Sleep restriction and circadian clock disruption are associated with metabolic disorders such as obesity, insulin resistance, and diabetes. The metabolic pathways involved in human sleep, however, have yet to be investigated with the use of a metabolomics approach. Here we have used untargeted and targeted liquid chromatography (LC)/MS metabolomics to examine the effect of acute sleep deprivation on plasma metabolite rhythms. Twelve healthy young male subjects remained in controlled laboratory conditions with respect to environmental light, sleep, meals, and posture during a 24-h wake/ sleep cycle, followed by 24 h of wakefulness. Two-hourly plasma samples collected over the 48 h period were analyzed by LC/MS. Principal component analysis revealed a clear time of day variation with a significant cosine fit during the wake/sleep cycle and during 24 h of wakefulness in untargeted and targeted analysis. Of 171 metabolites quantified, daily rhythms were observed in the majority (n = 109), with 78 of these maintaining their rhythmicity during 24 h of wakefulness, most with reduced amplitude (n = 66). During sleep deprivation, 27 metabolites (tryptophan, serotonin, taurine, 8 acylcarnitines, 13 glycerophospholipids, and 3 sphingolipids) exhibited significantly increased levels compared with during sleep. The increased levels of serotonin, tryptophan, and taurine may explain the antidepressive effect of acute sleep deprivation and deserve further study. This report, to our knowledge the first of metabolic profiling during sleep and sleep deprivation and characterization of 24 h rhythms under these conditions, offers a novel view of human sleep/wake regulation.circadian rhythms | total sleep deprivation | melatonin | depression | biomarker C ircadian clocks control the timing of most daily biological processes, including cyclic changes in metabolism and the sleep/wake cycle (1). There is a clear link between the circadian timing system and metabolism (2-4), with disrupted circadian rhythms, sleep restriction, and sleep deprivation associated with metabolic disorders (obesity, insulin resistance, diabetes) and cardiovascular disease (5-8). The underlying mechanisms linking metabolic disease, circadian clock misalignment, and sleep restriction are the subject of current research, elucidation of which will require a global "systems" approach (9). Transcriptomic studies have shown that rhythmic gene expression may be affected by sleep restriction, sleep deprivation, and mistimed sleep (10-12), but, as yet, no studies have directly investigated the effect that sleep and sleep deprivation may have on the metabolic profile. Metabolic profiling, or "metabolomics," is the profiling of small-molecule metabolites and offers the potential to characterize specific metabolic phenotypes associated with disrupted circadian timing and sleep loss. Metabolomics has an advantage over other "omics" techniques, in that it directly samples the metabolic changes in an organism and integrates information from changes at the gene, transcript, an...

The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), doselimiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).Patients and Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated 18 F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.Results: Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed >90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC >20 hÁmmol/L. Significant increase in plasma insulin and glucose levels, and >25% decrease in 18 F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. A patient with V600E BRAF-mutant melanoma and another with platinumrefractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.Conclusion: Pictilisib was safely administered with a doseproportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels !100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.

The main aim of phase I trials is to evaluate the tolerability and pharmacology of a new compound. However, investigating the potential for clinical benefit is also a key objective. Our phase I trial portfolio incorporates a range of new drugs, including molecular targeted agents, sometimes given together with cytotoxic agents. We performed this analysis of response rate, progression-free (PFS) and overall survival (OS) to assess the extent of clinical benefit rate (CBR: partial response (PR) þ stable disease (SD)) derived from current trials. We analysed 212 consecutive patients who were treated in 29 phase I studies, from January 2005 to June 2006. All patients had progression of disease prior to study entry. The median age was 58 years (range: 18 -86) with a male/female ratio of 2 : 1. A total of 148 patients (70%) were treated in 'first in human trials' involving biological agents (132 patients) or new cytotoxic compounds (16 patients) alone, and 64 patients (30%) received chemotherapy-based regimens with or without biological agents. After a median follow-up time of 34 weeks, the median PFS and OS were 11 and 43 weeks, respectively. The CBR was 53% (9% PR and 44% SD) after the first tumour evaluation after two cycles (between weeks 6 and 8) and has been maintained at 36 and 26% at 3 and 6 months, respectively. Treatment related deaths occurred in 0.47% of our patients and treatment had to be withdrawn in 11.8% of patients due to toxicity. A multivariate analysis (MVA) of 13 factors indicated that low albumin (o35 g l À1 ), lactate dehydrogenase4upper normal limit and 42 sites of metastasis were independent negative prognostic factors for OS. A risk score based on the MVA revealed that patients with a score of 2 -3 had a significantly shorter OS compared to patients with a score of 0 -1 (24.9 weeks, 95% CI 19.5 -30.2 vs 74.1 weeks, 95% CI 53.2 -96.2). This analysis shows that a significant number of patients who develop disease progression while receiving standard therapy derived benefit from participation in phase I trials. Risk scoring based on objective clinical parameters indicated that patients with a high score had a significantly shorter OS, and this may help in the process of patient selection for phase I trial entry.

CTC counts predict OS and provide independent prognostic information to time to disease progression; CTC dynamics following therapy need to be evaluated as an intermediate end point of outcome in randomised phase III trials.

This is the first prospective analysis confirming that a prognostic score based on objective markers, including albumin less than 35 g/L, LDH more than ULN, and more than two sites of metastasis, is a helpful tool in the process of patient selection for phase I trial entry.

Background. Tisotumab vedotin (TV; HuMax-TF-ADC), is a first-in-class antibody-drug conjugate directed against tissue factor (TF), which is expressed across multiple solid tumor types and is associated with poor clinical outcomes. We hypothesize that TV could have antitumor activity in tumors known to express TF. Methods. This is a phase 1/2 open-label, dose-escalation and-expansion study (innovaTV201; NCT02001623) evaluating the safety, tolerability, pharmacokinetics (PK) profile, and antitumor activity of TV in patients with locally advanced and/or metastatic solid tumors known to express TF. In the dose-escalation phase, patients were treated with TV intravenously once every 3 weeks in a traditional 3 + 3 design to determine the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D). Plasma was collected to characterize the PK profile of TV. In the dose-expansion phase, patients are treated at the RP2D in seven advanced solid tumor-type cohorts, including bladder, cervix, endometrium, esophagus, lung, ovary, and prostate cancers. Findings. In the dose-escalation phase, 27 patients with advanced solid tumors received TV in eight sequential dose cohorts between 0•3 and 2•2 mg/kg. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were observed at TV 2•2 mg/kg. TV at 2•0 mg/kg was identified as the MTD and the RP2D. The PK profile of TV was dose proportional. In the dose-expansion phase, 147 patients with solid tumors were treated with TV at 2•0 mg/kg. The most common (≥20%) treatment-emergent adverse events (AEs) of any grade included epistaxis, fatigue, nausea, alopecia, conjunctivitis, decreased appetite, and constipation. Across tumor

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at !200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1-11) lines of preolaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0-0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development