Spots Global Cancer Trial Database for Regorafenib Followed by Nivolumab in Patients With Hepatocellular Carcinoma (GOING)

Study Description

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.

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Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: ALL

Healthy Volunteers: No

Locations

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