A Two-Part Study of Givinostat in Patients with Polycythemia Vera: The Maximum Tolerated Dose Selection and the Proof of Concept Final Results

Background and purpose of the study: Several reports have documented that histone deacetylase inhibitors induce neoplastic cells to undergo growth arrest, differentiation and/or apoptotic cell death. Among these agents, Givinostat inhibits proliferation of cells bearing the JAK2^V617F mutation [Guerini et al., Leukemia 2008 Apr; 22(4): 740-7; Calzada et al., Exp. Hematol. 2012; 40 (8): 634-45]. In two phase II studies conducted in patients with chronic myeloproliferative neoplasms (cMPN), Givinostat was generally well tolerated at the maximum administered dose (150 mg/day) [Rambaldi et al., Br. J. Haematol. 2010; 150 (4): 446-55; Finazzi et al., Br. J. Haematol. 2013;161(5):688-94]. To formally assess the safety and tolerability, Maximum Tolerated Dose (MTD) and preliminary efficacy of Givinostat in patients with JAK2^V617F positive Polycythemia Vera (PV), this two-part, multicenter, open label, non-randomized, phase Ib/II study dose was conducted.

Methods:Part A of the study (i.e. phase Ib) was the dose optimization portion, while Part B was the cohort expansion part of the study, assessing the preliminary clinical efficacy of Givinostat at the MTD defined in Part A. Eligible patients for this study included JAK2^V617F positive PV patients of both genders, with active and/or uncontrolled disease, defined as: (i) Hematocrit (HCT) ≥ 45% or HCT <45% normalized by phlebotomy, and (ii) PLT > 400 x10⁹/L, and (iii) WBC > 10 x10⁹/L. Study therapy was administered in 28 day cycles (the cycle being defined as 4 weeks of treatment). Disease response was evaluated by the Investigators according to the clinico-hematological European LeukemiaNet (ELN) criteria [Barosi et al., Blood. 2009 May 14; 113(20): 4829-33] at Cycles 3 and 6. Disease-related symptoms were reported by the patients using the MPN-SAF QoL Form [Scherber et al., Blood, 2011 July 14; 118(2): 401-408; Emanuel et al., JCO November 20, 2012; 30 (33): 4098-4103]. The study lasted up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit were allowed to continue treatment with Givinostat in a long-term study (ClinicalTrials.gov ID: NCT01761968).

Results: In Part A, the MTD of Givinostat in PV patients has been defined as the daily dosage of 200 mg (chronic schedule).

In Part B, 36 patients with active and/or uncontrolled disease were treated with Givinostat at the starting dose of the MTD defined in Part A (200 mg/die).

Complete/partial response was observed in 86% of evaluable patients (ITT population; n = 30) at the primary endpoint assessment time, i.e. at Cycle 3. At that time, WBC, PLT and HCT values had been normalized in the majority of patients (93%, 77% and 77% - without phlebotomy -, respectively). A net improvement in term of QoL was noted both in the single and in the total symptom scores of MPN-SAF Form. In addition, a decrease of JAK2^V617F allele burden have been noted at Cycle 3. Givinostat treatment was confirmed to be generally well tolerated: no death nor grade 4 adverse drug reaction (ADR) occurred; only one serious ADR (grade 3 diarrhea, resolved in 7 days) and a total of eight grade 3 ADRs (mainly gastrointestinal and hematological events) were reported at the cut-off date of 21^st July 2017 (safety population; n = 36).

From Cycle 3 to the secondary endpoints assessment time at Cycle 6, the overall response rate as well as the hematological response rate further improved, with a good tolerability profile. Notably, complete/partial response was observed in more than 90% of evaluable patients at the cut-off date of 21^st July 2017, when 4 patients are still ongoing.

At the time of ASH Meeting 2017, the final data related to the primary objective (as above reported) and also to the secondary and explorative endpoints will be presented.

Conclusions : With a continuous dosing schedule, a daily dosage of 200 mg was identified in this study as the MTD for Givinostat in PV patients. At that dosage, Givinostat demonstrated to be an effective and well tolerated treatment for PV patients with active/uncontrolled disease.