Clinical Trials /

Optimization for Regorafenib in HCC

NCT04476329

Description:

This is a randomized, two arm, phase II study of 1st Cycle dose optimization for regorafenib treatment compared to standard dose of regorafenib treatment in HCC patients for whom the physician is intending to treat with regorafenib and who failed any 1st line systemic treatment.

Related Conditions:
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Optimization for Regorafenib in HCC
  • Official Title: A Randomized Phase II Study of First Cycle Optimization for Regorafenib Treatment Compared to Standard Dose of Regorafenib in Patients With HCC Who Failed Any 1st Line Systemic Treatment and for Whom the Physician is Intending to Treat With Regorafenib

Clinical Trial IDs

  • ORG STUDY ID: 21305
  • NCT ID: NCT04476329

Conditions

  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
Regorafenib 40 MGStivargaA

Purpose

This is a randomized, two arm, phase II study of 1st Cycle dose optimization for regorafenib treatment compared to standard dose of regorafenib treatment in HCC patients for whom the physician is intending to treat with regorafenib and who failed any 1st line systemic treatment.

Detailed Description

      In this study, the investigators intend to evaluate the regorafenib ReDOS strategy to
      optimize the dose of regorafenib in patients with unresectable HCC (uHCC) who progressed
      during or after the first-line systemic treatment. This would allow improving the
      tolerability profile for patients such as those not selected based on prior sorafenib
      tolerability. The proposed regorafenib dosing escalation strategy for subjects randomized to
      the Arm A starting 80 mg/day dose for one week (Cycle 1, Week 1) is, if absent significant
      drug-related toxicities, to escalate to 120 mg/day for another week (Cycle 1, Week 2), and
      then, again if absent significant related toxicities, escalate to a total dose of 160 mg/day
      (Cycle 1, Week 3) followed by a week-long break (Cycle 1, Week 4).

      Arm B, the comparative arm, will include a standard dose/schedule regorafenib of a 160 mg/day
      starting on Cycle 1, Day 1. The primary goal of this Arm is compare whether, or not, an 80
      mg/day starting dose of regorafenib that escalates weekly by 40 mg until 160 mg/day is
      non-inferior to the FDA approved labeling 160 mg starting dose of regorafenib in terms of
      Overall Survival (OS) in HCC subjects. The investigators will also compare the proportions of
      patients in each arm who complete two cycles of treatment and who intend to continue to a
      third cycle if no tumor progression is noted on the 8-week disease scan. Other outcomes such
      as Quality of Life measures, and toxicity profile with a focus on regorafenib related
      toxicities such as hand-foot skin reaction will also be assessed.

      Patients will be randomized 1:1 to either Arm A receiving the Cycle 1 Week-1 80 mg daily dose
      or Arm B the standard FDA labeling 160 mg daily starting dose, with subsequent dose
      adjustments as needed. Patients with unacceptable toxicities at the 80 mg dose may be
      considered for further dose reduction but will no longer be included in the overall survival
      analysis. After the conclusion of Cycle 2 (Week 8 of treatment), if toxicities have
      sufficiently resolved, re-escalation is allowed 40 mg at a time every four weeks to a maximum
      of 160 mg/day at the discretion of the treating investigator.

      Patients will continue treatment until progression, unacceptable adverse events, or patient
      refusal. Treatment will then be discontinued, and the patient will go to event monitoring.

      Additionally, a site-optional and subject-optional sub-study collecting blood serum samples
      at the Screening Visit for "hold and store" for future analysis of CD14, CD15, and CD16 cells
      as well as other potential biomarkers to be determined.
    

Trial Arms

NameTypeDescriptionInterventions
AActive ComparatorArm A: Regorafenib Cycle 1: 80 mg daily Week 1 120 mg daily Week 2 160 mg daily week 3 then 1 week off followed by Cycle 2+ (160 mg for 21 days/1 week off) Subsequent Treatment Cycles 160 mg daily for 21 days, then 1 week off.
  • Regorafenib 40 MG
BActive ComparatorArm B: Regorafenib Cycle 1: 160 mg daily for 21 days/then 1 week off Subsequent Treatment Cycles 160 mg daily for 21 days, then 1 week off
  • Regorafenib 40 MG

Eligibility Criteria

        Inclusion Criteria:

          1. Patients age ≥ 18 years.

          2. Histological, cytological confirmation of hepatocellular carcinoma or non-invasive
             diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD)
             criteria in patients with a confirmed diagnosis of cirrhosis.

          3. Locally advanced or metastatic and/or unresectable HCC that is not amenable or
             progressed after curative surgical and/or locoregional therapies.

          4. Patients who received one prior systemic treatment and for whom the treating physician
             has decided to treat with regorafenib.

          5. Life expectancy of ≥ 3 months.

          6. The following laboratory values obtained ≤ 7 days prior to randomization.

               -  Absolute neutrophil count (ANC) > 1500/mm3

               -  Platelet count > 60,000/mm3

               -  Hemoglobin > 9.0 g/dL

               -  Albumin > 2.7 gm/dL

               -  Total bilirubin < 2 mg/dl (Mildly elevated total bilirubin (< 6 mg/dL) is allowed
                  if Gilbert's syndrome is documented)

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5 x ULN

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance > 50 mL/min (calculated
                  using the Cockcroft-Gault formula)

               -  INR/PTT ≤ 1.5 x ULN

               -  Alkaline phosphatase limit ≤ 2.5 x ULN

          7. 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 1.1.

          8. Eastern Cooperative Oncology Group (ECOG) = 0 or 1

          9. Negative serum pregnancy test done ≤ 7 days prior to randomization, for females of
             childbearing potential only.

         10. Provide written informed consent.

         11. Patients with a prior liver transplant may be included if they have no history of
             graft rejection within the previous 6 months and stable graft function.

        Exclusion Criteria:

          1. Prior treatment with regorafenib.

          2. Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior
             to randomization.

          3. Congestive heart failure > New York Heart Association (NYHA) class 2.

          4. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
             months) or myocardial infarction less than 6 months prior to randomization.

          5. Cardiac arrhythmias requiring anti-arrhythmic therapy. Note: beta blockers or digoxin
             are permitted.

          6. Uncontrolled hypertension. (Systolic blood pressure > 150 mmHg or diastolic pressure >
             90 mmHg despite optimal medical management).

          7. History of or current pheochromocytoma.

          8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism ≤ 6
             months prior to randomization.

          9. Ongoing infection > grade 2 NCI-CTCAE version 5.0.

         10. Patients with seizure disorder requiring medication.

         11. Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from
             definitive therapy, has a negative imaging study within 4 weeks of randomization and
             is clinically stable with respect to the tumor at the time of randomization.

             NOTE: Patient must not be undergoing acute steroid therapy or taper (chronic steroid
             therapy is acceptable provided that the dose is stable for one month prior to and
             following screening radiographic studies).

         12. History of organ allograft (including corneal transplant), except prior liver
             transplant.

         13. Hepatic Encephalopathy requiring hospital admission within six (6) months prior to
             randomization.

         14. Ascites requiring paracentesis within four (4) weeks of randomization.

         15. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event > CTCAE
             grade 3 ≤4 weeks prior to randomization.

         16. Non-healing wound, ulcer, or bone fracture.

         17. Renal failure requiring hemo-or peritoneal dialysis.

         18. Substance abuse, medical, psychological, or social conditions that may interfere with
             the patient's participation in the study or evaluation of the study results.

         19. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
             the formulation.

         20. Interstitial lung disease with ongoing signs and symptoms at the time of informed
             consent.

         21. Persistent proteinuria of CTC Grade 3 or higher (> 3.5 g/24 hrs, measured by urine
             protein: creatinine ratio on a random urine sample).

         22. Patients unable to swallow oral medications.

         23. Any malabsorption conditions that will affect that absorption of regorafenib.

         24. Unresolved toxicity greater than CTCAE (version 5.0) Grade 1 attributed to any prior
             therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity ≤ Grade 2.

         25. Pregnant or nursing women and men or women of childbearing potential who are unwilling
             to employ adequate contraception because regorafenib is a chemotherapeutic agent that
             has known genotoxic, mutagenic, and teratogenic effects.

             NOTE: Men and women of childbearing potential must agree to use adequate contraception
             beginning at the signing of the ICF until at least 2 months after the last dose of
             study drug. The definition of adequate contraception will be based on the judgment of
             the principal investigator or a designated associate.

         26. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens.

         27. Immunocompromised patients and patients known to be HIV positive and currently
             receiving antiretroviral therapy.

        NOTE: Patients known to be HIV positive, but without clinical evidence of an
        immunocompromised state, are eligible for this trial. Active infection requiring systemic
        treatment, known infection with human immunodeficiency virus (HIV), or known acquired
        immunodeficiency syndrome (AIDS)-related illness 29. Pleural effusion or ascites that
        causes respiratory compromise (≥ CTCAE version 4.0 Grade 2 dyspnea).

        30. Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery,
        immunotherapy, biologic therapy, or tumor embolization) other than study treatment
        (regorafenib, other agents being investigated in combination with regorafenib).

        31. Use of any herbal remedies known to have interference with liver or other major organ
        functions. Patients must notify the investigator of all herbal remedies used during the
        study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:24 months
Safety Issue:
Description:The primary objective is to evaluate whether, or not, an 80 mg/day starting dose of regorafenib that escalates weekly by 40 mg until 160 mg/day is non-inferior compared to the FDA approved labeling 160 mg starting dose of regorafenib in terms of Overall Survival in HCC subjects.

Secondary Outcome Measures

Measure:Regorafenib treatment cycles
Time Frame:24 months
Safety Issue:
Description:Proportion of patients who complete two cycles of treatment and who intend to initiate Cycle 3 if no progression is noted on the planned 8-week scan
Measure:Tumor Progression
Time Frame:24 months
Safety Issue:
Description:Progression-free survival (PFS) per RECIST v1.1 with exploratory analysis of progression-free survival (PFS) per mRECIST where available
Measure:Dosing Patterns
Time Frame:24 months
Safety Issue:
Description:Evaluate the dosing schedule of regorafenib treatment, including: cumulative doses received during first and second cycles, duration of treatment (DOT) measured from Cycle 1 Day 1 to the 1 Month Follow-Up 30 days after the last dose of regorafenib, and summary of additional dose patterns or parameters such as the median daily dose for each treatment arm.
Measure:EORTC QOL-C30 Quality of Life Measurements
Time Frame:24 months
Safety Issue:
Description:The EORTC QOL-C30 Quality of Life questionnaire contains 30 questions around physical, day-to-day functioning, and side effects experienced measured on a 4 point Likert scale with a response range of "1-not at all," "2-a little bit," "3-quite a bit," and "4-very much." The results between the Arms, particularly for Cycle 1, will be compared.
Measure:Optional CD14-16 cell sub-study
Time Frame:36 months
Safety Issue:
Description:An optional sub-study, collect and hold blood samples from 100 subjects for analysis of mononuclear cells (CD14, 15 & 16 cells) and other potential biomarkers at a to-be-determined time point after completion of the study.
Measure:FACIT FACT-Hep Quality of Life Measurements
Time Frame:24 months
Safety Issue:
Description:The FACT-Hep Quality of Life questionnaire contains 46 questions around physical, social/family, emotional, day-to-day functioning, and side effects experienced measured on a 5 point Likert scale with a response range of "0-not at all," "1-a little bit," "3-somewhat," "4-quite a bit," and "5-very much." The results between the Arms, particularly for Cycle 1, will be compared..

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:SC Liver Research Consortium, LLC

Trial Keywords

  • Hepatocellular carcinoma
  • Liver Cancer
  • HCC
  • Regorafenib
  • Sorafenib
  • Stivarga

Last Updated

April 19, 2021