Title:
Safety and Clinical Activity of Combination Treatment with Regorafenib and Milciclib in Liver Transplant Patients with Hepatocellular Carcinoma Recurrence.
Authors and Affiliations:
Alessandro Pivetti, Lorenza Di Marco, Laura Bristot, Fabiola Milosa, Rosina Maria Critelli, Nicola De Maria, Fabrizio Di Benedetto, Vaseem Palejwala, Jules Jacob, Kunwar Shailubhai, Erica Villa; 1University of Modena & Reggio Emilia Via del Pozzo 7141124, Modena, Italy; University of Modena & Reggio Emilia Via del Pozzo 7141124, Modena, Italy; Liver Transplant center, AOU and University of Modena and Reggio Emilia, Modena, Italy; TIziana LifeSceinces, Doylestown, PA; jjacob@tizianalifesciences.com, Doylestown, PA; Policlinico di Modena, Modena, Italy
Background:
Recurrence of hepatocellular carcinoma after liver transplant (LT- HCC), affects ~40% of patients. As LT-HCC drastically limits therapeutic options, combination of drugs with different mechanism of actions might be an attractive approach. Primary objective of this MiHRCO (Milciclib and Half Regorafenib CO- administration) protocol (87/2019/COMP/MiHRCO) is to evaluate safety and clinical activity of combination of Regorafenib (a tyrosine kinase inhibitor with higher clinical activity in aggressive HCC) with Milciclib (a pan cyclin dependent kinase inhibitor with clinical activities in refractory solid malignancy patients and HCC) in LT-HCC patients.
Methods:
Seven patients with LT-HCC are enrolled to date. Regorafenib administered at half the prescribed dose (80mg/day) for 3 weeks followed by 1 week Off and milciclib at 100 mg daily for 4 day On/3 day Off. Patients were maintained on this combination regimen until disease progression and/or unacceptable side effects. Primary endpoint was safety and secondary endpoints included progression free survival, time to progression, and clinical benefit rate.
Results:
This single-arm, single-center operative protocol in LT-HCC patients with extra-hepatic metastasis, not eligible to first line therapy with sorafenib (Todesca P. et al. Hepatology; doi: 10.1002/hep.30588), is currently ongoing. The combination treatment is well-tolerated with manageable toxicities (mostly related with regorafenib), i.e. moderate diarrhea, slight increase of hypertension in previously hypertensive patients and moderate hand and foot syndrome. Patients continuing with therapy are currently in 2 to 10 months of treatment period. All patients are exhibiting stable disease with reduced clinical symptoms. The mean AFP (□- fetoprotein) level (1310±200 ng/ml) at enrollment was reduced by 20% with in the first month of therapy. Importantly, AFP levels in 2 patients, treated for longer period, were reduced by 50%.
Conclusions:
Regorafenib and milciclib combination was well-tolerated. Most patients showed disease stabilization along with reduction in AFP levels within the first month of therapy. The encouraging clinical activity in difficult-to-treat patients with LT-HCC warrants continuation of this protocol and further evaluation in a larger controlled study.