Title:
Phase 2a Safety and Efficacy of Milciclib, a Pan-Cyclin Dependent Kinase Inhibitor, in Unresectable, Sorafenib-Refractory or -Intolerant Hepatocellular Carcinoma Patients.
Authors and Affiliations:
Erica Villa, Fabio Piscaglia, Rabit Geva, George Dalecos, George Papatheodoridis, Marina Ciomei, Christina Davite, Patrizia Crivori, Vaseem Palejwala, Jules Jacob, Fayez Hamzeh, Kunwar Shailubhai, Armando Santoro, Angelo Sangiovanni; Policlinico di Modena, Modena, Italy; University of Bologna, Bologna, Italy; Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel; 5General University Hospital of Larissa, Thessaly, Greece; Laiko General Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece; Nerviano Medical Sciences, Nerviano, Italy; Clinical Organization for Strategies and Solutions (CLIOSS), NMS Group, Nerviano, Italy; Clinical Organization for Strategies and Solutions (CLIOSS), NMS Group, Nerviano, Italy, Nerviano, Italy; TIziana Life Sceinces, Doylestown, PA; jjacob@tizianalifesciences.com, Doylestown, PA; Humanitas Cancer Center, Humanitas University, Milan, Italy; Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
Background:
Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI), provide limited improvement in overall survival, suggesting the need to identify drugs with broad-spectrum mechanisms of action, used alone or in combination with a TKI or CI. Milciclib, a pan cyclin dependent kinase inhibitor, exhibited anti-cancer activity in refractory solid malignancy patients. The primary objective of this trial was to evaluate safety and tolerability of milciclib in sorafenib-refractory or intolerant advanced HCC patients.
Methods:
Single arm and multi-center study in advanced HCC patients was conducted in Italy, Greece and Israel. Milciclib was administered orally for up to 6 cycles. Each cycle consisted of 100mg milciclib daily for 4d on/3d off/week for 4 weeks. Safety assessment was the primary endpoint and secondary endpoints included progression free survival (PFS), time to progression (TTP) and clinical benefit rate (CBR).
Results:
A total of 31 patients were enrolled and 28 were evaluable for efficacy, of which 14 (50%) completed 6-months of treatment. Milciclib was well-tolerated with manageable toxicities. Eighteen of 31 treated patients had drug-related adverse events (AEs) with most frequent (≥5%) occurrence of drug-related diarrhea, nausea, asthenia, fatigue, retinal hemorrhage, rash and myalgia. No drug-related deaths were recorded. Nine of 14 patients (64%) continued treatment under Compassionate Use after study completion. Seven patients received milciclib until 9, 9, 10, 11, 13, 13 and 16 months. The remaining 2 patients are in the 16th month of treatment. Clinical response to treatment, assessed by mRECIST (independent radiological review), is shown in the Table. Both median TTP and PFS were 5.9 months.
Parameter n % 95%CI LL-UL
Objective Response (CR+PR) 1 3.6 0.1-18.4
CBR (CR+PR+SD) 17 60.7 40.6-78.5
Partial Response (PR)* 1 3.6
Stable Disease (SD) 16 57.1
Progressive Disease 10 35.7
Missing 1 3.6
*Unconfirmed
Conclusions:
Milciclib, acting via a new mechanism, was safe, well-tolerated and met primary and secondary endpoints with 61% CBR. These promising clinical data warrant further evaluation of milciclib.