Ignite Creation Date:
2024-05-06 @ 1:57 PM
Last Modification Date:
2024-10-26 @ 1:22 PM
Study NCT ID:
NCT04170556
Status:
COMPLETED
Last Update Posted:
2023-12-29
First Post:
2019-11-18
Brief Title:
Regorafenib Followed by Nivolumab in Patients With Hepatocellular Carcinoma GOING
Sponsor:
Fundacion Clinic per a la Recerca Biomédica
Organization:
Fundacion Clinic per a la Recerca Biomédica
Study Overview
Official Title:
The GOING Study Regorafenib Followed by Nivolumab in Patients With Hepatocellular Carcinoma Progressing Under Sorafenib or After Discontinuation of Atezolizumab Plus Bevacizumab
Status:
COMPLETED
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GOING
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 astheniafatigue 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-L1PD-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 12 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 ASTALT elevations however were generally asymptomatic and readily managed
For this reason the rationale of this Phase IIIa 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 andor 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
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 astheniafatigue 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-L1PD-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 12 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 ASTALT elevations however were generally asymptomatic and readily managed
For this reason the rationale of this Phase IIIa 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 andor 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
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2019-003108-10 | EUDRACT_NUMBER | None | None |