A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

PURPOSE: Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. PATIENTS AND METHODS: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics. RESULTS: During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity. CONCLUSIONS: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

The presenting visual symptoms of optic chiasmal disease.

Recognising optic chiasmal disease early is important in order to avoid irreversible visual loss and the potential risk of mortality for patients. Yet, there is frequently a delay in the initial diagnosis. Whilst the signs of optic chiasmal disease, particularly the perimetric findings, are well documented in the recent literature, the symptoms have been less well reported. Whilst some patients with optic chiasmal disease will be asymptomatic, many will complain of visual symptoms including symptomatic field defects, problems with central vision, difficulty with near tasks, binocular visual disturbances, colour vision disturbances, photophobia, phosphenes, glare, and rarely, oscillopsia and visual hallucinations. Others may have headache or the severe and sudden visual symptoms associated with pituitary apoplexy. The visual symptoms may be vague or non-specific, even when there are significant bitemporal visual field defects. We aim in this review to describe the presenting visual symptoms of optic chiasmal disease, and to illustrate these with selected qualitative descriptions from the literature. Our hope is that this will aid clinicians in eliciting a careful history of the sometimes subtle symptoms that may be present.

Retinal arterial pulsation as an indicator of raised intraocular pressure.

Ophthalmic emergencies are invariably challenging for the non-specialist to identify and evaluate, and may be complicated by occult but vision threatening raised intraocular pressure. We present a case of hypertensive uveitis accompanied by the finding of retinal arterial pulsation, which when visualised by direct ophthalmoscopy allows the non-specialist to identify significantly raised intraocular pressure requiring urgent evaluation by an ophthalmologist.

A Comparison of Conventional Intravitreal Injection Method vs InVitria Intravitreal Injection Method.

PURPOSE: To compare use of the conventional intravitreal injection method to the InVitria intravitreal injection device. Three outcome measures were studied: patient comfort, speed of injection and cost-effectiveness. PATIENTS AND METHODS: A prospective review of 58 patients was undertaken. Patients scored their perceived pain for each part of the conventional injection method using visual analogue scales (VAS), which allows pain to be scored from 0 (no pain) to 100. The same 58 patients scored their perceived pain for each part of the injection process with the InVitria on their follow-up visit. The procedure was timed in both settings and cost to the Trust was analysed. RESULTS: Pain scores when the InVitria was used were lower than when the conventional method was used for all aspects of the intravitreal injection procedure, in particular, when comparing insertion of drape/speculum (mean score 57.56) to insertion the InVitria (mean score 16.50), needle entry (mean score 37.76 to 27.86) and removal of the drape/speculum (mean score 38.72) to removal of the InVitria (11.07). The reduction in pain scores was statistically significant for all aspects of the procedure, except the initial instillation of drops. The InVitria was an average of 1 minute and 32 seconds faster than the conventional method. Use of the InVitria in place of the conventional method provides an annual saving of £24,300 to the Trust based on the number of injections currently performed. CONCLUSION: The introduction of the InVitria in the Newcastle Eye Centre has had a positive impact on patient comfort, time and cost to the Trust.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration.

PURPOSE: Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. DESIGN: Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). PARTICIPANTS: Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. METHODS: Subretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. MAIN OUTCOME MEASURES: The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. RESULTS: Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. CONCLUSIONS: Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.