Regorafenib Followed by Nivolumab in Patients With Hepatocellular Carcinoma (GOING)

NCT04170556 | Completed Phase 1

• 2 other identifiers: GOING2019-003108-10
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 7

Brief Summary

Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation. Regorafenib has shown in clinical trials an acceptable benefit-risk across different tumor types, including colorectal cancer (CRC), GastroIntestinal Stromal Tumors (GIST) and HCC. The most frequently observed adverse drug reactions (≥30%) in patients receiving regorafenib are pain, hand-foot skin reaction (HFSR), asthenia/fatigue, diarrhea, decreased appetite and food intake, hypertension, and infection. Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody to the programmed death (PD)-1 receptor, blocking the interaction with PD-ligand (PD-L)1/PD-L213 and restoring T-cell-mediated antitumor activity. Nivolumab was evaluated in second-line the CheckMate 040 Study (Escalation and Expansion cohort. In both cohorts of the CheckMate 040 Study, the safety profile was acceptable and there were no reported nivolumab-related deaths. In the dose-expansion cohorts from the Phase 1/2 CheckMate 040 Study, 65% of patients had treatment-related adverse events (TRAEs) of any grade 18% with Grade 3 or 4 TRAEs with fatigue, pruritus, and rash being the most common. Elevation of aspartate transaminase (AST) and alanine transaminase (ALT) were the most frequent Grade 3-4 TRAEs. AST/ALT elevations, however, were generally asymptomatic and readily managed. For this reason, the rationale of this Phase I/IIa trial is to optimize the action of regorafenib and nivolumab but bearing in mind the potential impact of the drug-interaction and enhancement of the severity and/or frequency of adverse events. Thus, regorafenib will be administered as monotherapy during the first 2 cycles (each cycle is 3 weeks on plus 1 week off) of treatment to enhance T cell trafficking and infiltration into the tumor bed to increase the benefits of anti-PD-PD-L1, specific stimuli while emitting Damage-associated molecular patterns (DAMPs), followed by regorafenib plus nivolumab to impact step 7 of the cancer immunity cycle described by Chen. The anti-PD-L1 effect under hypoxia was evaluated by Noman et al in a tumor model and they postulated that the abrogated myeloid-derived suppressor cells (MDSC)-mediated T cell suppression is achieved in part by modulating the cytokine production (IL-6 and IL-10). Specifically, hypoxia could promote immunosuppression by reducing the cytotoxic efficacy of immune cells, by increasing the peri-tumoral immunosuppressive cell populations infiltration of and priming the expression of immunosuppressive cytokines. Current options for first line are sorafenib and atezolizumab-bevacizumab. Lenvatinib has been shown to be non-inferior to sorafenib, but it is less frequently used and its toxicity profile mandates a stringent selection of patients. Sorafenib shares some molecular targets with regorafenib, but this has specific action against VEGFR-2, VEGFR-3, Tie-2, PDGFR, FGFR-1, c-Kit, RET and p38-alpha7. Both are antiangiogenic as bevacizumab, but while bevacizumab is limited to the VEGF pathway, they act on several additional target involved in cancer progression. Atezolizumab and nivolumab target the PD1 checkpoint but acting at different levels: PD-1 receptor for Nivolumab and PD-L1 for Atezolizumab. This implies a difference and if resistance to one of the antibodies emerges during treatment, the use of the other one may overcome such key event leading to treatment failure. Recently, the combination of tremelimumab and durvalumab improved OS in comparison to sorafenib; in addition, durvalumab monotherapy was not inferior to sorafenib. The aim of this study is to do a sequential treatment combining regorafenib, second- line treatment in hepatocellular carcinoma (HCC) with anti PD-1 to enhance the outcome of patients based on the synergy between both drugs.

Conditions

Hepatocellular Carcinoma

Keywords

hepatocellular; sorafenib; regorafenib; nivolumab

Outcome Measures

Primary Outcomes (3)

• Incidence of Treatment-Emergent Adverse Events

  Rate of adverse events (AE)

  Up to 24 months

• Incidence of related Treatment-Emergent Adverse Events

  Rate of related-AEs

  Up to 24 months

• Incidence of Treatment-Emergent Adverse Events

  Rate of death

  Up to 24 months

Secondary Outcomes (7)

• Overall survival (OS)

  Up to 24 months

• Time to progression (TTP)

  Up to 24 months

• Objective response rate (ORR)

  Up to 24 months

• Pattern of progression

  Up to 24 months

• Post-progression survival (PPS)

  Up to 24 months

Study Arms (1)

Regorafenib plus Nivolumab

EXPERIMENTAL

Regorafenib will be initiated at full dose (160 mg/day; 3 weeks on and 1 week off) in monotherapy for the first 8 weeks. After week 8, regorafenib will be continued in combination with nivolumab, until symptomatic tumor progression, unacceptable adverse events, patient decision or death

Drug: Regorafenib; Drug: Nivolumab

Interventions

Regorafenib DRUG

Regorafenib 160 mg/day 3 weeks on and 1 week off

Regorafenib plus Nivolumab

Nivolumab DRUG

Nivolumab at the dose of 1.5 mg/kg, 3 mg/kg or 240 mg/infusion every 2 weeks. Dose will be adjusted depending on the incidence of adverse events

Regorafenib plus Nivolumab

Eligibility Criteria

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

You may qualify if:

• Male or female subjects 18 years of age or older.
• Diagnosis of HCC based on histology or non-invasive criteria if the patients are cirrhotic according to AASLD guidelines.
• Adequate liver function
• Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 1.
• Adequate hematologic profile
• Adequate renal function
• All but sorafenib-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 first-line treatment must be resolved before starting regorafenib.
• Patients with Hepatocellular Carcinoma
• who are candidates to regorafenib treatment according to the definition in the RESORCE trial or
• who tolerated between 200 and 400 mg of sorafenib for at least 30 days and who did not experience adverse events of grade 3 or more (excluding dermatologic adverse events)(Cohort A).
• After discontinuation of atezolizuamab in combination with bevacizumab because of tumor progression or treatment related toxicity (Cohort B). Note that patients should have received at least 2 doses of atezolizumab in combination with bevacizumab.
• All subjects must have at least one measurable lesion by RECIST 1.1 criteria. Lesions previously treated by percutaneous ablation or TACE must not be considered as target lesion, only naïve target lesions.
• Subjects may be non-infected or have active chronic HCV or HBV infection.
• Subjects must consent to perform 2 hepatic or extra-hepatic tumor biopsies, the first one within 4 weeks before starting regorafenib (this biopsy should be performed at least 5-7 days after the last dose of sorafenib and 21 days after the last dose of atezolizumab in combination with bevacizumab) and the second-one before starting the combination phase (regorafenib plus nivolumab) of the study, allowing the acquisition of a tumor sample for performance of correlative studies.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug.

You may not qualify if:

• Subjects with myocardial infarction in the last year or active ischemic heart disease
• Subjects with any history of clinically meaningful variceal bleeding within the last three months.
• Subjects with severe peripheral arterial disease
• Subjects with cardiac arrhythmia under treatment with drugs different from beta-blockers or digoxin.
• Subjects with clinically meaningful ascites defined as ascites requiring non-pharmacologic intervention within 6 months prior to the first scheduled dose.
• Subjects with any history of encephalopathy within the last 12 months or requirement for medications to prevent or control encephalopathy.
• Unfeasibility to fulfill the follow-up schedule
• Co-infection with hepatitis B and C.
• Prior malignancy active within the previous 3 years
• Subjects with any active autoimmune disease or history of known or suspected autoimmune disease
• Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) defining opportunistic infection within the last year, or a current CD4 count \< 350 cells/μL. Patients with HIV infection are eligible if :
• They do not have another active viral infection.
• They have received antiretroviral therapy (ART\*) for at least 4 weeks prior to randomization, as clinically indicated.
• They continue on ART as clinically indicated while enrolled on study.
• CD4 counts and viral load are monitored per standard of care by a local health care provider.

Sponsors & Collaborators

• Fundacion Clinic per a la Recerca Biomédica: lead
• Apices Soluciones S.L.: collaborator

Study Sites (7)

Hospital Clinic

Barcelona, Spain

Location

Hospital Vall d'Hebron

Barcelona, Spain

Location

Hospital Gregorio Marañon

Madrid, Spain

Location

Hospital Puerta de Hierro

Madrid, Spain

Location

Hospital Ramon y Cajal

Madrid, Spain

Location

Hospital Central de Asturias

Oviedo, Spain

Location

Clinica Universidad de Navarra

Pamplona, Spain

Location

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

regorafenib; Nivolumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Maria Reig, MD

  BCLC group. Liver Unit. Hospital Clinic. Ciberehd

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Regorafenib followed by Nivolumab

Study Record Dates

• First Submitted: November 18, 2019
• First Posted: November 20, 2019
• Study Start: March 16, 2020
• Primary Completion: July 9, 2024
• Study Completion: July 9, 2024
• Last Updated: September 3, 2024

Record last verified: 2024-08

Locations

ES (7)