Continuous Schedule Research Articles

Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma

Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma

Prenatal light exposure influences gait performance and body composition in bobwhite quail chicks

Maternal nesting behavior, which includes periods of patterned inattention, provides key elements essential for avian embryonic development, including regulation of temperature and light. For example, avian research consistently shows the importance of prenatal light exposure for several developmental processes; however, this research has primarily focused on artificial light regimens (i.e. 24 hr, 0 hr light). Comparatively less is known about how exposure to naturally occurring light patterns during incubation influence motor performance, body composition (i.e. body mass, bone length), and developmental age (incubation length). Here we conducted two experiments which investigated the effects of prenatal light exposure on developmental age, body composition, and gait performance in 1-day-old bobwhite quail. Experiment 1 investigated crepuscular light exposure during the last two days of incubation under two light duration treatments (2 hr & 6 hr) compared to a 12 hr continuous light schedule. Results indicated crepuscular prenatal light experience extended the incubation period for 2 hr exposed embryos, but not for 6 hr exposed embryos and negatively influenced postnatal body composition and postnatal gait performance when compared to 12 hr continuous light embryos. Experiment 2 examined the influence of prenatal light duration (2 hr vs 6 hr) and light presentation (crepuscular vs sporadic). Results demonstrated sporadic light presentation improved gait performance in 2 hr exposed hatchlings, but not 6 hr exposed hatchlings, improved body composition in 6 hr exposed hatchlings, but not 2 hr exposed hatchlings, and did not alter incubation length when compared to crepuscular light counterparts. This study provides further evidence for the importance of maternally regulated sensory stimulation during the prenatal period on early postnatal motor development.

Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial

Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored. We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693. Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]). Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies. Betta Pharmaceuticals.

344P - A phase I study of XZP-3287, a novel oral CDK4/6 Inhibitor, administered on a continuous dosing schedule, in patients with advanced solid tumours

BackgroundXZP-3287 is a novel selective inhibitor of cyclin-dependent kinases 4/6 (CDK 4/6). Preclinical data suggested a comparable antitumor activity with Palbociclib and Abemaciclib, and a more favourable safety profile of mild myelosupression. A continuous dosing schedule (28days/cycle) is adopted in this first-in-human study to achieve sustained target inhibition. MethodsThe study is designed as an accelerated titration followed by a standard 3+3 dose escalation. Eligible patients are those with locally advanced or metastatic solid tumours, and who have progressed despite of refractory to standard therapy or no standard-of-care therapy is available. Results16 subjects were enrolled in this study by April 1, 2019. The DLT evaluation in 320mg QD dose group was completed. No DLT or drug related serious adverse event (SAE) was observed from 20mg QD to 320mg QD dose groups. The drug related adverse events (AE) were mainly CTCAE grade 1 and 2, and reversible. Drug-related AEs (≥10%) were diarrhea (31.3%), leucopenia (31.3%), blood creatinine increased (25%), anemia (18.8%), neutropenia (18.8%), vomiting (18.8%), ALT increased (12.5%), thrombocytopenia (12.5%), blood alkaline phosphatase increased (12.5%) and hyperuricaemia (12.5%). Myelosuppression was observed from 160mg QD level. A negative correlation was showed between the AUC/Cmax of steady state and the maximum percentage decrease from baseline of neutrophil/platelet counts (r=-0.57 to-0.48), which was consistent with pharmacological effects of CDK4/6 inhibition. Furthermore, clinical activity was observed at low and not yet optimal dose levels. Among 7 efficacy evaluable subjects, 3 achieved SD , and 4 experienced PD. 1 SD patient in 240mg QD dose group had sustained SD for over 8 months and the target lesions was reduced by 23.7% from baseline which previously treated by chemotherapy, The latest data (Apr.30.) showed that, all the 3 patients in 320mg QD dose group achieved SD (2 patients exhibited tumor shrinkage by 10.9% and 8.3% respectively). These data will be update at annual meeting. ConclusionsThis study demonstrated that single-agent XZP-3287 was well tolerated and showed the CDK4/6 inhibition activity in human. Legal entity responsible for the studyXuanzhu Biopharmaceutical Ltd. FundingXuanzhu Biopharmaceutical Ltd. DisclosureAll authors have declared no conflicts of interest.

LBA58 - BAROCCO: A randomized phase II study of weekly paclitaxel vs cediranib-olaparib combination given with continuous or intermittent schedule in patients with recurrent platinum resistant ovarian cancer (PROC)

BackgroundHypoxia induced by antiangiogenic agents could cause a functional impairment of homologous recombination, thus sensitizing wild-type (wt) BRCA tumor cells to PARP inhibition. In a phase II study the combination of cediranib-olaparib increased progression free survival (PFS) in women with recurrent platinum sensitive OC with respect to olaparib. Methods123 patients were allocated in a 1:1:1 ratio to receive: 80mg/m2 weekly paclitaxel up to 24 weeks (control), olaparib 600mg tablet (300mg twice daily) together with 20mg cediranib daily (continuous schedule) or 20mg cediranib given 5 days/week (intermittent schedule) until progression. PFS comparison between experimental schedules and the control arm (alpha one-sided 5%; power 80% to detect a HR of 0.5) was the primary objective. ResultsMedian platinum-free interval was 1.8 mos, 59% of patients were pretreated with >3 chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.7, and 3.8 mos. Estimated HR for PFS in continuous arm vs control was 0.76 (90% CI: 0.49-1.17), p=0.28 by log-rank test. HR for PFS in intermittent arm vs. control was 1.08 (90% CI: 0.71-1.64), p=0.76 by log-rank test. In the subgroup gBRCA wt (n=109) the median PFS for paclitaxel, the continuous, and the intermittent schedules were 2.1, 5.8 and 3.8 mos and HR for PFS in continuous arm vs control was 0.63 (95% CI: 0.36 to 1.10; p=0.10). The toxicity profile of the study arms was as expected and similar between experimental arms. 11%, 18%, and 7% in control, continuous and intermittent arm discontinued treatment for adverse events. Five serious adverse drug reactions occurred and two of these were fatal: one in the control and one in the continuous arm. ConclusionsThe combination of cediranib and olaparib is effective in heavily pretreated PROC patients with the advantage of an oral administration and good tolerability. The continuous schedule of cediranib-olaparib showed a promising trend towards improved PFS in comparison with weekly paclitaxel particularly in the BRCA wt population. Clinical trial identificationIRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740. Legal entity responsible for the studyIstituto di Ricerche Farmacologiche Mario Negri IRCCS. FundingAstraZeneca. DisclosureN. Colombo: Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: PharmaMar; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: BioCad; Advisory / Consultancy: Takeda. G. Tognon: Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Tesaro. M. Ratti: Travel / Accommodation / Expenses: Tesaro Bio. All other authors have declared no conflicts of interest.

Vehicle Routing Problem with Multiple Time Windows and Batch Splitting Based on Inferior First Bidirectional Search Algorithm

Considering continuous scheduling and full use of time in vehicle routing problem, we proposed a vehicle routing problem model with multi-time windows based on batch splitting, constructed an inferior-first bidirectional search algorithm (IFBSA) and established a quantitative measurement benchmark of “inferiority level” using Gaussian kernel function. We designed 30 examples based on some actual road network data and chose nearest neighbour search algorithm (NNSA) for comparing. Our results showed that, IFBSA reduced vehicles in 20 examples and got superior results in 23 examples for all examples compared with NNSA.

LBA25 - MONARCHplus: A phase III trial of abemaciclib plus nonsteroidal aromatase inhibitor (NSAI) or fulvestrant (F) for women with HR+/HER2- advanced breast cancer (ABC)

BackgroundAbemaciclib is an oral, selective CDK4 & 6 inhibitor dosed on a continuous schedule and approved in combination with endocrine therapy (ET) for HR+/HER2- ABC patients (pts) outside of China in more than 50 countries. MONARCHplus evaluated the efficacy and safety of abemaciclib plus ET in predominantly Chinese pts with HR+/HER2- ABC.Table: LBA25Summary of PFS and ORR in ITT populationTable: LBA25Cohort ACohort BAbemaciclib + NSAI (n=207)P + NSAI (n=99)Abemaciclib + F (n=104)P + F (n=53)Median PFS(months)NR*14.7311.475.59HR (95% CI)0.499 (0.346, 0.719)0.376 (0.240, 0.588)p-value.0001<.0001ORR (%)56.030.338.57.5p-value<.0001<.0001*NR= not reached. MethodsMONARCHplus was a randomized-controlled, double-blind phase III trial for postmenopausal women with endocrine sensitive (Cohort A) or endocrine resistant (Cohort B) HR+/HER2- ABC. In Cohort A, pts received abemaciclib (150mg Q12h)/ placebo (P) + NSAI (anatrozole or letrozole) as first-line ET. In Cohort B, pts received abemaciclib/P + F following progression to ET. Both cohorts were randomized at a 2:1 ratio. The primary objective was PFS in Cohort A with a key secondary objective of PFS in Cohort B. The trial was powered for Cohort A to 80% at 1-sided α=.025 assuming a hazard ratio (HR) of 0.626 in favor of abemaciclib + NSAI, with analyses at 119 and 170 PFS events. ResultsAt the pre-specified interim, 119 PFS events were observed in Cohort A (n=306) and 82 events in Cohort B (n=157). Abemaciclib +NSAI and abemaciclib + F statistically and significantly improved PFS and ORR (see Table). PFS benefit was consistent within all stratification factors and pre-specified sensitivity analyses. The safety profile for both abemaciclib arms was consistent with previous reports for abemaciclib plus ET and included neutropenia, diarrhea, leukopenia, and anemia as the most frequent adverse events (AEs). ConclusionsAbemaciclib in combination with NSAI or fulvestrant provided a statistically significant and clinically meaningful improvement in PFS in predominantly Chinese postmenopausal women with HR+/HER2- ABC with no new safety signals observed. The MONARCHplus interim analysis demonstrated benefit consistent with the MONARCH 2 and 3 studies. Clinical trial identificationNCT02763566. Legal entity responsible for the studyEli Lilly and Company. FundingEli Lilly and Company. DisclosureAll authors have declared no conflicts of interest.

331P - A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to non-small cell lung cancer (NSCLC) or melanoma (MEL)

BackgroundAbemaciclib, a selective CDK4 & 6 inhibitor, demonstrated single-agent activity in NSCLC and melanoma (Patnaik et al., 2016). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma (Sahebjam et al., 2016). MethodsStudy JPBO is a Simon 2-stage trial evaluating abemaciclib in 6pt cohorts with BM secondary to HR+ breast cancer, NSCLC, or melanoma. Here, we report NSCLC and melanoma cohorts. Pts with ≥1 new or not previously irradiated BM≥10mm or a progressive BM previously irradiated were eligible. Abemaciclib was orally administered BID on a continuous dosing schedule. Primary endpoint was objective intracranial response rate (OIRR; [confirmed CR+PR]) based on Response Assessment in Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, OS, and safety. Results28 (NSCLC) and 23 (MEL) pts were enrolled and 23 (NSCLC) and 22 (MEL) were evaluable. Pts had a median of 2 prior systemic therapies in the metastatic setting. 35% (NSCLC) and 46% (MEL) of pts had prior whole brain radiotherapy. 35% (NSCLC) and 27% (MEL) pts had stereotactic radiotherapy. Median time from radiation to study enrollment was 4.8 (NSCLC) to 5.6 (MEL) months. No confirmed intracranial response was observed (OIRR 0% for both cohorts). 21.7% (NSCLC) and 13.6% (MEL) of pts showed a decrease in the sum of their intracranial target lesions. ICBR (CR+PR+SD persisting for > 6 months) was 26.1% (NSCLC) and 9.1% (MEL). Median PFS was 1.5 months (95% CI, 1.4-2.8) for NSCLC and 1.2 months (95% CI, 1.0-1.6) for MEL. Median OS was 7.1 months (95% CI, 3.7-9.4) for NSCLC and 2.9 months (95% CI, 1.2-4.3) for MEL. Based on efficacy results, enrollment closed at end of stage 1. Safety and tolerability were similar as previously reported for abemaciclib. ConclusionsThere was limited intracranial clinical activity for abemaciclib monotherapy in NSCLC and MEL pts in this study; OIRR and short median PFS suggest that no further studies for abemaciclib monotherapy are warranted in this pt population. Clinical trial identificationNCT02308020. Editorial acknowledgementMedical writing assistance was provided by Kristi Gruver, employee of Eli Lilly and Company. Legal entity responsible for the studyEli Lilly and Company. FundingEli Lilly and Company. DisclosureE. Le Rhun: Advisory / Consultancy, Research grant / Funding (institution), Oscar Lambert Center, Lille, FR: Mundipharma; Research grant / Funding (institution), University Hospital, Lille, FR: Amgen; Advisory / Consultancy, personal fees: Novartis; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. G. Jerusalem: Advisory / Consultancy, Non-remunerated activity/ies, per patient investigator fee: Eli Lilly and Company; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Roche; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Pfizer; Advisory / Consultancy, personal fees: Celgene; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Amgen; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: BMS; Advisory / Consultancy, personal fees: Puma Technology; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. D. Subramaniam: Advisory / Consultancy, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Takeda Oncology; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech. Y. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment, employee and stock options: Eli Lilly and Company. P.F. Conte: Research grant / Funding (self): Novartis; Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses, travel grant: Celgene; Travel / Accommodation / Expenses, travel grant: Tesaro. All other authors have declared no conflicts of interest.

The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor–Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy—MONARCH 2

Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated. To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET. MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019. Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02. Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib. Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy. ClinicalTrials.gov identifier: NCT02107703.

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor–Positive Metastatic Breast Cancer

Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus. To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer. The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis. Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus. The primary end point was progression-free survival (PFS). Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16). The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant. ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

Implementation of continuous free play schedules in Australian childcare services: A cross‐sectional study

Modifying the scheduling of physical activity opportunities to provide children with more frequent opportunities for outdoor free play has been demonstrated to increase child physical activity while in care. The primary aim of this study was to describe the implementation of continuous free play schedules to allow children to access outdoor play areas, consistent with sector guidelines in a national sample of Australian childcare services. Secondary aims were to investigate the associations between the implementation of such schedules and service characteristics, and assess the perceived barriers and enablers to implementation. A cross-sectional study was undertaken with a random sample of 326 centre-based childcare services located across Australia. Childcare service characteristics, continuous free play scheduling and perceived barriers and enablers to implementation were assessed via a survey administered to service managers online or via telephone. A total of 203 service managers (62%) reported implementing a continuous free play schedule, for three periods of 126minutes per period, each day on average. Service type (long day care services), size (services with higher numbers of child enrolments [≥80 children]) and socio-economic area (services located in lower socio-economic areas) were associated with the implementation of a continuous free play schedule. The most prevalent barriers to implementation included insufficient staff to ensure adequate supervision of children (69%) and service layout being unsuitable (65%), while the most prevalent enablers included advice on how to overcome staffing or supervision issues (89%) and to re-orientate the service layout (54%). There is scope to support the implementation of continuous free play schedules consistent with childcare sector guidelines. SO WHAT?: Future intervention research that targets the reported barriers and enablers to implementation is needed.

Multi-product continuous plant scheduling: combination of decomposition, genetic algorithm, and constructive heuristic

We propose a polylithic method for medium-term scheduling of a large-scale industrial plant operating in a continuous mode. The method combines a decomposition approach, a genetic algorithm (GA) and a constructive MILP-based heuristic. In the decomposition, decisions are made at two levels, using the rolling horizon approach. At the upper level, a reduced set of products and the time period is chosen to be considered in the lower level. At the lower level, a short-term scheduling MILP-model with event-based representation is used. A heuristic solution to the lower level problem is found using a constructive Moving Window heuristic guided by a genetic algorithm. The GA is applied for finding efficient utilisation of critical units in the lower level problem. For solving the one unit scheduling problem, a parallel dynamic programming algorithm is proposed. Implementation of the dynamic programming algorithm for a graphics processing unit (GPU) is incorporated in the GA for improving its performance. The experimental study of the proposed method on a real case of a large-scale plant shows a significant improvement of the solution quality and the solving time comparing to the pure decomposition algorithm proposed in the earlier study, and confirmed suitability of the proposed approach for the real-life production scheduling. In particular, the reduction of the number of changeovers and their duration in the obtained solution as well as the CPU time of solving the problem was about 60% using the new approach.

Analysis of bathtub congestion with continuous scheduling preference

The bathtub model provides a vital analysis tool to capture the features of traffic jam, especially that of hypercongested traffic. For reducing the complication of analysis, previous studies adopted the constant α-β-γ preferences for travel time, arrival early and late penalties. This treatment not only destroys the continuity of user equilibrium (UE) departure rate, but also leaves out of considering the influences of continuity of schedule preference. In this paper, we investigate a specific bathtub model with continuous schedule preference (CSP) and explore the UE and social optimum (SO) solutions. Analytical and numerical results show that the introduction of CSP lets departure rate continuous. In the UE state, it results in traffic congestion being more costly and duration of hypercongestion being longer than existing bathtub models. In the SO state, the system cost becomes lower. Our study extends the knowledge about bathtub models and provides more insight into downtown traffic congestion.

Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial

BackgroundSignaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies. Patients and MethodsWe conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343. ResultsFrom March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor–positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57). ConclusionContinuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population.

Efficacy and Safety of a 1-Year Segesterone Acetate and Ethinyl Estradiol Contraceptive Vaginal System

To report the efficacy and safety of a ring-shaped, 1-year (13 cycles) contraceptive vaginal system (CVS) releasing systemically a daily mean of segesterone acetate 150 mcg and ethinyl estradiol 13 mcg. Efficacy and safety are reported from two multicenter, 1-year, open-label, Phase 3 trials (one U.S., one international); a 1-year pharmacokinetic study; and three safety substudies from a Phase 3 study. Twenty-seven clinical study sites inside and outside of the United States. Women ages 18–40 years who were sexually active and had regular menstrual cycles. Participants were instructed to use the CVS on a 21/7-day, in–out continuous schedule and to not remove the CVS for more than 2 hours during the ring-in period. The primary efficacy outcome was the Pearl Index (PI) for women 35 years old or younger. The intention-to-treat Kaplan–Meier life-table analysis was a secondary outcome. Safety was assessed by adverse events (AEs) and substudy data evaluating endometrial, vaginal microbiology, and liver protein changes. A total of 2,265 participants’ data were analyzed for efficacy and 2,308 for safety. The primary PI of 2.98, 95% CI [2.13, 4.06], indicated excellent efficacy. Women who followed use instructions had greater efficacy, PI = 2.10, 95% CI [1.37, 3.06], than those who removed the CVS for more than 2 hours, PI = 5.89, 95% CI [3.46, 9.27], p = .0024. The CVS was 97.3% effective in life-table analyses. Most women were satisfied/very satisfied with the CVS (91%), found it easy to use (91%), and would recommend it to a friend (84%). Treatment-related AEs most frequently reported included headache (n = 601, 26%), nausea (n = 420, 18%), vaginal discharge–vulvovaginal mycotic infection (n = 242, 10%), and abdominal pain (n = 225, 10%). Discontinuations for these complaints were low (<1.5%). Four (0.2%) women experienced venous thromboembolism, 3 of whom had thrombosis risk factors. Substudies revealed no unexpected safety signals. The segesterone acetate and ethinyl estradiol CVS, recently approved by the U.S. Food & Drug Administration, is an effective, 1-year, procedure-free, user-controlled contraceptive that women found acceptable. Efficacy was lower for those who removed the CVS for more than 2 hours during the ring-in period, an important topic for nurses to emphasize when counseling their patients. The CVS also has a safety profile in line with other ethinyl estradiol–based hormonal contraceptives.

Results of the PI3Kδ inhibitor ME-401 alone or with rituximab in relapsed/refractory (R/R) follicular lymphoma (FL).

7512 Background: ME-401, a potent and selective oral PI3kδ inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938). 70 pts were treated; we report here results in FL. Methods: Pts with ECOG ≤2, no prior PI3K therapy and progression of disease (POD) after ≥1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg) then in 60 mg expansion cohorts as monotherapy or in combination with rituximab. ME-401 was given initially on a daily continuous schedule (CS) until POD or unacceptable toxicity. An intermittent schedule (IS) on days 1-7 of a 28-day cycle was then evaluated after 2 cycles (n = 18) or ≥3 cycles (n = 9) of CS. Toxicity on CS managed by switch to IS. POD on IS managed by switch to CS. Results: 48 FL pts received ME-401 alone (n = 39) or with rituximab (n = 9). Median age 64.5 yrs. (range 38-81), median prior therapies 2 (range 1-10), 30 had ≥3 prior therapies and 25 were POD24. 28 pts remain on therapy with median follow-up of 9.3 months (range 0.5-22.5) and 20 discontinued: 9 POD, 4 adverse events (AEs), 4 withdrew consent, and 3 for stem cell transplant. Delayed (&gt; Cycle 2) grade 3 immune related AEs (irAEs), primarily diarrhea/colitis and rash, reported in 9/30 (30%) on CS and 2/18 (11%) switched to IS after 2 cycles, with irAEs noted 15 and 18 days after switch. 4 pts with grade 3 irAEs had a drug holiday and corticosteroids then resumed ME-401 on IS without AE recurrence. Objective responses in 34/43 pts (79%) with follow-up disease assessment: 79% with ME-401 alone (including 26% morphologic/metabolic CR), 78% with ME-401 plus rituximab, 91% in POD24, and 75% in ≥3rd line therapy. 24/27 (89%) IS pts continue therapy, 20 on IS and 4 who switched to CS due to POD on IS, and 3 pts discontinued due to persistent POD after switch to CS. Conclusions: ME-401 achieves a high rate of durable responses in R/R FL. IS appears to reduce the incidence of irAEs and maintains responses. POD on IS can be salvaged by reverting to CS. A randomized study to evaluate ME-401 given by IS or CS is enrolling pts with R/R FL, with switch to IS for irAEs and switch to CS if POD on IS. Clinical trial information: NCT02914938. [Table: see text]

Model-driven metronomic vinorelbine in heavily pre-treated metastatic NSCLC and PM patients: Results of a phase I/II study.

e20505 Background: A phase I/II trial (NCT02555007) of oral metronomic Vinorelbine derived from a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Progression free survival, toxicity and PK/PD endpoints were the main objectives. Methods: Metronomic scheduling was selected using a simplified phenomenological model to identify the best continuous scheduling and dosing of oral vinorelbine with a total dose of 150 mg QW. Patients were monitored on a weekly basis, efficacy was evaluated by CT scans (RECIST). Toxicity was monitored using standard CTCAE criteria. Total tumor size (TTS) was the sum of diamaters of all lesions. Computation of individual PK parameters was done with Monolix software using population approach. Results: The PK/PD model proposed the following schedule: 60 mg D1, 30 mg D2, 60 mg D4. A total of 36 patients (30 evaluable) were enrolled (22M, 13F, 24 NSCLC, 11 mesothelium, median age 69.5, range 33-85.2). Patients were all heavily pre-treated (median 3 lines, range 1-9). Grade 3+ Neutropenia was observed in 30% patients. Median PFS was 11 weeks (range: 6-16.9). Best responses included 4 PR (13%) and 18 SD (60%). Baseline total tumor size was associated with reduced PFS (HR: 1.09, p = 0.026). A large variability in drug exposure (AUC 53 %, range 26 – 501 ng.h/ml) and PK parameters (Cl 82 %, range 45-605 l/h) was observed among patients. Exposure was not associated with efficacy, apart in patients with larger TTS (i.e., &gt; 70 mm) who seemed to have longer PFS (125 days VS. 40 days, p = 0.057). Vinorelbine exposure tended to be associated with higher risk for grade 2+ neutropenia, especially in patients with BSA &lt; 1.8 m² (60% VS. 25.5%, p = 0.055). A non-significant trend towards baseline NLR and PFS was observed (i.e., NLR &lt; 4: 80 days, NLR &gt; 4: 60 days, p = 0.077). Conclusions: Metronomic vinorelbine was characterized by huge variability in drug exposure among patients. However and despite being all heavily pre-treated, 60% of stable disease and 13% of PR were achieved in these patients. Plasma exposure yielded conflicting results depending on the initial tumor burden, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker is intriguing and should be confirmed in larger cohort.

A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC).

1017 Background: Abemaciclib is a selective CDK4 &amp; 6 inhibitor approved to treat HR+, HER2- MBC pts on a continuous dosing schedule as monotherapy or in combination with endocrine therapy (ET). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma. Methods: JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ MBC, non-small cell lung cancer, or melanoma. Here, we report on HR+, HER2- MBC pts. Eligible pts had ≥1 new or not previously irradiated measurable BM ≥10mm or a progressive previously irradiated BM. Pts receiving ET at the time of enrollment were permitted to continue the same ET provided that extracranial (EC) disease was stable ≥3 months and the CNS progression occurred on the ET. Abemaciclib was orally administered 200mg BID. Primary endpoint was objective intracranial response rate (OIRR; [CR+PR]) based on Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, and safety. Results: 58 HR+, HER2- MBC pts were enrolled and 52 pts were evaluable. Pts had a median of 4 prior systemic therapies, 75% of pts had prior chemotherapies (0-6, median of 2), and 71% of pts had prior ET (0-4, median of 1), in the metastatic setting. 50% of pts had prior whole brain radiotherapy, 39% stereotactic radiosurgery, and 8% surgical resection of BM. Median time from radiation to study enrollment was 9.4 months. Out of the 52 evaluable patients, 3 pts had a confirmed intracranial response (6% OIRR), and 38% of pts showed a decrease in the sum of their intracranial target lesions. Intracranial clinical benefit rate (CR+PR+SD persisting for ≥ 6 months) was 25%. Median PFS was 4.4 months (95% CI, 2.6-5.5). Safety and tolerability were similar to previous reports for abemaciclib. Conclusions: Abemaciclib demonstrated intracranial clinical benefit in heavily pretreated HR+, HER2- MBC pts with BM in this study. Further evaluations are ongoing to identify ABC patients with BM who might benefit most from abemaciclib. Clinical trial information: NCT02308020.

Drug stability and product performance characteristics of a dapivirine-releasing vaginal ring under simulated real-world conditions.

In two recent Phase III clinical trials, use of a 25 mg dapivirine vaginal ring significantly reduced HIV acquisition rates. Post hoc analysis from one of the trials indicated higher rates of protection among women over the age of 21 years when compared to younger women, most likely due to reduced adherence in the latter group. There is currently no information available on how release of dapivirine from the ring is affected by either its intermittent removal from the vagina or women's cleaning of the ring before re-insertion. Here, in vitro drug stability and product performance characteristics of the dapivirine ring were assessed under simulated conditions of real-world use. The impact of systematic deviations from the 28-day continuous use protocol upon in vitro release performance, was investigated. Also, the effect of ring exposure to a range of common household chemicals - including bath salts, bleach, detergent and personal lubricants - was examined through measurement of dapivirine content and stability. Dapivirine in vitro release under intermittent schedules was similar to that obtained under the normal continuous schedule ignoring the periods of interruption. Ring exposure to various household chemicals had no discernible impact on dapivirine assay value, degradation or stability.

Effects of dietary Ampithoe sp. supplementation on the growth, energy status, antioxidant capacity, and ammonia-N tolerance of the shrimp Litopenaeus vannamei: Continuous versus interval feeding

A 48-day feeding trial and an acute ammonia-N stress test were performed to investigate the effects on the growth performance, energy status, antioxidant status, and ammonia-N tolerance of Litopenaeus vannamei (5.0 ± 0.2 cm, 1.6 ± 0.4 g) when commercial feed was supplemented with freeze-dried powder of Ampithoe sp. (FDPA) on an interval and a continuous schedule. Shrimp fed with commercial feed were defined as the control group. For the interval feeding group (INF group), commercial feed supplemented with FDPA was provided once every 4 days, while commercial feed was used on the remaining days. The continuous feeding group (COF group) received commercial feed with added FDPA every day. The shrimp in the INF group and COF group showed better growth performance than did the control shrimp, and the survival rate and average yield in the COF group were significantly higher than those in the control group. During the culture period, the concentrations of glucose, triglycerides and total cholesterol in the hemolymph of shrimp were generally higher in the INF and COF groups than in the control group, and the concentrations in the COF group were generally higher than those in the INF group. Compared with the control group, shrimp in the INF and COF groups had elevated glutathione peroxidase (GSH-Px) activity, total antioxidant capacity (T-AOC), and expression levels of ATPase-α and PFK in the hemolymph or hepatopancreas, along with reduced malondialdehyde (MDA) concentrations and expressions of AMPK-α and FAS in the hepatopancreas. At 48 to 192 h during the ammonia-N stress test, the concentrations of urea-N and ammonia-N in the hemolymph generally remained lower in the INF group and COF groups than in the control group. At the end of the ammonia-N stress test, the shrimp mortality rates in the INF and COF groups were 28.1% and 40.6%, respectively, which were lower than the rate of 75.0% observed in the control group. In conclusion, dietary supplementation with FDPA had a positive influence on shrimp growth performance, energy status, antioxidant status and ammonia-N tolerance, and continuous feeding appeared to be more effective than interval feeding at improving antioxidant capacity.