Azacitidine In Patients Research Articles

A Phase Ib/II Study of the Histone Methyltransferase Inhibitor Pinometostat in Combination with Azacitidine in Patients with 11q23-Rearranged Acute Myeloid Leukemia

A Phase Ib/II Study of the Histone Methyltransferase Inhibitor Pinometostat in Combination with Azacitidine in Patients with 11q23-Rearranged Acute Myeloid Leukemia

Early Intervention with Hypomethylating Agents in Transfusion-Independent Patients with Myelodysplastic Syndrome

Early Intervention with Hypomethylating Agents in Transfusion-Independent Patients with Myelodysplastic Syndrome

A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

A Phase II Trial of Azacitidine (AZA) in Combination with Ruxolitinib (RUX) in Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)

High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib (AG-120) and Azacitidine

High Rate of IDH1 Mutation Clearance and Measurable Residual Disease Negativity in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib (AG-120) and Azacitidine

AGILE: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adult Patients with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation

AGILE: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adult Patients with Previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation

Updated Study Results of CX-01, an Inhibitor of CXCL12/CXCR4, and Azacitidine for the Treatment of Hypomethylating Agent Refractory AML and MDS

Hypomethylating agents (HMAs) are standard first line therapy for patients with high risk MDS and older patients with AML. Outcomes for patients who do not respond or progress on HMAs are poor, and there are no standard treatment options for these patients. The interaction between leukemic blasts and the bone marrow microenvironment is thought to play an important role in disease pathogenesis and possibly chemotherapy resistance, so we hypothesized that blocking the CXCL12/CXCR4 axis with CX-01 may improve response rates to azacitidine in patients who have failed HMA therapy. CX-01 is a low molecular weight heparin derivative with minimal anticoagulant activity that binds CXCL12 as well as neutralizes PF4, a negative regulator of megakaryopoiesis. We report updated study results of a single institution a pilot study (NCT02995655) that enrolled patients with HMA-refractory (received 4 or more cycles of HMA without response or disease progression on HMA therapy) AML or MDS (INT-1 or greater). Patients received 7 day continuous infusion of CX-01 (0.25 mg/kg/hr) and azacitidine 75 mg/m2 daily days 1-7, in 28 day cycles. The primary objective of this trial was to assess the overall response rate (ORR). 20 patients were enrolled between May 2017 and February 2018. The median age was 74 years (range 62-88 years) and 35% were female. Nine patients had MDS and 11 had AML, with 7 patients having antecedent MDS and 2 having therapy-related AML. Half of the patients had high risk cytogenetic abnormalities and 3 had TP53 mutations. Patients had a median of 2 prior lines of therapy (range 1-3) with median of 6 prior cycles of HMA therapy (range 4-20). Only 4 patients had a confirmed response to prior HMA therapy. Of the 20 patients that were enrolled, 15 were considered evaluable for response with a bone marrow biopsy after cycle 2. Of the 5 unevaluable patients, 3 were removed from the trial before completing C1 due to transaminitis, discovery of a second primary malignancy, and an elevated PTT on day 2. One patient had grade 5 sepsis during C1, and another withdrew for unrelated reasons. As expected with azacitidine therapy in this patient population, hematologic toxicity was common with 16 instances of grade 3/4 neutropenia/leukopenia, 5 instances of grade 3/4 anemia, and 10 instances of grade 3/4 thrombocytopenia. Other common grade 3/4 adverse events were various infections (20), febrile neutropenia (13), hypertension (10), electrolyte disturbance (9), and transaminitis (3). Mild prolongations in PTT (22) and INR (7) were common, and there was one instance of grade 3 PTT prolongation, two instances of grade 3 epistaxis, and one instance of grade 3 hematuria. The incidences of bleeding were not thought related to CX-01 infusion. The 15 evaluable patients received a median of 3 cycles of CX-01 and azacitidine (range 2-9). Of 15 evaluable patients, there was 1 CR and 3 bone marrow CRs (mCR, with incomplete blood count recovery), 9 stable disease, and 2 progressive disease for an ORR of 27%. Of the 3 patients with a mCR after cycle 2, two had hematologic improvement of their neutrophil and platelet counts, respectively, by the end of cycle 4. A patient with stable disease also had hematologic improvement in platelets. The median OS of evaluable patients was 221 days (95% CI 179 days-not reached) and median overall survival was not significantly different between AML patients at 221 days and MDS patients at 248 days (p = 0.8). In this pilot study we demonstrated the feasibility of treating HMA-refractory AML and MDS with CX-01 and azacitidine. While this study is limited by its small sample size, we observed higher than expected response rate and favorable OS compared to historical controls. Figure Disclosures Cashen: Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. DiPersio:Incyte: Consultancy, Research Funding; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Magenta Therapeutics: Equity Ownership; Amphivena Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy. Jacoby:Celgene: Speakers Bureau; Novo Nordisk: Consultancy; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy.

Impact of cytogenetic abnormalities on response to azacitidine in patients with myelodysplastic syndrome

Abstract Background The AZA-001 phase III randomized study showed that azacitidine (AZA) significantly improved overall survival (OS) compared with conventional care in high- risk myelodysplastic syndrome (MDS), but prolonged treatment of 4-6 cycles is required before a failure to achieve response can be declared. Although selection of patients who are unlikely to derive benefit from AZA has become a top clinical priority, prognostic factors for response to and survival with AZA remain unclear. Here we examined prognostic factors for AZA in MDS patients in our hospital. Patients and Methods We retrospectively analyzed MDS patients treated with AZA between November 2011 and June 2018 in our hospital. Predictors of response were baseline cytogenetic characteristics (including IPSS-R cytogenetic classification) and the number of cytogenetic abnormalities. Univariate analyses were performed with log-rank tests and OS was measured from the onset of AZA. Results The male: female ratio was 4:1. Median age was 72 years, and median number of cycles of AZA was 11. Univariate analysis identified high score for IPSS-R cytogenetic classification and large number of cytogenetic abnormalities as factors associated with poor OS. In particular, patients with 17p abnormalities, possibly related to the presence of TP53 mutation, showed significantly shorter OS. Most rapidly developed leukemia and treatment became difficult to continue (median number of cycles of AZA, 2). Conclusion In the group with a high score for IPSS-R cytogenetic classification and large number of cytogenetic abnormalities, few patients showed survival advantage or delayed transformation to a leukemic state despite receiving AZA. An alternative to AZA monotherapy is considered necessary for patients expected to show poor response to AZA.

Economic Evaluation of Azacitidine in Elderly Patients with Acute Myeloid Leukemia with High Blast Counts.

BackgroundAzacitidine is an hypomethylating agent widely adopted for the treatment of acute myeloid leukaemia (AML) in patients who are ineligible for curative-intent chemotherapy. Patients with low bone marrow blast counts (< 30%) experience improved survival with azacitidine, but the benefits are significantly lower in patients with > 30% blasts in the bone marrow. As such, there is uncertainty around the economic benefit of azacitidine in patients with higher blast counts.ObjectiveWe present a cost-utility analysis of azacitidine in patients with AML with > 30% blasts to determine the economic value of azacitidine in this patient population from the perspective of a third-party payer.MethodsA Markov model was developed with a time horizon of 25 months divided into 22 cycles of 35 days each. The cost utility of azacitidine was compared with that of conventional care regimens (which include best supportive care, low-dose cytarabine and induction chemotherapy). A Canadian public healthcare system perspective was selected.ResultsIn the base case, the incremental cost per quality-adjusted life-year gained (incremental cost-effectiveness ratio [ICER]) for azacitidine compared with conventional care regimens was $Can160,438, year 2018 values. The estimated ICER was insensitive to a longer time horizon but sensitive to the cost of azacitidine and to assumptions relating to survival in both treatment regimens, although the ICER always remained greater than Can$80,000 in all scenarios.ConclusionAzacitidine is unlikely to be cost effective given that the estimated ICER exceeds the willingness to pay commonly used in the Canadian healthcare system.Electronic supplementary materialThe online version of this article (10.1007/s41669-019-00180-z) contains supplementary material, which is available to authorized users.

IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia

IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia

Gilteritinib for the treatment of relapsed and/or refractory FLT3-mutated acute myeloid leukemia

ABSTRACTIntroduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML.Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research.Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.

A Study of Azacitidine for Patients With Int/High -Risk MDS and AML-MRC

A Study of Azacitidine for Patients With Int/High -Risk MDS and AML-MRC

Interim results from a phase Ib/II clinical study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in patients with advanced myelodysplastic syndrome (MDS).

7037 Background: Glutaminase (GLS) is an enzyme that catalyzes conversion of glutamine to glutamate, providing key metabolic fuel for tumor cells. GLS is highly expressed in AML and high-risk MDS, particularly in the setting of complex cytogenetics. Preclinical studies of primary AML cells demonstrate dependence on glutamine; glutaminase inhibition led to reduced cell growth and induced apoptosis. This study was designed to evaluate the safety and efficacy of the oral glutaminase inhibitor CB-839 in combination with azacitidine for MDS. Methods: This is a single arm Phase Ib/II trial of CB-839, evaluating the dose of 600 mg BID orally daily in combination with azacitidine (AZA) for intermediate and high-risk MDS in 28-day cycles. The primary outcome for the Phase 1 portion was to confirm the safety and recommended Phase 2 dose of CB-839 in combination with AZA. Secondary endpoints evaluate efficacy and clinical activity using IWG response criteria for MDS including hematological improvement (HI), complete response (CR), marrow CR (mCR), stable disease (SD) and no response (NR). Results: A total of 10 pts with MDS were enrolled; the Phase I portion is now complete, confirming CB-839 600 mg BID with standard AZA. Median age was 71 [47-76], 90% were men. 7 pts were treatment naïve, 3 pts had prior HMA exposure. 6 pts were intermediate-2, and 4 pts intermediate-1 by IPSS with high-risk mutations. 3 pts had complex cytogenetics. The most frequent mutations were ASXL1 (n = 5), TET2 (n = 4) and TP53 (n = 4). Median number of cycles was 3 [1-9]. The most common non-hematological AEs were grade 1-3 nausea (60%) and constipation (50%). No DLTs were identified; one pt experienced grade 3 transaminitis requiring dose reduction of CB-839 (to 400 mg BID) with resolution. Seven pts (70%) achieved mCR/CR with HI, 2 pts had SD, and 1 pt had NR. The median time to mCR was 3 months [1-3]. 4 pts proceed to hematologic stem cell transplant (HSCT) after 2-4 cycles. 1 pt progressed to AML after 3 cycles of therapy, and 3 pts remain on study. Conclusions: 600 mg BID CB-839 is safe and well tolerated in combination with azacitidine in pts with MDS. The Phase II portion is ongoing. Clinical trial information: NCT03047993.

Preventive Use of Azacitidine in Patients with Acute Myeloid Leukemia after Haploidentical Allo-BMT

Background. Haploidentical bone marrow transplantation (BMT) can be a reliable alternative if a fully matched donor is not available. The main challenges after BMT are a relapse of major disease, graft-versus-host disease (GVHD), and infections. Azacitidine possesses antileukemic effect together with immunomodulating properties and being administered soon after BMT can significantly improve the outcome. Aim. To study azacitidine effect on the outcome of haploidentical BMT in patients with acute myeloid leukemia (AML) in the early post-transplantation period. Materials &amp; Methods. The trial included 18 AML patients who received haploidentical BMT at VA Almazov National Medical Research Center. In all patients MRD-negative remission was achieved on the 30&lt;sup&gt;th&lt;/sup&gt; day after BMT. Azacitidine therapy was initiated not earlier than 2 months after BMT with a complete engraftment of transplant and no GVHD. Azacitidine 100 mg/day was administered on D1-D5 every 28 days within a year after BMT. When a molecular relapse was detected, donor lymphocytes were additionally infused during every other cycle of therapy. Results. Eleven patients received preventive azacitidine treatment, 7 patients were included in control group. Median onset of azacitidine treatment after haploidentical BMT was 4 months (range 2-10 months), median number of azacitidine courses was 3.5 (range 1-9). During azacitidine treatment acute GVHD was identified in 5 (45.4 %) patients. In 4 of them an exacerbation of earlier GVHD was detected (3 with cutaneous form and 1 with intestinal form), and only in 1 patient de novo acute intestinal GVHD was discovered. Conclusion. Azacitidine treatment of AML patients after haploidentical allo-BMT is safe and well tolerated. Preventive azacitidine treatment after haploidentical BMT improves overall survival of AML patients.

Survival Benefit with Standard-Dose Decitabine Versus Standard-Dose Azacitidine in Patients with Lower-Risk Myelodysplastic Syndromes

Introduction: Hypomethylating agents (HMAs) are used for the treatment of patients with myelodysplastic syndromes (MDS). Two HMAs, decitabine and azacitidine, are currently available for such treatment. Numerous studies have analyzed the clinical efficacy of HMAs in patients with MDS; however, reports directly comparing decitabine and azacitidine in patients with lower-risk (low and intermediate-1) MDS are limited. The clinical efficacy of standard-dose HMA treatment in lower-risk MDS remains controversial.Patients and methods: The Korea University MDS registry is a longitudinal cohort that contains data on 452 patients consecutively diagnosed with MDS from October 2006 to December 2017 in Korea University Medical Center (Korea University Anam, Guro, and Ansan Hospital). In the Korea University MDS registry, 357 patients were classified as having lower-risk MDS. Among them, 115 patients were treated with HMA (decitabine or azacitidine); 111 patients were eligible for the study. We compared treatment responses, survival outcomes, and adverse events between standard-dose decitabine (20 mg/m2 daily for 5 days every 4 weeks) and azacitidine (75 mg/m2 daily for 7 days every 4 weeks) in lower-risk MDS patients. Treatment responses were assessed according to the modified 2006 International Working Group response criteria. Patients who were evaluated received at least one cycle of HMA therapy. The overall response rate (ORR) included complete remission (CR), partial remission, marrow CR, and hematologic improvement. Progression-free survival (PFS) was measured from the time of treatment initiation until disease progression or death from MDS.Results: The CR rates were 16.4% (10/61) in the decitabine group and 6.0% (3/50) in the azacitidine group with borderline significance (P = .090). The ORRs were 67.2% (41/61) and 44.0% (22/50) for decitabine and azacitidine, respectively (P = .014). The erythroid responses for decitabine and azacitidine were 68.3% (41/60) and 44.2% (19/43), respectively (P = .014). In the multivariable analysis, treatment with decitabine (hazard ratio [HR] 2.553; 95% confidence interval [CI] 1.116-5.840; P = .026), hemoglobin (Hb) concentration of <8 g/dL (HR 3.073; 95% CI 1.340-7.048; P = .008), and ≥5% BM blasts (HR 3.739; 95% CI 1.102-12.683; P = .034) were significantly associated with higher ORRs. The median progression-free survival was significantly better in patients treated with decitabine than in those treated with azacitidine (33 vs. 19 months; P = .019). There were no significant differences in the event-free survival and in the overall survival between the two HMAs. In the multivariable analysis, treatment with decitabine (HR 0.496; 95% CI 0.257-0.957; P = .037) and achievement of CR (HR 0.122; 95% CI 0.015-0.993; P = .049) were significant prognostic factors for better survival, whereas ANC below 0.8 × 109/L (HR 1.905; 95% CI 1.032-3.515; P = .039) was a significant prognostic factor for poor prognosis. The poor cytogenetic risk group, as classified by International Prognostic Scoring System (HR 2.136; 95% CI 0.992-4.556; P = .052), also affected the survival unfavorably with borderline significance. There were no significant differences in grade 3 or higher hematologic adverse events between the two HMAs.Conclusions: The standard-dose decitabine therapy showed significantly better ORR, erythroid response, and longer PFS than did standard-dose azacitidine in patients with lower-risk MDS. The frequencies of hematologic adverse events did not differ between the patients who received decitabine and those who received azacitidine. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

FT-2102, an IDH1m Inhibitor, in Combination with Azacitidine in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Ayndrome (MDS): Results from a Phase 1 Study

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients. Mutated IDH1 metabolizes alpha-ketoglutarate into 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA), a hypomethylating agent (HMA), is a standard of care for MDS and for AML patients unfit for intensive therapy. We present Phase 1 clinical data from the ongoing Phase 1/2 study of FT-2102 in combination with azacitidine (FT-2102+AZA) in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: A Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion. FT-2102 was administered daily (150 QD or 150 BID) until disease progression or unacceptable toxicity; AZA was administered at 75 mg/m2 IV or SC daily for 7 days of each 28-day cycle. Eligible patients had IDH1m AML/MDS that was relapsed/refractory (R/R) or treatment-naive (TN), were eligible for AZA therapy and had adequate liver and renal function. Prior IDH1 inhibitors and hypomethylating agents were allowed, and there were no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: At the time of the data cutoff, 07 April 2018, 27 patients had been enrolled and 26 had been treated with FT-2102+AZA, with a median of 3 months on treatment (range: 0.2 to 12 months). Of the 27 enrolled patients, 24 had AML (20 R/R; 4 TN) and 3 patients had MDS (all TN). The median number of prior antileukemia therapies was 3 (range: 0-5) in the AML patients. Doses of FT-2102 were 150 mg QD (n=7) and 150 mg BID (n=20). Thirteen (50%) patients discontinued treatment, with the most common reasons for treatment discontinuation were hematopoietic stem cell transplant (n=4), death (n=2), and progressive disease (n=2). No patients discontinued due to an AE. Severe (≥ Grade 3) AEs occurring in ≥ 5% of patients included febrile neutropenia (27%), anemia, thrombocytopenia, leukocytosis (19% each), fatigue, hypertension, neutropenia (15% each), nausea, pneumonia, hypokalemia (12% each) and abdominal pain (8%). Three patients had differentiation syndrome (IDH-DS), which resolved with FT-2102 temporary interruption, and treatment with dexamethasone, hydroxyurea, and supportive care in all three. Five patients died within 28-days of the last dose of study drug, none of which were considered related to FT-2102+AZA. No DLTs were observed during dose escalation. PK analysis demonstrated no impact of AZA on steady-state exposure of FT-2102. 2-HG levels to normal levels by C2D1. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been seen as early as 1 month on treatment, and stable disease for greater than 6 months; 50% of patients remain on treatment. Conclusions: FT-2102+AZA is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Clinical activity has been observed, with an ORR of 42%. Durable CRs (>12 months) have been observed. The current data support the continued evaluation of FT-2102 150 mg BID+AZA in the Phase 2 study. Three Phase 2 combination therapy cohorts are currently open for enrollment in patients Disclosures Cortes:Pfizer: Consultancy, Research Funding; Arog: Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Ferrell:Incyte: Research Funding. Jonas:LP Therapeutics: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Glycomimetics: Research Funding; AbbVie: Consultancy, Research Funding; Forma: Research Funding; Accelerated Medical Diagnostics: Research Funding; Tolero: Consultancy; Esanex: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding. Wei:Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Amgen: Honoraria, Other: Advisory committee, Research Funding; Celgene: Honoraria, Other: Advisory committee, Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment.

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)

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 (<6 months) due to lack of response. Response evaluation is performed after 2 and 6 cycles of therapy, and then every 6 months or as clinically indicated; analyses are descriptive. At a planned interim analysis, a pre-defined discontinuation rate due to adverse events (AEs) of ≤10% in the first 3 cycles (“early discontinuations”), a rate comparable to that observed with azacitidine alone in the prior study, and an overall response rate (ORR) of ≥20% were deemed desirable and would support expansion into Stage 2, wherein approximately 20 additional patients will be treated for a total of 60 evaluable patients. The study Independent Data Monitoring Committee (IDMC) in conjunction with the study Sponsor was to determine whether the study would expand based on the discontinuation rate.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. DisclosuresKhaled: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.

Oral Vitamin C Supplementation to Azacitidine in Patients with Myeloid Cancer: Normalization of Plasma Vitamin C Induces Epigenetic Changes

▪IntroductionHematological cancer patients are often vitamin C deficient, and vitamin C is essential for the TET induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylsytosine (5hmC); the first step in active DNA demethylation. In tissue culture, we have shown that restoration of vitamin C to normal concentrations can potentiate the effect of DNA methyltransferase inhibitors (DNMTis) by activation of DNA demethylation and induction of genes in the viral defense pathway, so called ‘viral mimicry’ (Liu et al. PNAS 2016). Here, we investigated whether oral vitamin C supplementation can correct vitamin C deficiency, enhance the efficacy of active DNA demethylation and induce upregulation of genes in the viral defense pathway in patients with myeloid cancers treated with the DNMTi 5-azacytidine.Study Design and MethodsA randomized, placebo-controlled clinical trial of myelodysplastic syndrome (MDS; n=9), chronic myelomonocytic leukemia (CMML; n=4) and acute myeloid leukemia (AML; n=7) patients was performed during 3 cycles/12 weeks of DNMTi treatment (5-azacytidine, 100mg/m2 day 1 to 5 in a 4-week cycle) supplemented by oral dose of 500mg vitamin C (n=10) or placebo (n=10) daily during the last 8 weeks (Figure 1). Blood samples were drawn on day 1 and 5 of each treatment cycle before 5-azacytidine was administered and on day 28 of the third treatment cycle. Total plasma vitamin C was measured by HPLC in samples that had been acidified by 10% meta-phosphoric acid immediately after blood drawn. Mutational status of the 20 most commonly mutated genes in MDS were conducted by targeted next-generation sequencing. Global levels of 5mC and 5hmC were measured with LC-MS/MS in DNA extracted from MACS-sorted malignant cells and quoted relative to total levels of deoxyguanine. Total RNA-seq was performed on 20 RNA samples from 6 patients; cDNA libraries were prepared using KAPA RNA HyperPrep Kits and sequencing on a NextSeq 500 instrument (Illumina).ResultsFourteen patients were deficient in plasma vitamin C (<23 µM) and 4 of the remaining 6 patients took vitamin supplement at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (<11.4 µM; P=0.004) and borderline significantly higher in DNMTi naïve (n=11) compared to non-naïve patients (P=0.095). At baseline, global 5hmC/5mC levels were lower in the 7 patients with TET2 mutations (n=7; P= 0.013). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (P<0.0005). We show for the first time that active DNA demethylation, estimated as the change in global 5hmC/5mC levels, was significantly increased in patients receiving vitamin C compared to placebo (P=0.041). Preliminary RNA sequencing data show increased upregulation of genes involved in the viral defense pathway, including IRF7 and IFIT1, in vitamin C supplemented patients that were DNMTi naïve at study inclusion.ConclusionsThe increase in active DNA demethylation, indicated by the elevation of 5hmC/5mC levels in myeloid cells from vitamin C supplemented patients compared to placebos, plus the increased expression of viral defense genes in vitamin C treated DNMTi naïve patients, suggest that the efficacy of 5-azacytidine might be increased by oral supplementation of vitamin C. We suggest that normalization of plasma vitamin C by oral supplementation may enhance the biological effects of DNMTis in patients and prompts the investigation of the clinical relevance of vitamin C supplementation to DNMTis in a large randomized placebo controlled trial.Figure 1. Study design. Days 1, 5, and 28: before vitamin C/placebo exposure. Day 32: after short-term vitamin C/placebo exposure. Days 56, 60, and 84: after longer-term vitamin C/placebo exposure. C = cycle, D = day in cycle. [Display omitted] DisclosuresJones:ZYMO Corporation: Consultancy. Grønbæk:Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen Pharma: Membership on an entity's Board of Directors or advisory committees.

Addition of the SMO Inhibitor Sonidegib to Azacitidine in Patients with Higher Risk Myelodysplastic Syndrome (MDS) Who Failed to Respond or Lost Response to AZA Alone: Results of a Phase 1-2 Add-on Study By the GFM

Background: although azacitidine (AZA) is an established frontline therapy for HR-MDS, approximately 40% of the patients fail to respond and virtually all of the responders will ultimately relapse. We previously reported the poor outcome of patients who failed AZA treatment for whom a median survival of 6 months is expected (Prebet, J Clin Oncol. 2011;29(24):3322). Overexpression of SMO a member of the hedgehog pathways has been observed in HR-MDS. Preclinical data have shown the activity of hedgehog pathway inhibitors and suggested synergism with Hypomethylating agents (HMA) (Zou, PLoSONE 2015; 10(8):e0136843). To harness potential synergism, we designed an add-on trial in which sonidegib (LDE-225), an oral inhibitor, was added to AZA in patients who failed AZA monotherapy.Patients and methods:Eligible patients should have IPSS Int-2 or HR-MDS or AML, (to have 10% to 30% marrow blasts), have received a minimum of 6 cycles of AZA monotherapy and to have failed to achieve a response to AZA (defined as CR, CRi, PR or HI as per IWG criteria) in the absence of marrow progression or have relapsed after achieving a response. Patients were scheduled to receive sonidegib daily from day 1 to 28 of 28-day cycles while continuing on AZA at the maximum previously tolerated dose (ie 50 to 75 mg/m²/d for 5-7 days). Two sonidegib dose levels were evaluated in the phase 1 part of the trial (400 and 800 mg/d) according to a classical 3+3 scheme.Results:23 patients, median age 76, were included in the study. One withdrew consent before starting the study treatment and is not included in the analysis. Characteristics of the remaining 22 patients are summarized in the Table. At the 800 mg/d dose level, 3 pts experienced DLT (grade 4 ASAT elevation (1 pt); grade 4 CPK elevation (2 pts)). The recommended dose for the expansion phase was 400 mg/d and no DLT was observed. 19 patients received 400 mg/d. Pts received a median of 3.5 cycles [IQR 2 ; 5], and 5 pts (23 %) received ≥ 6 cycles. All of them were withdrawn from study: 5 (26%) for disease progression (including 1 pt who progressed before starting cycle 1 and did not received treatment), 5 (26%) for death (all due to infection in the context of active disease) and 9 for miscellaneous reasons. 25 SAEs were reported including 23 infections, 1 intra cranial hemorrhage and 1 urinary retention. The most frequent non-hematologic toxicity was infection that occurred in 16/22 (73%) pts. In addition, 243 non hematologic toxicities of any grade were recorded in 20 pts for a total of 83 cycles, all but 3 of grade 1-2, including GI, cutaneous and musculo-skeletal toxicities and fatigue. Hospitalization was required in 45% of the pts. Only 3 responses were observed (1 CR, 1 marrow CR and 1 PR). Response durations were 1, 9 and 15 months .With a median follow-up of 23 months, 13 pts have died and the median overall survival is 6.8 months.ConclusionSonidegib at the dose of 400 mg/d can be given in combination with azacitidine with an acceptable toxicity. With a response rate of only 13%, our results indicate that the addition of sonidegib failed to reverse resistance to azacitidine in pts with higher risk MDS. This contrasts with the positive effect of the combination of glasdegib, another hedgehog pathway inhibitor with cytarabine in pts with AML and MDS (Cortes, Blood 2016 128:99). Besides potential differences in drug potency, our results may highlight the difficulty to identify active agents in the difficult-to-treat patient population selected after HMA therapy failure. The recommended dose-schedule of AZA-sonidegib established here could be used for further investigation in previously untreated patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)