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Hepatocellular CarcinomaPhase 2HCCNCT05134532

Regorafenib After Progression on Atezolizumab Plus Bevacizumab in Advanced HCC

A Phase 2 study testing regorafenib in people with Hepatocellular Carcinoma, run by CHA University at 2 sites in South Korea.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial summary

To investigate efficacy and toxicity of regorafenib after treatment with atezolizumab and bevacizumab combination Read more about this study

Who is it for?
Ages 19 years and older
Conditions the study is for
Hepatocellular Carcinoma
What is being tested?
regorafenib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
2 sitesSouth Korea
Study dates
24 Dec 2021to 30 Oct 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 19 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Diagnosis of HCC according to AASLD guidelines
  • Disease that is not amenable to a curative treatment (e.g. surgery, transplant, radiofrequency ablation)
  • Prior treatment with atezolizumab plus bevacizumab combination as 1st line treatment for unresectable HCC
  • Progression after atezolizumab plus bevacizumab treatment, The duration of atezolizumab plus bevacizumab must be 2 consecutive treatment cycles or more
  • Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless the adverse events are clinically non-significant and/or stable on supportive therapy
  • Life expectancy of 12 weeks or longer
Show all 23Show fewer
  • Age ≥ 19 years old
  • ECOG performance status of 0, 1
  • Adequate hematological function
  • Absolute neutrophil count (ANC) ≥ 1.5 x109/L
  • Platelets ≥ 75 x 109/L
  • Hemoglobin ≥ 10 g/dL
  • Adequate renal function
  • serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockroft-Gault equation) AND
  • urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g
  • Child-Pugh Score of 5 or 6
  • Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L)
  • Serum albumin > 2 g/dL (> 20 g/L)
  • Alanine aminotransferase (ALT) < 3.0 upper limit of normal (ULN)
  • Antiviral therapy per local standard of care if active hepatitis B (HBV) infection
  • Capable of understanding and complying with the protocol requirements and signed informed consent
  • Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment
  • Female subjects of childbearing potential must not be pregnant at screening.

Who cannot join

  • Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma
  • Prior regorafenib treatment
  • Prior systemic treatment for HCC, except for atezolizumab plus bevacizumab (i.e. regorafenib must be 2nd line systemic treatment)
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization.
  • Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low dose LMWH are permitted.
  • The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
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  • Cardiovascular disorders including i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment iii. Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months iv. Thromboembolic event within 3 months. Subjects with thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumour are eligible b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation/bleeding: i. Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months
  • Major surgery within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before registration. Subjects with clinically relevant co d. Cavitating pulmonary lesion(s) or endobronchial disease
  • Lesion invading a major blood vessel (eg, pulmonary artery or aorta)
  • Clinically significant bleeding risk including the following within 28 days of registration: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors
  • Gastric or esophageal varices that require interventional treatment within 28 days prior to registration. Prophylaxis with pharmacologic therapy (e.g. non-selective beta blocker) is permitted.
  • Moderate or severe ascites (Radiologically detected but clinically insignificant ascites is allowed)
  • Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 21 days of registration
  • If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.
  • Previously identified allergy or hypersensitivity to components of the study treatment formulations
  • Pregnant or lactating females
  • Diagnosis of another malignancy within 2 years before randomization, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy
  • Other clinically significant disorders that are judged by investigators to be unsuitable for the clinical trial

Trial locations and contacts

2 sites in 1 country.

South Korea2 sites

  • CHA Bundang Medical Center

    Seongnam-si, Gyeonggi-do, 13520

  • Asan Medical Center

    Seoul

Other trials in South Korea

About this study

Official title: Phase II Trial of Regorafenib in Patients With Unresectable Hepatocellular Carcinoma After Progression on First Line Atezolizumab Plus Bevacizumab (REGONEXT Trial)

To investigate efficacy and toxicity of regorafenib after treatment with atezolizumab and bevacizumab combination

Read the detailed description
  • There is preclinical and clinical data on synergistic activity of angiogenesis inhibitors and anti-programmed death-1 (anti-PD-1) targeted therapy. Targeting VEGFR decreased T-regulatory cells and Myeloid-derived suppressor Cells. In addition, VEGF-A produced in the tumor microenvironment enhanced expression of PD-1 involved in CD8 T cell exhaustion8. The combination of targeted therapy and immune-checkpoint inhibitors (ICIs), either in a parallel or sequential manner, could theoretically lead to enhanced anti-tumor responses, reflected in durable responses and prolonged survival. However, there have been lack of clinical data of targeted agents who developed progressive disease with ICIs.
  • In previous phase I study, pharmacodynamics indicated a sustained occupancy of > 70% of PD-1 molecules on circulating T-cells ≥ 2 months following infusion. Based on these findings, ICI use may retain the prolonged effect even after discontinuation. There was a case report of a sorafenib-refractory patient experiencing progressive disease during ICI combination treatment with the anti-PD-1 antibody and the anti-GITR antibody within phase I trial followed by a prolonged tumor response during third-line regorafenib monotherapy.
  • In patients with advanced HCC, anti-VEGF monoclonal antibodies, multi-kinase inhibitor (sorafenib, regorafenib, cabozantinib and lenvatinib) and ICIs are available treatment options, however, treatment sequencing and combination strategy are challenging.
  • Atezolizumab plus bevacizumab demonstrated survival benefit and established as a new first-line therapy, hence it is clinically important to study the efficacy and toxicity of regorafenib after treatment with ICIs or ICI combination.
Being tested
regorafenib
Keywords
Hepatocellular carcinoma, Liver Cancer
Medical subject headings
Carcinoma, Hepatocellular, Liver Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • regorafenibDrug

    Regorafenib 160 mg orally every day for 3 weeks of every 4-week cycle (i.e. 3 weeks on, 1 week off) plus best supportive care

Study groups in NCT05134532
Study groupRoleWhat they receive
interventionExperimentalPotential subjects will be screened to determine if they meet the eligibility criteria. The screening period is 21 days. Subjects who meet all the eligibility criteria will be commenced regorafenib 160mg once daily for the first 3 weeks of each 4-week cycle.
Receives: Drug: regorafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival (PFS) by RECIST v 1.1

    the time from start of study treatment to first documentation of objective tumor progression, or to death due to any cause

    Measured: up to 36 months

Secondary outcomes (5)

  1. Overall survival

    the time from start of study treatment to date of death due to any cause

    Measured: up to 36 months

  2. Time to progression by RECIST v 1.1

    the time from start of study (Cycle 1 Day 1) to first documentation of objective tumor progression.

    Measured: up to 36 months

  3. Overall response rate by RECIST v 1.1

    the proportion of patients with confirmed complete response or confirmed partial response according to the RECIST v 1.1, relative to the total evaluable patient population.

    Measured: up to 36 months

  4. Disease control rate by RECIST v 1.1

    the percent of patients with confirmed complete response, partial response, or stable disease for at least 12 weeks on study according to RECIST v 1.1, relative to the total evaluable patient population.

    Measured: up to 36 months

  5. Safety profiles by NCI-CTCAE version 5

    For the evaluation of adverse reactions following medication, using NCI-CTCAE version 5

    Measured: up to 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Nov 2021
  2. Study start24 Dec 2021
  3. Primary completion30 Oct 2024 (estimated)
  4. Study completion30 Oct 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
40 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05134532
Sponsor's protocol ID
2021-05-048-007
Acronym
HCC
Status last verified
Apr 2023
First submitted
2 Nov 2021
Last updated
26 Apr 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 27932229

  • Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.

    PubMed 32402160

  • Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klumpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.

    PubMed 29972759

  • Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3.

    PubMed 29875066

  • 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.

    PubMed 28434648

  • Cao M, Xu Y, Youn JI, Cabrera R, Zhang X, Gabrilovich D, Nelson DR, Liu C. Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab Invest. 2011 Apr;91(4):598-608. doi: 10.1038/labinvest.2010.205. Epub 2011 Feb 14.

    PubMed 21321535

  • Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013 Jan 15;73(2):539-49. doi: 10.1158/0008-5472.CAN-12-2325. Epub 2012 Oct 29.

    PubMed 23108136

  • Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoue F, Yagita H, Tartour E, Taieb J, Terme M. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015 Feb 9;212(2):139-48. doi: 10.1084/jem.20140559. Epub 2015 Jan 19.

    PubMed 25601652

  • Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75. doi: 10.1200/JCO.2009.26.7609. Epub 2010 Jun 1.

    PubMed 20516446

  • Joerger M, Guller U, Bastian S, Driessen C, von Moos R. Prolonged tumor response associated with sequential immune checkpoint inhibitor combination treatment and regorafenib in a patient with advanced pretreated hepatocellular carcinoma. J Gastrointest Oncol. 2019 Apr;10(2):373-378. doi: 10.21037/jgo.2018.11.04.

    PubMed 31032109

  • Ilangumaran S, Villalobos-Hernandez A, Bobbala D, Ramanathan S. The hepatocyte growth factor (HGF)-MET receptor tyrosine kinase signaling pathway: Diverse roles in modulating immune cell functions. Cytokine. 2016 Jun;82:125-39. doi: 10.1016/j.cyto.2015.12.013. Epub 2016 Jan 25.

    PubMed 26822708

  • Benkhoucha M, Santiago-Raber ML, Schneiter G, Chofflon M, Funakoshi H, Nakamura T, Lalive PH. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6424-9. doi: 10.1073/pnas.0912437107. Epub 2010 Mar 23.

    PubMed 20332205

  • Rutella S, Bonanno G, Procoli A, Mariotti A, de Ritis DG, Curti A, Danese S, Pessina G, Pandolfi S, Natoni F, Di Febo A, Scambia G, Manfredini R, Salati S, Ferrari S, Pierelli L, Leone G, Lemoli RM. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood. 2006 Jul 1;108(1):218-27. doi: 10.1182/blood-2005-08-3141. Epub 2006 Mar 9.

    PubMed 16527888

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing regorafenib in people with Hepatocellular Carcinoma, run by CHA University at 2 sites in South Korea.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 26 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (PFS) by RECIST v 1.1 (time frame: up to 36 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05134532, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Apr 2023.

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