Regorafenib followed by Nivolumab in patients with Hepatocellular Carcinoma progressing under sorafenib

Phase 1

• Conditions: Hepatocellular carcinoma; MedDRA version: 20.0 Level: PT Classification code 10073071 Term: Hepatocellular carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2019-003108-10-ES
• Lead Sponsor: Fundació Clinic per a la Recerca Biomèdica

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-11-06
• Last Update Posted: 1 February 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 60

Inclusion Criteria

1. Male or female subjects 18 years of age or older.
2. Heptatocellular carcinoma (HCC) diagnosed according to American Association for the Study of Liver Diseases (AASLD) guideline.
3. Presence of a naïve target lesion.
4. Adequate liver function: albumin > 2.8 g/dL; total bilirubin < 3 mg/dL; alanine and aspartate aminotransferases < 5 times the upper limit of the normal range, and Child-Pugh score <7 points.
5. Performance status 0-1
6. Controlled arterial hypertension and/or stable peripheral vascular disease
7. Adequate hematologic profile: platelet count > 60x109/L; haemoglobin > 8.5g/dL; and prothrombin time > 50%.
8. Adequate renal function: serum creatinine < 1.5 times the upper limit of the normal range.
9. All but first-line-related dermatologic adverse events must be grade I according to Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Early dermatologic adverse events related to sorafenib must be resolved before starting regorafenib.
10. Radiological tumor progression to first-line treatment within the 2 months of inclusion in the study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion Criteria

1. Myocardial infarction in the last year or active ischemic heart disease
2. Acute variceal bleeding in the last month
3. Severe peripheral arterial disease
4. Cardiac arrhythmia under treatment with drugs different from beta-blockers or digoxin
5. Uncontrolled ascites
6. Encephalopathy
7. Unfeasibility to fulfill the follow-up Schedule.
8. Co-infection with hepatitis B (HBV) and C (HCV) as evidenced by detectable HBV surface antigen or HBV DNA and HCV RNA or Hepatitis D infection in subjects with HBV.
9. Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, prostate cancer without evidence of PSA progression or carcinoma in situ such as the following: gastric, prostate, cervix, colon, melanoma, or breast.
10. Subjects with any active autoimmune disease or history of known or suspected autoimmune disease except for subjects with vitiligo, resolved childhood asthma/atopic, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
11. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
12. Known active drug or alcohol abuse
13. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways);
14. Prior organ allograft or allogeneic bone marrow transplantation
15. All but dermatologic toxicities attributed to first-line treatment must have resolved to Grade 1 (NCI CTCAE version 5) or baseline before administration of study drug. Subjects with toxicities attributed to first-line treatment therapy that are not expected to resolve and result in long-lasting sequelad are not permitted. Neuropathy must have resolved to Grade 2 (NCI CTCAE version 5). Dermatologic toxicities must be resolved.
16. Active bacterial or fungal infections requiring systemic treatment within 7 days.
17. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or at least 5 half-lives (whichever is longer) before study drug administration.
18. Known or underlying medical conditions that, in the Investigator’s opinion, would make the administration of the study drug hazardous to the subjects or obscure the interpretation of toxicity determination or adverse events.
19. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
20. Laboratory evidence of any underlying medical conditions that, in the Investigator’s opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the safety of regorafenib in combination with Nivolumab.;<br> Secondary Objective: Time to progression (TTP)<br> Pattern of progression under early phase of regorafenib and under the combination of regorafenib plus nivolumab<br> Overall survival (OS)<br> Post-progression survival<br> Rate of patients who develop new extra-hepatic spread Objective response rate (ORR)<br> ;<br> Primary end point(s): Rate and type of AEs leading to treatment discontinuation<br> Rate and type of AEs<br> Rated and type of Serious AEs (SAEs)<br> Rate of related-AE<br> Rate of death.<br> ;Timepoint(s) of evaluation of this end point: During treatment and 30 days after the last dose.

Secondary Outcome Measures

Name	Time	Method
<br> Secondary end point(s): Time to progression<br> Pattern of progression under early phase of regorafenib and under the combination of regorafenib plus nivolumab<br> Overall survival<br> Post-progression survival<br> Rate of patients who develop new extra-hepatic spread Objective Rate Response (ORR)<br> ;Timepoint(s) of evaluation of this end point: During treatment and follow-up period