Regorafenib Plus Tislelizumab as First-line Systemic Therapy for Patients With Advanced Hepatocellular Carcinoma

NCT04183088 | Unknown Phase 2 DMC

• 1 other identifier: 201911021MIFB
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 1

Brief Summary

Combination of anti-angiogenic molecular targeted therapy and anti- programmed cell death -1 immune checkpoint inhibitor (ICI) therapy has shown promising antitumor activity in multiple cancer types, including patients with advanced hepatocellular carcinoma (HCC). The safety profile and optimal dosage of targeted therapy should be carefully evaluated by clinical trials. Regorafenib is one of the standard second-line systemic therapy for advanced HCC. The present study will test the safety and efficacy of combination of regorafenib and tislelizumab, an anti-programmed cell death-1 ICI. The investigator(s) thus hypothesized that combination of tislelizumab and regorafenib is a tolerable regimen and may improve treatment efficacy for patients with advanced HCC. The present study will explore safety and efficacy of the combination of tislelizumab plus regorafenib as first-line therapy for advanced HCC.

Conditions

Advanced Hepatocellular Carcinoma

Outcome Measures

Primary Outcomes (3)

• Safety cohort: 14 participants with treatment related serious adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) V5.0.

  14 or fewer participants who experience grade 3 or greater treatment-related adverse events at the 80 mg per day level, as defined by Common Terminology Criteria for Adverse Events (CTCAE)V5.0.

  Day 1, Change from Day 1 to 23-37 days after the last dose of study drug treatment.

• Randomized cohorts: Objective response rate (ORR) (co-primary)

  The percentage of 100 participants with radiologically complete or partial response as determined by the investigator according to Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)

  about 1 year

• Randomized cohorts: Progression-free survival (PFS) (co-primary)

  PFS is measured from the date of study enrollment to radiographically documented progression according to RECIST 1.1 or death from any cause (whichever occurs first).

  about 1 year

Secondary Outcomes (7)

• Safety cohort: safety as assessed by 25 participants experiencing who incidence and severity of total AE, liver related AE, and immune-related AE.

  Day 1, Change from Day 1 to 23-37 days after the last dose of study drug treatment.

• Safety cohort: Proportion of 25 participants who may escalate the dose of regorafenib (continuous dosing) during study drug treatment

  Day 1 of each cycle

• Safety cohort: Objective response rate (ORR)

  about 1 year

• Randomized cohort: safety as assessed by 100 participants experiencing who incidence and severity of total AE, liver related AE, and immune-related AE.

  Day 1, Change from Day 1 to 23-37 days after the last dose of study drug treatment.

• Randomized cohort: Objective response rate (ORR)

  about 1 year

Study Arms (3)

Part 1: Tislelizumab intravenously + regorafenib orally

EXPERIMENTAL

Part 1 is a single-arm study. All eligible patients will receive tislelizumab 200 mg intravenously on day 1 every 3 weeks plus regorafenib orally 80 mg per day.

Drug: Tislelizumab+regorafenib for part 1;Tislelizumab+regorafenib for group 1 of part 2; Regorafenib for group 2 of part 2.

Groups (1) of part 2: Tislelizumab intravenously + regorafenib

EXPERIMENTAL

Tislelizumab 200 mg intravenously on Day 1+Regorafenib its dosage in the randomized cohort will be determined according to results in the safety cohort.

Drug: Tislelizumab+regorafenib for part 1;Tislelizumab+regorafenib for group 1 of part 2; Regorafenib for group 2 of part 2.

Groups (2) of part 2: regorafenib

ACTIVE COMPARATOR

Daily dose of regorafenib 80mg/day is for week 1; Daily dose of regorafenib 120mg/day is for week 2; Daily dose of regorafenib 160mg/day is for week 3; Dosing-free interval is for week 4. * The dose of regorafenib will not be escalated if treatment-related AE \> grade 1 occurs at the previous dose level. * For subjects in the group 2, when imaging evaluation of tumor response indicates stable disease or progressive disease, according to RECIST v1.1, study treatment will be shifted to regorafenib + tislelizumab combination regimen.

Drug: Tislelizumab+regorafenib for part 1;Tislelizumab+regorafenib for group 1 of part 2; Regorafenib for group 2 of part 2.

Interventions

Tislelizumab+regorafenib for part 1;Tislelizumab+regorafenib for group 1 of part 2; Regorafenib for group 2 of part 2. DRUG

There will be no dose reduction for tislelizumab in this study. In the part 1(safety cohort), if the subjects do not experience grade 2 or greater regorafenib-related adverse events after 2 cycles (6 weeks) of treatment, the dosage of regorafenib may be escalated. For subjects who escalate the regorafenib dosage to Level 2, if the subjects do not experience grade 2 or greater regorafenib-related adverse events after 2 cycles of study drug treatment, the dosage of regorafenib may be further escalated to Level 3. During study drug treatment, dose delay/ interruption of regorafenib will be done depending on the occurrence and severity of regorafenib-related adverse events. After dose reduction of regorafenib, if the subjects tolerate the reduced dose of regorafenib well, the investigators may consider re-escalation of regorafenib to the previous dose level, depending on the types and severity of adverse events that led to dose reduction.

Also known as: Stivarga, BAY-73-4506, BGB-A317

Groups (1) of part 2: Tislelizumab intravenously + regorafenib; Groups (2) of part 2: regorafenib; Part 1: Tislelizumab intravenously + regorafenib orally

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
• Age ≥ 20 years, according to local regulation in Taiwan, at time of signing Informed Consent Form.
• Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology.
• Disease that is not amenable to curative surgical and/or locoregional therapies, or progressive disease after surgical and /or locoregional therapies
• Agreement to have a new tumor biopsy for eligibility to this study
• No prior systemic therapy (including systemic investigational agents) for HCC.
• For patients with chronic hepatitis B virus (HBV) infection: agreement to receive anti-HBV treatment (per local standard of care; e.g., entecavir) prior to study entry and willingness to continue treatment for the length of the study.
• At least one measurable (per RECIST 1.1) lesion. Patients who received prior local therapy (e.g., radiofrequency ablation or transarterial chemoembolization, etc.) are eligible provided the 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 version 1.1.
• The liver tumors, if any, should occupy ≤ 50% of estimated liver volume.
• Eastern Cooperative Oncology Group Performance Status of 0 or 1 within 7 days prior to first dose of study drug treatment.
• Child-Pugh class A within 14 days prior to first dose of study drug treatment.
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 7 days prior to first dose of study drug treatment, unless otherwise specified:
• Absolute neutrophil count≥1.5 \* 109/L without granulocyte colony-stimulating factor support; platelet count ≥75 \*109/L without transfusion; and hemoglobin≥(9 g/dL (patients may be transfused to meet this criterion).
• Liver transaminases (AST and ALT) ≤5 x upper limit of normal (ULN)
• Serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula)

You may not qualify if:

• Histological diagnosis of fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• Liver tumor(s) with main portal vein thrombosis.
• Known human immunodeficiency virus (HIV) infection.
• History of esophageal/gastric varices or active peptic ulcers that are considered to have high risk of bleeding.
• History of upper gastrointestinal bleeding within 1 year.
• Underlying medical conditions that, in the investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or AEs."
• Prior allogeneic stem cell or solid organ transplantation.
• Treatment with investigational therapy within 28 days prior to initiation of study treatment.
• Prior therapy with an anti-Programmed cell death protein(PD)-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte protein 4 antibody (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways).
• Local therapy to liver (e.g., radiofrequency ablation, transarterial chemoembolization, etc.) within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure.
• Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to initiation of study treatment, except for palliative radiotherapy to bone lesions. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.
• Patients with a history of treated and, at the time of screening, asymptomatic central nervous system(CNS) metastases are eligible, provided they meet all the following:
• Brain imaging at screening shows no evidence of interim progression
• Have measurable disease outside the CNS
• No ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed

Sponsors & Collaborators

• National Taiwan University Hospital: lead
• National Taiwan University Hospital, Yun-Lin Branch: collaborator

Study Sites (1)

National Taiwan University Hospital

Taipei, Zhongzheng Dist, 100, Taiwan

RECRUITING

MeSH Terms

Interventions

regorafenib; tislelizumab

Study Officials

• Ann-Lii Cheng, MD, PhD

  National Taiwan University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chiun HSU, MD, PhD

CONTACT

+886-2312-3456; chsu1967@ntu.edu.tw,hsuchiun@gmail.com

Yu-Chun Liu, BS

CONTACT

+886-2312-3456; 105596@ntuh.gov.tw

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Masking is None (open label) and the allocation is N/A for part 1.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This trial consists of 2 parts. Part 1 is a single-arm study. Part 2 of this trial is a randomized study. Subjects will be 1:1 randomized to 2 treatment groups: (1) regorafenib + tislelizumab combination regimen as used in Part 1, versus (2) regorafenib therapy. For subjects in the group 2, when imaging evaluation of tumor response indicates stable disease or progressive disease, according to RECIST v1.1, study treatment will be shifted to regorafenib + tislelizumab combination regimen.

Study Record Dates

• First Submitted: November 25, 2019
• First Posted: December 3, 2019
• Study Start: December 16, 2020
• Primary Completion: March 1, 2024
• Study Completion: March 1, 2025
• Last Updated: December 23, 2020

Record last verified: 2020-12

Locations

TW (1)