Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study.
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SUBMITTER: Rambaldi A
PROVIDER: S-EPMC7387307 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study.
Rambaldi Alessandro A Iurlo Alessandra A Vannucchi Alessandro M AM Noble Richard R von Bubnoff Nikolas N Guarini Attilio A Martino Bruno B Pezzutto Antonio A Carli Giuseppe G De Muro Marianna M Luciani Stefania S McMullin Mary Frances MF Cambier Nathalie N Marolleau Jean-Pierre JP Mesa Ruben A RA Tibes Raoul R Pancrazzi Alessandro A Gesullo Francesca F Bettica Paolo P Manzoni Sara S Di Tollo Silvia S
Leukemia 20200211 8
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Project description:IntroductionPolycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned.Areas coveredWe present an overview of PV, current treatment guidelines, and the putative mechanism(s) of action of givinostat. We discuss the preclinical and clinical studies of givinostat in PV and briefly review approved and investigational competitor compounds.Expert opinionHDAC inhibitors have long been known to be active in PV, but chronic toxicities can be challenging. Givinostat, however, is active and well tolerated, and is entering a pivotal Phase III randomized trial. Givinostat offers the possibility of replacing hydroxyurea as the standard first-line cytoreductive choice for PV patients. This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.
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Project description:Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone-deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight-treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109 /L, WBC ≤10 × 109 /L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.
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Project description:Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow, mainly due to a Janus kinase 2 gene mutation (JAK2V617F). Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2V617F cell growth, has demonstrated good efficacy and safety in three phase 1/2 studies in patients with PV. This manuscript focuses on the 4-year mean (2.8 year median) follow-up of an open-label, long-term study that enrolled 51 patients with PV (out of a total of 54 with MPN) who received clinical benefit from givinostat in these previous studies or on compassionate use, and who continued to receive givinostat at the last effective and tolerated dose. The primary objectives are to determine givinostat's long-term safety and tolerability, and efficacy evaluated by the investigators according to internationally recognized response criteria. During follow-up, only 10% of PV patients reported Grade 3 treatment-related adverse events (AEs), while none had Grade 4 or 5 treatment-related AEs. The overall response rate for the duration of follow-up was always greater than 80% in patients with PV. In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.
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Project description:A man in his late 60s presented with symptoms for a few months of itching and head ache after shower. Physical examination was unremarkable except for ruddy complexion and splenomegaly. Complete blood count showed haemoglobin of 18.1 g/dL and haematocrit of 56.6%. To rule out secondary causes of erythrocytosis, such as congenital heart disease with a right to left shunt, a transthoracic echocardiogram was performed, which showed normal left ventricular function with an apical area of dyskinesis and a large left ventricular apical thrombus measuring 3.0 cm×2.0 cm. Further laboratory investigations showed low erythropoietin level and Jak V617F mutation consistent with the diagnosis of polycythemia vera. He was treated with aspirin, enoxaparin, phlebotomy and hydroxyurea with no reported complications during the stay.
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