Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma.

This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.

Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.

The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A(2A) receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations.

Multimodality diagnosis of liver tumors: feature analysis with CT, liver-specific and contrast-enhanced MR, and a computer model.

RATIONALE AND OBJECTIVES: The purpose of this study was to measure and to clarify the diagnostic contributions of image-based features in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. MATERIALS AND METHODS: Six experienced abdominal radiologists each read images from 146 cases (including a contrast material-enhanced computed tomographic [CT] scan and contrast-enhanced and unenhanced magnetic resonance [MR] images) following a checklist-questionnaire requiring them to rate quantitatively each of as many as 131 image features and then reported on each of the two differentiations. The diagnostic value of each feature was assessed, and linear discriminant analysis was used to develop statistical prediction rules (SPRs) for merging feature data into computerized "second opinions." For the two differentiations, accuracy (area under the receiver operating characteristic curve [Az]) was then determined for the radiologists' readings by themselves and for each of three SPRs. RESULTS: Thirty-seven candidate features had diagnostic value for each of the two differentiations (a slightly different feature set for each). Radiologists' performance at both differentiations was excellent (Az = 0.929 [benign vs malignant] and 0.926 [hepatocyte-containing vs non-hepatocyte-containing]). Performance of the SPR that operated on the features from all modalities together was better than that of radiologists (Az = 0.936 [benign vs malignant] and 0.951 [hepatocyte-containing vs non-hepatocyte-containing]), but this difference was of marginal statistical significance (P = .11). Contrast-enhanced MR imaging and contrast-enhanced CT each made significant adjunctive contributions to accuracy compared with unenhanced MR imaging alone. CONCLUSION: Many CT- and MR imaging-based features have diagnostic value in differentiating benign from malignant and hepatocyte-containing from non-hepatocyte-containing liver lesions. Radiologists could also benefit from the fully informed SPR's "second opinions."

Istradefylline for Parkinson's disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study.

BACKGROUND: Istradefylline (KW-6002) is a selective adenosine A(2A) receptor antagonist investigated as adjunctive therapy to levodopa in PD patients with motor response complications. In Phase 2b/3 studies, Istradefylline reduced OFF time without worsening troublesome dyskinesia and was well tolerated. METHODS: A randomized, 12-week, double-blind, placebo-controlled parallel-group study evaluated the efficacy of 10, 20, and 40 mg/day of Istradefylline in patients on levodopa therapy with motor response complications. The primary outcome measure was change from baseline to endpoint in the percentage of awake time/day spent in the OFF state as determined by patient diary. RESULTS: Six hundred and ten patients were randomized. Five hundred and eighty four patients were included in the Intent-to-treat (ITT) group-146 placebo patients and 149 in the 10 mg, 144 in the 20, and 145 patients in the 40 mg Istradefylline groups. Baseline demographics were similar between groups. Treatment cohorts had been diagnosed an average of 9 years diagnosis and 3.6 years from the onset of motor fluctuations; at baseline they had an average of 6.7 h of OFF time and an average UPDRS motor score of 22 when ON. At endpoint, the amount and percentage of OFF time did not differ between Istradefylline and placebo, however a dose-ordering response was observed. Changes from baseline in the UPDRS motor score in the on state for the 40 mg were modest but significant compared to placebo (2.9 vs. 0.8; p < 0.05). CONCLUSIONS: Although Istradefylline did not impact OFF time duration, it significantly improved motor score at 40 mg/day.