Increasing doses of regorafenib for advanced liver cancer

Dose-escalation Strategy of Regorafenib in Patients With Advanced Hepatocellular Carcinoma

This study is testing if increasing doses of regorafenib can help people with advanced liver cancer feel better and live longer after their first treatment didn't work.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 28 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Instituto do Cancer do Estado de São Paulo (other)
• Drugs / interventions: atezolizumab, bevacizumab, levantinib, immunotherapy, Radiation
• Locations: 1 site (São Paulo)
• Trial ID: NCT05622136 on ClinicalTrials.gov

What this trial studies

This trial evaluates the tolerability, quality of life, and efficacy of a dose-escalation regimen of regorafenib in patients with advanced hepatocellular carcinoma who have progressed after first-line treatment. Participants will start with an initial dose of 80mg, increasing weekly by 40mg up to a maximum of 160mg during the first two treatment cycles. The study aims to determine the maximum tolerated dose while monitoring for adverse events and assessing overall survival and quality of life. The primary endpoint is the proportion of patients completing the fourth treatment cycle.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with advanced hepatocellular carcinoma who have previously received at least one line of systemic treatment.

Not a fit: Patients who have previously been treated with regorafenib or those with Child-Pugh C liver function will not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could improve the tolerability of regorafenib, enhancing treatment options for patients with advanced liver cancer.

How similar studies have performed: Previous studies have shown that dose escalation strategies for regorafenib in other cancers have improved tolerability, but this specific approach in advanced HCC is novel.

Eligibility criteria

Inclusion Criteria:

1. Age 18 years or older;
2. Hepatocellular carcinoma with histological or cytological confirmation or that meet radiological criteria for the diagnosis of HCC21;
3. BCLC-B stage not candidate for locoregional treatment or BCLC-C;
4. Have been previously treated with at least 1 line of systemic treatment with sorafenib, levantinib, atezolizumab plus bevacizumab or other immunotherapy-based regimen;
5. Have received the last dose of first-line systemic treatment between 2 and 6 weeks before starting study treatment;
6. Recovery to baseline or ≤ grade 1 from toxicities related to any previous treatments, unless the adverse event is not clinically significant as determined by the investigator (according to the Common Terminology Criteria for Adverse Events (CTCAE) v522);
7. Not having received previous treatment with regorafenib;
8. Child-Pugh A or B7 (in the absence of clinical ascites);
9. Measurable disease as defined by the RECIST 1.1 criteria. Target lesions must not have undergone previous local or locoregional treatment (example: ablation, transarterial chemoembolization, radiotherapy or selective internal radiotherapy)
10. Performance status: ECOG 0 or 1.
11. Adequate hematologic, hepatic and renal functions as defined below:

    i. Hemoglobin ≥ 8.5 g/dl ii. Absolute neutrophil count ≥ 1,000 /mm3 iii. Platelet count ≥ 50,000 /mm3 iv. Total bilirubin \< 2.0 x upper limit of normality (ULN) v. ALT or AST \<5 x LSN vi. Creatinine clearance (CrCI) ≥ 30 mL/min (according to Cockroft-Gault formula) vii. Serum albumin ≥ 2.8 mg/dl
12. Ability to understand informed consent and comply with the treatment protocol.
13. Informed consent form and clarification signed by the patient, impartial witness or legal representative.
14. Sexually active patients of childbearing potential and their partners must agree to use highly effective methods of contraception that result in a rate of less than 1% per year when used consistently and correctly throughout the study and 6 months after treatment discontinuation;
15. Female participants of childbearing potential cannot be pregnant at screening.

Exclusion Criteria:

1. Fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular cholangiocarcinoma;
2. Previous use of regorafenib;
3. Hepatic encephalopathy or medication requirement to control hepatic encephalopathy in the last 60 days before randomization;
4. Clinically significant ascites (ie, ascites that requires parcentesis or increased dose of diuretics) within 30 days prior to randomization.
5. Patients who have received local therapies (ablation, transarterial chemomebolization or surgery) within 28 days prior to randomization. Radiation treatments with the aim of pain control of bone metastases are allowed.
6. Known or suspected brain metastasis or cranial epidural disease unless adequately treated with surgery or radiotherapy and stable for at least 8 weeks from randomization.
7. Any participant who cannot be submitted neither to computed tomography (CT) nor magnetic resonance imaging (MRI) due to contra-indication to contrast media used.
8. The participant has an uncontrolled disease, or a significant complication in the last 28 days of randomization, such as:

   1. Cardiovascular disorders:

      * i. Class III or IV congestive heart failure as defined by the New York Heart Association, unstable angina pectoris, or symptomatic arrhythmias;
      * ii. Uncontrolled hypertension (defined as systolic blood pressure greater than 160 mmgHg or diastolic pressure \> 95 mmHg despite antihypertensive therapy);
      * iii. Stroke, myocardial ischemia, or any ischemic event within the 6-month period prior to randomization;
   2. Gastrointestinal disorders, including those associated with a high risk of perforation:

      * i: active peptic ulcer disease, inflammatory bowel disease, tumors invading the gastrointestinal tract, diverticulitis, cholecystitis, appendicitis, acute pancreatitis and cholangitis;
      * ii: Abdominal fistula, gastro-intestinal perforation or abdominal abscess in the last 6 months;
      * iii: Esophageal varices that have not been adequately treated or that have been incompletely treated with bleeding or high risk of bleeding. Participants treated with adequate endoscopic therapy with no bleeding in the past 6 months are eligible;
   3. Clinically detected hematuria, hematemesis, melena, hemoptysis (\>2.5 ml) or other clinically significant bleeding within the last 3 months of randomization.
   4. Cavitating pulmonary lesion or known manifestation of endobronchial disease;
   5. Other clinically significant diseases, at the discretion of the attending physician.
9. Majority surgery within 28 days of randomization. Minor surgeries within 10 days of randomization. Participants must have complete healing of the procedures prior to randomization;
10. History of psychiatric illness that is likely to interfere with the ability to understand the study procedures;
11. Pregnant or breastfeeding women;
12. Inability to swallow pills;
13. Known allergies to study drug components;
14. Any other known malignancy active at the time of randomization or diagnosis of another malignancy within two years of randomization, except superficial skin carcinomas or low-grade localized tumors considered cured and not treated with systemic therapy.

Where this trial is running

São Paulo

• ICESP - Instituto do Câncer do Estado de São Paulo — São Paulo, Brazil (RECRUITING)

Study contacts

• Study coordinator: Leonardo Fonseca, MD

Conditions: Liver Cancer, Hepatocellular Carcinoma, Regorafenib, Hepatocellular carcinoma, Dose, Tolerability, Quality of life