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The RECIST guideline defines four categories of response to treatment for cancer patients according to post-baseline changes in tumor burden, hence ignoring disease history. However, if left untreated, tumors grow exponentially, implying that pretreatment changes in tumor size are key to thoroughly assess efficacy. We present a model-based approach to estimate the rates of changes in tumor mass, before and after treatment onset. Sixty-eight patients were eligible for the analysis of tumor size data from a Phase 1 study evaluating the effect of emactuzumab. In addition to tumor size measured at baseline and every six weeks during treatment, a pre-baseline measurement was gathered for each patient. A longitudinal regression model was used to estimate the rates of tumor size change before and after treatment onset. The median pre-treatment tumor growth exponential rate was equal to 0.022 month-1, corresponding to a tumor size doubling time of 4 months, and the on-treatment median tumor shrinkage exponential rate was equal to 0.001 month-1. Among sixteen patients categorized as stable disease per RECIST, only five had similar slopes before and after treatment while nine actually improved. One patient in particular had a therapeutically induced stabilization of the disease. Our analysis emphasizes the importance of collecting pre-baseline scans to distinguish therapeutically induced stable disease from cases where the tumor growth is not perturbed by treatment.

BackgroundThis phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors.MethodsBoth emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments.ResultsThree dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients.ConclusionEmactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses.Trialregistration number NCT02760797.

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450–1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation.

In this study we investigated the correlation between affinity, efficacy, peripheral receptor occupancy, and kinetic properties of D2 dopamine receptor ligands with time-course evaluations of prolactin release in rat blood. We profiled typical and atypical antipsychotic antagonists at D2 receptors, the partial agonist aripiprazole, and four novel partial agonist compounds with different properties. Clozapine and quetiapine revealed lower prolactin release and fast dissociation kinetics, linking fast dissociation and prolactin-sparing properties. Surprisingly, haloperidol, a highly prolactin-releasing antagonist, shared intermediate dissociation properties. Factors other than kinetic properties may thus contribute to prolactin-releasing properties of antagonists. Partial agonists sharing similar efficacies and receptor occupancies differed markedly in their ability to induce hyperprolactinaemia. Aripiprazole moderately released prolactin even at high receptor occupancies, with slow dissociation from D2 receptors. Other compounds displaying low affinities and fast dissociations released prolactin substantially, although less than haloperidol. The effect augmented after repeated administrations. Compounds with high affinities and slow dissociation rates stimulated moderate prolactin release at high receptor occupancies, reaching a ceiling effect at 50–60% occupancy. Moreover, the effect developed tolerance. In conclusion, we investigated the affinity and kinetic properties of D2 partial agonists associated with their ability to induce prolactin release in blood. We propose that for D2 partial agonists, at comparable intrinsic activities and peripheral occupancies, the prolactin-releasing properties are linked to their kinetic rate properties. Differently from D2 antagonists, partial agonists display slow dissociation and high affinity associated with a low prolactin release profile.

This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

SummaryPurpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

We investigate the determinants of geographical distances to parents. We focus on the role of family members who live outside the household (the parents themselves, and siblings), and on the distinction between the effects of life events and effects related to the timing with which these events have been experienced in the life course. We use data from the Netherlands Kinship Panel Study and linear regression models on the logarithm of distance. We find that life-course characteristics are much more important to the distance to parents than parental characteristics. Sibling characteristics, most notably the presence of a sister, also have an impact on this distance.

We investigate the determinants of geographical distances to parents. We focus on the role of family members who live outside the household (the parents themselves, and siblings), and on the distinction between the effects of life events and effects related to the timing with which these events have been experienced in the life course. We use data from the Netherlands Kinship Panel Study and linear regression models on the logarithm of distance. We find that life-course characteristics are much more important to the distance to parents than parental characteristics. Sibling characteristics, most notably the presence of a sister, also have an impact on this distance.

We explore the strong linkages between macro changes and the dynamics of educational, occupational, family, and household careers of young Spanish adults born between 1945 and 1974. We review theory and evidence on macro factors: changes in the welfare system, centrality of the family as a service provider, and the changing role of women. We outline some hypotheses of how life course trajectories, and their heterogeneity, change across cohorts. We build data on sequences of states using FFS. In our analysis, we find an increase in the discontinuity of careers and of the heterogeneity among cohort members, especially for employment. Women’s careers are becoming more similar to those of men. Family and household formation is postponed, with a limited spread of post-nuclear family forms.

In countries with so-called \"lowest-low\" fertility, the lowest fertility levels are seen in the cities. The main reasons for this development is the difference in the cost of living expenses, combined with income constraints in cities, as compared to these same aspects in rural areas. If we focus our attention on the center of an urban area, migration needs to be taken into account, since it can contribute to particularly low yield fertility. In this paper we use the Turin Longitudinal Study, which has data on all people who have ever been residents in Turin (Italy) during the period 1971-2001. We study the interdependencies between fertility and out-migration choices for a selected group, from the 1956 birth-cohort. In order to fully understand fertility, we need to consider how fertility acts on out-migration choices. Our findings underline the important role of economic resources and life cycle events in such a context which seem to guide both fertility and migration behaviors. Moreover, while having a child significantly hampers long-distance migration, it also has a lower impact on short-distant moves.