Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients

A phase II study was undertaken to determine the safety of combining flutamide with gemcitabine, with response rate being the primary end point. Twenty-seven patients with histologically proven, previously untreated, unresectable pancreatic adenocarcinoma received gemcitabine, 1 g m−2 intravenously on days 1, 8 and 15 of a 28 day cycle, and flutamide 250 mg given orally three times daily. Treatment was halted if there was unacceptable toxicity, or evidence of disease progression. Toxicity was documented every cycle. Tumour assessment was undertaken after cycles 2 and 4, and thereafter at least every additional four cycles. One hundred and seventeen cycles of treatment were administered, median four cycles per patient (range 1–18). Gemcitabine combined with flutamide was well tolerated, with most toxicities being recorded as grade 1 or 2 and only nine treatment cycles associated with grade 3 toxicity. The most frequent toxicity was myelosuppression. One case of transient jaundice was recorded. The commonest symptomatic toxicity was nausea and vomiting. The response rate was 15% (four partial responses), median survival 6 months and 22% of patients were alive at 1 year. These results suggest antitumour activity of the combination therapy to be equivalent to single agent gemcitabine

Using Drug Development Methodology to Improve Survivorship and Supportive Care Intervention Trials.

This is the peer reviewed version of the following article: Howells, L., Hulbert-Williams, N. J. & Blagden, S. P. (2019). Using drug development methodology to improve survivorship and supportive care intervention trials (Invited Editorial). Psycho-Oncology, 28(7), which has been published in final form at https://doi.org/10.1002/pon.5100. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-ArchivingN/

"A different world" exploring and understanding the climate of a recently re-rolled sexual offender prison

Understanding how sexual offenders experience prison and its environment is important because such experiences can impact on rehabilitation outcomes. The purpose of this research investigation was to explore the rehabilitative and therapeutic climate of a recently re-rolled sexual offender prison. The research took a mixed methods approach and consisted of quantitative and qualitative phases. There were differences between prisoners and staff on their perception of the prison climate and for prisoner and staff relationships. The qualitative results helped to explain the quantitative findings and added a more nuanced understanding of the experience of the prison, the nature of prisoner and staff relationships and the opportunities for personal growth within the prison. The study has important implications for prisons that co-locate sexual offenders and want to provide an environment conducive to rehabilitation

The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5′TOP sequence

La-related protein 1 (LARP1) regulates the stability of many mRNAs. These include 5′TOPs, mTOR-kinase responsive mRNAs with pyrimidine-rich 5′ UTRs, which encode ribosomal proteins and translation factors. We determined that the highly conserved LARP1-specific C-terminal DM15 region of human LARP1 directly binds a 5′TOP sequence. The crystal structure of this DM15 region refined to 1.86 Å resolution has three structurally related and evolutionarily conserved helix-turn-helix modules within each monomer. These motifs resemble HEAT repeats, ubiquitous helical protein-binding structures, but their sequences are inconsistent with consensus sequences of known HEAT modules, suggesting this structure has been repurposed for RNA interactions. A putative mTORC1-recognition sequence sits within a flexible loop C-terminal to these repeats. We also present modelling of pyrimidine-rich single-stranded RNA onto the highly conserved surface of the DM15 region. These studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signaling to ribosome biogenesis

Serendipitous isolation of a disappearing conformational polymorph of succinic acid challenges computational polymorph prediction

A conformational polymorph (γ) of succinic acid was discovered in an attempt to purify a leucine dipeptide by cocrystallization from a methanol solution in the presence of various impurities, such as trifluoroacetic acid. The new γ form was found to have crystallized concomitantly with the most stable β form. In light of this situation, a crystal structure prediction study was undertaken to examine the polymorph landscape. These studies reveal that the γ polymorph is thermodynamically competitive with the other observed polymorphs; having a more stable folded conformation than the planar crystalline conformation in the β form, but being stabilized less by the intermolecular interactions. Simulations and experiment show that the folded conformation is dominant in solution, but that trapping long-lived crystals of the new metastable polymorph may be challenging. Thus the γ polymorph provides a stringent test of theories for predicting which thermodynamically plausible structures may be practically important polymorphs

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors

Inmunomodulación; Linfocitos T; Microambiente tumoralImmunomodulació; Limfòcits T; Microambient tumoralImmunomodulation; T-Lymphocytes; Tumor microenvironmentBackground OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. Methods Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. Results Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1–9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. Conclusion No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.This study was funded by Incyte Corporation (Wilmington, USA)

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m−2) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m−2) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m−2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m−2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug–drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m−2 and 420 mg pertuzumab following a loading dose of 840 mg

The osteoporosis treatment gap in patients at risk of fracture in European primary care : a multi-country cross-sectional observational study

Summary This study in 8 countries across Europe found that about 75% of elderly women seen in primary care who were at high risk of osteoporosis-related fractures were not receiving appropriate medication. Lack of osteoporosis diagnosis appeared to be an important contributing factor. Introduction Treatment rates in osteoporosis are documented to be low. We wished to assess the osteoporosis treatment gap in women ≥ 70 years in routine primary care across Europe. Methods This cross-sectional observational study in 8 European countries collected data from women 70 years or older visiting their general practitioner. The primary outcome was treatment gap: the proportion who were not receiving any osteoporosis medication among those at increased risk of fragility fracture (using history of fracture, 10-year probability of fracture above country-specific Fracture Risk Assessment Tool [FRAX] thresholds, T-score ≤ − 2.5). Results Median 10-year probability of fracture (without bone mineral density [BMD]) for the 3798 enrolled patients was 7.2% (hip) and 16.6% (major osteoporotic). Overall, 2077 women (55%) met one or more definitions for increased risk of fragility fracture: 1200 had a prior fracture, 1814 exceeded the FRAX threshold, and 318 had a T-score ≤ − 2.5 (only 944 received a dual-energy x-ray absorptiometry [DXA] scan). In those at increased fracture risk, the median 10-year probability of hip and major osteoporotic fracture was 11.2% and 22.8%, vs 4.1% and 11.5% in those deemed not at risk. An osteoporosis diagnosis was recorded in 804 patients (21.2%); most (79.7%) of these were at increased fracture risk. The treatment gap was 74.6%, varying from 53% in Ireland to 91% in Germany. Patients with an osteoporosis diagnosis were found to have a lower treatment gap than those without a diagnosis, with an absolute reduction of 63%. Conclusions There is a large treatment gap in women aged ≥ 70 years at increased risk of fragility fracture in routine primary care across Europe. The gap appears to be related to a low rate of osteoporosis diagnosis

A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer

© 2020 American Association for Cancer Research Inc.. All rights reserved. Purpose: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (GþC) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. Patients and Methods: Patients received either GþC (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). Results: Of 100 patients treated, 51 received GþC and 49 received TC, of which 27 crossed over to GþC. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the GþC and TC groups, respectively; P ¼ 0.07). However, the 6-month PFS rate was significantly higher in the GþC group (37% vs. 11% in TC group; P ¼ 0.003). The incidence of grade 3 or higher toxicity was similar in GþC and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the GþC group. Conclusions: Although this trial did not show superiority for PFS of GþC versus TC, the 6-month PFS increased in GþC treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection