Rationale and Design of a Phase 3b Multicenter, Randomized, Double-Blind Placebo-Controlled, Parallel-Group Trial with an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Avatrombopag for the Treatment of Pediatric Patients with Immune Thrombocytopenia

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts (PCs) caused by a combination of both impaired platelet production and increased peripheral platelet destruction. ITP in children often resolves on its own, but it may become chronic and symptomatic in a proportion of children affected. After failure of first-line therapies (e.g. corticosteroids or immunoglobulin), treatment options for children include immunosuppressants, such as rituximab, and thrombopoietin receptor agonists (TPO-RAs). Avatrombopag (AVA) is an orally administered small molecule TPO-RA. It binds the human c-Mpl at a different site than endogenous TPO, stimulating signal transduction mimicking the biological effects of endogenous TPO in a non-competitive manner. In a phase 3 trial (NCT01438840) in adults with ITP, the primary efficacy endpoint of cumulative number of weeks with PC ≥50×10 9/L during 6 months of treatment in the absence of rescue therapy, was statistically significant favoring AVA over placebo. The most common treatment-emergent adverse events (AEs) in the phase 2 and 3 trials in adults (n=128) were headache, fatigue, and contusion. AVA has no significant hepatotoxicity, is administered with food, and has no restrictions on meal composition. AVA is approved by FDA and EMA for treatment of primary chronic ITP in adult patients with an insufficient response to a previous treatment. For pediatric patients with ITP, there is an unmet need for new treatment options, given the difficult administration requirements and variable, transient response, frequent relapse, and associated toxicities of available treatments. Study Design and Methods: Described here is the rationale and design of a phase 3b multicenter, randomized, double-blind placebo-controlled, parallel-group trial with an open-label extension phase (NCT04516967), evaluating the efficacy and safety of AVA for the treatment of pediatric patients with ITP for ≥6 months with an insufficient response to a previous treatment. Main inclusion criteria (Core phase) include: Age ≥1 and <18 years; informed consent; primary ITP for ≥6 months duration and an insufficient response to previous treatment; an average of 2 PCs <30×10 9/L, with no single count >35×10 9/L. Main exclusion criteria: secondary ITP; inherited thrombocytopenia; history of arterial or venous thrombosis, myelodysplastic syndrome; or congenital heart abnormalities or arrhythmias. Subjects will be randomized to blinded therapy of AVA or placebo (3:1 ratio) for 12 weeks, stratified by age cohort and baseline PC (Figure). AVA or placebo will be administered as an oral tablet (20 mg, age cohort 1 and 2) or as an age-appropriate pediatric formulation (10 mg, age cohort 3). Subjects who complete the Core Phase and are eligible may continue to the open label extension phase (2 years). The primary endpoint is durable platelet response, defined by the proportion of subjects achieving ≥6 out of 8 weekly PCs ≥50×10 9/L during the last 8 weeks of the 12 week treatment period in the Core Phase, in the absence of rescue medication. Secondary endpoints include proportion of subjects with ≥2 consecutive PCs ≥50×10 9/L during the Core Phase (12 weeks) in the absence of rescue medication; percentage of weeks with PC ≥50×10 9/L, and between ≥50×10 9/L and ≤150×10 9/L, during Core Phase (12 weeks) in the absence of rescue therapy; proportion of subjects with PC ≥50×10 9/L at day 8, proportion of subjects who require rescue medications during Core Phase; incidence and severity of bleeding symptoms; safety and PK/PD parameters. Statistics: The primary endpoint will be tested using the Cochran-Mantel-Haenszel 2-sided test at α=0.05, adjusting for age cohort and baseline PC (≤15×10 9/L vs >15×10 9/L), or the Fisher's exact test, when data is sparse. In addition, the numbers and percentages of responders in each treatment group, the associated 95% confidence intervals (CI), and the 95% CI for the difference between AVA and placebo will be estimated. Study Status: This global study is currently enrolling patients and aims to include at least 72 patients in total, at approximately 62 sites. Figure 1 Figure 1. Disclosures Grace: Principia: Membership on an entity's Board of Directors or advisory committees; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Novartis: Research Funding. Xue: Dova Pharmaceuticals, a Sobi company: Current Employment. Jamieson: Sobi, Inc.: Current Employment. OffLabel Disclosure: Avatrombopag is an orally administered thrombopoietin receptor agonist (TPO-RA) that mimics the biologic effects of TPO in stimulating the development and maturation of megakaryocytes, resulting in increased platelet count. It is approved by the European Medicines Agency (EMA) and the US Food & Drug Administration (FDA) for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure, and for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

INCB84344-201: Ponatinib and steroids in frontline therapy of unfit patients with Ph+ acute lymphoblastic leukemia

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL aged ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/day for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/day from days -14 to 29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) was reached in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of April 24, 2020, median event-free survival was 14.31 months (95% CI 9.30, 22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increased (15.9%), erythema (15.9%), and gamma-glutamyltransferase increased (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%) of patients, respectively. Dose reductions/interruptions/discontinuations due to TEAEs occurred in 43.2%/43.2%/27.3% of patients; 5 patients had fatal TEAEs. Ponatinib and prednisone had efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. (This trial is registered at www.clinicaltrials.gov as NCT01641107).

Electrospun coaxial hyaluronan-based fiber networks for ophthalmic drug release

A micro-sized core-shell drug release device has been prepared by coaxial electrospinning based on a polylactide shell and the inner core phase made of high molecular weight hyaluronan or a cross-linked hyaluronan network. Timolol, which was inserted into the core phase, is widely used as drug for glaucoma treatment to depress the intraocular eye pressure and should be released over a longer time period from this fiber networks. Release studies of drug loaded fiber devices showed an only moderate burst release of timolol in the first days followed by a continuous longlasting drug release period over several weeks. With these findings, coaxial electrospinning represents a promising approach for the development of drug release systems with long-lasting, relatively constant drug delivery.

Managing pasireotide-associated hyperglycemia: a randomized, open-label, Phase IV study

Purpose Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. Methods Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing’s disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. Results Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. Conclusion Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.

First long-term results on efficacy and safety of long-acting pasireotide in combination with everolimus in patients with advanced carcinoids (NET) of the lung/thymus: Phase II LUNA trial.

8574 Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI <70%. PAS +EVE combination showed clinical benefit in terms of PFS and BPFS compared to PAS and EVE alone as shown in Table. At least one dose reduction of PAS or EVE was reported in >50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. [Table: see text]

Core–Shell Droplet Generation Device Using a Flexural Bolt-Clamped Langevin-Type Ultrasonic Transducer

Droplets with a core–shell structure formed from two immiscible liquids are used in various industrial field owing to their useful physical and chemical characteristics. Efficient generation of uniform core–shell droplets plays an important role in terms of productivity. In this study, monodisperse core-shell droplets were efficiently generated using a flexural bolt-clamped Langevin-type transducer and two micropore plates. Water and silicone oil were used as core and shell phases, respectively, to form core–shell droplets in air. When the applied pressure of the core phase, the applied pressure of the shell phase, and the vibration velocity in the micropore were 200 kPa, 150 kPa, and 8.2 mm/s, respectively, the average diameter and coefficient of variation of the droplets were 207.7 μm and 1.6%, respectively. A production rate of 29,000 core–shell droplets per second was achieved. This result shows that the developed device is effective for generating monodisperse core–shell droplets.

Моделирование размерных эффектов при фазовых превращениях в субмикронных частицах сплава Au-Pt-Pd

Size effects act at phase equilibria in micro- and nanoparticles They appear as shifts of the characteristic lines and points in the phase diagrams. We simulated and visualized these effects in ternary systems, such as Au–Pt–Pd solid solution. We applied methods of chemical thermodynamics to study the influence of the alloy composition on the region where core-shell states for the particles with a radius of 250 nm exist. It was shown that the splitting area of the alloy decreases and splits due to competing core-shell states, with Pt segregation in either core or shell phase. The phase diagram contains nodes of stable and metastable core-shell equilibrium states. We studied some of the properties of these states (composition of coexisting solutions, radius of the core phase). The described effects are relevant for understanding the catalytic activity of Au–Pt–Pd alloy particles.

Sedimentary micro-phase and reservoir display characteristics in shale Oil

Sedimentary microphilic and its exhibition feature is of great significance for identifying the distribution of remaining oil. This paper studies the development of geological characteristics of Zhidan Oil Zone, mineralogue and scanning electron microscopy experiments, and obtains the sedimentary micro-phase and reservoir display characteristics. The results show that combined with logging data, the core phase analysis, logging phase analysis, single well phase analysis, etc. Taking the leading edge of the Delta, the microphase type such as the river, the diversion bay and the underwater natural embankment is developed under water, due to the lifting of the lake, form a number of invested, plus, replenishment, in which water The downstream river is facilitating the advantages of the reservoir. The sedimentary phase and the angle effect of the zone are dominated by 4 + 5, chang 6 oil and gas, showing the characteristics of the rock sex reservoir. The type of reservoir is a rock sex reservoir. The main development of sandstone is impaired and the sandstone lens is a rock sex reservoir. The reservoir is an important influencing factor in the reservoir. The area has no uniform oil and water interface, lacking edge, bottom water.