MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study

Idasanutlin, an MDM2 antagonist, showed clinical activity and rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label, phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily, days 1-5 of each 28-day cycle. The primary endpoint was composite response (hematocrit control and spleen volume reduction >35%) in patients with splenomegaly, and hematocrit control in patients without splenomegaly at week 32. Key secondary endpoints included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n=27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n=13), 9 (69%) attained any spleen volume reduction and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (n=6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥3 nausea and vomiting experienced in 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. Registration: NCT03287245.

Acupuncture For The Treatment of Diarrhoea-Predominant Irritable Bowel Syndrome (ATIBS-D): A Pilot Randomized Controlled Trial

Background: Diarrhoea-predominant irritable bowel syndrome (IBS-D) is a common disease without an established optimal treatment. Acupuncture has promising effects on IBS-D, but high-quality evidence is scarce.Methods: In this parallel, multicenter, randomized controlled trial, participants with IBS-D were assigned to three groups: specific acupoints (SA), non-specific acupoints (NSA) and non-acupoints (NA). Participants received 12 sessions (3 sessions per week) treatment over 4 weeks. The primary endpoint was a composite response rate at week 4 of treatment. An eligible composite responder was responded in both abdominal pain intensity and stool consistency, defined as at least 30% decrease in the weekly average of worst abdominal pain score and 50% or greater reduction in the number of Type 6 or 7 stool days weekly compared with baseline.Results: Of 201 screened patients with IBS-D, 90 (44.8%) patients were enrolled, and 88.9% patients completed this study (26 in NSA; 27 in SA and NA). The composite response rates at week 4 were 46.7%, 46.7% and 26.7% (P＞0.05) of the participants who received SA, NSA and NA acupuncture, respectively. Adverse events were reported in 2 (6.7%) patients in SA, 3 (10%) patients in NSA and NA. There were no serious adverse events.Conclusions: The present study suggests that acupuncture treatment is feasible and safe for IBS-D patients. The further adequately powered trials can be achieved by recruiting more patients, increasing treatment dose, prolonging follow-up, choosing specific acupoints, setting up sham-acupuncture control, or a combination thereof.Trial registration: Chinese Clinical Trial Registry, ChiCTR2000030670. Registered on 9 March 2020. https://www.chictr.org.cn/edit.aspx?pid=50167&htm=4

EFFECT OF MANUFACTURING ON THE TRANSVERSE RESPONSE OF THERMOSET COMPOSITES

This study presents a finite element (FE) based virtual test procedure to investigate the effect of the manufacturing process on the transverse composite response. Computational models of the composite microstructures are generated and analyzed in commercial FE solver Abaqus supplemented by user-written subroutines. Several realizations of the composite microstructure with random fiber arrangement are analyzed assuming appropriate initial stress state and material definitions. The virtual test procedure is established to define the evolution of process-induced in-situ matrix properties through direct and inverse process modeling approaches. Subsequently, the composite microstructures are virtually tested in transverse tension to predict the transverse composite properties by implementing progressive damage models. In order to quantify the effect of manufacturing on the transverse composite response, predictions from the two approaches are compared to a third case which assumes an initial stress-free state and neglects the effect of processing conditions on the in-situ matrix properties. Variations of ±5% in average strength and 18% in standard deviations are observed with respect to ideally cured RVEs. It is established that process modeling in necessary to optimize the residual stress state and improve composite performance.

Response surface method for optimization of prepared satranidazole powder layered pellets

Background The purpose of the present study was to evaluate layered of satranidazole powder using natural polysaccharides as coating materials for colon targeting that were inexpensive and natural with a non-toxic nature using a composite response design of 3 levels and 2 factors for each of the four responses in the quadratic model. The independent variables were the ratio of coating consistency % (X1) and coating level % (X2) in the pellet. The dependent factors were % release of drug at 2 h. (Y1), % release of drug at 6 h. (Y2), % release of drug difference in presence & absence of colonic enzyme (Y3) and mean dissolution time (Y4). The various models were fitted for the responses with an explanation of suitable statistical methods. Variance analysis and different factor levels of responses were constructed by response surface plots. Results Satranidazole pellets were efficiently prepared by the variable amount of ingredients that showed compatibility with possible pellet characterization and drug dissolution profiles to optimize the formulation. Conclusions The strategy of response surface can be a successful tool for improving the prepared satranidazole pellets which can be an appropriate replacement of regular one.

Framework for Predicting Failure in Polymeric Unidirectional Composites through Combined Experimental and Computational Mesoscale Modeling Techniques

As composites continue to be increasingly used, finite element material models that homogenize the composite response become the only logical choice as not only modeling the entire composite microstructure is computationally expensive but obtaining the entire suite of experimental data to characterize deformation and failure may not be possible. The focus of this paper is the development of a modeling framework where plasticity, damage, and failure-related experimental data are obtained for each composite constituent. Mesoscale finite elements models consisting of multiple repeating unit cells are then generated and used to represent a typical carbon fiber/epoxy resin unidirectional composite to generate the complete principal direction stress-strain curves. These models are subjected to various uniaxial states of stress and compared with experimental data. They demonstrate a reasonable match and provide the basic framework to completely define the composite homogenized material model that can be used as a vehicle for failure predictions.

Response rates in acute myeloid leukemia patients treated with attenuated durations of venetoclax in combination with hypomethylating agents.

e19008 Background: The combination of the Bcl-2 inhibitor, venetoclax, with hypomethylating agents (HMA) recently emerged as an efficacious treatment for older adults with acute myeloid leukemia (AML) who are not eligible for intensive induction therapy. In a phase III randomized controlled trial of HMA +/- venetoclax, DiNardo et al demonstrated impressive composite complete response rate and complete response with incomplete recovery (CR+CRi) of 66% in the venetoclax arm as compared to 28% in the placebo arm. Despite HMA/Venetoclax being lower intensity, 83% of patients developed grade 3 hematologic adverse events, and 42% of patients experienced febrile neutropenia in the venetoclax arm, as compared to 19% in the placebo arm. In the trial, venetoclax was given continually for 28 day cycles, with some patients receiving shortened durations of venetoclax (21 days) due to toxicity. To reduce toxicity, some institutions have further limited the duration of venetoclax in cycle 1. Here, we report response rates with attenuated durations of venetoclax with HMA. Methods: We conducted a retrospective study of AML patients who received venetoclax in combination with HMA, excluding those with prior chemotherapy for AML or MDS, or previous exposure to HMA or venetoclax. Demographic, cytogenetic, pathology, and outcome data were collected including bone marrow biopsy results at diagnosis and after cycle 1 (day +28) or cycle 2 (day +56). The primary outcome was composite response rate (CR+CRi) following cycle 1 or cycle 2 defined by 2017 ELN criteria. Results: 25 patients were identified with median age of 73 (range 63-82). 9 patients received 14 or less days of venetoclax (attenuated duration): < 8 days in 1 patient and 8-14 days in 8 patients. 16 patients received 21 days or more (standard duration): 21 days in 14 patients, and 28 days in 2 patients. Of the patients who received an attenuated duration, the median age was 74 (68-82), 22% had either a TP53 mutation or deletion, 56% had complex karyotype, and 44% had received prior cytotoxic chemotherapy. Of the patients who received standard duration therapy, the median age was 71 (63-81), 44% had either a TP53 mutation or deletion, 75% had complex karyotype, and 6% had received prior cytotoxic chemotherapy. The composite response rate was 78% in the attenuated duration group and 75% in the standard duration group (p > 0.99). Conclusions: Though a limited sample size, this data suggests high response rates can be observed with attenuated courses of venetoclax. With appropriately selected patients, the feasibility of attenuated venetoclax courses could be further explored in larger prospective studies.[Table: see text]

ARC-6: A phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC).

5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( > 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

Rotary Friction Welded C45 to 16NiCr6 Steel Rods: Statistical Optimization Coupled to Mechanical and Microstructure Approaches

This work represents the production of dissimilar friction welded joints between C45 carbon steel and nickel-chromium alloy steel 16NiCr6. Central Composite Response Surface (RSM) methodology, optical microscopy, scanning electron microscopy (SEM), backscattered electron diffraction (EBSD) and bending test were performed for this study. Physicochemical characterization was used to reveal the welded joint microstructures. The bending test was done in order to measure the ultimate bending strength (UBS). As a conclusion, regarding the optimization of the parameters, friction time and the rotation speed were the most effective parameters on the joint strength. These parameters revealed that the maximum bending strength of 1406.892 MPa can be obtained at a rotational speed of 2000 rpm, a friction pressure of 24.77 MPa and a friction time of 13 seconds. On the weld samples it was also noted that the particle size decreases significantly as the units of the parameters increase, which led to note that the optimization of these parameters converges towards an average particle size, where were found a good accommodation between hardness and young’s modulus.