Kooperativer Bibliotheksverbund

In: Annals of the Rheumatic Diseases, BMJ, Vol. 77, No. 3 ( 2018-03), p. 412-416

Abstract: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. Methods Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0–11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. Results 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were −1.2 (95% CI −2.1 to −0.3; P=0.0099) and −1.2 (95% CI −2.0 to −0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. Conclusions We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. Trial registration number 65360827, 2010-021430-64; Results.

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

URL: Article

DOI: 10.1136/annrheumdis-2017-212268

DOI: 10.1136/annrheumdis-2017-212268.supp1

Language: English

Publisher: BMJ

Publication Date: 2018

detail.hit.zdb_id: 1481557-6

In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 894-894

Abstract: Background Binding of E-selectin (E-sel), an adhesion molecule expressed in the vasculature of the bone marrow, to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. GMI-1271 is a novel E-selectin antagonist that disrupts activation of cell survival pathways, enhances chemotherapy response with improved survival in mouse xenograft and syngeneic models and protects from chemotherapy toxicity in vivo (Becker 2013; Winkler 2013, 2014, 2016). We added GMI-1271 to salvage with MEC for relapsed/refractory AML patients or to induction with 7+3 for older treatment naïve (TN) AML patients. Methods A Phase (Ph) 1 trial escalated GMI-1271 (5-20 mg/kg) combined with MEC (mitoxantrone, etoposide, cytarabine) in pts with R/R AML, to evaluate safety, tolerability and anti-leukemic activity. Dose limiting toxicity (DLT) was defined as persistent cytopenias in the absence of disease or any Grade 3-5 non-hematologic toxicity beyond day 42. The recommended Ph 2 dose (RP2D) of GMI-1271 was 10 mg/kg. A Ph 2 study then enrolled 47 pts with R/R AML for GMI-1271 plus MEC chemotherapy. Responders could receive 1 cycle of consolidation with GMI-1271 plus MEC. We also enrolled a separate Ph 2 cohort of 25 pts ≥60 yrs with TN AML for GMI-1271 (10 mg/kg) plus cytarabine and idarubicin (7+3). Two cycles of induction were allowed. Responders could receive 3 cycles of consolidation with GMI-1271 plus intermediate dose cytarabine. Prior treatment of MDS was allowed; for R/R disease prior SCT was allowed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post chemotherapy. E-sel ligand expression on leukemic blasts in blood and bone marrow was assessed by flow cytometry, for the percentage of blasts binding to E-sel-Fc chimera and HECA452 (antibody to sialyl Lex). Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47, TN=25). Median age for R/R pts was 59 yrs (range 26-84) and 62% were males. Prior AML history included 32% primary refractory, 33% CR1 & lt;6 mos; 17% prior SCT; 58% unfavorable cytogenetics by SWOG (CG). GMI-1271 was well tolerated with no DLT, and adverse events were typical for AML chemotherapy with no unexpected toxicities. Grade 3/4 mucositis was & lt;4% with MEC. Median time to ANC 500 was 32d (range 23-66). 30 and 60 d mortality were 2 and 9%, respectively; all deaths within 60 d involved persistent disease. At RP2D in R/R, remission rate (CR/CRi) was 41% and ORR (CR/CRi/MLFS/PR) was 50%. In Ph 1, median OS was 7.6 mos; median DFS was 11.1 mos. In Ph 2, median OS and DFS are not yet reached; median follow up is 5 mos. 9 (14%) proceeded to SCT by data cut-off. Correlative studies demonstrated increased percentage of circulating blasts expressing E-sel ligand at baseline, 12 and 48 hrs (Figure) post-first dose of GMI-1271 in responding patients (CR/CRi/MLFS) versus nonresponders (p=0.03, p & lt;0.001, p & lt;0.001, respectively for timepoint). Median E-sel ligand expression at baseline was 28% (range, 1-85%) of bone marrow blasts, was higher in those achieving remission (p=0.002), and correlated with Event-Free Survival (r=0.47, p=0.03). Median age for TN pts was 67 yrs (range, 60-79) 56% were males, and 32% had high-risk CG. 56% had secondary AML (sAML), 43% of sAML had prior hypomethylating therapy. GMI-1271 was well tolerated, adverse events were typical for AML induction in the TN population, and Grade 3/4 mucositis was not seen. 30 and 60 d mortality were 8 and 12%, respectively; two deaths were from sepsis before response assessment and one involved persistent disease. Median time to ANC 500 was 28d (range 21-63). 8 pts required two induction courses, and 4 (16%) proceeded to SCT by data cut-off. The CR/CRi rate was 68% (73% for de novo and 64% for sAML) and ORR was 80%. Median OS and DFS are not yet reached; median follow up is 6 mos. Median E-sel ligand expression (binding to HECA452) at baseline was 31% (range, 2-92%) of bone marrow blasts. Conclusion The addition of GMI-1271 to chemotherapy was well tolerated with high remission rate, low induction mortality, and low rate of mucositis suggesting improved tolerance of chemotherapy. In R/R AML, correlative studies showed blasts expressing the E-sel ligand were predictive of response. Initial survival outcomes are promising and updated survival outcomes will be presented at ASH. FDA granted Breakthrough Therapy Designation to GMI-1271 for treatment of adults with R/R AML and randomized trials are planned. Disclosures DeAngelo: Amgen: Consultancy, Research Funding; BMS: Consultancy; Immunogen: Honoraria, Research Funding; Celgene: Research Funding; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Jonas: Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Rigel: Consultancy. Liesveld: Seattle Genetics: Honoraria; Onconova: Honoraria. Advani: Pfizer: Consultancy; Takeda/ Millenium: Research Funding. O'Dwyer: Onkimmune Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; GlycoMimetics Inc: Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Magnani: GlycoMimetics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray: GlycoMimetics, Inc.: Employment, Equity Ownership. Becker: GlycoMimetics, Inc.: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.894.894

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 331-331

Abstract: Background Binding of E-selectin (E-sel) to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Expression of the E-sel ligand (E-sel-L) is associated with increased relapse and poor survival. Uproleselan (GMI-1271), a novel E-sel antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity with improved survival in vivo. We added uproleselan to mitoxantrone, etoposide, cytarabine (MEC) chemotherapy for R/R AML patients (pts) and to cytarabine and idarubicin (7+3) induction for older, treatment naïve (TN) AML pts. Here we report on final outcomes and correlative studies. Methods A Phase (Ph) 1/2 trial evaluated safety and efficacy of escalating doses of upro (5-20 mg/kg) combined with MEC in pts with R/R AML. The recommended Ph 2 dose (RP2D) was 10 mg/kg. Ph 2 added pts ≥60 yrs with TN AML treated with upro and 7+3. Uproleselan was given 24 hrs prior, every 12 hrs during and 48 hrs post chemotherapy. Responders could receive consolidation therapy (1 cycle MEC or 1-3 cycles IDAC) with uproleselan. Baseline E-sel-L expression on AML blasts (CD45+,SSC) and leukemic stem cells (LSC, CD34+CD38-CD123+) in blood and bone marrow (BM) was assessed by flow cytometry, for percentage of blasts binding to E-sel-Fc chimeric protein and HECA452 (antibody to sialyl Lex). Post-induction measurable residual disease (MRD-/MRD+) was assessed locally. Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47. TN=25). Median age in R/R pts was 59 yrs (26-84) with 22/66 (33%) primary refractory, 22 (33%) CR1 〈 6 months (m); 17% prior SCT; 50% had adverse risk (ELN). Uproleselan was well tolerated, with no increase in adverse events. Grade 3/4 mucositis was 2% at RP2D. R/R CR/CRi rate was 41% (RP2D), 39% (all doses), 30% (primary refractory/CR1 〈 6m). 11/16 (69%) evaluable pts were MRD- . 42/66 (64%) received further anti-leukemic therapy including 17 (26%) SCT. At RP2D, median (95%CI) OS was 8.8 m (5.7-11.4); remission duration was 9.1 m (3.2-15.2); 1-year OS was 35%. For R/R/MRD-, 1-year OS was 73%. E-sel-L was detectable on BM blasts in all 36 evaluable pts: median expression 26% (1-85) of blasts. In a subset of MRD evaluable pts (N=10), E-sel-L expression was higher in those who were MRD- (55% vs 35%). Functional E-sel binding was higher in those achieving CR/CRi (N=14, p=0.003, at 12 hrs; p=0.001 at 48 hrs post uproleselan). In BM blasts (Figure N=36), LSC expression of E-sel-L correlated with blast E-sel-L (R2=0.75, p 〈 0.0001), consistent with hypothesis that E-sel/E-sel-L interaction may be an LSC mechanism of chemoresistance. R/R responders (CR/CRi) also had higher LSC/E-sel-L expression than non-responders (41% [0-98] vs 19% [0.7-83] p=0.06). Median OS for LSC/E-sel-L ≥10% (N=22) vs LSC/E-sel-L 〈 10% (N=14) was 12.7m (8.3-NR) and 5.2 m (2.3-9.4), respectively (p 〈 0.006). Median age in TN pts was 67 yrs (60-79). 48% had adverse risk (ELN) and 52% secondary AML (sAML). Uproleselan was well tolerated, with no increase in adverse events, no Grade 3/4 mucositis, and mortality 8% (30d) and 12% (60d). CR/CRi was 72% (all), and 69% (sAML). 5/9 (56%) evaluable pts were MRD-. 19/25 (76%) proceeded to further anti-leukemic therapy; 11 (44%) proceeded to SCT. Median (95% CI) EFS, OS, and remission duration were 9.2 m (3.0-12.6), 12.6 m (9.9-NR), and 10.4 m (7.1-17.8) respectively; 1-year OS was 52%. For sAML, median (95% CI) EFS and OS were 7.7 m (1.1-9.5) and 10.5m (4.4-NR), respectively. For TN/MRD-, 1-year OS was 60%. E-sel-L was detectable on BM blasts in all 24 evaluable pts: median expression 31% (2-92) of blasts. In a subset of MRD evaluable pts (N=8), E-sel-L expression was higher in those who were MRD+ (35% vs 8%). In BM blasts (Figure N=24), LSC expression of E-sel-L correlated with blast E-sel-L (R2=0.87, p 〈 0.0001). TN responders (CR/CRi) had LSC/E-sel-L expression similar to non-responders (21% [0-96] vs 21% [0-94] p=NS). Median OS for LSC/E-sel-L ≥10% (N=15) vs LSC/E-sel-L 〈 10% (N=7) was 10.5 m (4.4-NR) and not reached, respectively (p=NS). Conclusion The addition of uproleselan to chemotherapy was well tolerated, with low oral mucositis rates, high remission rates, high MRD- and transplant rates, and promising survival outcomes in pts with R/R and TN AML. High E-sel-L expression is associated with improved remission and survival with uproleselan treatment in R/R AML. Phase III studies in pts with R/R and (older) TN AML are underway. Figure. Figure. Disclosures DeAngelo: Shire: Honoraria; Amgen: Consultancy; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Takeda: Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Takeda: Honoraria; Incyte: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; ARIAD: Consultancy, Research Funding. Jonas:Glycomimetics: Research Funding; Genentech/Roche: Research Funding; Celgene: Consultancy, Research Funding; Accelerated Medical Diagnostics: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Tolero: Consultancy; Kalobios: Research Funding; LP Therapeutics: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Research Funding. Liesveld:Onconova: Other: DSMB; Abbvie: Honoraria. Bixby:GlycoMimetics: Research Funding. Advani:Glycomimetics: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Marlton:GlycoMimetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Fogler:GlycoMimetics: Employment, Equity Ownership. Wolfgang:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Becker:GlycoMimetics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114286

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4049-4049

Abstract: Background The treatment of patients with relapsed acute myeloid leukemia (AML) remains a significant challenge with poor outcomes due to a low response rate. Although cytotoxic chemotherapy remains the standard approach for treatment, novel agents are needed to improve clinical outcomes. Binding of leukemic blasts to E-selectin (E-sel), an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-sel, putatively disrupting leukemia cell survival pathways and enhancing chemotherapy response. We performed a phase 1/2 trial of GMI-1271 plus MEC (mitoxantrone, etoposide and cytarabine) for the treatment of relapsed/refractory (R/R) and a pilot study adding GMI-1271 to 7+3 for previously untreated elderly patients with AML. Methods A phase 1/2 open label trial of patients with R/R AML, with escalation of a single cycle of GMI-1271 across 3 dose levels combined with MEC, was conducted to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antileukemic activity. In addition, a pilot study was performed at the recommended phase 2 dose (RP2D) plus infusional cytarabine and idarubicin (7+3) in patients ≥60 years with untreated AML. Eligible patients (R/R AML) had an ECOG score of 0-2, received ≤2 prior induction regimens, WBC 〈 20K (raised to 〈 40K after 2 dose levels), no active CNS disease, and adequate renal and hepatic function. Eligibility for elderly patients in the untreated AML group was similar. GMI-1271 was administered with chemotherapy (24 hours prior, throughout, and 48 hours post induction). Dose limiting toxicity (DLT) was defined as myelosuppression beyond day 42 in the absence of disease or Grade 3 non-hematologic toxicity attributable to GMI-1271 and not resolving to Grade 2 by day 42. PK data were analyzed by population PK methods. PD for on-target activity was assessed by change from baseline in plasma sE-selectin levels (sE-sel) compared by 2-way analysis of variance. Results The phase 1 (Ph1) dose escalation in the R/R AML arm was completed with 19 subjects treated with GMI-1271 BID at 5 mg/kg (N=6), 10 mg/kg (N=7), and 20 mg/kg (N=6). The median age was 51 (range 26-77); 13 were male; 6 were refractory to prior intensive induction; 10 relapsed in ≤12 mos and 3 in 〉 12 mos; number of prior induction regimens: 1 (N=15) and 2 (N=4); risk based on the SWOG cytogenetic classification was intermediate (9) or unfavorable (10). There were no DLTs observed in the R/R dose escalation and no early deaths (30 d). Transient mucositis developed in only 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (5 mg/kg). Median time to count recovery was 37d (ANC 〉 1K) and 35 d (platelets 〉 100K) in responders. AEs were typical for MEC. Ph1 CR/CRi rate was 47% (42% CR%) with no observable dose response; 26% proceeded to subsequent stem cell transplant. Six of 9 remain in CR at data cut-off. Median OS and PFS have not been reached. One subject 〉 70yrs with refractory disease who achieved CR (negative by flow) was retreated with GMI-1271/MEC again off protocol and remains in CR (9mo). PK analysis showed linear kinetics; an average 50 y.o. had clearance 1.28 L/h with elimination t1/2 〉 3h; Cl decreased 2%/yr of increased age, and was 28% lower than in healthy adults. No accumulation was seen. Time over IC50 for E-sel binding was 〉 50% of the dosing interval for most patients at 10 mg/kg, and well in excess of effective preclinical exposure. PD analysis showed sE-sel on Day 8 decreased below baseline (p˂0.0013) with no dose response, suggesting on-target activity at all dose levels. Normal HSCs were not mobilized into the periphery after sentinel GMI-1271 dose. RP2D was determined to be 10 mg/kg BID based on drug exposure, time over IC50 for E-sel binding, lack of DLT, and similar on-target PD and clinical outcomes. To date, 10 patients enrolled on the Ph2 R/R AML arm; an additional 37 will be enrolled. In the previously untreated elderly AML arm, 3 patients enrolled in the safety run-in and no DLTs were observed, therefore an additional 22 patients will be enrolled. Updated response data will be presented at ASH. Conclusion We report on early clinical assessment of novel E-selectin antagonist GMI-1271 in R/R AML patients, with a high response rate (CR/CRi 47%) in this challenging group. No significant toxicities and no DLT were observed for GMI-1271. Ph2 dose expansion is ongoing. Disclosures DeAngelo: Celgene: Consultancy; Ariad: Consultancy; Baxter: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Liesveld:Onconova: Other: Data safety monitoring board; Astex: Honoraria; glycomimetics: Research Funding. O'Dwyer:Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Becker:GlycoMimetics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4049.4049

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 139, No. 8 ( 2022-02-24), p. 1135-1146

Abstract: Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi] ) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression & gt;10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021010721

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2690-2690

Abstract: Leukemic myeloblasts expressing E-selectin ligand (E-sel ligand) adhere to E-selectin on bone marrow endothelium resulting in environment-mediated drug resistance (EMDR). Uproleselan, a potent E-selectin inhibitor, disrupts the adhesion of AML cells in the bone marrow, re-sensitizing blasts to the cytotoxic effects of chemotherapy. Retrospective data demonstrated that E-sel ligand expression in AML patients is higher in relapsed disease compared to newly diagnosed AML, is more commonly seen in biologically adverse risk patients, and is present on leukemic stem cells (Chien et al ASH 2018). Preliminary data from a phase 1-2 trial of uproleselan combined with mitoxantrone, etoposide, cytarabine (MEC) chemotherapy in R/R AML demonstrated enhanced survival in patients with E-sel ligand expression on AML cells of 〉 10% compared to lower levels (DeAngelo et al ASH 2018). In order to more fully understand the relationship of E-sel ligand to the activity of uproleselan, we examined the clinical variables of patients with both high ( 〉 10%) and low E-sel ligand levels in comparison to the total population of patients treated on the phase 1-2 trial. Uproleselan, combined with MEC chemotherapy was studied in 66 patients with relapsed and/or refractory AML. The expression level of E-sel ligand on the surface of AML cells (blasts/leukemic stem cells (LSCs)) in the bone marrow was measured by a flow cytometric assay using the HECA 452 antibody that recognizes a functional trisaccharide domain shared by sialyl Lea and sialyl Lex and known to bind to E-selectin. Data on E-sel ligand was available in 36 patients at study entry in the phase 1-2 study and E-sel ligand was detectable on blasts in all patients. E-sel ligand on LSCs was demonstrated at levels ≥ 10% in 22 patients (61%) and at levels 〈 10 % in 14 patients (39%). Overall, the clinical characteristics confirmed a highly resistant population of R/R AML patients (see table) with 79% categorized as either poor risk by the European Prognostic Index (EPI) for first salvage therapy or ≥ second salvage, with an expected 1 year survival of less than 20% (Breems et al JCO 2005, Giles et al Cancer 2005). Although the sample size was small (n=36), substantially more patients with high E-sel ligand had achieved an initial remission and were in relapse (68%) whereas low E-sel ligand patients were more likely to be primary refractory (57%) (p=0.17). Patients with high E-sel ligand were more likely to have adverse ELN risk disease (55%) compared to low E-sel ligand patients (28%) (p=0.053). These data are consistent with previous findings demonstrating that higher E-sel ligand expression contributes to clinical chemotherapy resistance, particularly increasing the risk of relapse, whereas alternative resistance mechanisms may more commonly contribute to primary resistance. Importantly, the 45% response rate and 12.7 months median overall survival (OS) in the high E-sel ligand patients suggests that E-selectin inhibition by uproleselan contributed to their significantly improved outcomes when compared to the historically dismal outcomes with standard of care alone in these poor risk R/R AML patients. Table. Disclosures DeAngelo: Incyte Corporation: Consultancy; Celgene Corporation: Consultancy; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Shire: Consultancy; Amgen: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Jazz Pharmaceuticals, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Advani:Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Abbvie: Research Funding; Macrogenics: Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. O'Dwyer:Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics Inc: Research Funding; BMS: Research Funding. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Feldman:GlycoMimetics Inc: Employment. Thackray:GlycoMimetics Inc: Employment. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123744

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2650-2650

Abstract: Background Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand, on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Higher expression of E-sel ligand is associated with relapse and poor survival. Uproleselan (GMI-1271), a novel E-selectin antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination of uproleselan with chemotherapy improves response without additional toxicity. A phase 1/2 study (NCT02306291) of uproleselan added to chemotherapy (mitoxantrone, etoposide, cytarabine, MEC) in R/R AML showed promising outcomes at the recommended phase 2 dose (RP2D), including a CR/CRi rate of 41% and median OS of 8.8 m (95% CI 5.7-11.4). 11/16 (69%) evaluable patients were MRD negative (DeAngelo et al ASH 2018). Patients with sufficient expression of the appropriate E-selectin ligand (the target of the E-selectin inhibitor) exhibited higher CR/CRi rate and longer survival. Median OS for Leukemic blasts/E-sel ligand ≥10% vs leukemic blasts/E-sel ligand 〈 10% was 12.7m and 5.2 m, respectively (report in progress). Collectively, these data indicate that high E-sel ligand expression may contribute to clinical chemotherapy resistance, particularly increasing the risk of relapse, which can be reversed with E-sel inhibition. In addition, chemotherapy is well known to cause severe mucositis, with resultant infections, prolongation of hospital stay, morbidity and mortality, and a dramatic reduction in the expected incidence and severity of mucositis was seen with uproleselan in combination with MEC. At the RP2D, Grade 3/4 mucositis was 2%. Breakthrough Therapy Designation was granted by FDA for treatment of patients with R/R AML. A pivotal phase 3 study (NCT03616470) is underway. The aims of this phase 3, double-blind, placebo controlled study are to assess the efficacy and safety of uproleselan with standard salvage chemotherapy in R/R AML, evaluate the incidence of MRD, and assess for correlation of E-sel ligand expression on blasts with outcomes in R/R AML. Study Design and Methods This study is a global, randomized, double-blind, placebo-controlled phase 3 registration trial. Major Eligibility Criteria ≥18 to ≤75 years old Primary refractory AML, first or second relapse of AML Prior transplant (HSCT) is allowed Must be medically eligible for chemotherapy ECOG performance status ≤2 Study treatment and endpoints Treatment is MEC or FAI (fludarabine, cytarabine, idarubicin) induction with blinded study drug (uproleselan/placebo at 1:1 ratio) administered 1 day prior (sentinel dose) and then BID through 2 days post chemotherapy. Consolidation (HiDAC/IDAC) with uproleselan/placebo (same assignment) up to 3 cycles is allowed. The primary endpoint is overall survival; key secondary endpoints include the incidence of severe oral mucositis during induction and CR/CRh rate. Measurable residual disease, event free survival, safety, and pharmacokinetics will also be evaluated. In addition, the relationship between E-sel ligand expression on leukemic cells in the bone marrow and clinical outcomes in AML will be determined. Statistical methods The phase III primary endpoint will compare overall survival between the treatment arms using a stratified log-rank test. Stratification factors will be age group, disease status, backbone chemotherapy and prior transplant status. Median time to event values will be estimated using the Kaplan-Meier method. The study is powered to detect an improvement in median OS using a log-rank test (HR= 0.68, one-sided 0.025 type I error rate). A hierarchical testing procedure will be used to assess the statistical significance of the key secondary analyses, incidence of severe oral mucositis and remission rate (CR/CRh, CR). Study status This trial is expected to enroll 380 patients across approximately 9 countries in North America, Europe, and Australia. The first patient was enrolled in November 2018. Disclosures DeAngelo: Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Abbvie: Research Funding; GlycoMimetics: Research Funding; Celgene: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Shire: Consultancy. Erba:Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. O'Dwyer:AbbVie: Consultancy; GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Bhatnagar:Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support; Karyopharm Therapeutics: Other: Research support. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Cull:Amgen: Other: Travel, accommodation ; AbbVie: Other: Travel, accommodation; Glycomimetics: Other: Travel, accommodation. Armstrong:GlycoMimetics: Consultancy. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Thackray:GlycoMimetics Inc: Employment. Feldman:GlycoMimetics Inc: Employment. Advani:Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123816

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Quality of Life Research, Springer Science and Business Media LLC, Vol. 31, No. 4 ( 2022-04), p. 1191-1198

Type of Medium: Online Resource

ISSN: 0962-9343 , 1573-2649

URL: Article

DOI: 10.1007/s11136-021-03012-y

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2008960-0

SSG: 5,1

In: Arthritis & Rheumatology, Wiley, Vol. 69, No. 7 ( 2017-07), p. 1440-1450

Abstract: To investigate whether rituximab, an anti–B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS). Methods We conducted a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group trial that included health economic analysis. Anti‐Ro–positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre‐ and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost‐effectiveness. Results All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo‐treated patients and 24 of 61 rituximab‐treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group). Conclusion The results of this study indicate that rituximab is neither clinically effective nor cost‐effective in this patient population.

Type of Medium: Online Resource

ISSN: 2326-5191 , 2326-5205

URL: Issue

URL: Article

DOI: 10.1002/art.v69.7

DOI: 10.1002/art.40093

Language: English

Publisher: Wiley

Publication Date: 2017

detail.hit.zdb_id: 2754614-7

In: BMJ Open, BMJ, Vol. 8, No. 2 ( 2018-02), p. e018618-

Abstract: Acute colorectal surgery forms a significant proportion of emergency admissions within the National Health Service. There is limited evidence to suggest minimally invasive surgery may be associated with improved clinical outcomes in this cohort of patients. Consequently, there is a need to assess the clinical effectiveness and cost-effectiveness of laparoscopic surgery in the acute colorectal setting. However,emergency colorectal surgical trials have previously been difficult to conduct due to issues surrounding recruitment and equipoise. The LaCeS (randomised controlled trial of Laparoscopic versus open Colorectal Surgery in the acute setting) feasibility trial will determine the feasibility of conducting a definitive, phase III trial of laparoscopic versus open acute colorectal resection. Methods and analysis The LaCeS feasibility trial is a prospective, multicentre, single-blinded, parallel group, pragmatic randomised controlled feasibility trial. Patients will be randomised on a 1:1 basis to receive either laparoscopic or open surgery. The trial aims to recruit at least 66 patients from five acute general surgical units across the UK. Patients over the age of 18 with a diagnosis of acute colorectal pathology requiring resection on clinical and radiological/endoscopic investigations, with a National Confidential Enquiry into Patient Outcome and Death classification of urgent will be considered eligible for participation. The primary outcome is recruitment. Secondary outcomes include assessing the safety profile of laparoscopic surgery using intraoperative and postoperative complication rates, conversion rates and patient-safety indicators as surrogate markers. Clinical and patient-reported outcomes will also be reported. The trial will contain an embedded qualitative study to assess clinician and patient acceptability of trial processes. Ethics and dissemination The LaCeS feasibility trial is approved by the Yorkshire and The Humber, Bradford Leeds Research Ethics Committee (REC reference: 15/ YH/0542). The results from the trial will be presented at national and international colorectal conferences and will be submitted for publication to peer-reviewed journals. Trial registration number ISRCTN15681041 ; Pre-results.

Type of Medium: Online Resource

ISSN: 2044-6055 , 2044-6055

URL: Article

DOI: 10.1136/bmjopen-2017-018618

Language: English

Publisher: BMJ

Publication Date: 2018

detail.hit.zdb_id: 2599832-8