Intermittent Schedule Research Articles

Applying underfloor heating system for improvement of thermal comfort in historic mosques: the case study of Salepçioğlu Mosque, Izmir, Turkey

Mosques differ from other types of buildings by having an intermittent operation schedule. Due to five prayer times per day throughout the year, mosques are fully or partially, yet periodically, occupied. This paper examines the potential of using an underfloor heating system for improvement of indoor thermal comfort in a historic mosque, which is naturally ventilated, heated and cooled, based on adaptive thermal comfort method. The selected Salepçioğlu Mosque, housing valuable wall paintings, was built in 1905 in Kemeraltı, Izmir, Turkey. It requires specific attention with its cultural heritage value. Firstly, indoor microclimate of the Mosque was monitored for one-year period of 2014-15. Then, dynamic simulation modelling tool, DesignBuilder v.4.2 was used to create the physical model of the Mosque. The ASHRAE Guideline 14 indices were utilized to calibrate the model, by comparing simulated and measured indoor air temperature to achieve hourly errors within defined ranges. The results of calibrated baseline model indicate that the Mosque does not satisfy acceptable thermal comfort levels for winter months that provided by the adaptive method. Then, the effect of underfloor heating was examined in the second model by the

Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study.

BackgroundStandard treatment with sunitinib for patients with metastatic renal cancer provides an ‘on-off’ schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity.ObjectiveThe objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment.MethodsPatients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles).ResultsTwenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension −82%, stomatitis −71%, cutaneous toxicity −69%). A reduction in ‘on-off symptoms’ (−86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression-free survival was 16.4 months and median overall survival was 41.3 months.ConclusionsDespite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life.

Nucleus Accumbens MC4-R Stimulation Reduces Food and Ethanol Intake in Adult Rats Regardless of Binge-Like Ethanol Exposure during Adolescence.

The melanocortin (MC) system regulates feeding and ethanol consumption. Recent evidence shows that melanocortin 4 receptor (MC4-R) stimulation within the nucleus accumbens (NAc) elicits anorectic responses and reduces ethanol consumption and ethanol palatability in adult rats. Ethanol exposure during adolescence causes long-lasting changes in neural pathways critically involved in neurobehavioral responses to ethanol. In this regard, binge-like ethanol exposure during adolescence reduces basal alpha-melanocyte-stimulating hormone (α-MSH) and alters the levels of agouti-related peptide (AgRP) in hypothalamic and limbic areas. Given the protective role of MC against excessive ethanol consumption, disturbances in the MC system induced by binge-like ethanol exposure during adolescence might contribute to excessive ethanol consumption during adulthood. In the present study, we evaluated whether binge-like ethanol exposure during adolescence leads to elevated ethanol intake and/or eating disturbance during adulthood. Toward that aim, Sprague-Dawley rats were treated with ethanol (3 g/kg i.p.; BEP group) or saline (SP group) for 14 days (PND 25 to PND 38). On PND73, all the groups were given access to 20% ethanol on an intermittent schedule. Our results showed that adult rats given intermittent access (IAE) to 20% ethanol achieved high spontaneous ethanol intake that was not significantly enhanced by binge-like ethanol pretreatment during adolescence. However, BEP group exhibited an increase in food intake without a parallel increase in body weight (BW) relative to SP group suggesting caloric efficiency disturbance. Additionally, we evaluated whether binge-like ethanol exposure during adolescence alters the expected reduction in feeding and ethanol consumption following NAc shell administration of a selective MC4-R agonist in adult rats showing high rates of ethanol consumption. For that, animals in each pretreatment condition (SP and BEP) were divided into three subgroups and given bilateral NAc infusions of the selective MC4-R agonist cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 μg). Results revealed that MC4-R stimulation within the NAc reduced feeding and ethanol intake in high ethanol-drinking adult rats, regardless of previous binge-like ethanol exposure during adolescence, which adds new evidence regarding the dual ability of MC compounds to control excessive ethanol and food intake.

Curriculum-Based Measurement of Reading Growth: Weekly Versus Intermittent Progress Monitoring

We examined the idea that leaner schedules of progress monitoring (PM) can lighten assessment demands without undermining decision-making accuracy. Using curriculum-based measurement of reading, we compared effects on decision accuracy of 5 intermittent PM schedules relative to that of every-week PM. For participating students with high-incidence disabilities—all receiving special education reading instruction ( N = 56)—intermittent schedules of PM performed as well as every-week PM. These findings signal a need for research on the relative accuracy and timeliness of curriculum-based measurement decision making for intermittent and weekly PM.

Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients

Regorafenib was approved as third-line therapy for advanced Gastrointestinal Stromal Tumour (GIST) at a starting dose of 160 mg daily 3 weeks on, 1 week off, based on improvement in progression free survival over placebo (4.8 vs. 0.9 months), but the response rate was low at 4.5%. Given the high toxicity rate in GIST patients, there is variability in the post-marketing dosing of regorafenib. We aimed to summarize our experience regarding prescribing patterns, efficacy and toxicity of regorafenib and determine the role of response assessment by Choi criteria in GIST patients. We included 28 patients who received regorafenib from our pharmacy. Baseline patient characteristics and treatment outcomes were recorded and an independent radiologist assessed response using Choi and RECIST. Seventy-nine percent of patients started at a 120 mg continuous daily dosing schedule, different from the standard intermittent dosing schedule. Grade 3/4 adverse events were experienced by 43% of patients. Median progression-free survival was 8.7 months. Continuous dosing with regorafenib at 120 mg daily is the preferred prescribing pattern and appears to be better tolerated and with comparable efficacy to the current standard dose. Similar to imatinib, the partial response rate for regorafenib by Choi (29%) was higher compared to RECIST (4%).

Chemoprevention of colon cancer: advantage of intermittent pulse treatment schedules quantified by computer simulation of human colon crypts

Chemoprevention of colon cancer: advantage of intermittent pulse treatment schedules quantified by computer simulation of human colon crypts

Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial

Androgen-deprivation therapy in patients with prostate cancer who have relapsed with rising prostate-specific antigen concentration only (PSA-only relapse), or with non-curable but asymptomatic disease at diagnosis, could adversely affect quality of life at a time when the disease itself does not. We aimed to compare the effect of immediate versus delayed androgen-deprivation therapy on health-related quality of life over 5 years in men enrolled in the TOAD (Timing of Androgen Deprivation) trial. This randomised, multicentre, open-label, phase 3 trial done in 29 public and private cancer centres across Australia, New Zealand, and Canada compared immediate with delayed androgen-deprivation therapy in men with PSA-only relapse after definitive treatment, or de-novo non-curable disease. Patients were randomly assigned (1:1) with a database-embedded, dynamically balanced algorithm to immediate androgen-deprivation therapy (immediate therapy group) or to delayed androgen-deprivation therapy (delayed therapy group). Any type of androgen-deprivation therapy was permitted, as were intermittent or continuous schedules. The European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaires QLQ-C30 and PR25 were completed before randomisation, every 6 months for 2 years, and annually for a further 3 years. The primary outcome of the trial, reported previously, was overall survival, with global health-related quality of life at 2 years as a secondary endpoint. Here we report prespecified secondary objectives of the quality-of-life endpoint. Analysis was by intention to treat. Statistical significance was set at p=0·0036. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12606000301561, and ClinicalTrials.gov, number NCT00110162. Between Sept 3, 2004, and July 13, 2012, 293 men were recruited and randomly assigned; 151 to the delayed therapy group and 142 to the immediate therapy group. There was no difference between the two groups in global health-related quality of life over 2 years from randomisation. There were no statistically significant differences in global quality of life, physical functioning, role functioning, or emotional functioning, fatigue, dyspnoea, insomnia, or feeling less masculine over the entire 5 years after randomisation. Sexual activity was lower in the immediate therapy group than in the delayed group at 6 and 12 months (at 6 months mean score 29·20 [95% CI 24·59-33·80] in the delayed group vs 10·40 [6·87-13·93] in the immediate group, difference 18·80 [95% CI 13·00-24·59], p<0·0001; at 12 months 28·63 [24·07-33·18] vs 13·76 [9·94-17·59], 14·86 [8·95-20·78], p<0·0001), with the differences exceeding the clinically significant threshold of 10 points until beyond 2 years. The immediate therapy group also had more hormone-treatment-related symptoms at 6 and 12 months (at 6 months mean score 8·48 [95% CI 6·89-10·07] in the delayed group vs 15·97 [13·92-18·02] in the immediate group, difference -7·49 [-10·06 to -4·93], p<0·0001; at 12 months 9·32 [7·59-11·05] vs 17·07 [14·75-19·39], -7·75 [-10·62 to -4·89], p<0·0001), but with differences below the threshold of clinical significance. For the individual symptoms, hot flushes were clinically significantly higher in the immediate group (adjusted proportion 0·31 for delayed therapy vs 0·55 for immediate therapy, adjusted odds ratio 2·87 [1·96-4·21], p<0·0001) over the 5-year period, as were nipple or breast symptoms (0·06 vs 0·14, 2·64 [1·61-4·34], p=0·00013). Immediate use of androgen-deprivation therapy was associated with early detriments in specific hormone-treatment-related symptoms, but with no other demonstrable effect on overall functioning or health-related quality of life. This evidence can be used to help decision making about treatment initiation for men at this disease stage. Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia, Tolmar Australia.

An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer.

The principles governing evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of BRAF amplification (BRAFamp) in patient-derived tumor xenografts (PDX) treated with a direct ERK inhibitor, alone or in combination with other pathway inhibitors. Single cell sequencing and multiplex-fluorescence in situ hybridization mapped the emergence of extra-chromosomal amplification in parallel evolutionary tracts, arising in the same tumor shortly after treatment. The evolutionary selection of BRAFamp is determined by the fitness threshold, the barrier subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for ERK signaling inhibitors, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of RAF, MEK and ERK, however, imposes a sufficiently high fitness threshold to prevent the propagation of subclones with high-level amplification. Administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11-lung cancer and melanoma PDX without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and merit testing in patients.

Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial.

Although traditionally dosed combined oral contraceptives (COCs) (21 days of active pills, 7 days of inactive pills) have not been demonstrated as superior to placebo for the treatment of premenstrual dysphoria (PMD), some randomized controlled trials (RCTs) indicate that oral contraceptives administered with a shortened or eliminated hormone-free interval are superior to placebo. However, results of such trials are mixed, and no existing studies have directly compared continuous and intermittent dosing schedules of the same oral contraceptive. The present study compared placebo, intermittent dosing of oral contraceptives, and continuous dosing of contraceptives for the treatment of PMD. Fifty-five women with prospectively confirmed PMD completed a three-arm, RCT in which they were randomized to 3 months of placebo (n = 22), intermittent drospirenone/ethinyl estradiol dosed on a 21-7 schedule (n = 17), or continuous drospirenone/estradiol (n = 16) following a baseline assessment month. All three groups demonstrated similar, robust reductions in premenstrual symptoms over time. A marked placebo response was observed. The study fails to replicate a uniquely beneficial effect of continuous COC on PMD. Additional work is needed to understand the psychosocial context bolstering the placebo response in women with PMD.

A pharmacokinetic-pharmacodynamic model predicting tumour growth inhibition after intermittent administration with the mTOR kinase inhibitor AZD8055.

AZD8055 is a potent orally available mTOR kinase inhibitor with in vitro and in vivo antitumour activity against a range of tumour types. Preclinical studies showed that AZD8055 induced a dose-dependent pharmacodynamic effect in xenograft models in vivo, but a lack of understanding of the relative contributions of the maximum inhibition of the biomarkers and the duration of inhibition to the antitumour effect, limited the rational design of experiments to optimize the dose and schedules of treatment. In this study, a mathematical modelling approach was developed to relate pharmacodynamics and antitumour activity using preclinical data generated in mice bearing U87-MG xenografts. Refinement and validation of the model was carried out in a panel of additional human tumour xenograft models with different growth rates and different sensitivity to AZD8055 (from partial growth inhibition to regression). Finally, the model was applied to accurately predict the efficacy of high, intermittent dosing schedules of AZD8055. Overall, this new model linking pharmacokinetics, pharmacodynamic biomarkers and efficacy across several tumour xenografts with different sensitivity to AZD8055 was able to identify the optimal dose and route of administration to maximize the antitumour efficacy in preclinical models and its potential for translation into man.

Abstract 297: The novel orally available sub-nanomolar potent and selective checkpoint kinase 1 inhibitor CASC-578 is highly active in mantle cell lymphoma as a single agent and in combination with Wee1 inhibition

Abstract Background: Checkpoint kinase 1 (Chk1) is a serine/threonine protein kinase that regulates cell division by arresting progression in the S &amp; G2 phases of the cell cycle in response to genotoxic stress. Pharmacological inhibition of Chk1 uncouples the completion of DNA replication from G2/M phase transition in tumor cells that have impaired DNA damage response networks, resulting in DNA damage induction, mitotic catastrophe and cell death. These properties make Chk1 inhibition an attractive therapeutic approach as a single agent, or to enhance the efficacy of other cancer drugs that target DNA damage response pathways. Methods and Results: This report highlights the activity of the orally bioavailable, selective, small molecule Chk1 inhibitor, CASC-578, in multiple mantle cell lymphoma (MCL) models in vitro and in tumor mouse xenograft studies. MCL have the common genetic biomarker t(11;14)(q13;q32), a chromosomal translocation leading to the constitutive expression of the oncogene CCND1 which encodes cyclin D1, a cell cycle-regulating protein. This genotypic characteristic has been observed in the clear majority of patients with MCL in the clinic and may provide a rationale for sensitivity to Chk1 inhibition. Consistent with this idea, CASC-578 demonstrated remarkable potency as a single agent in blocking the proliferation of MCL cell lines in vitro, with an average IC50 of 61 nM. Treatment with CASC-575 as a single agent resulted in the induction of DNA damage, as measured by phosphorylated histone H2AX and activation of apoptosis, as measured by cleaved caspase. In a JEKO-1 xenograft tumor study, CASC-578 as a single agent completely regressed subcutaneously implanted tumors in the majority of mice after oral drug administration using 20 mg/kg daily or when dosed on an intermittent schedule at 25 mg/kg, with minimal effects on body weight. In addition to the observed single agent activity of CASC-578, the combination of CASC-578, and the Wee1 inhibitor AZD-1775, was highly synergistic in MCL cell lines including JEKO-1, REC-1, Z-138 and MAVER-1 in vitro. CASC-578 was also highly potent as a single agent, and in combination with AZD-1775, in blocking the proliferation of a variety of leukemia derived cell lines in vitro. Taken together, these data support the advancement of CASC-578 into clinical development as a potential therapeutic agent for the treatment of MCL, as well as other hematological malignancies. Citation Format: Robert Rosler, Janelle Taylor, Dina Leviten, Teresa Sierra, Ashley Dozier, Kevin Klucher, Rich Boyce, Bob Boyle, Alex Vo, Scott Peterson. The novel orally available sub-nanomolar potent and selective checkpoint kinase 1 inhibitor CASC-578 is highly active in mantle cell lymphoma as a single agent and in combination with Wee1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 297. doi:10.1158/1538-7445.AM2017-297

Abstract 160: High target binding affinity with long lasting cellular target engagement and high dose intermittent schedule of PI3K inhibitor copanlisib contribute to the potent anti-tumor activity and good safety profile

Abstract Introduction: Several generations of PI3K inhibitors have been tested in clinic. However, thus far, clinical activity has been moderate. Different from other oral PI3K inhibitors dosed continuously, copanlisib (BAY 80-6946) is an intravenous PI3K inhibitor given intermittently to patients. Copanlisib dosed once weekly demonstrated clinical benefit with an improved safety profile, and therefore challenges the concept of default continuous dosing of PI3K inhibitors. However, it is still unclear if this concept can be generalized and whether ‘micropharmacokinetic parameters’ also contributed to the potent anti-tumor profile of copanlisib. Here, we report the characterization of binding kinetics for copanlisib, as well as the functional consequence in vivo. Methods: A set of PI3K inhibitors were characterized in 1) a kinetic probe competition assay (kPCA); 2) a cellular nanoBRET target engagement assay; 3) a cellular washout study with the assessment on pathway engagement; and 4) in vivo pharmacokinetics analysis. Results: Copanlisib showed nearly diffusion-controlled on- and relatively slow off-rates with kon = 3.45E+7 [M-1*s-1] and koff = 1.67E-3 [s-1] to PI3Kα. Consequently, it exhibited very high affinity to PI3Kα ( Ki ePCA = 9.31E-11[M] and KD kPCA = 4.77E-11 [M]). In a cellular nanoBRET target engagement assay, the apparent half-life (t1/2) of ca. 2 hours greatly surpassed the 6.9 min measured using kPCA. The high affinity to PI3Kα also translated into potent cellular pathway engagement demonstrated by inhibition of p-AKT and p-PRAS40 in the PIK3CAmut KPL4 cell line. In a cellular washout study, p-AKT and p-PRAS40 were assessed till 168 h after incubation with copanlisib for 1 h followed by a washout step. A dose- and time-dependent pathway engagement was observed even at 72 h post washout. This result indicated that in cells, copanlisib engages PI3Kα for an extremely long time, likely due to rebinding effects facilitated by the fast equilibration kinetics of the compound and its micropharmacokinetic properties. Interestingly, in vivo, BAY 80-6946 levels were approximately 100-fold higher in the tumor than in plasma at 48 hours and drug clearance from the tumor occurred more slowly than from plasma. This high and prolonged tumor exposure might be explained, at least in part, by the high expression of PI3Kα and long lasting target occupancy of copanlisib in tumors. Conclusion: Copanlisib demonstrated high affinity to PI3Kα with protracted target engagement at cellular and in vivo levels. This ‘micropharmacokinetic feature’ not only supports intermittent dosing but likely also explains the high exposure in tumors vs plasma, potent anti-tumor activity and good safety profiles. Citation Format: Amaury E. Fernández-Montalván, Victoria Georgi, James Vasta, Sarah Glaeske, Vera Puetter, Matthew B. Robers, Ursula Moenning, Andrea Sturz, Julien Lefranc, Karl Ziegelbauer, Michael Brands, Christian Stegmann, William J. Scott, Ningshu Liu. High target binding affinity with long lasting cellular target engagement and high dose intermittent schedule of PI3K inhibitor copanlisib contribute to the potent anti-tumor activity and good safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 160. doi:10.1158/1538-7445.AM2017-160

Diverse Roads to Relapse: A Discriminative Cue Signaling Cocaine Availability Is More Effective in Renewing Cocaine Seeking in Goal Trackers Than Sign Trackers and Depends on Basal Forebrain Cholinergic Activity.

Stimuli associated with taking drugs are notorious instigators of relapse. There is, however, considerable variation in the motivational properties of such stimuli, both as a function of the individual and the nature of the stimulus. The behavior of some individuals (sign trackers, STs) is especially influenced by cues paired with reward delivery, perhaps because they are prone to process information via dopamine-dependent, cue-driven, incentive salience systems. Other individuals (goal trackers, GTs) are better able to incorporate higher-order contextual information, perhaps because of better executive/attentional control over behavior, which requires frontal cortical cholinergic activity. We hypothesized, therefore, that a cue that "sets the occasion" for drug taking (a discriminative stimulus, DS) would reinstate cocaine seeking more readily in GTs than STs and that this would require intact cholinergic neurotransmission. To test this, male STs and GTs were trained to self-administer cocaine using an intermittent access schedule with periods of cocaine availability and unavailability signaled by a DS+ and a DS-, respectively. Thereafter, half of the rats received an immunotoxic lesion that destroyed 40-50% of basal forebrain cholinergic neurons and later, after extinction training, were tested for the ability of noncontingent presentations of the DS+ to reinstate cocaine seeking behavior. The DS+ was much more effective in reinstating cocaine seeking in GTs than STs and this effect was abolished by cholinergic losses despite the fact that all rats continued to orient to the DS+ We conclude that vulnerability to relapse involves interactions between individual cognitive-motivational biases and the form of the drug cue encountered.SIGNIFICANCE STATEMENT The most predictable outcome of a diagnosis of addiction is a high chance for relapse. When addicts encounter cues previously associated with drug, their attention may be unduly attracted to such cues and these cues can evoke motivational states that instigate and maintain drug-seeking behavior. Although sign-tracking rats were previously demonstrated to exhibit greater relapse vulnerability to Pavlovian drug cues paired with drug delivery, here, we demonstrate that their counterparts, the goal trackers, are more vulnerable if the drug cue acts to signal drug availability and that the forebrain cholinergic system mediates such vulnerability. Given the importance of contextual cues for triggering relapse and the human cognitive-cholinergic capacity for the processing of such cues, goal trackers model essential aspects of relapse vulnerability.

連続強化スケジュール,間欠強化スケジュール,消去がハトのキーつつき反応の位置次元および距離次元における行動変動性に及ぼす効果(特集号 行動変動性の実験研究とその応用可能性22巻2号追加論文)

連続強化スケジュール,間欠強化スケジュール,消去がハトのキーつつき反応の位置次元および距離次元における行動変動性に及ぼす効果(特集号 行動変動性の実験研究とその応用可能性22巻2号追加論文)

A study of vistusertib in combination with selumetinib in patients with advanced cancers: TORCMEK phase Ib results.

2548 Background: PI3K/mTOR and MAPK pathways are aberrantly activated in many tumours and interact to promote tumour growth and therapeutic resistance. Activity of single pathway inhibition is limited due to compensatory activation of alternative signalling pathways. Dual pathway inhibition has demonstrated synergistic activity in preclinical models, with broad activity across a range of molecular backgrounds. This study was designed to evaluate the optimal doses and schedule of vistusertib (dual mTOR1/2 inhibitor) and selumetinib (MEK1/2 inhibitor) when given in combination. Methods: Thisphase Ib/IIa trial with a dose escalation part (Ib) in treatment refractory advanced solid tumours and expansion cohorts in TNBC, squamous and non-squamous NSCLC (KRASmt &amp; WT) (IIa). Both, continuous daily (CC) (25, 35, 50mg BD) and intermittent (IC) schedules (50, 100, 125mg BD 2ds on, 5 ds off) of vistusertib were investigated. Selumetinib dose was given at a dose of 75mg BD daily. Treatment was given until PD (RECIST 1.1) or intolerable toxicity. The primary endpoint was DLTs. Secondary endpoints included response, clinical benefit, PFS and PK. Results: 23 evaluable patients were enrolled in the PhaseIb part. For the intermittent schedule, no DLTs were reported at any of the dose levels IC1-3. For the continuous schedule, 2 out of 9 patients treated at dose level C2C developed DLTs (G3 mucositis, dizziness and rash). Dose level C3C was not tolerated with DLTs observed in 2 out of 3 patients (G3 mucositis and G3 LFTs). Separate MDTs were determined for intermittent (I3C) and continuous schedules (C2C). Adverse events were in keeping with established single agent safety profiles. Anti-tumour efficacy was demonstrated at various dose levels and across tumour types including uveal melanoma, breast, cervical, uterine, skin or colorectal cancers. There were no objective responses but confirmed stable disease for &gt; 16 weeks were observed in 7 patients with a duration of response ranging up to 55+ weeks. Conclusions: Based on DLTs, dose intensity and cumulative toxicity, the intermittent schedule I3C was selected as RP2D for expansion cohorts. Preliminary anti-tumour activity was observed. Clinical trial information: NCT02583542.

Multi-center phase Ib study of intermittent dosing of the MEK inhibitor, selumetinib, in patients with advanced uveal melanoma not previously treated with a MEK inhibitor.

TPS9597 Background: Uveal melanoma (UM) is a rare subtype of melanoma with no effective therapy for advanced disease. UM is characterized by mutations in GNAQ and GNA11 leading to constitutive activation of the mitogen activated protein kinase (MAPK) pathway. We have previously shown that targeting the MAPK pathway though MEK inhibition with Selumetinib (AZD6244, ARRY-142886) using a continuous dosing schedule improved progression free survival (PFS) in a randomized Phase II study of Selumetininb versus chemotherapy in patients with metastatic UM; however, no PFS or overall survival (OS) benefit was observed in a subsequent randomized Phase III study of Selumetinib and chemotherapy versus chemotherapy alone. We hypothesize that an intermittent dosing schedule of Selumetinib may be more effective than continuous dosing by achieving higher dose levels, better drug tolerability, and more complete target inhibition. We propose a Phase Ib study of Selumetinib in UM using an intermittent dosing schedule. Methods: A total of 28 subjects will be enrolled using the time to event continual reassessment method (TITE-CRM). Key inclusion criteria include a diagnosis of advanced UM, measurable disease by RECIST v1.1, and no prior MEK inhibitor therapy. Eligible subjects will be treated with Selumetinib starting at a dose level of 125 mg orally twice a day, using a 3-days-on and 4-days-off per week schedule. The primary goal of this study is to estimate the maximum tolerated dose (MTD) of intermittently dosed Selumetinib. Secondary endpoints are response rate, PFS and OS. Responses will be evaluated every 8 weeks by a CT scan of the chest and CT or MRI of the abdomen/ pelvis using RECIST v1.1 criteria. Mandatory tumor biopsies will be obtained at baseline, cycle 1 day 3 (Selumetinib-on day), and between cycle 1 day 11-14 (Selumetinib-off day) in 20 subjects, and optionally at progression. Tumor tissue will be assessed for MAPK pathway inhibition and reactivation at each time point, as well as mechanisms of resistance. Recruitment is currently ongoing. Clinical trial information: NCT02768766.

Phase I first-in-man trial of a novel bromodomain and extra-terminal domain (BET) inhibitor (BI 894999) in patients (Pts) with advanced solid tumors.

2504 Background: The BET family (BRD2, BRD3, BRD4) regulates transcription, epigenetic memory and cell growth, emerging as a novel therapeutic strategy. BI 894999 is a highly potent and selective orally available BET inhibitor. Methods: BI 894999 was given once a day, continuously (1 cycle = 3 weeks; Arm A). An intermittent schedule was explored: once a day, D1-14 Q21 days (1 cycle = 3 weeks; Arm B). Bayesian Logistic Regression Model was used to guide dose escalation. HEXIM1, HIST2H2BF and CCR2 gene expressions were used as pharmacodynamic (PD) markers. Results: 28 pts were treated: 21 in Arm A, 7 in Arm B. Median number of cycles was 2 (range: 1-12). Pts were treated at 6 dose levels in Arm A (0.2-5 mg) and 2 dose levels in Arm B (1.5 and 2 mg). The maximum tolerated dose (MTD) was exceeded at 2 mg in Arm A. In Arm B, dose escalation was halted due to the observation of ECG changes in 3 pts and raised serum troponin in 8 pts, pending cardiology review. MTD in Arm A was defined as 1.5 mg. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). DLTs included: thrombocytopenia grade (G) 4 (n=3), increased troponin G3 (n=1), hypophosphatemia G3 (n=1), multiple G2 events in 1 pt preventing adequate dose intensity in cycle 1. Of 27 evaluable pts, 3 had partial response (PR; one was confirmed) and 1 had stable disease (SD) lasting &gt;4 cycles. Cmax and AUC increased with dose in a greater than linear fashion particularly at higher dose levels. Mean terminal T1/2 was ~1 day with high interpatient variability. PD analyses showed target engagement in all 3 genes at doses ≥1 mg in both schedules. Conclusions: BI 894999 showed target engagement at doses ≥ 1 mg and demonstrated clinical activity (3 PRs and 1 SD lasting &gt;4 cycles). Thrombocytopenia prevented continuous dosing and 1.5 mg was defined the MTD for Arm A, whilst dose escalation was halted in Arm B due to cardiac findings. Mitigating hematological toxicity of BI 894999 via synergistic drug combinations should be explored. Clinical trial information: NCT02516553.

TAX-TORC: A phase I trial of vistusertib (AZD2014) in combination with weekly paclitaxel with integrated pharmacodynamic (PD) and molecular characterization (MC) studies.

2571 Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m2IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.

Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study.

The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function. A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug's effect on the elimination of mutant cells and the maintenance of crypt function. Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug. An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.

Metastatic BRAF K601E-mutated melanoma reaches complete response to MEK inhibitor trametinib administered for over 36\xa0months

BackgroundThe BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E-mutated melanoma do not have access to such drugs.Case presentationA female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation. After chemotherapy failure, she underwent compassionate treatment with trametinib. Trametinib showed good activity and efficacy, with 48% shrinkage of a metastatic lymphadenopathy after 4 months’ treatment. However, the patient reported treatment-related skin toxicity that required dosage reduction and a personalized intermittent trametinib dosing schedule. After over 36 months from the first trametinib administration, and resection of a metastatic lymphadenopathy, the patient experienced complete response.ConclusionsThis case report shows that trametinib could be a valid therapeutic option in patients with metastatic melanoma harboring the rare BRAF K601E mutation.