Subject(s)
Cat-Scratch Disease/diagnosis , Gastritis, Hypertrophic/diagnosis , Mitochondrial Diseases/diagnosis , Cat-Scratch Disease/drug therapy , Child , Child, Preschool , Diagnosis, Differential , Edema/etiology , Female , Gastritis, Hypertrophic/blood , Humans , Infant , Male , Mitochondrial Diseases/therapyABSTRACT
MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on ß-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m(2), with subsequent increments of 0.6 mg/m(2) until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1-10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m(2) (1/6 patients) and at 4.5 mg/m(2) (1/7 patients). The MTD was determined to be 3.3 mg/m(2) (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m(2) once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing.
Subject(s)
Neoplasms/drug therapy , Neoplasms/pathology , Quinazolines/therapeutic use , Tubulin Modulators/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Contrast Media , Demography , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Staging , Quinazolines/adverse effects , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Tubulin Modulators/adverse effects , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacokineticsABSTRACT
AIMS: We report 2-year outcomes in a large unselected drug-eluting stent population (N=7,492) in the TAXUS Express2 ARRIVE post-market surveillance programme (101 U.S. sites). METHODS AND RESULTS: No specific inclusion/exclusion criteria were mandated; patients enrolled at procedure initiation. Two-year follow-up was 94%, with independent adjudication of major cardiac events, monitoring of patients with cardiac events and an additional 10-20% sample by site. Most ARRIVE cases (64%, n=4,794) typified expanded use based on patient/lesion characteristics outside the simple use (single vessel/stent) pivotal trial populations. These expanded use patients had higher 2-year rates than simple use patients for mortality (7.8% vs. 4.2%, P<0.001), myocardial infarction (MI, 3.9% vs. 2.2%, P<0.001), target lesion revascularisation (TLR, 9.2% vs. 5.4%, P<0.001), and stent thrombosis (3.3% vs. 1.4%, P<0.001). Among subgroups with renal disease, chronic total occlusion (CTO), lesion >28 mm, reference vessel diameter (RVD) <2.5 mm, multivessel stenting, acute MI, bifurcation, vein graft, or in-stent restenosis, TLR ranged from 3.8% to 8.9% in year one, and from 1.3% to 6.0% during year two. CONCLUSIONS: Mortality and stent-related events were higher in expanded use than simple use patients in the pivotal trials. ARRIVE provides a detailed estimate of procedural and 2-year outcomes in such real-world patients.
