ДОСЛІДЖЕННЯ РОБОТИ СИСТЕМ КЕРУВАННЯ ДОЗУВАЛЬНИМ ОБЛАДНАННЯМ БЕЗПЕРЕРВНОЇ ДІЇ З «ПІ» ТА «ПІД» РЕГУЛЯТОРАМИ

Purpose. Investigation of transients in the control system of continuous dosing equipment for bulk materials using PI and PID regulators and evaluation of their impact on the quality of work elements.Method. Using the Mathlab: Simulink software environment to develop a mathematical model, conduct experimental research and assess the impact on the working bodies of the control system of continuous dosing equipment.Researchresults. Control of motor parameters (motor characteristics) by means of standard regulators of their comparison of advantages and disadvantages. described in many standards and scientific papers. However, modeling the engine operation process in dosing systems is significantly complicated due to the inertness and adhesion of bulk material dosed in the core of the hopper, it can significantly affect the final result of the finished mixture. continuous operation equipment using PI and PID controllers, an experiment was performed on a mathematical model using PI and PID controllers to assess their impact on the control system of the plate feeder continuous action. The results of the simulation can be used to decide on the type of controller control of transient characteristics of the engine, at development of control system of plate feeders in mixing complexes of continuous action.Scientificnovelty. Scientific novelty. The parameters influencing the frequency with which the motor of the plate feeder of continuous action rotates are determined. The time of the transient process of engine operation and the value of the maximum dynamic deviation are determined. The expediency of using regulators of one or another type for certain modes of operation of feeders is proved.Practical significance. The obtained results will reduce the transient time in the operation of the feeder motor and increase the operating time until the failure of the entire system. Design changes are proposed that will reduce the amount of ripple and improve the performance of continuous dosing equipment.

Refractory Head and Neck Lymphatic Malformation in Infants Treated With Sirolimus: A Case Series

BackgroundExtensive and complex head and neck lymphatic malformations (LMs) are challenging to manage through traditional therapy. The purpose of this retrospective study was to assess the efficacy and safety of sirolimus in infants with refractory head and neck LMs.MethodsSirolimus was administered orally on a continuous dosing schedule. Patients were seen every month for the first three months and then subsequently every three months. The primary endpoints were safety and efficacy based on clinical and radiological evaluations.ResultsEight patients, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, the response and safety to medication was evaluated: all patients experienced reductions in LMs bulk, ranging from modest to significant. Some minor adverse effects were reported: mouth sores, eczema, gastrointestinal reaction, dyslipidemia, and neutropenia.ConclusionSirolimus was efficient in children with refractory head and neck LMs and was well tolerated.

Phase I safety and efficacy study of autophagy inhibition with hydroxychloroquine to augment the antiproliferative and biological effects of preoperative palbociclib plus letrozole for estrogen receptor-positive, HER2-negative metastatic breast cancer (MBC).

1067 Background: Endocrine therapy with a CDK4/6 inhibitor is standard of care for patients (pts) with estrogen-receptor-positive (ER+), HER2-negative MBC, yet resistance ultimately develops. We have shown that low doses of palbociclib activates autophagy, which reverses initial G1 cell cycle arrest. High concentrations of palbociclib induce senescence, but these are off target effects of the drug. The autophagy inhibitor hydroxychloroquine (HCQ) induces senescence at a lower (i.e. on-target) continuous dosing of palbociclib, in in vitro and in vivo models. This strategy is being tested in a phase I/II trial (NCT03774472). Results from the phase I portion are reported here. Methods: The phase I part of this study uses a dose escalation 3+3 design testing HCQ, 400, 600 and 800 mg daily (6 pts at 800 mg) with continuously dosed palbociclib at 75 mg and letrozole 2.5 mg daily. Dose limiting toxicity (DLT) includes any study drug-related grade ≥ 3 nonhematological (lab) toxicity. Responding pts may continue on therapy beyond 8 weeks for up to 52 weeks. Primary objective is to determine safety, tolerability and the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives are overall tumor response and time to progression. Eligible pts are ≥18 years of age, postmenopausal (ovarian suppression allowed) with ER+/HER2-negative MBC, ECOG performance status score of ≤1 and with adequate renal, hepatic, and hematologic function. Response is assessed per RECIST v1.1. Results: Between 9/24/18 and 12/15/20, 14 pts were evaluable for safety. Median age was 41 with Asian (1, 7.1%), Black (2, 14.3%) White (11, 78.6%) patients enrolled. No DLTs were observed. One pt progressed during the DLT period and 2 withdrew consent (one during the DLT period); two pts were replaced for DLT assessment. Reasons for coming off study were grade 3 skin toxicity (1), per protocol at 8 weeks (non-measurable or pt/physician preference, 9), and (2) full duration treatment at 50 and 52 weeks. Adverse events (AEs) of grade ≥3 were hematologic (29), metabolism/nutrition (2), musculoskeletal/ connective tissue (1), and skin/subcutaneous tissue (3), with no serious AEs reported. The percent of palbociclib doses held per pt due to neutrophil level ranged from 0-37.5% with no apparent relation to HCQ dose. Best response was partial (2) stable (11); and progression (1). For measurable disease, tumor decreases of 11%, 12%, 21%, 26%, 30%, 55% and increase in 1 pt by 55% were seen. Conclusions: This phase I study showed acceptable safety and no HCQ dose-toxicity relationship. The RP2D of HCQ is 800 mg/day with continuous dosing palbociclib at 75 mg/day and letrozole at 2.5 mg/day. The phase 2 trial will proceed in the neoadjuvant setting, with Ki67 proliferative index response as the primary endpoint. Clinical trial information: NCT03774472 .

A phase I/IB study of ipatasertib in combination with carboplatin or carboplatin/paclitaxel or capecitabine and atezolizumab in patients with metastatic triple-negative breast cancer.

1078 Background: Ipatasertib (ipat) is an AKT inhibitor which has shown efficacy in combination with paclitaxel and atezolizumab in patients with triple negative breast cancer (TNBC). In previous trials, ipat was given 21 days on 7 days off due to gastrointestinal toxicities. The current trial was designed to test the safety and efficacy of ipat continuous dosing in combination with carboplatin (carbo) or carboplatin/paclitaxel (carbo/taxol). The trial was later amended to include an additional arm using ipat 21 days on 7 days off with capecitabine/atezolizumab (cape/atezo) to explore the safety of the combination. Methods: Patients with metastatic TNBC and up to 2 lines of prior chemotherapy were enrolled to receive the following: Arm A, ipat 400 mg daily, carbo AUC 2 and taxol 80 mg/m2 IV days 1, 8, 15, every 28 days; Arm B, ipat 400 mg daily, carbo AUC 2 IV days 1, 8, 15, every 28 days; Arm C, ipat 300 mg daily 21 days on 7 days off, cape 750 mg/m2 7 days on 7 days off, atezo 840 mg IV every 28 days. Ipat continuous dosing was used for Arms A and B. Ipat 21 days on 7 days off dosing was used for Arm C. The primary endpoint is safety and recommended phase II dose (RP2D). Secondary endpoints are response rate (RR) and overall survival (OS). Results: Twenty-three patients with median age 49 (29-75) were enrolled from 04/2019 to 12/2020, with 9 in Arm A, 10 in Arm B, and 4 in Arm C. A total of 15/23 (65%) had dose delay and 10/23 (43%) had dose modification. 3/4 (75%) of patients in Arm A had dose limiting toxicities (DLT) including diarrhea and gastric pain, which led to de-escalation to dose -1 with ipat (300 mg daily). 5 more patients were treated at dose -1 of Arm A with only 1 DLT (maculo-papular rash). No DLTs were observed in Arm B. Of the 4 patients treated in Arm C, 1 had DLT (maculo-papular rash). The RP2D for Arms A and B are: ipat 300 mg/carbo AUC2/taxol 80 mg/m2; ipat 400 mg/carbo AUC2. RP2D for Arm C has not been determined and accrual is ongoing. There were no clinically significant G4 toxicities in Arm A; G3 toxicities included 4/9 (44%) diarrhea, 1/9 (11%) hypertension, 1/9 (11%) stomach pain, and 1/9 (11%) neutropenia. For Arm B, G3 toxicities included 2/10 (20%) diarrhea, 1/10 (10%) anemia, 1/10 (10%) maculo-papular rash, and 1/10 (10%) hyperglycemia. For Arm C, there was 1/4 (25%) G3 maculo-papular rash. Best overall responses for Arm A were: 2/9 (22%) PR, 4/9 (44%) SD, and 3/9 (33%) PD. Best responses for Arm B were 2/10 (20%) PR, 6/10 (60%) SD, and 2/10 (20%) PD. For Arm C, best responses were 3/4 (75%) SD, and 1 not evaluable (repeat biopsy showed HER2+ disease). With a median follow up of 8.1 months, the median PFS was 4.0 months (95% CI [2.6, 5.3]). Conclusions: Continuous dosing of ipatasertib in combination with carbo or carbo/taxol is well-tolerated with modest efficacy. Clinical trial information: NCT03853707 .

Phase 1 study of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in patients with advanced solid tumors: Final results.

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with Cmax > 2,000 ng/ml and AUC > 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. Tmax was 2 hours and T1/2 was 6-8 hours. OKI-179 treatment resulted in > 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.

Efficacy and safety of intermittent versus continuous dosing schedule of apatinib combined with docetaxel as second-line treatment for advanced gastric cancer.

e16018 Background: Apatinib, a VEGFR-2 tyrosine kinase inhibitor, is wildly used for the treatment of advanced or metastatic gastric cancer. However, dose modification and interruption are happened frequently due to poor patient conditions and treatment-related toxicity. This study was designed to explore the efficacy and safety of intermittent or continuous apatinib therapy in combination with docetaxel. Methods: This was an open-label, randomized clinical trial. Patients with advanced gastric cancer who progressed from first-line treatment were randomly assigned in a ratio of 1:1 to receive intermittent or continuous dosing schedule. In the intermittent dose group (IG), patients received oral apatinib 500 mg/d for 5 days followed by 2 days off. In the continuous dose group (CG), patients received 500 mg daily without interruption. Docetaxel 60 mg/m2 was administered intravenously to patients on Day 1 in a 21-day cycle in both groups. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS), and the safety. Results: Between September 15, 2017 and November 30, 2020, 80 patients were screened for eligibility, of which 76 patients were randomly assigned into two groups (38 in the IG and 38 in the CG). In the IG and CG, 38 and 37 patients had ECOG PS 0-1, 16 and 19 patients had history of surgery, both 11 patients with more than 2 metastases, respectively. The baseline characteristics of the two groups were balanced. ORR in the IG was 21.05% vs 18.42% in the CG, and DCR was 60.53% vs 60.53%, respectively. Median PFS were 3.88 months (95% CI, 1.723-6.031) vs 3.98 months (95% CI, 1.055-6.896, p= 0.546), and median OS was 9 months (95% CI, 5.306-12.698) vs 9.40 months (95% CI, 5.204-13.588, p= 0.310) in two groups. The incidence of all grade adverse events (AEs) in the IG and CG were 94.7% and 92.1%, of which the most common AEs were hypertension (55.3% vs 65.8%), anemia (55.3% vs 63.2%), proteinuria (26.3% vs 31.6%), hand-foot syndrome (21.1% vs 26.3%). The incidence of grade ≥3 AEs were 36.8% and 39.5% in the IG and CG, respectively. In addition, the doses of 7 patients were reduced to the 250 mg in the IG, while that of 13 patients in the CG. Conclusions: Apatinib administered intermittently (5 days on/ 2 days off) exhibited similar efficacy to continuous schedule, while with less toxicity. Intermittent dosing schedule of apatinib may be an option for second-line treatment of patients with advanced gastric cancer. Clinical trial information: NCT03334591.

Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant-ineligible multiple myeloma patients

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued; treatment continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS (mPFS) was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, mPFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov (#NCT01850524).