Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies

Abstract

Background Pracinostat is a potent histone deacetylase inhibitor with antitumor activity in both solid tumor and acute myeloid leukemia (AML) cell lines. Pracinostat has modest clinical activity in advanced solid tumors. Given the higher preclinical sensitivity of hematologic malignancies to pracinostat, we conducted a phase 1 study to assess the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), efficacy, pharmacokinetics and pharmacodynamics of pracinostat in advanced hematological malignancies. Methods Pracinostat was administered orally thrice weekly for 3 weeks on a 28-day cycle. Patients were assigned to seven dose levels using a 3+3 dose escalation design. Results Forty-four patients were enrolled, 25 had AML and 14 had myelodysplastic syndrome (MDS). The MTD was 120 mg and the RP2D was 60 mg. Two AML patients achieved a response; 1 complete remission (CR) and 1 complete cytogenetic response. Despite dose-dependent increase in the plasma concentration of pracinostat, similar increase in histone acetylation was not observed. As an extension, 10 additional MDS patients were enrolled to assess the safety and efficacy of pracinostat in combination with azacitidine. Six patients achieved CR and 3 achieved CR without platelet recovery with no added toxicity. Conclusions Pracinostat is safe with modest single-agent activity in hematological malignancies.

Evaluation of the bioequivalence and food effect on the bioavailability of CC-486 (oral azacitidine) tablets in adult patients with cancer

“…Injectable azacitidine 75 mg/m 2 /day, administered intravenously (IV) or subcutaneously (SC) for 7 days per 28-day treatment cycle, is approved in several countries for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1,2]. Azacitidine has also been investigated in a variety of other hematologic malignancies and solid tumors [3][4][5][6]. In addition to direct cytotoxicity of proliferating malignant cells, azacitidine is incorporated into both RNA and DNA (in human AML KG1a cells, the RNA:DNA incorporation ratio was 65:35 [7]) and reduces hypermethylation in promoter regions of DNA, leading to re-expression of tumor suppressor genes and promoting differentiation of hematopoietic progenitor cells [7][8][9].…”

A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy

“…Preclinical and pilot clinical experiences suggested the potential benefit of adding HDAC inhibitors to HMA as combination epigenetic therapy in myeloid malignancies. Data from a prior study that evaluated an HMA/pracinostat combination in subjects with MDS demonstrated preliminary clinical activity (Abaza et al , ). Based on these findings, we designed the current study to assess the safety and efficacy of the addition of pracinostat in MDS patients failing treatment with single agent HMA.…”

“…Vorinostat, panobinostat and pracinostat are oral, pan‐HDAC inhibitors. Each of these demonstrated early promise when used in combination with HMAs in single arm phase I trials (Dokmanovic et al , ; Prebet & Vey, ; Abaza et al , ). However, more recent multi‐arm randomized controlled trials have shown mixed or, in some cases, negative outcomes when combination therapy was compared with HMA monotherapy.…”

“…The anti‐tumour activity of pracinostat has been demonstrated in several xenograft mouse models of solid and haematological malignancies as well as in phase I and pilot phase II clinical trials (Yong et al , ; Razak et al , ; Novotny‐Diermayr et al , ; Quintas‐Cardama et al , ; Eigl et al , ). Synergistic interactions have also been observed with multiple cytotoxic and targeted anti‐cancer therapeutics, notably with azacitidine (Novotny‐Diermayr et al , ; Abaza et al , ). Recent data from a pilot phase I trial suggested clinical activity of an HMA/pracinostat combination in heavily treated patients with higher‐risk MDS and in acute myeloid leukaemia (AML) (Quintás‐Cardama et al , ; Garcia Manero et al , ).…”

Minor structural modifications to Pracinostat produce big changes in its biological responses

“…The hydroxamic acid‐based compounds are among those HDAC inhibitors, which received the widely studies (Mottamal, Zheng, Huang, & Wang, ). Among them, Pracinostat 1 is a promising compound, which has been granted breakthrough therapy designation by FDA for the treatment of patients with newly diagnosed acute myelocytic leukemia (AML) who are ≥75 years of age or unfit for intensive chemotherapy(Abaza et al., ; Garcia‐Manero et al., ). Currently, Pracinostat is undergoing phase III clinical trials (Abaza et al., ; Ganai, ; Garcia‐Manero et al., ; Kang et al., ; Novotny‐Diermayr et al., ).…”