Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Background: Thrombocytopenia is prevalent at presentation and following induction chemotherapy (chemo) regimens in patients (pts) with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML). Eltrombopag (EPAG), oral, nonpeptide thrombopoietin (TPO)-receptor agonist, is currently approved for treatment of chronic immune thrombocytopenia, hepatitis-associated thrombocytopenia, and aplastic anemia. It has also been evaluated as a strategy to mitigate chemo-induced thrombocytopenia in pts with solid tumors, myelodysplastic syndrome, and following allotransplant. Prior studies have demonstrated that EPAG can directly inhibit the proliferation of human AML cells in vitro. Although EPAG has been studied following induction and consolidation chemo in the frontline AML setting, to date, the tolerability and efficacy of EPAG in pts receiving salvage chemo for R/R AML is not known. Objectives: This study's objectives were to (a) estimate the maximum tolerated dose (MTD) and tolerability of EPAG, (b) examine platelet (plt) response (defined as plt count ≥ 100 x 10 9/L), and (c) anti-leukemic activity of EPAG in pts receiving high dose cytarabine (HiDAC) and mitoxantrone (Mito) for R/R AML. Methods: In this phase I open-label study, adult pts (³ 18 yrs) with R/R AML with adequate organ functions and grade 4 thrombocytopenia following HiDAC (given every 12 hrs (3 g/m 2 for age < 50; 1.5 g/m 2 for age ≥50) for 12 doses) and Mito (dosed at 12 mg/m 2 x 3 doses every other day) were eligible. All pts must have had marrow hypoplasia demonstrated on Day 14 ± 3 days from the initiation of HiDAC. EPAG was started daily on Day 14 ± 3 days with dose determined using a standard '3+3' dose-escalation design. EPAG was discontinued if an adequate plt response was achieved or following 9 weeks of therapy. The dose-limiting toxicity (DLT) window was defined as the first 15 days of EPAG dosing. Results: Nine pts with R/R AML were enrolled (Table 1). Median age was 64 yrs (range, 33-80), and 5 pts were men. All pts had intermediate (6/9, 67%), adverse (2/9, 22%), or unknown (1/9, 11%) cytogenetic risk disease. One (1/9) pt had NPM1+FLT3-ITD+ disease. Five pts (56%) had relapsed disease (2pts had prior allotransplant). All pts received HiDAC+Mito chemo and started on EPAG on Day 14 ± 3 days. Three received EPAG 150 mg, and 6 pts received 200 mg daily. The median duration on EPAG was 26 days (range, 11-82). One pt experienced a DLT of grade 3 myocardial ischemia while receiving EPAG 200 mg/day and was taken off study. No other DLTs were reported, and no MTD was determined. The most frequent grade ³3 adverse events (AEs, Table 2): were bacteremia (56%), neutropenic fever (44%), and hyperbilirubinemia (33%). Similarly, common grade 1-2 AEs consisted of hyperbilirubinemia, tachycardia, and confusion (33% each, respectively). At a median follow-up of 30.3 months (mo), all 9 pts had discontinued EPAG. Six pts (67%) achieved plt response (3 each in 150 mg and 200 mg/day dose level). The median time to achieve plt response and the duration of plt response was 27 days (range, 14-41) and 40.5 mo (range, 2-49.6), respectively. Three other pts discontinued EPAG therapy: 1 each due to cardiac ischemia, donor lymphocyte infusion, and patient choice, respectively (Table 3). Of note, 7/9 pts (78%) had clinical response: CR in 5 (56%), CRc (CR+CRp) in 6 (67%), MLFS in 1 (11%, Table 4). Two (2/7 responders) went on to subsequent allotransplant, and 6 died; 2-progressive disease, one each from pneumonia, failure to thrive, encephalopathy, and unknown cause, respectively. Among the 6 pts who achieved plt recovery on EPAG, 5 achieved CR and 1-MLFS following HiDAC+Mito. Conclusion: This phase 1 dose-finding study demonstrated that EPAG 150-200 mg daily following HiDAC+Mito chemo for R/R AML was well tolerated with one DLT of cardiac ischemia (200 mg dose). Two-thirds (67%) of pts achieved plt recovery on EPAG after a median of 27 days (range, 14-41). In these small number of pts (n=9), addition of EPAG therapy did not seem to adversely affect clinical outcomes (CRc 67%) and may have contributed to long-term platelet recovery. Further studies are required to determine the optimal schedule and potential benefit of EPAG added to chemo regimens for R/R AML. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Boston Biomedical: Consultancy; Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Elshoury: Bristol Meyers Squibb: Other: advisory board. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Safety and Efficacy of Subcutaneous (SC) Blinatumomab for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL)

Background Blinatumomab is a BiTE ® (bispecific T cell engager) molecule that engages patients' T cells to the CD19 antigen on lymphoid tumor cells. Blinatumomab administered as a 28-day continuous intravenous infusion (cIV) is approved in multiple regions for the treatment of R/R B-ALL in adults and children. Subcutaneous delivery may improve the convenience and satisfaction of patients with R/R B-ALL who are candidates for blinatumomab therapy. Here we report the results from the first cohort of adults with R/R B-ALL receiving SC blinatumomab. Methods In this ongoing multicenter, single arm, open-label, phase 1b dose-finding study (NCT04521231), patients received multiple cycles of SC blinatumomab. Each cycle included a treatment period and a treatment-free interval. In cohort 1, cycle 1, patients received a lower first dose of SC blinatumomab for several days followed by a higher dose multiple times weekly; in subsequent cycles, patients received the higher dose several times weekly during the treatment period. Bone marrow (BM) evaluation was performed on day 27 of each cycle. Results Six patients from cohort 1 were included in this June 22, 2021 data cutoff. Median age was 64 (range 38-83) years. The number of prior therapies ranged from 2-4. Two patients had disease refractory to primary therapy or salvage therapy, 2 patients relapsed after chemotherapy, and 2 patients relapsed after prior allogeneic hematopoietic stem cell transplant. Median BM blast count at study start was 85% (range 28%-95%). Only 1 patient had <50% BM blasts (BM blasts=28%). At enrollment, all patients had an ECOG score of 0-1. The median number of SC blinatumomab cycles initiated was 1 (range 1-3). Preliminary pharmacokinetic results support the SC dosing intervals used in this study and potentially longer intervals. Exposures for SC doses were similar to the efficacious exposures of the approved cIV regimen: mean average concentrations at steady state of 215 and 853 pg/mL for the lower and higher SC dosing regimens of cohort 1, respectively, vs mean steady state concentrations of 228 and 616 pg/mL for 9 and 28 µg/day cIV dosing, respectively. The pharmacodynamic profile following SC blinatumomab of peripheral immune cell redistribution (circulating CD3+ and CD8+ CD69+ T cells), transient cytokine elevation (IL-6, IL-10, IFN-γ) and CD19+ B cell counts declining below the detection limit was consistent with the historical pharmacodynamic profile following cIV blinatumomab. No grade ≥3 cytokine release syndrome events were reported (Table). One patient developed herpes encephalitis and experienced a grade 5 neurological event unrelated to blinatumomab; no other neurological events were reported. Two patients discontinued treatment because of adverse events (injection site reaction in patient with no response, hyperleukocytosis due to disease progression). Three patients had complete hematological response (CR) with no measurable residual disease (MRD) (<10 -4) within 2 cycles and 1 patient had a morphological partial response (95% BM blasts at start of cycle 1 to 22% blasts on day 15). This patient discontinued on day 15 of cycle 1 after progression of extramedullary disease. At the time of the data cutoff, 2 patients remained on study. These patients had CR with no MRD. Conclusions In this phase 1b dose-finding study, SC blinatumomab has demonstrated encouraging anti-leukemia activity in heavily pretreated patients with R/R B-ALL. Pharmacokinetic and pharmacodynamic results support the use of SC dosing in this population. The safety profile was manageable and consistent with that reported for cIV blinatumomab. Figure 1 Figure 1. Disclosures Gordon: Amgen: Current Employment, Current equity holder in publicly-traded company. Schwartz: Morphosys: Research Funding; Pfizer: Honoraria, Speakers Bureau; Gilead: Other: Travel grants, Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Rossi: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Sanofi: Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wong: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment. Markovic: Amgen: Current Employment, Current equity holder in publicly-traded company. Katlinskaya: Amgen: Current Employment, Current equity holder in publicly-traded company. Panwar: Amgen: Current Employment, Current equity holder in publicly-traded company. Zugmaier: Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company.

First-in-Human Dose-Finding Study of AAVhu37 Vector-Based Gene Therapy: BAY 2599023 Has Stable and Sustained Expression of FVIII over 2 Years

Background Gene therapy for hemophilia A has the potential to reduce the treatment burden for patients and their care providers by eliminating the need for regular factor VIII (FVIII) prophylaxis through long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. Ongoing phase 3 gene therapy trials for hemophilia A show promise but can result in unpredictable FVIII expression of uncertain durability. Gene therapy must evolve to meet patient expectations of a durable, efficacious and safe treatment. BAY 2599023 (AAVhu37.hFVIIIco) is the first, clinical stage adeno-associated virus (AAV) gene therapy vector, based on the AAVhu37 serotype. BAY 2599023 is a non-replicating AAV vector and contains a single-stranded DNA genome encoding a B-domain-deleted FVIII, under the control of a liver-specific promoter/enhancer combination, optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic clade E family and was selected based on preclinical studies demonstrating efficient, liver-directed FVIII gene transfer, favorable biodistribution and durable FVIII expression. Here, we report safety and FVIII activity levels achieved to date in this first-in-human, dose-finding study of BAY 2599023. Methods The ongoing BAY 2599023 phase 1/2, open-label, dose-finding study (NCT03588299) included male patients aged ≥18 years with severe hemophilia A, no history of FVIII inhibitors, no detectable neutralizing immunity against AAVhu37 (neutralizing antibody titer ≤5), and ≥150 exposure days to FVIII products. Patients received a single intravenous infusion of BAY 2599023 and were enrolled sequentially into three dose cohorts (0.5 × 10 13 GC/kg, 1.0 × 10 13 GC/kg and 2.0 × 10 13 GC/kg), each comprising at least two patients. Patients to be enrolled in a fourth cohort will receive a single infusion of 4 × 10 13 GC/kg (Figure 1). Primary endpoints were adverse events (AEs), serious AEs (SAEs) and AEs/SAEs of special interest (S/AESIs). The secondary endpoint was FVIII activity over time. Informed patient consent and ethics committee approval were obtained. Results Three cohorts of ≥2 patients each (N = 9) were enrolled sequentially (Figure 1). At the data cutoff (May 2021), FVIII activity data were available for the first eight patients. BAY 2599023 delivered sustained FVIII expression levels for up to >23 months, with evidence of bleed protection. Patients in Cohorts 2 and 3 have all been off prophylaxis with FVIII products since approximately 6-12 weeks after gene transfer. To date, it has been observed that no spontaneous bleeds requiring treatment have been reported once FVIII levels >11 IU/dL were achieved. Of the 9 patients treated, 5 patients developed an AESI: mild/moderate alanine aminotransferase (ALT) elevations observed in Cohort 2 (n =1) and Cohort 3 (n = 3) were managed with corticosteroid treatment; another ALT elevation was reported as study-drug-related SAE in Cohort 3 (n = 1) but returned to normal a few weeks after interruption of the H2 blocker famotidine. The latest follow-up data for up to 28 months will be presented. Conclusions BAY 2599023 was designed to enhance efficacy and durability of FVIII expression with a favorable safety profile. Sustained FVIII levels allowed suspension of FVIII prophylaxis in the majority of patients, with asymptomatic ALT elevations that responded to corticosteroids, making BAY 2599023 a key candidate in the evolution of gene therapy in hemophilia A. Figure 1 Figure 1. Disclosures Pipe: Genventiv: Consultancy; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Sheehan: BioMarin: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Coppens: Portola/Alexion: Research Funding; CSL Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Roche: Research Funding; Daiichi Sankyo: Research Funding; Sanquin Blood Supply: Research Funding; uniQure: Research Funding; Medcon International: Consultancy; MEDtalks: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Sobi: Consultancy. Eichler: Takeda: Consultancy, Honoraria; BioMarin: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Pfizer: Research Funding; Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Honoraria; Bayer: Consultancy, Research Funding. Linardi: Bayer: Current Employment. Wiegmann: Bayer: Current Employment. Hay: Pfizer: Consultancy, Research Funding; Inspiration: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Spark Therapeutics: Consultancy, Research Funding. Lissitchkov: Bayer: Other: Principal Investigator of Clinical Trials; Catalist: Other: Principal Investigator of Clinical Trials; Grifols: Other: Principal Investigator of Clinical Trials.

CTNI-51. ADJUVANT TROTABRESIB, A REVERSIBLE POTENT BROMODOMAIN AND EXTRATERMINAL INHIBITOR, PLUS TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: INTERIM RESULTS FROM A PHASE 1B DOSE-FINDING STUDY

Trotabresib (CC-90010) demonstrated antitumor activity as monotherapy in patients with advanced malignancies (Moreno et al. ESMO 2020. Abstract 5270) and enhanced the antiproliferative effects of temozolomide in preclinical studies. CC-90010-GBM-002 (NCT04324840) is a phase 1B dose-finding study investigating standard-of-care temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide or concomitant trotabresib + temozolomide + radiotherapy followed by adjuvant trotabresib + temozolomide, post-resection, in patients with newly diagnosed glioblastoma. We present interim results for adjuvant trotabresib + temozolomide. Patients received trotabresib 15, 30, or 45 mg daily (4 days on/24 days off) + temozolomide administered per label for 6 cycles, followed by trotabresib 45 mg monotherapy daily (4 days on/24 days off). Primary objectives are to establish the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of trotabresib. Preliminary efficacy, pharmacokinetics, and pharmacodynamics are also being investigated. Of 13 patients enrolled, 5, 6, and 2 received trotabresib 15, 30, and 45 mg, respectively, plus temozolomide. Grade 3/4 treatment-related adverse events were reported in 2, 4, and 1 patients receiving trotabresib 15, 30, and 45 mg, respectively. MTD and RP2D are not yet reached; dose limiting toxicity (grade 4 thrombocytopenia) was reported in 1 patient in the 30-mg group. Of 10 evaluable patients, 1 had complete response and 7 had stable disease per RANO criteria. Trotabresib exposure increased proportionally with dose. Day 4 time to peak trotabresib concentration was 0.5–2.0 hours; mean terminal half life was 60–70 hours. Day 4 blood CCR1 RNA 2–4 hours post-dose was downregulated below baseline in the 15-mg group and ≥ 50% in the 30-mg group. Adjuvant trotabresib + temozolomide appears well tolerated, with promising preliminary efficacy. Treatment was ongoing at data cutoff in 9 patients in the adjuvant cohort; enrollment is continuing in the adjuvant and concomitant therapy dose-escalation cohorts.

Finding study on the level of exhaustion of medical workers

In this article we present the results obtained following a study on the level of burnout of doctors, nurses and resident doctors. We discuss about symptoms of occupational stress, but also the categories of factors that generate occupational stress. The weight of the theoretical aspect is presented by the two models: procedural and three-dimensional of burnout – the first theoretical models proposed to explain the burnout phenomenon.

A novel paclitaxel coated balloon with increased drug transfer for treatment of complex vascular lesions

Background Drug coated balloons (DCB) with paclitaxel (Ptx) dose of 2–3.5 μg/mm2 balloon surface inhibit restenosis with different effectiveness and duration of success. A clinical dose finding study is not known for any of the currently marketed products. The aim of the present preclinical trial was to investigate a novel DCB coated with 6 μg Ptx/mm2 in a porcine model. Methods and results The current study investigated a DCB with a novel, modified iopromide based matrix with 6 μg Ptx/mm2. Drug transfer to the vessel wall of peripheral arteries was compared with a dose of 3 μg Ptx/mm2 and two fully overlapping DCB with 3 μg Ptx/mm2, each. Ptx concentration in the vessel wall after drug transfer was about twice as high for balloons with 6 μg/mm2 (1957±1472 μg/g) and two overlapping DCB with 3 μg Ptx/mm2, each (1287±619 μg/g) compared to a single balloon with 3 μg Ptx/mm2, (787±738 μg/g), with statistical significant differences for 1x6 μg/mm2 vs. 1x3 μg/mm2 (p = 0.017) but not for 2x3 μg/mm2 vs. 1x3 μg/mm2 (p = 0.184) and 1x6 μg/mm2 vs. 2x3 μg/mm2 (p = 0.178). The proportion of residual Ptx on balloon after treatment was similar for all groups between 6±1% and 10±3% of dose on balloon. Conclusion The dose of 6 μg Ptx/mm2 was successfully as well as reproducibly coated on conventional balloon catheters. Increased Ptx on balloons resulted in increased drug concentration in the vessel wall. A single balloon with 6 μg Ptx/mm2 seems to provide double dose compared to 3 μg Ptx/mm2, facilitates the procedure, and may reduce medico-economic cost compared to the use of two standard DCB.