The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
Guillermo Garciamanero - One of the best experts on this subject based on the ideXlab platform.
-
Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia results of a phase 2 study
Blood Advances, 2019Co-Authors: Guillermo Garciamanero, Yasmin Abaza, Samer K Khaled, Koichi Takahashi, Bruno C Medeiros, Martha Arellano, Mrinal M Patnaik, Olatoyosi Odenike, Hamid Sayar, Mohan TummalaAbstract:Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of Pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received Pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT01912274","term_id":"NCT01912274"}}NCT01912274.
-
a phase 3 randomized study of Pracinostat pran in combination with azacitidine aza versus placebo in patients 18 years with newly diagnosed acute myeloid leukemia aml unfit for standard induction chemotherapy ic
Journal of Clinical Oncology, 2018Co-Authors: Guillermo Garciamanero, Silvia Mappa, Chun Yew Fong, Adriano Venditti, Riccardo Spezia, Lionel AdesAbstract:TPS7078Background: AML is associated with poor survival rates in patients ineligible for IC or stem cell transplant due to advanced age, comorbidities, and/or disease risk factors. Non-intensive th...
-
correlation between mutation clearance and clinical response in elderly patients with acute myeloid leukemia aml treated with azacitidine and Pracinostat
Journal of Clinical Oncology, 2017Co-Authors: Koichi Takahashi, Yasmin Abaza, Ehab Atallah, Bruno C Medeiros, Martha Arellano, Mrinal M Patnaik, Sam Khal, Richard Ghalie, Guillermo GarciamaneroAbstract:7034Background: In a phase II study in 50 elderly patients (pts) with AML who were not eligible for intensive chemotherapy, treatment with Pracinostat + azacitidine (AZA) was well tolerated, led to...
-
phase 2 randomized double blind study of Pracinostat in combination with azacitidine in patients with untreated higher risk myelodysplastic syndromes
Cancer, 2017Co-Authors: Guillermo Garciamanero, Guillermo Montalbanbravo, Jesus G Berdeja, Yasmin Abaza, Elias Jabbour, James Essell, Roger M Lyons, Farhad Ravandi, Michael B Maris, Brian HellerAbstract:BACKGROUND The prognosis of patients with higher risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have demonstrated activity in patients with MDS and in vitro synergy with azacitidine. METHODS A phase 2 randomized, placebo-controlled clinical trial of azacitidine and Pracinostat was conducted in patients who had International Prognostic Scoring System intermediate-2–risk or high-risk MDS. The primary endpoint was the complete response (CR) rate by cycle 6 of therapy. RESULTS Of 102 randomized patients, there were 51 in the Pracinostat group and 51 in the placebo group. The median age was 69 years. The CR rate by cycle 6 of therapy was 18% and 33% (P = .07) in the Pracinostat and placebo groups, respectively. No significant differences in overall survival (median, 16 vs 19 months, respectively; hazard ratio, 1.21; 95% confidence interval, 0.66-2.23) or progression-free survival (11 vs 9 months, respectively; hazard ratio, 0.82; 95% confidence interval, 0.546-1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the Pracinostat group (98% vs 74%), leading to more treatment discontinuations (20% vs 10%). CONCLUSIONS The combination of azacitidine with Pracinostat did not improve outcomes in patients with higher risk MDS. Higher rates of treatment discontinuation may partially explain these results, suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination. Cancer 2017. © 2017 American Cancer Society.
-
final results from a phase 2 study of Pracinostat in combination with azacitidine in elderly patients with acute myeloid leukemia aml
Blood, 2015Co-Authors: Guillermo Garciamanero, Samer K Khaled, Ehab Atallah, Martha Arellano, Mrinal M Patnaik, Todd A Butler, Carla Ashby, Bruno C MedeirosAbstract:Background: Combination studies with histone deacetylase (HDAC) inhibitors plus hypomethylating agents (HMA) have suggested beneficial clinical activity in higher risk MDS and AML, though exceptions have also been reported. Pracinostat is a potent oral HDAC inhibitor selective for class I, II and IV isoforms. A pilot phase Ib study of Pracinostat in combination with azacitidine (AZA) in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). Preliminary data on 33 patients from a multi-center, open-label, single-arm Phase II study of Pracinostat in combination with AZA in elderly AML also reported a high CR/CRi rate (ASH 2014). Herein we report the latest survival and response results for this study. Methods: Eligibility includes previously untreated AML (≥20% bone marrow blasts), age ≥65 years, unsuitable for intensive therapy due to co-morbidities and/or AML related features, and intermediate or high-risk cytogenetics. Study therapy includes Pracinostat, 60 mg p.o. 3 alternate days/week for 3 weeks plus AZA, 75 mg/m2) days 1-7 or days 1-5 and 8-9 either s.c. or i.v. with cycles repeated every 28 days until progressive disease, lack of response or intolerance. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) per IWG criteria. Response assessments occur at the end of cycle 1 or 2 then every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, a=0.10, power=0.90. Stage 1 n=27 and total stage 2 n=40. Secondary endpoints include overall response rate (ORR; CR+CRi+MLFS+partial response [PR]+PRi), duration of response and overall survival. Results: Between Dec 2013 and Dec 2014, 50 patients from 15 study sites were enrolled. At this time, 50 are evaluable for efficacy. Baseline disease characteristics for all patients include: median age 75 (range 66-84); 32 de novo AML, 13 evolved from AHD, 5 were treatment-related; 28 intermediate-risk and 20 high-risk cytogenetics and 2 unknown; baseline bone marrow blast counts ranged from 20% to 89% with a median of 40%. Thirty-one patients (62%) continue to be followed for survival (range: 8.5 to 18.5 months). Median overall survival has not been reached in the overall study population and neither in patients with high-risk cytogenics or those with AML secondary to MDS or prior anti-cancer therapy. The 1-year overall survival estimate is 60%. The primary endpoint of CR +CRi +MLFS has been observed in 27/50 evaluable patients (54%) to date, including 21/50 (42%) CR. The 60-day all-cause mortality rate is 10% (5/50). Treatment emergent adverse events (TEAEs) Grade ≥3 seen in >5% of patients: febrile neutropenia 30%; thrombocytopenia 22%; neutropenia 10%; cellulitis 10%; anemia 8%; fatigue 8%; sepsis 6%, and pancytopenia 6%. TEAE9s leading to study therapy discontinuation: peripheral motor neuropathy (1), parainfluenza (1), atrial fibrillation/prolonged QTc (1), subdural hematoma after a fall (1), and sepsis (3). Conclusions: Pracinostat plus AZA produces a high rate of durable responses in this AML population. Median overall survival has not been reached; 1-year overall survival is estimated at 60%. Final response data and overall survival estimates will be presented at the meeting. Disclosures Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Khaled:Sequenom: Research Funding. Arellano:Cephalon Oncology: Research Funding. Butler:MEI Pharma, Inc.: Employment. Ashby:MEI Pharma, Inc.: Employment. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria.
Ehab Atallah - One of the best experts on this subject based on the ideXlab platform.
-
phase ii study of lower dose Pracinostat plus azacitidine safety and efficacy in patients with high very high risk myelodysplastic syndromes
Journal of Clinical Oncology, 2020Co-Authors: Ehab Atallah, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Riccardo Spezia, Joanne Li, Michael K KengAbstract:7556Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate...
-
Phase II study of lower-dose Pracinostat plus azacitidine safety and efficacy in patients with high/very high-risk myelodysplastic syndromes.
Journal of Clinical Oncology, 2020Co-Authors: Ehab Atallah, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Riccardo Spezia, Joanne Li, Michael K KengAbstract:7556 Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that Pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of Pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304 .
-
Phase I Study of Pracinostat in Combination with Gemtuzumab Ozogamicin (PraGO) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)
Blood, 2019Co-Authors: Talha Badar, Ehab Atallah, Subramanian Guru Murthy, Lyndsey Runaas, Karen-sue B. Carlson, Laura C. Michaelis, Alexandra M. Harrington, Sameem AbedinAbstract:Background: Relapsed/Refractory AML (RR-AML) represents an area in urgent need for new treatments, particularly among patients ineligible for intensive chemotherapy. Newer options exist for AML with mutations involving IDH1, IDH2, or FLT3, but in AML without these mutations, only gemtuzumab ozogamicin (GO) is currently approved. GO is a calicheamicin-conjugated antibody directed against the CD33 antigen, commonly found on AML. Mechanistically, GO binds to the CD33 antigen on AML forming a complex which is internalized, resulting in intracellular delivery of calicheamicin, DNA double-strand breaks and cell death.GO recently received re-approval for patients with RR-AML on the basis of the Mylofrance-1 trial, which demonstrated a CR rate estimated at 26%. This clinical trial was designed to assess the safety of adding Pracinostat, a histone deacetylase inhibitor (HDACi) to GO. Inhibition of histone deacetylases has been shown to induce an open chromatin structure and potentially restore transcription of critically silenced genes. In AML, single agent Pracinostat has demonstrated potential anti-leukemic activity (Abaza et al. Cancer 2017). We hypothesize that, HDACi may mediate histone unwinding, a more open chromatin structure, and potentiate DNA-targeted delivery of calicheamicin within AML blasts. Further, pre-clinical data suggests HDAC inhibition could also increase CD33 expression in myeloid leukemia cells, thereby allowing for increased GO binding to AML blasts (ten Cate et al. Leukemia 2007). Previously, vorinostat, another HDACi, has been used in combination with GO and azacitidine in AML. While that trial reported limited efficacy, this trial will incorporate a fractionated GO dosing schedule, as well as the use of a more potent HDACi, both of which may improve efficacy. Study Design and Methods: This is a prospective, investigator-initiated, phase 1 clinical study that is aimed at determining the safety of Pracinostat + GO (PraGO) combination in patients with R/R AML (ClinicalTrial.gov identifier NCT03848754). Secondary end points are to evaluate response rates, 6-month progression free survival (PFS) and overall survival (OS). Eligible patients are either aged ≥ 60 years with RR- AML to at least one line of therapy, or patients 18-59 years with RR-AML to at least two lines of intensive induction chemotherapy, or one line of therapy if deemed unsuitable for further intensive chemotherapy. Diagnosis of acute promyelocytic leukemia (APL), hematopoietic stem cell transplantation (HCT) within 60 days of enrollment, evidence of veno-occlusive disease (VOD) at any time post-transplant, or active graft versus host disease (GVHD) requiring systemic immunosuppressive therapy are major exclusion criteria. Patients will be enrolled into two potential dosing cohorts. Cohort 1 will receive Pracinostat at 45mg orally, three times weekly for three weeks. GO will be administered at 3 mg/m2 on Days 1, 4, and 7. The first dose of GO will be administered two hours after the first Pracinostat dose. Responding patients will subsequently receive maintenance with GO alone at 2 mg/m2 on Day 1. Up to 5 cycles of GO will be administered to responders. Cohort 2 will receive Pracinostat at 60 mg orally, three times weekly for three weeks. GO administration will remain the same for induction. Responding patients in this cohort will be eligible for maintenance with Pracinostat at 45 mg orally, three times weekly for three weeks. GO will still only be given D1 in each maintenance cycle. A standard 3+3 design will be utilized to determine escalation to Cohort 2. DLTs will be assessed during the 1st cycle only. The study schema is diagrammatically illustrated in figure 1. With the hypothesis that HDAC inhibition may lead to increased CD33 expression, RNA seq will be performed on blasts isolated on BM aspirate, pre- and post Pracinostat treatment. Other potential antibody targets will also be assessed, including CD22 and CD38. To date, one patient has been enrolled. This 72 years old male with MPN/MF transformed to AML, refractory to CLAG (cladribine, cytarabine, G-CSF) induction. On study, he achieved a partial remission after 1st induction cycle (bone marrow blast from 20% --> 6.4%), with normalization of counts albeit with very short follow up, no SAE or DLTs were observed. Figure 1 Disclosures Runaas: Agios: Honoraria; Blueprint Medicine: Honoraria. Michaelis:Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; Macrogeneics: Research Funding; Pfizer: Equity Ownership, Research Funding; ASTEX: Research Funding; Bioline: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Millenium: Research Funding; Janssen: Research Funding. Atallah:Helsinn: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy. Abedin:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria; Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding.
-
planned interim analysis of a phase 2 study evaluating the combination of Pracinostat a histone deacetylase inhibitor hdaci and azacitidine in patients with high very high risk myelodysplastic syndrome mds
Blood, 2018Co-Authors: Michael K Keng, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Ehab AtallahAbstract:Introduction: Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the Pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of Pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes. Methods: The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the Pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with Pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation ( Results: At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study. Conclusions: The interim analysis of this study evaluating the efficacy and safety of Pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of Pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented. Disclosures Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.
-
correlation between mutation clearance and clinical response in elderly patients with acute myeloid leukemia aml treated with azacitidine and Pracinostat
Journal of Clinical Oncology, 2017Co-Authors: Koichi Takahashi, Yasmin Abaza, Ehab Atallah, Bruno C Medeiros, Martha Arellano, Mrinal M Patnaik, Sam Khal, Richard Ghalie, Guillermo GarciamaneroAbstract:7034Background: In a phase II study in 50 elderly patients (pts) with AML who were not eligible for intensive chemotherapy, treatment with Pracinostat + azacitidine (AZA) was well tolerated, led to...
Jorge E Cortes - One of the best experts on this subject based on the ideXlab platform.
-
Treatment of Relapsed/Refractory Acute Myeloid Leukemia
Current Treatment Options in Oncology, 2017Co-Authors: Prithviraj Bose, Pankit Vachhani, Jorge E CortesAbstract:Approximately 40–45% of younger and 10–20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled. These advances have paved the way for rational drug development as new “drugable” targets have emerged. Although no new drug has been approved for AML in over four decades, with the exception of gemtuzumab ozogamycin, which was subsequently withdrawn, there is progress on the horizon with the possible regulatory approval soon of agents such as CPX-351 and midostaurin, the Food and Drug Administration “breakthrough” designation granted to venetoclax, and promising agents such as the IDH inhibitors AG-221 and AG-120, the smoothened inhibitor glasdegib and the histone deacetylase inhibitor Pracinostat. In our practice, we treat most patients with relapsed/refractory AML on clinical trials, taking into consideration their prior treatment history and response to the same. We utilize targeted sequencing of genes frequently mutated in AML to identify “actionable” mutations, e.g., in FLT3 or IDH1/2 , and incorporate small-molecule inhibitors of these oncogenic kinases into our therapeutic regimens whenever possible. In the absence of actionable mutations, we rationally combine conventional agents with other novel therapies such as monoclonal antibodies and other targeted drugs. For fit patients up to the age of 65, we often use high-dose cytarabine-containing backbone regimens. For older or unfit patients, we prefer hypomethylating agent-based therapy. Finally, all patients with relapsed/refractory AML are evaluated for allogeneic HSCT.
-
Pracinostat in combination with azacitidine produces a high rate and rapid onset of disease remission in patients with previously untreated acute myeloid leukemia aml
Blood, 2014Co-Authors: Guillermo Garciamanero, Jorge E Cortes, Ehab Atallah, Bruno C Medeiros, Olatoyosi Odenike, Vanessa Esquibel, Samer K KhaledAbstract:Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of <0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent Pracinostat showed activity in AML and a pilot Phase II study of Pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% ( Proc ASH :3821, 2012). We report initial results from a Phase II study of Pracinostat with azacitidine in previously untreated, elderly AML. Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients. Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are ‘too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease. | Patient Number | Days on Study | Baseline BM Blast % | 1st On-Study BM Blast % | Subsequent On-Study BM Blast % | Best Response on Study | || | 2 | 172+ | 22 | 1 (C2) | \---| | CR | | 3 | 165+ | 24 | 4 (C1) | 0 (C4) | CRi | | 5 | 162+ | 27 | 9 (C1) | 1 (C4) | CRi | | 6 | 156+ | 81 | 9 (C1) | 0 (C4) | CRi | | 7 | 148+ | 78 | 44 (C1) | 17 (C3), 0 (C5) | CR | | 8 | 114+ | 89 | 4 (C1) | \---| | CR | | 10 | 86+ | 45 | 3 (C1) | \---| | CRi | | 12 | 81+ | 41 | 2 (C2) | \---| | CRi | | 4 | 90 | 22 | 43 (C2) | Off due to SAE | SD | | 11 | 56 | 37 | 60 (C2) | \---| | PD | | 15 | 28 | 70 | \---| | | Patient Withdrew | | 17 | 28 | 60 | \---| | | PD | | 1 | 26 | 70 | \---| | | Off due to AE | | 9 | 26 | 38 | \---| | | Off due to AE | * +=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive Disease Abstract 947. Table 1 Conclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting. Disclosures Garcia-Manero: MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike: Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity's Board of Directors or advisory committees. Medeiros: MEI Pharma, Inc: Research Funding. Cortes: Celgene: Research Funding. Esquibel: MEI Pharma, Inc.: Employment. Cha: MEI Pharma, Inc.: Employment. Khaled: Sequenom: Research Funding.
-
Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML)
Blood, 2014Co-Authors: Guillermo Garcia-manero, Jorge E Cortes, Ehab Atallah, Bruno C Medeiros, Olatoyosi Odenike, Vanessa Esquibel, Samer K KhaledAbstract:Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of
-
therapy with the histone deacetylase inhibitor Pracinostat for patients with myelofibrosis
Leukemia Research, 2012Co-Authors: Alfonso Quintascardama, Gautam Borthakur, Zeev Estrov, Hagop M Kantarjian, Jorge E Cortes, Srdan VerstovsekAbstract:Abstract Approximately half of the patients with myelofibrosis (MF) carry mutant JAK2 V617F proteins. JAK2 V617F has been recently shown to translocate to the nucleus and modify specific histones, thus regulating transcription. We report on a phase II study testing the activity and tolerability of the histone deacetylase inhibitor Pracinostat given at 60 mg every other day for three weeks per month in 22 patients with intermediate or high risk MF. Eight (36%) patients experienced clinical benefit, with 6 (27%) experiencing reductions in splenomegaly (median 3 cm, range 1–4 cm). According to International Working Group criteria, 2 (9%) patients had clinical improvement (anemia response in both cases). The most frequent side effect associated to Pracinostat therapy was fatigue, which occurred in 20 (91%) patients (grade 2 in 3 patients). Grade 3–4 neutropenia, anemia, and thrombocytopenia occurred in 13%, 0%, and 21%, respectively. Twenty-one patients permanently discontinued Pracinostat, mainly due to lack of efficacy. In conclusion, Pracinostat at the dose tested is reasonably tolerated and has modest activity in patients with MF.
Samer K Khaled - One of the best experts on this subject based on the ideXlab platform.
-
Phase II study of lower-dose Pracinostat plus azacitidine safety and efficacy in patients with high/very high-risk myelodysplastic syndromes.
Journal of Clinical Oncology, 2020Co-Authors: Ehab Atallah, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Riccardo Spezia, Joanne Li, Michael K KengAbstract:7556 Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that Pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of Pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304 .
-
phase ii study of lower dose Pracinostat plus azacitidine safety and efficacy in patients with high very high risk myelodysplastic syndromes
Journal of Clinical Oncology, 2020Co-Authors: Ehab Atallah, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Riccardo Spezia, Joanne Li, Michael K KengAbstract:7556Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate...
-
Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia results of a phase 2 study
Blood Advances, 2019Co-Authors: Guillermo Garciamanero, Yasmin Abaza, Samer K Khaled, Koichi Takahashi, Bruno C Medeiros, Martha Arellano, Mrinal M Patnaik, Olatoyosi Odenike, Hamid Sayar, Mohan TummalaAbstract:Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of Pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received Pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT01912274","term_id":"NCT01912274"}}NCT01912274.
-
planned interim analysis of a phase 2 study evaluating the combination of Pracinostat a histone deacetylase inhibitor hdaci and azacitidine in patients with high very high risk myelodysplastic syndrome mds
Blood, 2018Co-Authors: Michael K Keng, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Ehab AtallahAbstract:Introduction: Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the Pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of Pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes. Methods: The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the Pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with Pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation ( Results: At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study. Conclusions: The interim analysis of this study evaluating the efficacy and safety of Pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of Pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented. Disclosures Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.
-
a phase 2 study of Pracinostat and azacitidine in elderly patients with acute myeloid leukemia aml not eligible for induction chemotherapy response and long term survival benefit
Blood, 2016Co-Authors: Guillermo Garcia Manero, Prapti A Patel, Samer K Khaled, Ehab Atallah, Martha Arellano, Mrinal M Patnaik, Olatoyosi Odenike, Hamid Sayar, Mohan Tummala, Richard GhalieAbstract:Background: Pracinostat, a potent oral Class I, II, IV histone deacetylase (HDAC) inhibitor, exhibited modest single-agent activity in relapsed AML. Inhibition of histone deacetylation and DNA hypermethylation induces re-expression of silenced genes in myeloid malignancies in a synergistic fashion. A pilot study of Pracinostat with azacitidine (AZA) in myelodysplastic syndromes showed the combination to be active and well tolerated (Blood2012;120:3821). We conducted a Phase 2 study to evaluate Pracinostat + AZA in patients ≥65 years with AML not eligible for induction chemotherapy. Minimum 1-year survival data were reported previously (Blood 2015;126:453). Here we report long-term survival and response analyses. Methods: Main eligibility: Age ≥65, untreated de novo or secondary AML, ≥20% bone marrow (BM) blasts, not candidate for intensive therapy due to co-morbidities and/or AML features, intermediate or high-risk cytogenetics, and no prior treatment with HDAC inhibitors or hypomethylating agents. Treatment consisted of Pracinostat 60 mg orally 3 days/week on alternate days for 3 weeks and AZA 75 mg/m2 subcutaneously or intravenously daily for 7 days, with cycles repeated every 28 days until disease progression, lack of response or poor tolerability. The primary endpoint was a composite complete response rate (cCR) of CR + CRi+ MLFS by IWG criteria. Response was assessed at the end of Cycles 2, 4, 6 and then every 3 cycles or when clinically indicated. Secondary endpoints included overall response rate (cCR + PR), duration of response and overall survival (OS). Study registered under NCT01912274. Results: Between December 2013 and December 2014, 50 patients were enrolled at 15 U.S. sites. Baseline characteristics: Median age 75 years (range 66-84 years); 33 de novo and 17 secondary AML; 27 intermediate-risk and 21 high-risk cytogenetics and 2 not known; median BM blasts 40% (range 20%-89%), ECOG performance status 0-1 in 84% and 2 in 16%. The median number of treatment cycles was 6.5 (range 1-24+). A CR was achieved in 21 patients (42%), CRi in 2 (4%), and MLFS in 3 (6%) for a cCR rate of 52%. Median time to BM blasts 5% of patients: Fatigue 34%; anorexia 10%, cellulitis, pneumonia, asthenia and sepsis in 8%; urinary tract infection, nausea, back pain, hypoxia, hyponatremia, and syncope in 6%. Grade ≥ 3 hematologic toxicities in> 5% of patients: thrombocytopenia 46%; febrile neutropenia 44%; neutropenia 36%; anemia 30%; pancytopenia 6%. The 30-day and 60-day mortality rates were 2% and 10%. Conclusions: Pracinostat + AZA led to a high rate of responses in elderly patients with AML. Responses were durable and observed irrespective of age, cytogenetics risk, ECOG performance status, and de novo or secondary AML. Marrow remission was typically achieved early, but prolonged exposure was required in some patients to maximize response. The results compare favorably with historical single-agent AZA data in a similar AML population. A phase 3 study of AZA +/- Pracinostat in untreated patients with AML unfit for standard induction chemotherapy is starting. Disclosures Atallah:Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Arellano:Cephalon: Research Funding. Odenike:Geron: Research Funding; Incyte: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Suneisis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Ghalie:MEI Pharma: Employment.
Silvia Mappa - One of the best experts on this subject based on the ideXlab platform.
-
Phase II study of lower-dose Pracinostat plus azacitidine safety and efficacy in patients with high/very high-risk myelodysplastic syndromes.
Journal of Clinical Oncology, 2020Co-Authors: Ehab Atallah, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Riccardo Spezia, Joanne Li, Michael K KengAbstract:7556 Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate (ORR=CR+PR) with HMA alone is approximately 30%, with a 2-year overall survival (OS) rate of 50.8%. Preclinical studies show that Pracinostat (PRAN), an oral histone deacetylase inhibitor, synergizes with HMA. A study in pts with untreated IPSS intermediate-2/high-risk MDS receiving 60 mg PRAN plus AZA resulted in early discontinuations, mainly due to adverse events (AE), potentially leading to diminished clinical benefit. This follow-up phase II study evaluates a lower dose of PRAN (25% reduction) in combination with AZA in order to reduce toxicity, decrease early discontinuations, and improve outcomes. An interim analysis showed low discontinuation rate and promising efficacy, allowing trial expansion. Herein, we report preliminary safety and efficacy in the overall population. Methods: Open-label, II-stage, phase II trial (NCT03151304) in pts (≥18 years) naive to HMA therapy and with IPSS-R of high/very high-risk MDS. Planned enrollment was 60 pts. Pts received 45 mg PRAN 3 days/week for 3 consecutive weeks plus standard AZA dose for 7 days of each 28-day cycle. Primary objectives were to define the safety/tolerability of the combination and to assess the ORR (CR+PR). OS was a secondary endpoint. Results: Sixty-four pts were enrolled and received ≥1 dose of treatment. Most pts were male (67%), median age was 68 years (range 47–89), and the proportion of pts with high/very high-risk MDS was similar. After 17.6 months’ median follow-up, 31% of pts remain on treatment; 69% of pts discontinued treatment due to stem cell transplant (25%), disease progression (17%), AEs (11%), consent withdrawal (3%), pt noncompliance (3%), death (3%), lost to follow-up (2%), and other (5%). Most common nonhematologic AEs were constipation (55%), nausea (52%), fatigue (45%), decreased appetite (39%), peripheral edema (36%), diarrhea, and dyspnea (31% each). Frequent hematologic AEs were decreased neutrophil count (50%), anemia (39%), decreased platelet count (38%), febrile neutropenia (36%), and thrombocytopenia (30%). ORR was 33% (95% CI 22-46), with 33% achieving CR; 34% of pts had marrow CR. Median OS was 23.5 months (95% CI 16.4-nc), with an estimated 1-year OS of 77%. Conclusions: In pts with high/very high-risk MDS, a lower dose of Pracinostat in combination with AZA demonstrated a tolerable safety profile and promising efficacy. Clinical trial information: NCT03151304 .
-
phase ii study of lower dose Pracinostat plus azacitidine safety and efficacy in patients with high very high risk myelodysplastic syndromes
Journal of Clinical Oncology, 2020Co-Authors: Ehab Atallah, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Riccardo Spezia, Joanne Li, Michael K KengAbstract:7556Background: Hypomethylating agents (HMA), such as azacitidine (AZA), are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (MDS). However, overall response rate...
-
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
British Journal of Haematology, 2020Co-Authors: Fevzi Firat Yalniz, Jesus G Berdeja, James Essell, Roger M Lyons, Michael B Maris, James A Reeves, Prapti A Patel, Mikkael A Sekeres, Amanda Hughes, Silvia MappaAbstract:: Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding Pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding Pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced Pracinostat dose may improve tolerability and efficacy.
-
A Phase 3 Randomized Study (PRIMULA) of the Epigenetic Combination of Pracinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor, with Azacitidine (AZA) in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Unfit for Standard Intensive Chemother
Blood, 2019Co-Authors: Guillermo Garcia-manero, Silvia Mappa, Maciej Kaźmierczak, Chun Yew Fong, Pau Montesinos, Adriano Venditti, Riccardo Spezia, Lionel AdesAbstract:Background: AML is associated with poor survival rates in patients ineligible for IC or stem cell transplant due to advanced age, comorbidities, and/or disease and patient-specific risk factors. Non-intensive therapies, including the hypomethylating agent (HMA) AZA, have historically been used in this setting; however, response rates and survival remain dismal. Pre-clinical studies in myeloid malignancies indicate that the epigenetic combination of HMAs and HDAC inhibitors induce re-expression of silenced genes in a synergistic fashion. Pracinostat, an oral pan-HDAC (class I, II, and IV isoforms) inhibitor, has shown superior pharmacokinetic and pharmacodynamic properties compared with other HDAC inhibitors. The activity of Pracinostat has been shown in xenograft tumor models of AML and synergistic interactions have been observed with multiple cytotoxic and targeted anti-cancer therapeutics, including AZA. In a Phase 2 study in AML patients ≥65 years not eligible for IC, the epigenetic combination of Pracinostat and AZA showed promising efficacy (Garcia Manero, Blood 2016) with a 64% overall response rate and 19.1 months median overall survival. Favorable responses were also seen in patients with high risk molecular features and adverse prognostic factors. The safety profile of Pracinostat/AZA is comparable to each administered as monotherapy, with no significant added toxicity. Study Design and Methods: The Phase 3, multicenter, double-blind, randomized PRIMULA study (NCT03151408) evaluates the efficacy and safety of Pracinostat administered with AZA in adult patients with newly diagnosed AML who are ineligible to receive IC based on either 1) age ≥75 years or 2) age <75 years plus a protocol-defined comorbidity. A total of 500 patients (randomized 1:1 to either Pracinostat/AZA or placebo/AZA) are planned to be enrolled at ~140 study centers worldwide. Randomization is stratified by cytogenetic risk (intermediate vs. unfavorable-risk) and ECOG Performance Status (0-1 vs. 2). Treatments are administered as 28-day cycles, with Pracinostat given orally as a 60 mg capsule QD, 3x/week for 3 weeks followed by one week off, and AZA administered for 7 days of each cycle. Patients are to receive a minimum of 6 cycles as long as there is no evidence of disease progression or non-manageable toxicity. The primary endpoint is overall survival; secondary efficacy endpoints include morphologic and cytogenetic complete remission (CR) rates, CR without minimal residual disease and transfusion independence ≥8 weeks. Safety is assessed primarily through treatment-emergent adverse events. Overall survival will be tested for superiority of Pracinostat/AZA over placebo/AZA using the stratified log-rank test at the alpha = 0.025 level of significance (one-sided). One interim analysis is planned when 260 events (i.e., deaths due to any cause) have occurred. Enrollment is open and as of July 8, 2019 257 patients have been randomized. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Fong:Amgen: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Montesinos:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Venditti:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mappa:Helsinn Healthcare SA: Employment; Helsinn Healthcare SA: Patents & Royalties. Spezia:Helsinn Healthcare: Employment. Ades:Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. OffLabel Disclosure: Pracinostat is an HDAC inhibitor not yet approved by the FDA
-
planned interim analysis of a phase 2 study evaluating the combination of Pracinostat a histone deacetylase inhibitor hdaci and azacitidine in patients with high very high risk myelodysplastic syndrome mds
Blood, 2018Co-Authors: Michael K Keng, Silvia Mappa, Samer K Khaled, Brenda Cooper, Erica D Warlick, David A Ramies, Ehab AtallahAbstract:Introduction: Higher risk MDS is a serious disease associated with poor survival with hypomethylating agents (HMAs) the standard of care in patients ineligible for stem cell transplantation. Unfortunately, HMAs are only effective in 30-40% of patients with duration of response typically shorter than 1.5 years (Fenaux, Lancet Oncol 2009) leading to evaluation of combination therapies to improve outcomes in higher risk MDS. Inhibition of both histone deacetylation and DNA hypermethylation has been shown to induce re-expression of silenced genes in myeloid malignancies in a synergistic fashion. Studies have evaluated HMAs in combination with HDACi but the results have been disappointing due to increased toxicity and early discontinuations. Pracinostat, a potent oral Class I, II, IV HDAC inhibitor, has been studied in combination with standard dose azacitidine in a prior Phase 2 study in 102 patients with untreated IPSS intermediate-2/high risk MDS (Garcia-Manero, Cancer 2017). Pracinostat was administered at 60 mg/day on 3 alternate days/week for 3 weeks/month, with step down dose to 45 mg in case of poor tolerability. Toxicity, primarily cytopenias, nausea, vomiting and fatigue resulted in early discontinuations and insufficient treatment exposure, potentially leading to diminished efficacy and no observed benefit of the Pracinostat/azacitidine combination. This follow-up study is evaluating a lower dose of Pracinostat (25% reduction) in combination with standard dose azacitidine with the goal of reducing toxicity, decreasing early discontinuations, and improving outcomes. Methods: The primary objective of this Phase 2, two-stage study at 24 sites is to determine the safety/tolerability and efficacy of the Pracinostat/azacitidine combination in patients with IPSS-R high-/very high-risk MDS previously untreated with HMAs. Up to 40 subjects were to enroll in Stage 1, treated with Pracinostat at 45 mg, 3 days each week for 3 consecutive weeks, followed by 1 week of rest, along with azacitidine at the standard dose of 75 mg/m2 for 7 days of each 28-day cycle. Study drugs are to be administered until disease progression or intolerable toxicity, avoiding early discontinuation ( Results: At the time of the interim analysis (25 May 2018), 39 patients had received ≥1 dose of study treatment and 20 were evaluable for assessment of early discontinuations. Median age was 67 years, 69% were male, and 59% had high-risk MDS. Of the 20 evaluable patients, 2 patients (10%) discontinued prior to the end of Cycle 3 due to AEs (1 febrile neutropenia, Day 45 and 1 fungal infection, Day 90). In 18 subjects evaluated for response at the end of Cycle ≥2, the ORR was 28% (1 complete response, 4 partial responses). Most common Grade ≥3 AEs in the 33 patients with >1 week follow-up were decreased neutrophil count (33%), anemia (30%), febrile neutropenia (27%), and dyspnea (12%). Non-hematologic AEs of fatigue and gastrointestinal events were reduced in this initial group of patients relative to that seen in the prior study. Conclusions: The interim analysis of this study evaluating the efficacy and safety of Pracinostat + azacitidine in patients with IPSS-R high-/very high-risk MDS revealed a discontinuation rate and an efficacy response rate meeting the predefined thresholds to allow for expansion of the study. These findings suggest that a reduced dose of Pracinostat may allow patients to remain on treatment longer, thus increasing the likelihood of a treatment response. Based on these data, the study IDMC approved expansion of this study to enroll 60 evaluable patients. Updated data, including 6 months efficacy data on the initial cohort, will be presented. Disclosures Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Ramies:MEI Pharma, Inc: Employment. Mappa:Helsinn Healthcare: Employment. Atallah:Jazz: Consultancy; BMS: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.