Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors.

PURPOSE: AZD7762 is a Chk1 kinase inhibitor which increases sensitivity to DNA-damaging agents, including gemcitabine. We evaluated the safety of AZD7762 monotherapy and with gemcitabine in advanced solid tumor patients. EXPERIMENTAL DESIGN: In this Phase I study, patients received intravenous AZD7762 on days 1 and 8 of a 14-day run-in cycle (cycle 0; AZD7762 monotherapy), followed by AZD7762 plus gemcitabine 750-1,000 mg/m(2) on days 1 and 8, every 21 days, in ascending AZD7762 doses (cycle 1; combination therapy). RESULTS: Forty-two patients received AZD7762 6 mg (n = 9), 9 mg (n = 3), 14 mg (n = 6), 21 mg (n = 3), 30 mg (n = 7), 32 mg (n = 6), and 40 mg (n = 8), in combination with gemcitabine. Common adverse events (AEs) were fatigue [41 % (17/42) patients], neutropenia/leukopenia [36 % (15/42) patients], anemia/Hb decrease [29 % (12/42) patients] and nausea, pyrexia and alanine aminotransferase/aspartate aminotransferase increase [26 % (11/42) patients each]. Grade ≥3 AEs occurred in 19 and 52 % of patients in cycles 0 and 1, respectively. Cardiac dose-limiting toxicities occurred in two patients (both AZD7762 monotherapy): grade 3 troponin I increase (32 mg) and grade 3 myocardial ischemia with chest pain, electrocardiogram changes, decreased left ventricular ejection fraction, and increased troponin I (40 mg). AZD7762 exposure increased linearly. Gemcitabine did not affect AZD7762 pharmacokinetics. Two non-small-cell lung cancer patients achieved partial tumor responses (AZD7762 6 mg/gemcitabine 750 mg/m(2) and AZD7762 9 mg cohort). CONCLUSIONS: The maximum-tolerated dose of AZD7762 in combination with gemcitabine 1,000 mg/m(2) was 30 mg. Although development of AZD7762 is not going forward owing to unpredictable cardiac toxicity, Chk1 remains an important therapeutic target.

Movement disorders in multiple sclerosis.

Movement disorders constitute a subspecialty of neurology focusing on a variety of conditions characterized by hypokinetic, hyperkinetic, or abnormally coordinated movements including, among others, tremor, dystonia, parkinsonism, myoclonus, chorea, ballismus, tics, restless limbs, and ataxia. The term "movement disorders" may be used to refer to either abnormal movements or syndromes that cause these abnormal movements. The classification of movement disorders is based on phenomenology, individual syndromes, or etiology. This article reviews terminology used to describe movement disorders, discusses individual movement disorders and their occurrence in patients with multiple sclerosis, and reviews treatment options.

An unsuccessful trial of immunomodulatory therapy in delayed posthypoxic demyelination.

INTRODUCTION: Delayed posthypoxic demyelination may rarely complicate an episode of severe hypoxia, with or without exposure to carbon monoxide. Following recovery from initial coma, progressive neurologic deterioration ensues with outcomes ranging from death to full recovery. Delayed posthypoxic demyelination is hypothesized to be immunemediated, with support coming from recent animal experiments. METHODS: We report a 46-year-old man who developed progressive cognitive deficits with abulia approximately 3 weeks after recovering from coma related to alcohol and morphine intoxication. RESULTS: Despite treatment with high-dose steroids and plasmapheresis, he continued to deteriorate and remained in a vegetative state until his death under hospice care more than 2 months after his initial hypoxic insult. Serial brain imaging and postmortem examination showed bilateral necrosis of the globi pallidi and extensive demyelination in the centrum semiovale and corona radiata. CONCLUSIONS: Based on an immune-mediated model of disease and given a lack of effective treatments, future use of immunomodulatory therapy may still be worth considering early in the course of this rare and potentially devastating condition.