2 IIH Pressure – a randomised, controlled, double blind physiology study of the effect of Exenatide on intracranial pressure

IntroductionRaised intracranial pressure (ICP) causes significant morbidity and mortality in a range of conditions including idiopathic intracranial hypertension (IIH) and traumatic brain injury (TBI). Exenatide is a GLP-1 receptor agonist; pre-clinical data demonstrates its ability to reduce ICP. GLP-1R agonists have also been shown to have neuro-protective properties in pre-clinical models of TBI. The objectives of this study are to assess the biological effect of a Glucagon-like Peptide 1 (GLP-1) agonist on ICP in a cohort of participants with IIH, a raised ICP model.MethodsRandomised, placebo controlled, double-blind physiology study of Exenatide in women with active IIH (>25 cmCSF lumbar puncture opening pressure and papilloedema). Telemetric, intraparenchymal ICP monitors were implanted to enable gold standard, long-term ICP monitoring (Raumedic p-Tel, Helmbrechts, Germany). Participants were randomised 1:1 to receive Exenatide (10 mcg BD sub-cutaneous) or placebo for 12 weeks. ICP was recorded over a 24-hour baseline visit, at two weeks and 12 weeks. Monthly headache diaries were completed at baseline and 8–12 weeks. Significance was set at p<0.1 as an early phase trial.ResultsOf the 16 participants recruited, 15 were randomised and completed the study: age 29.5 ±9.5 years, BMI 38.1 ±6.2 kg/m2, ICP 30.6±5.1 cmCSF. All ICP monitor implants were well tolerated and allowed successful ICP quantification. A significant reduction in ICP was noted at all timepoints: at 2.5 hours -5.7 cm CSF (p=0.031), at 24 hours -6.3 cmCSF (p=0.095), and at 12 weeks -5.6 cmCSF (p=0.064).ConclusionsWe report the first human study to assess the biological effect of the GLP-1 agonist Exenatide on ICP in IIH utilising highly accurate implantable telemetric ICP monitors. Exenatide reduced ICP at all timepoints including acutely at 2.5 hrs and during chronic dosing. New therapies for ICP modulation are a significant un-met need in both military and civilian spheres.

Online monitoring of patient self-reported adverse events in early phase clinical trials: Views from patients, clinicians, and trial staff

Background/aims New classes of cancer drugs bring a range of unknown and undesirable adverse events. Adverse event monitoring is essential in phase I trials to assess toxicity and safety. In phase II, the focus is also on efficacy but robust data on adverse events continue to inform the safety and the adverse event profile. Standard, clinician-led monitoring has been shown to underestimate patients’ symptoms. Hence, patient-reported adverse event monitoring has been argued to complement and improve the information on adverse events in early phase clinical trials. With advances in information technology, real-time patient self-reported adverse events in trials are feasible. This study explored the experiences and procedures for reporting adverse events in early phase trials among patients, clinical staff, and trial staff, and their views on using an electronic patient-reported outcome adverse event system in this setting. Methods Qualitative interviews were conducted with patients, purposively sampled across ages, gender, and different phases of trials, and with clinical and trial-related staff involved in early phase trials (e.g. consultants, research nurses, hospital-based trial assistants/data managers, trial unit management staff). Interviews explored patient experiences and views on current adverse event reporting processes and electronic patient-reported outcome adverse event reporting. Framework analysis techniques were used to analyse the data. Results Interviewees were from two hospital trusts with early phase portfolios in England and a trial unit, and included sixteen patients, five consultants, four research nurses, five hospital-based trial staff, and two trial unit staff. Interviews identified three key themes (patient experiences, data flow, and views on electronic patient-reported outcome adverse event reporting). Stakeholders emphasised the intensity of trials for patients and the importance of extensive information provision within the uncertainty of early phase trial drugs. Regular face-to-face appointments for patients supplemented by telephone contact aimed to capture any adverse events. Delayed or under-reporting of mild- or low-severity symptoms was evident among patients. Hospital-based staff highlighted the challenges of current data collection including intense timescales, monitoring by trial sponsors, and high workload. Positive views on electronic patient-reported outcome adverse events highlighted that this could provide a more comprehensive and accurate view on the side effects of new drugs. Clinical staff emphasised patient safety and the need for clear responsibilities for monitoring. The need for careful decision-making about data flow and symptom attribution was highlighted; with trial unit staff emphasising the need for clinician review. Conclusion Technology advances mean it is timely to explore the benefits and challenges of electronic patient-reported outcome adverse event reporting. This is a complex area warranting further consideration within the trial community. We have developed an online patient self-reporting tool and a small pilot with early phase trial patients is underway.

Drug Development in Soft Tissue Sarcomas: Novel Targets and Recent Early Phase Trial Results

ABSTRACT Soft tissue sarcomas are a heterogeneous group of rare malignancies with few effective standard therapies. Our understanding of the underlying biology driving tumorigenesis in these mesenchymal tumors have led to a growth in drug development for soft tissue sarcomas. This review focuses on novel targets in soft tissue sarcomas, describes early clinical trial results of drugs directed at these targets, and discusses the data surrounding the use of these compounds in clinical practice and rationale for possible future US Food and Drug Administration approvals.

Is the optimal biological dose of oncologic molecular-targeted therapies also clinically effective?

3060 Background: The determination of the optimal biological dose (OBD) defined as the lowest safe dose associated with biological efficacy, appears to be a promising endpoint for defining the recommended phase 2 trial dose (RP2D) of novel oncologic targeted therapies in early-phase clinical trials. However, the clinical relevance of OBD is still unknown. We conducted a review to assess if the OBDs of molecular targeted therapies defined during early phase trials were useful during subsequent drug development and for oncologic drug approvals. Methods: A systematic review was conducted to identify all the molecular targeted therapies approved by FDA in solid and hematological malignancies, and for which early phase trials defined OBDs. The publications of efficacy trials leading to the first FDA approvals were reviewed, as were the FDA approved doses and dosing schedules, which were compared to OBDs found in the early phase trials. Results: OBDs were reported in the early phase trial articles of 39.5% (32/81) FDA approved targeted therapies from 1999 to 2017 (19 small molecules and 13 monoclonal antibodies (mAbs)). The maximum tolerated doses (MTD) had not been reached for 59.4% (19/32) of these drugs. When both MTD and OBD had been defined, OBD were lower than MTD in 84.6% of cases, and equal for the others. The OBDs were chosen as the RP2Ds for 56.3% of the molecules. In that case, the final FDA approved doses were consistent with the OBDs for 83.3% of the drugs. These percentages did not differ in between small molecules and mAbs. OBDs mainly relied on indirect effects on the involved signaling pathway elements for small molecules (11/19, 57.9%), and on involved receptor occupancies for mAbs (6/13, 46.2%). In total, 23.5% of all FDA approved molecular targeted therapies were approved at their OBDs. Conclusions: Although still poorly investigated, OBD may represent a relevant complementary endpoint in in early phase trials of novel anti-cancer targeted therapies, as OBDs are selected as the final FDA approved doses in 83.3 % of cases when chosen as the RP2Ds, which is much higher than the previously reported 58.0 % when MTDs are chosen as the RP2Ds (Fontes-Jardim et al. JNCI 2015).

Itraconazole targets cell cycle heterogeneity in colorectal cancer

Cellular dormancy and heterogeneity in cell cycle length provide important explanations for treatment failure after adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC), yet the molecular control of the dormant versus cycling state remains unknown. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumor cells. Unexpectedly, we demonstrate that dormant CRC cells are differentiated, yet retain clonogenic capacity. Mouse organoid drug screening identifies that itraconazole generates spheroid collapse and loss of dormancy. Human CRC cell dormancy and tumor growth can also be perturbed by itraconazole, which is found to inhibit Wnt signaling through noncanonical hedgehog signaling. Preclinical validation shows itraconazole to be effective in multiple assays through Wnt inhibition, causing both cycling and dormant cells to switch to global senescence. These data provide preclinical evidence to support an early phase trial of itraconazole in CRC.