 year

Study Arms (1)

REGONIVO

EXPERIMENTAL

Nivolumab - 480 mg IV on Day 1, every 4 weeks Regorafenib \- 80 mg per oral once daily for 21 consecutive days starting on Day 1, every 4 weeks.

Drug: Regorafenib/Nivolumab

Interventions

Regorafenib/Nivolumab DRUG

Combination of regorafenib and nivolumab

REGONIVO

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 19 years at time of signing Informed Consent Form
• Ability to comply with the study protocol, in the investigator's judgment
• HCC that was histologically/cytologically confirmed or clinically diagnosed by AASLD criteria in cirrhotic patients. Patients without liver cirrhosis require histological confirmation of HCC
• Locally advanced unresectable or metastatic disease that is not amenable to curative surgical and/or locoregional therapies, or that progressed after surgical and/or locoregional therapies
• No prior systemic therapy for HCC
• At least one measurable (per RECIST 1.1) lesion as confirmed by imaging within 28 days prior to initiation of study treatment
• Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) are eligible provided that other target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST 1.1.
• Pre-treatment tumor tissue sample (if available)
• If tumor tissue is available, approximately 10 to 30 slides containing unstained, freshly cut, serial sections will be required subsequently for translational research.
• If tumor tissue is not available (e.g., depleted because of prior diagnostic testing), patients are still eligible.
• ECOG Performance Status score 0 or 1
• Child-Pugh class A
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, unless otherwise specified:
• ANC ≥ 1.0 x 109/L (1000/microL) without granulocyte colony-stimulating factor support
• Platelet count ≥ 75 x 109/L (75,000/mciroL) without transfusion

You may not qualify if:

• Patients who are diagnosed with fibrolamellar HCC, sarcomatoid HCC, or combined type of cholangiocarcinoma and HCC
• Patients with a history of malignancy other than HCC within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, and Stage I uterine cancer
• Patients with a history of leptomeningeal seeding
• Patients with symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
• Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:
• The patients must have at least one measurable lesion, per RECIST 1.1, other than CNS metastases
• The patient must not have a history of intracranial hemorrhage or spinal cord hemorrhage
• The metastatic lesions have to be limited in cerebellum or supratentorial region (e.g., not to the midbrain, pons, medulla, or spinal cord)
• There must be no evidence of interim progression between the completion of CNS-directed therapy and initiation of the study treatment
• The patient must not undergo stereotactic radiotherapy within 7 days, whole-brain radiotherapy within 14 days, or neurosurgical resection within 28 days prior to initiation of the study treatment
• The patient must not have ongoing requirement for corticosteroids for CNS disease
• Anticonvulsant therapy at a stable dose is permitted.
• Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.
• Patients with current of past history of autoimmune disease or immunodeficient disease (including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis) with the following exceptions:
• Patients with autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible.

Sponsors & Collaborators

• Asan Medical Center: lead
• Samsung Medical Center: collaborator
• Bundang CHA Hospital: collaborator

Study Sites (3)

Bundang CHA Hospital

Seongnam, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Related Publications (5)

• Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. Epub 2016 Dec 6.

  PMID: 27932229 BACKGROUND

• Yoo C, Park JW, Kim YJ, Kim DY, Yu SJ, Lim TS, Lee SJ, Ryoo BY, Lim HY. Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma. Invest New Drugs. 2019 Jun;37(3):567-572. doi: 10.1007/s10637-018-0707-5. Epub 2018 Dec 7.

  PMID: 30523474 BACKGROUND

• Yoo C, Ryu YM, Kim SY, Kim J, Ock CY, Ryu MH, Kang YK. Association between the exposure to anti-angiogenic agents and tumour immune microenvironment in advanced gastrointestinal stromal tumours. Br J Cancer. 2019 Nov;121(10):819-826. doi: 10.1038/s41416-019-0596-1. Epub 2019 Oct 14.

  PMID: 31607749 BACKGROUND

• El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2. Epub 2017 Apr 20.

  PMID: 28434648 BACKGROUND

• Kim HD, Jung S, Lim HY, Ryoo BY, Ryu MH, Chuah S, Chon HJ, Kang B, Hong JY, Lee HC, Moon DB, Kim KH, Kim TW, Tai D, Chew V, Lee JS, Finn RS, Koh JY, Yoo C. Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial. Nat Med. 2024 Mar;30(3):699-707. doi: 10.1038/s41591-024-02824-y. Epub 2024 Feb 19.

  PMID: 38374347 DERIVED

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

regorafenib; Nivolumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Changhoon Yoo, MD, PhD

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 13, 2020
• First Posted: March 17, 2020
• Study Start: June 16, 2020
• Primary Completion: May 30, 2022
• Study Completion: November 30, 2022
• Last Updated: December 6, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

KR (3)