A Phase I/II Study to Investigate the Safety and Clinical Activity of the Protein Arginine Methyltransferase 5 Inhibitor GSK3326595 in Subjects with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Background Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme responsible for symmetric arginine dimethylation of multiple proteins that impact cell proliferation. Its substrates include proteins involved in mRNA splicing, signal transduction, gene transcription, and DNA repair. PRMT5 overexpression occurs in many cancers and correlates with poor prognosis. GSK3326595 is a potent, specific, and reversible inhibitor of PRMT5 that inhibits proliferation and induces cell death in a broad range of solid and hematologic tumor cell lines. It also exhibits potent anti-tumor activity in vivo in animal models, including in preclinical models of myeloid malignancies. One mechanism of action of GSK3326595 is via inhibition of cellular mRNA splicing and upregulation of tumor suppressor function. Mutations in splicing factors are frequent in myeloid malignancies (including approximately 40% of patients with myelodysplastic syndrome [MDS], and over 60% of patients with chronic myelomonocytic leukemia [CMML]), and further inhibition of mRNA splicing via GSK3326595 may lead to a synthetic lethal phenotype specifically in splicing mutant disease. Study 208809 is the first trial of a PRMT5 inhibitor in participants with myeloid malignancies. Methods Study 208809 is a Phase I/II study to evaluate the safety, tolerability, and clinical activity of GSK3326595 monotherapy in participants with relapsed and refractory MDS, CMML, and hypoproliferative acute myeloid leukemia (AML) that has evolved from an antecedent MDS. Part 1 will identify a tolerated dose and establish preliminary evidence of efficacy in this population. At the end of Part 1, if pre-specified criteria are met, then the study will be expanded with three additional Parts that will be opened in parallel. Part 2A is a Phase II randomized comparison of monotherapy GSK3326595 versus investigator's choice of best available care in participants with relapsed and refractory MDS, CMML, and hypoproliferative AML. Part 2B is a single-arm investigation of safety and efficacy of GSK3326595 plus 5-azacitidine in participants with newly diagnosed high-risk MDS. Part 2C is a single-arm investigation of the safety and efficacy of monotherapy GSK3326595 in participants with relapsed or refractory AML whose tumors harbor mutations in components of the pre-mRNA splicing machinery. All participants enrolled in this study have a diagnosis of MDS, CMML, or AML, with enrollment into each cohort as defined above. Participants are adults with adequate organ function as defined in the protocol. Prior allogeneic transplant is permitted. There are no required biomarkers for enrollment to Parts 1, 2A, and 2B, though central confirmation of pre-mRNA splicing factor mutations will be performed to stratify participants for overall analysis. Enrollment to Part 2C is limited to participants with splicing factor mutations. It is estimated that a maximum of 302 participants will be enrolled in the study, divided as follows: Approximately 41 participants in Part 1, approximately 192 participants in Part 2A, approximately 41 participants in Part 2B, and approximately 28 participants in Part 2C. In Part 1, the primary endpoint is clinical benefit rate, as defined as the percentage of participants achieving a complete remission, complete marrow remission, partial remission (PR), stable disease lasting at least 8 weeks, or hematologic improvement, as per standard criteria. In Part 2A, the primary endpoint is overall survival. In Part 2B and Part 2C, the primary endpoint is overall response rate (ORR), defined as the percentage of participants achieving a PR or better. Samples are collected to evaluate symmetric dimethylated arginine (SDMA), the enzymatic product of PRMT5. This has been demonstrated to be a pharmacodynamic marker of PRMT5 inhibition in plasma and tumor tissue. In addition, participants will be stratified based on the presence or absence of spliceosome mutations and analyzed separately to evaluate the effect of these mutations on clinical activity. As of 1 August 2019, recruitment is ongoing across six centers in the United States and Canada; ten participants have been enrolled, all into Part 1. ClinicalTrials.gov identifier: NCT03614728 Study is funded by GlaxoSmithKline Disclosures Watts: Takeda: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bradley:AbbVie: Other: Advisory Board. Brunner:Novartis: Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Papadantonakis:Agios: Consultancy, Honoraria. Abedin:Actinium Pharmaceuticals: Research Funding; Pfizer Inc: Research Funding; Helsinn Healthcare: Research Funding; Agios: Honoraria; Jazz Pharmaceuticals: Honoraria. Baines:GlaxoSmithKline: Employment, Equity Ownership. Barbash:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties, Research Funding. Gorman:GlaxoSmithKline: Employment, Equity Ownership. Kremer:GlaxoSmithKline: Employment, Equity Ownership. Borthakur:Cantargia AB: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agensys: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding.

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EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Blood ◽

10.1182/blood-2019-121460 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 758-758 ◽

Cited By ~ 4

Author(s):

Pieternella Lugtenburg ◽

Rogier Mous ◽

Michael Roost Clausen ◽

Martine E.D. Chamuleau ◽

Peter Johnson ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Clinical Activity ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a median of 5 doses (range: 1-14); treatment is ongoing in 6 pts. Twelve pts discontinued treatment due to progressive disease. Six pts died (2 during treatment, 4 during survival follow-up), all due to disease progression and unrelated to treatment. The most common (n≥5) treatment-emergent AEs were pyrexia (n=8), local injection-site reactions (n=7), diarrhea (n=5), fatigue (n=5), and increased aspartate aminotransferase (n=5). The most common Grade (G) 3/4 AEs were anemia (n=3) and neutropenia (n=3). Despite increasing GEN3013 doses, all CRS events were non-severe (initial observation: 3/8 pts, G1: n=1, G2: n=2; following modification of premedication plan [corticosteroids for 3 days]: 6/10 pts, G1: n=4, G2: n=2). Increases in peripheral cytokine (IL6, IL8, IL10, IFNγ, TNFα) concentrations after GEN3013 dosing correlated with clinical symptoms of CRS in most pts. No pts had tumor lysis syndrome or neurological symptoms. No DLTs were observed. GEN3013 PK profiles reflect SC dosing; Cmax occurred 2-4 days after dosing. No ADAs were detected. PD effects following GEN3013 dosing were observed at dose levels as low as 40 µg and included rapid, complete depletion of circulating B cells (if present after prior anti-CD20 therapy) and peripheral T-cell activation and expansion. The first evidence of clinical activity was observed at a dose level of 120 µg, with complete metabolic response observed in a pt with DLBCL. Conclusions: Subcutaneously administered GEN3013, a potent CD3×CD20 bsAb, shows good tolerability and early evidence of clinical activity at low dose levels in heavily pretreated pts with relapsed or refractory B-NHL. All CRS events were non-severe and did not lead to discontinuation. No DLTs were observed. Dose escalation is ongoing; updated data will be presented. Dose expansion will begin upon determining the recommended Phase 2 dose (RP2D) (NCT03625037). Disclosures Lugtenburg: Janssen Cilag: Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria, Research Funding. Mous:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Clausen:Abbvie: Other: Travel grant to attend ASH 2019. Johnson:Boehringer Ingelheim: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Oliveri:Genmab: Employment, Equity Ownership. DeMarco:Genmab: Employment, Equity Ownership. Hiemstra:Genmab: Employment, Equity Ownership, Other: Warrants. Chen:Genmab: Employment. Azaryan:Genmab: Employment. Gupta:Genmab: Employment, Equity Ownership. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Hutchings:Incyte: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pfizer: Research Funding.

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Nascent Transcript and Single Cell Rnaseq Analysis Defines the Mechanism of Action of the LSD1 Inhibitor INCB059872 in Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130458 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2509-2509

Author(s):

Gretchen Johnston ◽

Haley E. Ramsey ◽

Kristy Stengel ◽

Shilpa Sampathi ◽

Pankaj Acharya ◽

...

Keyword(s):

Bone Marrow ◽

Drug Treatment ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Myeloid Differentiation ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Upregulated Genes

Drugs targeting chromatin-modifying enzymes have entered clinical trials for myeloid malignancies, including INCB059872, a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1). LSD1 is a component of the CoREST complex, in which it associates with histone deacetylases 1 and 2, the transcriptional co-repressor, mSin3A or mSin3B, and the REST corepressor (RCOR1), so a role in gene expression was expected. While initial studies of LSD1 inhibitors have suggested these compounds may be used to induce differentiation of acute myeloid leukemia, the mechanisms underlying this effect and dose-limiting toxicities are not well understood. Here, we have used precision nuclear run-on sequencing (PROseq) and single-cell RNA-sequencing (scRNAseq) to show that INCB059872 de-represses GFI1/GFI1B-regulated genes to promote a myeloid differentiation gene signature in AML cells while stalling maturation of megakaryocyte progenitor cells. Within 3 days of treatment with INCB059872, the majority of THP-1, which contain an the MLL-translocation, undergo myeloid differentiation. RNAseq analysis indicated that 24h drug treatment upregulated genes involved in hematopoietic cell lineage, which is consistent with the differentiation. In addition, PROseq was used to measure the effects of INCB059872 on nascent transcription at genes and enhancers, as this is one of the best methods to define enhancer activity. In THP-1 cells after 24h treatment, there were 203 genes with at least a 1.5-fold increase in transcription, while there are nearly 1300 enhancers meeting this threshold. Upregulated genes include those associated with myeloid cell differentiation, such as CSF1R and CD86. Given that LSD1 catalyzes the removal of mono- and di-methyl marks from histone H3, we expected that INCB059872 would cause a buildup of histone methylation. Surprisingly, ChIPseq for H3K4me2 and H3K4me1 showed only subtle changes in these marks after 48h drug treatment in THP-1. Only a handful of LSD1i-induced enhancers overlapped with detectable changes in H3K4 methylation. However, our PROseq data is consistent with the increases in H3K27 acetylation seen with OG86 (a compound that disrupts the LSD1:GFI1 interaction) at GFI1 binding sites (PMID: 29590629). Indeed, motif analysis of INCB059872-upregulated enhancers identified the GFI1 recognition sequence as the most highly enriched. Moreover, siRNA inhibition of key components of LSD1-containing chromatin remodeling complexes pinpointed the CoREST complex as mediating the THP-1 myeloid differentiation effects of INCB059872. To investigate on-target thrombocytopenia seen with LSD1 inhibitors in preclinical studies, we analyzed the bone marrow of wild-type mice treated daily with INCB059872 for 0, 4, or 6 days before harvesting and sorting lin-bone marrow cells for scRNA-seq. Notably, one of the most highly upregulated genes in treated cells was Gfi1b. Unsupervised clustering identified 22 clusters, corresponding to unique subpopulations (Fig. 1A). While the distribution of cells into different progenitor populations was mostly unaffected by drug treatment, these data revealed a striking increase in the proportion of cells from treated mice assigned to a megakaryocyte stem/progenitor cluster. Cells within this expanded cluster expressed stem cell markers such as MYCN and PBX1, but also expressed VWF (Fig. 1B). Thus, LSD1 inhibition caused accumulation of megakaryopoiesis-biased stem cells that failed to mature into efficient platelet producers. Finally, we used scRNAseq to analyze bone marrow from an AML patient who responded to treatment with INCB059872 plus azacytidine (AZA). A pre-treatment bone marrow sample was divided into separate cultures to study the effects of INCB059872, AZA, or the combination. Remarkably, unsupervised clustering of patient cells assigned the majority of INCB059872 and combination-treated cells to clusters that were not found in control- or AZA-treated samples. Cells exposed to INCB059872 had upregulated GFI1 and GFI1B, as well as differentiation-related genes that were also observed in AML cell lines. Overall, these data indicate that INCB059872 affects gene expression with kinetics consistent with a loss of CoREST activity to stimulate differentiation of AML blasts, but the inactivation of GFI1/GFI1B impairs megakaryocyte maturation likely explaining thrombocytopenia seen in preclinical models. Disclosures Stubbs: Incyte Corporation: Employment, Equity Ownership. Burn:Incyte: Employment, Equity Ownership. Hiebert:Incyte Corporation: Research Funding. Savona:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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Comparative Efficacy Among 3rd Line Post-Imatinib Chronic Phase-Chronic Myeloid Leukemia (CP-CML) Patients after Failure of Dasatinib or Nilotinib Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood.v124.21.4551.4551 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4551-4551 ◽

Cited By ~ 2

Author(s):

Jeffrey H. Lipton ◽

Dhvani Shah ◽

Vanita Tongbram ◽

Manpreet K Sidhu ◽

Hui Huang ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitors ◽

Cytogenetic Response ◽

Comparative Efficacy ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract INTRODUCTION Patients with chronic myeloid leukemia (CP-CML) failing 1st line imatinib are most commonly treated with the second-generation (2G) tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib. However, for patients who experience resistance or intolerance (R/I) to 2G-TKIs in 2nd line, there currently is no consensus on the optimal therapy sequence for 3rd line treatment. The comparative efficacy of using ponatinib in the 3rd line after 2G TKI failure was examined in a previous study (Lipton et al., ASH 2013). This study assesses the comparative efficacy of ponatinib versus sequential treatment of alternate 2G TKIs in 3rdline setting in two separate patient populations, post-imatinib and dasatinib patients and post-imatinib and nilotinib patients. METHODS A systematic review was conducted in MEDLINE, EMBASE and the Cochrane Libraries (2002-2014), as well as 3 conferences (ASH (2008-2014), ASCO (2008-2014), and EHA (2008-2013)). Studies evaluating any TKI were included if they enrolled 10 or more post-imatinib adult patients with CP-CML who were also R/I to dasatinib or nilotinib. All study designs were considered and no restriction was applied with respect to therapy dose, due to incomplete reporting of doses in the available studies. Analyses was run on two groups of patients, those failing imatinib and dasatinib (Group Ima/Das) and those failing imatinib and nilotinib (Group Ima/Nil). Bayesian methods were used to synthesize major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) from individual studies and estimate the overall response probability with 95% credible interval (CrI) for each treatment. Bayesian analysis also was used to estimate the likelihood that each treatment offers the highest probability of CCyR/MCyR based on available evidence. RESULTS Six studies evaluating bosutinib, nilotinib and ponatinib for Group Ima/Das (n= 419) and five studies evaluating bosutinib, dasatinib and ponatinib for Group Ima/Nil (n=83) were included in the analysis. All studies reported CCyR in both groups. Five studies evaluating bosutinib, nilotinib and ponatinib reported MCyR in Group Ima/Das and three studies evaluating bosutinib and ponatinib reported MCyR in Group Ima/Nil. Synthesized treatment-specific probabilities and 95% CrI for CCyR are presented in Figure 1. Synthesized treatment-specific probabilities of CCyR for Group Ima/Das were 27% for nilotinib, 20% for bosutinib and 54% (95% CrI 43%% to 66%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Das were 41% for nilotinib, 28% for bosutinib and 66% (95% CrI 55%% to 77%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Das was estimated to be >99% for both CCyR and MCyR. Synthesized treatment-specific probabilities of CCyR for Group Ima/Nil were 25% for dasatinib, 26% for bosutinib and 67% (95% CrI 51%% to 81%) for ponatinib. Treatment-specific probabilities of MCyR for Group Ima/Nil were 33% for bosutinib and 75% (95% CrI 60%% to 87%) for ponatinib. The probability of ponatinib providing superior response to all other included treatments for group Ima/Nil was estimated to be >99% for both CCyR and MCyR. CONCLUSIONS The post imatinib and dasatinib group included more studies with larger sample sizes compared with the post imatinib and nilotinib group. Overall, response rates appear higher for TKIs in the post imatinib and nilotinib group compared with the post imatinib and dasatinib group. For both groups, patients on ponatinib had higher CCyR and MCyR rates compared with the sequential 2G TKIs included in this analysis. Based on available data, ponatinib appears to provide a higher probability of treatment response for patients failing imatinib and dasatinib/ nilotinib compared with sequential 2G TKI therapy commonly used in this indication. Figure 1 Figure 1. Disclosures Lipton: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shah:Ariad Pharmaceuticals: Research Funding. Tongbram:Ariad Pharmaceuticals: Research Funding. Sidhu:Ariad Pharmaceuticals Inc.: Research Funding. Huang:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. McGarry:ARIAD Pharmaceutical, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc: Employment, Equity Ownership. Hawkins:Ariad Pharmaceuticals Inc.: Research Funding.

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Final Phase I Results of Perifosine In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed or Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v116.21.3064.3064 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3064-3064

Author(s):

Andrzej J Jakubowiak ◽

Paul G Richardson ◽

Todd M Zimmerman ◽

Melissa Alsina ◽

Jonathan L. Kaufman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Activity ◽

Final Phase ◽

Employment Equity ◽

Advisory Committees ◽

Prior Therapy ◽

Ortho Biotech ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3064 Introduction: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid , Rev) a novel, oral immunomodulatory drug has activity against MM when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination (ASH 2008 # 3691). We now report the final phase I results of this study which aimed to determine the MTD and to evaluate activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM. Methods: Four cohorts ( 6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded. Results: 32 pts (17M/15F, median age 64 y, range 37 – 79) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4) with a median PS of 1. Relapsed (53%), Refractory to last therapy prior to study entry (47%). Prior therapy included dex (94%), thalidomide (75%), bortezomib (44%), and stem cell transplant (72%). Two pts (6%) were previously treated with Rev. 63% (15/24) of the prior thalidomide + dex (Thal/Dex) treated pts had progressed on a Thal/Dex regimen while 43% (6/14) of the prior bortezomib (Vel) treated pts had progressed on a prior Vel based regimen. Two pts did not complete one full cycle (non-compliance and adverse event not related to study drugs – both in cohort 3) and were not included in the efficacy analysis. 31/32 pts were evaluable for safety (non-compliant patient never took study drug and was excluded). The most common grade 1/2 events (any causality) included fatigue (48%), diarrhea (45%), upper respiratory infection (35%), nausea (32%) and hyperglycemia (32%). Grade 3/4 events > 10% included neutropenia (26%); hypophosphatemia (23%); thrombocytopenia (16%) and leucopenia (13%). There was one reported DLT in cohort 3 (Nausea). No grade 3/4 events of peripheral neuropathy or DVT were reported. Rev dose was reduced in 11 pts, Peri reduced in 9 pts and Dex reduced in 7 pts: 30 pts are evaluable for response, with best response as follows: Median progression-free survival (PFS) for all pts was 10.8 mos (CI: 4.6, 27.7) and 7 pts have not progressed. The median overall survival (OS) was 30.6 mos (CI: 16.7, NR) with 15/30 pts still alive. Of the 8 thalidomide naïve pts, 4 have progressed with a median projected PFS of 30 mos and all 8 pts remain alive (range 28 – 43 mos). Conclusions: Pts have tolerated Peri + Rev + Dex well with manageable toxicity, and with promising clinical activity demonstrated by an ORR (≥ PR) of 50%, an extended PFS and OS. Given that most pts were exposed to Thal/Dex with more than half refractory to a prior Thal/Dex regimen, the encouraging response rates and survival appear to suggest benefit with the addition of perifosine to Rev/Dex. This data thus warrants further study, including a potential randomized trial to confirm the activity of perifosine added to Rev/Dex. A randomized phase III trial of Peri/Vel/Dex vs. Vel/Dex is underway for previously Vel exposed MM patients. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Off Label Use: Perifosine in combination with Lenalidomide and Dexamethasone. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Millennium, Celgene: Speakers Bureau. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

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Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽

10.1182/blood.v118.21.3768.3768 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3768-3768 ◽

Cited By ~ 5

Author(s):

Richard A. Larson ◽

Udomsak Bunworasate ◽

Anna G. Turkina ◽

Stuart L. Goldberg ◽

Pedro Dorlhiac-Llacer ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial

Blood ◽

10.1182/blood.v120.21.163.163 ◽

2012 ◽

Vol 120 (21) ◽

pp. 163-163 ◽

Cited By ~ 20

Author(s):

Jorge E. Cortes ◽

Dong-Wook Kim ◽

Javier Pinilla-Ibarz ◽

Philipp le Coutre ◽

Ron Paquette ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Treatment Options ◽

Response Rates ◽

Cytogenetic Response ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

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CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.2510.2510 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2510-2510 ◽

Cited By ~ 6

Author(s):

Tara L. Lin ◽

Laura F. Newell ◽

Robert K. Stuart ◽

Laura C. Michaelis ◽

Stephen E. Rubenstein ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Dose Adjustment ◽

Cardiac Repolarization ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar ratio. It is highly effective in patients with high-risk acute myeloid leukemia (AML). This study evaluated the impact of CPX-351 (100 units/m2) on cardiac repolarization. Methods: This open-label, Phase II, pharmacokinetic (PK) and pharmacodynamic (PD) study entered AML and acute lymphocytic leukemia (ALL) patients with good risk hepatic function (Child-Pugh scores <7), and normal cardiac function (LVEF≥50%, QTcF<470 ms). Cardiac repolarization changes were assessed using conventional ECG and Holter monitor recordings. PK was assessed during the first 21 days for total cytarabine, daunorubicin, Ara-U and daunorubicinol. The relationship between CPX-351 PK, QTcF, and renal function using the equation to calculate the estimated glomerular filtration rate (eGFR) was evaluated. Results: Twenty-six patients entered the study and 21 were evaluable for QT interval change from baseline. Evidence that CPX-351 prolongs the QTcF interval was not observed. The largest absolute and mean change from time-matched baseline was 12.56 and 8.03 ms, respectively (Day 1, hour 4). Mean QTcF change on Day 5 was unchanged from baseline. QTcF intervals >480 ms were never observed and no consistent QTcF intervals >450 ms were noted. Absolute QTcF increases between 30 and 60 ms were present in 4 of 25 patients and no changes >60 ms were observed. CPX-351 plasma concentration vs. time curves for day 1 and 5 exhibited a volume of distribution approximately equal to the plasma volume with prolonged single-exponential elimination half-lives for cytarabine and daunorubicin of ≥24 hours. The PK of CPX-351 was independent of renal function. Patients with moderately impaired (eGFR=30-59 mL/min/1.73m2) renal function exhibited similar drug exposure as those with mild and normal renal function. Table 1. Impact of renal function impairment on Day 5 CPX-351 PK parameters (mean, %CV): Analyte Renal Function Cmax (ng/mL) AUClast (ng*hr/mL) AUCinf (ng*hr/mL) T1/2 (hr) Cytarabine Normal (n=3) Mean 59333 2893146 2902641 42.5 %CV 28.7 68.8 69 34.1 Mild (n=7) Mean 58071 3599512 3606695 41.0 %CV 31.9 52.4 52.4 21.8 Moderate (n=3) Mean 57333 3149303 3156738 38.0 %CV 46.6 50.7 50.6 21.9 Daunorubicin Normal (n=3) Mean 25967 754646 870861 24.9 %CV 23.1 63 65.3 56.0 Mild (n=7) Mean 28686 865034 1021420 30.5 %CV 43.9 43.5 43.6 25.3 Moderate (n=3) Mean 21933 671542 814732 35.4 %CV 50.9 35.9 33.5 31.2 Table 2 summarizes response and transplant outcomes. One of two ALL patients achieved CR and was transplanted. Among AML patients there were 7 CR and 2 CRi of which three went on to transplant. An additional four patients became morphologically leukemia free (MLF) and were transplanted before full documentation of CR was achieved. A large majority of patients given first-line treatment with CPX-351 responded or became suitable for transplant (10/13, 77%). Table 2. 206 Study Efficacy Diagnosis n ResponseCR/CRi Transplanted in CR/CRi Induced MLF and Transplanted No Response ALL-Relapsed 2 1/0 1/0 0 1 AML-First Line de novo 8 5/0 0 1 2 AML-First Line sAML 5 1/2 1/1 1 1 AML-Salvage 11 1/0 1/0 2 8 Conclusions: Clinically relevant prolongation of QTcF is not a feature of CPX-351 treatment. CPX-351 exposure was independent of renal function, indicating no need for dose adjustment when renal function is impaired. The high rate of complete remission and referral for transplant corroborate the high level of efficacy observed in earlier studies with CPX-351. Disclosures Stuart: Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Pentikis:Celator Pharmaceuticals: Consultancy. Alvarez:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Mayer:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase According to Reasons for Switching from Imatinib to Nilotinib: Subgroup Analysis from ENESTop

Blood ◽

10.1182/blood.v128.22.792.792 ◽

2016 ◽

Vol 128 (22) ◽

pp. 792-792 ◽

Cited By ~ 13

Author(s):

Timothy P. Hughes ◽

Carla Maria Boquimpani ◽

Naoto Takahashi ◽

Noam Benyamini ◽

Nelma Cristina D Clementino ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Employment Equity ◽

Advisory Committees ◽

Loss Of Response ◽

Equity Ownership ◽

Treatment Free Remission

Abstract Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference. Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL. In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure. Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups. Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL. Figure. Figure. Disclosures Hughes: Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.

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Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Blood ◽

10.1182/blood.v130.suppl_1.896.896 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 896-896

Author(s):

Carlo Gambacorti-Passerini ◽

Michael W. Deininger ◽

Michael J. Mauro ◽

Charles Chuah ◽

Dong-Wook Kim ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Cumulative Incidence ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P <0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P <0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

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