None listed
Conditions
Interventions
Drug : * Investigational arm(Regorafenib+Pembrolizumab)
1. Regorafenib:
-90 mg (3 x 30 mg tablets) orally
-q.d for 3 weeks of a 4-week cycle (i.e., 3 weeks on, 1 week off). The regorafenib break must
Sponsors
Inje University Haeundae Paik Hospital
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed and dated PICF obtained prior to any protocol related procedure that is not part of standard patient care. 2. Patient is = 18 years-old at the time of PICF signature (or the legal age of consent in the jurisdiction in which the trial is taking place). 3. Confirmed diagnosis of HCC based on: • Histopathological findings from tumor tissue, and/or • Diagnostic imaging on dynamic CT or MRI according to AASLD criteria (https://www.aasld.org/publications/practice-guidelines).17 4. Intermediate-stage HCC, defined as follows: • Multinodular HCC (more than 3 tumors in the liver or 1 to 3 tumors with at least 1 that is larger than 5 cm), localized to the liver. • No evidence of MVI or EHS on the screening or any prior imaging. • Not amenable to curative treatment (e.g., surgery or transplantation or curative ablation). • Liver function status Child-Pugh Class A (Appendix 1: Child-Pugh Classification). Child-Pugh status should be calculated based on clinical findings and laboratory results during the screening period. • ECOG PS 0 or 1 at screening (Table 13). • ALBI grade 1 or 2 at screening (Appendix 2: Albumin-Bilirubin (ALBI) Grade). 5. Beyond up-to-7 criteria, defined as an HCC exceeding the up-to-7 criteria (Up-to-7 criteria = largest tumor diameter (cm) + number of tumors =7). 6. Disease amenable to TACE or TARE and no contraindication to intra-arterial treatment. All liver disease should be able to be controlled with the protocol-required TACE/TARE procedures (see section 5.4.2.1), in the opinion of the Investigator. 7. Measurable disease by CT or MRI as per RECIST 1.1 criteria (Appendix 6: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1) based on radiographic tumor assessment performed = 28 days prior to randomization. 8. No prior systemic or locoregional therapy for HCC, with the exception of patients previously treated with resection and/or ablation that meet ALL the following criteria: • Prior resection/ablation (latest procedure prior to enrollment) achieved complete response. • Time from completion of prior resection/ablation (latest procedure prior to enrollment) until diagnosis of recurrence is = 6 months (i.e., = 180 days) • HCC recurrence comprises at least 2 untreated lesions (i.e., not previously ablated/resected) having each = 10 mm in longest diameter and showing intratumoral arterial enhancement, according to radiographic tumor assessment performed = 28 days prior to randomization. 9. Adequate hematologic and organ function as assessed by the following laboratory tests performed = 7 days before randomization: • Hematological: • Platelet count = 75,000 /mm3 • Hemoglobin = 9.0 g/dL • Absolute neutrophil count = 1,500 /µL Note: Patients who received blood products during screening for the purposes of meeting eligibility criteria, will not be eligible. • Hepatic/Pancreatic: • Total bilirubin = 2.0 × the upper limit of normal (ULN). Total bilirubin (=3 x ULN) is allowed if Gilbert’s syndrome is documented. • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 5.0 x ULN • Lipase = 2 x ULN • Amylase = 2 x ULN • Coagulation: • International normalized ratio (INR) < 2.3 and activated partial thromboplastin time (aPTT) < 1.5 x ULN unless receiving treatment with therapeutic anticoagulation • Renal: • Serum creatinine = 1.5 x ULN or calculated creatinine clearance =40 mL/min (using the Cockcroft-Gault formula) 10. Patient
Exclusion criteria
Exclusion criteria: 1. No measurable tumor of a diffuse infiltrative HCC type. 2. Fibrolamellar HCC, sarcomatoid HCC or mixed hepatocellular/cholangiocarcinoma subtypes. 3. Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g., paracentesis) to maintain symptomatic control, = 6 months prior to randomization. Patients with ascites that have required pharmacologic intervention (e.g., diuretics) and who have been on stable doses of diuretics for ascites for greater than or equal to 2 months are eligible. 4. Prior treatment with regorafenib, a PD-1, PD-L1/PD-L2, or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 5. Previous treatment with a live replication-competent vaccine = 30 days prior to the planned date of trial treatment start. 6. Treatment with a strong CYP3A4 inducer or strong CYP3A4 inhibitor = 14 days prior to the planned date of trial treatment start (see section 5.6.6). 7. Concurrent participation in another clinical trial, unless it is: (a) an observational (non interventional) clinical trial, or (b) the follow-up period of an interventional trial and patient did not receive an investigational agent/device = 28 days before randomization (or = 5 half-lives of the drug, whichever is longer). 8. Known hypersensitivity to any of the trial drugs or their formulation components. 9. Major surgical procedure, open biopsy or significant traumatic injury =28 days prior to randomization. Patients must have recovered adequately from the toxicity and/or complications from the intervention before randomization. 10. Active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus, connective tissue diseases, scleroderma, inflammatory bowel disease, Crohn’s, ulcerative colitis, hepatitis; and patients with a history of TEN, SJS, or phospholipid syndrome. Note: Patients with the following diseases are not excluded: • Controlled Type I diabetes • Hypothyroidism (provided it is managed with hormone replacement therapy only) • Celiac disease controlled by diet alone • Skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis, alopecia) • Any other disease that is not expected to recur in the absence of external triggering factors 11. Requirement of systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medications = 14 days prior to randomization. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: • Adrenal replacement steroid (dose = 10 mg daily of prednisone or equivalent) • Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption • Short course (= 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a nonautoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen) 12. Uncontrolled diabetes or > Grade 1 l
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| PFS | — |
Secondary
| Measure | Time frame |
|---|---|
| PFS, OS, ORR, TTUP, DOR | — |
Countries
Korea, Republic of
Contacts
Public ContactInJung Kim
Korean Cancer Study Group
Outcome results
None listed