Phase I clinical trial of vinorelbine in tumor-bearing cats.

BACKGROUND: Vinorelbine (VRL) has been investigated in dogs, but its use in cats has not been studied. HYPOTHESIS/OBJECTIVES: To determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of VRL in tumor-bearing cats. ANIMALS: Cats were included in this prospective phase I trial if they had confirmed malignancy, received ≥1 VRL treatment, and had adequate follow-up. Previous treatment was acceptable, but concurrent chemotherapy or radiotherapy was not permitted. METHODS: Using a modified phase I design, cats were enrolled in cohorts of 3 at a starting dosage of 9 mg/m(2) . Cats tolerating the first treatment well were eligible to receive additional VRL treatments at escalating dosages; escalations beyond the perceived MTD were permitted based on individual tolerance. Intended treatment interval was 7 days. Patient histories, physical examinations, and complete blood counts were performed weekly. RESULTS: Nineteen cats were included. Sixty-one VRL treatments were administered. Median number of treatments was 2 (range, 1-9). Starting dosages were 9-12 mg/m(2) . Maximal dosage administered was 15.5 mg/m(2) . The MTD was 11.5 mg/m(2) . Acute DLTs were neutropenia, vomiting, and nephrotoxicity. Other notable toxicities were weight loss and anemia. CONCLUSIONS AND CLINICAL IMPORTANCE: Vinorelbine is tolerated in cats at a weekly interval. Recommended starting dosage is 11.5 mg/m(2) . Neutropenia was transient, lasting <7 days; vomiting was self-limiting in most cases. Although VRL-associated nephrotoxicity has not been reported, potential attribution of this toxicity to VRL must not be discounted. Further investigation of the efficacy of VRL in feline malignancies is warranted.

Carotid MR angiography: phase II study of safety and efficacy for MS-325.

PURPOSE: To evaluate the safety and efficacy of MS-325 in patients suspected of having carotid arterial disease. MATERIALS AND METHODS: Fifty carotid arteries in 26 patients were imaged with three-dimensional spoiled gradient-recalled-echo magnetic resonance (MR) angiography at 5 and 50 minutes after injection of MS-325. MS-325 was administered intravenously as a single dose of 0.01, 0.03, or 0.05 mmol per kilogram of body weight as determined with a dose randomization scheme for four, nine, and 13 patients, respectively. Safety, including clinical laboratory changes and electrocardiographic monitoring, was assessed until approximately 3 days after injection. Conventional contrast agent-enhanced angiography was used as the standard of reference. Independent readers blinded to the dose interpreted the MR angiographic and conventional images. Images were assessed for location and extent of carotid arterial stenosis. RESULTS: There were no severe or serious adverse events. For the determination of clinically significant stenosis (>70%) on the 5-minute images, sensitivity, specificity, and accuracy (P =.07, three-way comparison) were 100%, 100%, and 100%; 63%, 100%, and 88%; and 40%, 75%, and 55% at 0.01, 0.03, and 0.05 mmol/kg, respectively. Sensitivity and specificity for images at 50 minutes after MS-325 administration showed the same trends as the 5-minute images. CONCLUSION: Overall accuracy for MS-325-enhanced carotid MR angiography performed during steady-state conditions of circulating contrast agent approximately 5 minutes after injection was high (88%-100%) at 0.03 and 0.01 mmol/kg. MS-325 was well tolerated at all evaluated doses.

A multicenter, randomized, double-blind study to evaluate the safety, tolerability, and efficacy of OptiMARK (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in patients with liver pathology: results of a Phase III clinical trial.

The purpose of this study was to evaluate the safety and efficacy of OptiMARK (gadoversetamide injection) compared with Magnevist (gadopentetate dimeglumine) in hepatic MRI of patients with suspected liver pathology. A Phase III, multicenter, randomized, double-blind, parallel group study was performed in adults with suspected liver pathology. All patients underwent contrast-enhanced computed tomography within 3 weeks prior to magnetic resonance scanning. Ninety-nine patients received OptiMARK, and 94 patients received Magnevist at a dose of 0.1 mmol/kg. Precontrast T1- and T2-weighted spin-echo imaging and T1-weighted gradient-echo imaging were performed, followed by T1-weighted gradient-echo imaging at 15-20 seconds, 1 minute, and 5 minutes after intravenous contrast injection. Three primary efficacy endpoints (confidence in lesion diagnosis, level of conspicuity, and lesion border delineation) were evaluated on the precontrast image set and compared with the pre plus postcontrast image set. Vital signs, physical examination, electrocardiograms (ECGs), and laboratory parameters (chemistry, hematology, and urinalysis) were measured at various time points. Adverse events were recorded. The study design and statistical analyses were chosen to demonstrate presumed equivalence of OptiMARK and Magnevist. There were no statistically significant differences in efficacy between OptiMARK and Magnevist as assessed by either blinded readers or the on-site principal investigators. No serious or unexpected adverse events were noted. Of the 193 patients receiving contrast media, 82 experienced a total of 154 adverse events. Thirty-three (21.4%) of these 154 adverse events were felt by the on-site investigators to be probably related to either study agent: 15 events in 9 patients in the OptiMARK group, and 18 events in 13 patients in the Magnevist group. Headache was the most common adverse event, occurring in 10.1% of the OptiMARK patients and 12.8% of the Magnevist patients. No clinically relevant trends were observed in any laboratory parameter or ECG findings in either treatment group. The results demonstrate the safety, efficacy, and equivalence of OptiMARK and Magnevist at a dose of 0.1 mmol/kg in hepatic magnetic resonance imaging of patients with suspected liver pathology.

Pharmacokinetics, safety, and tolerability of gadoversetamide injection (OptiMARK) in subjects with central nervous system or liver pathology and varying degrees of renal function.

The pharmacokinetic parameters, safety, and tolerability of OptiMARK (gadoversetamide injection), a gadolinium-based magnetic resonance imaging (MRI) contrast agent, were evaluated in 163 subjects with either central nervous system (CNS) or liver pathology with and without renal insufficiency, for which a contrast-enhanced MRI was indicated. A multicenter, double-blind, randomized, placebo-controlled, parallel-group design was used in which subjects received 0.1, 0.3, or 0.5 mmol/kg of OptiMARK or placebo intravenously. Samples were analyzed for total gadolinium by inductively coupled plasma/mass spectrometry. Gadolinium pharmacokinetics were affected by renal impairment: area under the curve, half-life, and steady-state distribution volume significantly increased with declining renal function, while total body clearance decreased. In subjects with normal renal function, neither age, gender, nor liver versus CNS pathology altered gadolinium pharmacokinetics. No clinically significant changes from baseline were noted in vital signs, laboratory measures, electrocardiograms, or physical examinations. OptiMARK is safe and well-tolerated following a single intravenous injection in subjects with either liver or CNS pathology despite a prolonged elimination half-life in subjects with renal impairment.