Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers.

This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B(2) endpoints in healthy volunteers. Eight male and 8 female volunteers participated in this open-label, randomized, two-treatment, two-way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2-week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB(2) by 64% +/- 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB(2) for 24 hours. Two-day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB(2). These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB(2) levels, and that meloxicam is selective for COX-2.

The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial.

OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer. METHODS: Ninety-five patients were randomized to intravenous BI 2536 on day 1 (200 mg) or days 1 to 3 (50 or 60 mg) of a 21-day treatment course. BI 2536 doses were escalated beyond course 2 if well tolerated. The primary objective was response, and the secondary objectives were progression-free survival (PFS) and overall survival (OS), quality of life, safety, and pharmacokinetics. Primary statistical aim was to demonstrate the difference in objective response rate to historical placebo for both treatment groups. RESULTS: Four patients (4.2%) had a partial response; two were confirmed by independent review. Median PFS was 8.3 weeks (58 days 95% confidence interval [CI]: 48-85) and 7 weeks (49 days 95% CI: 46-70) assessed by investigator and independent review, respectively. Median OS was 28.7 weeks (201 days 95% CI: 180-305). No statistically significant difference was observed between the two treatment schedules regarding clinical benefit, PFS, or OS. Grade 4 neutropenia occurred in 37% of patients; common nonhematologic adverse events were fatigue (31%) and nausea (27%). Two deaths (pulmonary hemorrhage and sepsis) were considered drug related. There was a trend in favor of the days 1 to 3 dosing schedule in quality of life. BI 2536 displayed moderate interpatient variability. CONCLUSIONS: BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication.

Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI).

AIMS: BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and pharmacokinetics of BI 2536 in five solid tumour types. PATIENTS AND METHODS: Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were 18years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4weeks ago. BI 2536 200-250mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. RESULTS: Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3-4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14-15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536. CONCLUSIONS: BI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies.

Phase I trial with the CD44v6-targeting immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma.

CD44v6 is a tumor associated antigen abundantly expressed in head and neck squamous cell carcinomas (HNSCC) and in normal squamous epithelium. The immunoconjugate bivatuzumab mertansine (BIWI 1) consists of a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. The maximum tolerated dose (MTD), safety and efficacy of BIWI 1 administered IV in patients with HNSCC has not been determined. In a clinical phase I trial, adult patients with recurrent or metastatic HNSCC were treated intravenously with BIWI 1. Starting with 25mg/m(2), the dose was escalated in steps of 25mg/m(2) until dose limiting toxicity was observed. Six women and 25 men were included. The MTD was 300 mg/m(2). Twelve patients were treated with at least the MTD. The principal toxic effects were maculopapular rashes, focal blister formation and skin exfoliation. Three patients had partial responses at doses of 200, 275 and 325 mg/m(2). The concept that bivatuzumab can direct mertansine activity to CD44v6 expressing tumors was confirmed. Although CD44v6 was abundantly expressed in all tumors, the response to BIWI 1 was variable. Binding to CD44v6 on skin keratinocytes mediated serious skin toxicity with a fatal outcome in a parallel trial, which led to the termination of the development program of bivatuzumab mertansine and the present study.

Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study.

The purpose of this study was to investigate the safety, pharmacokinetics and preliminary efficacy of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer. Anthracycline and taxane-pretreated patients with metastatic breast cancer that expressed CD44v6 received one single infusion of bivatuzumab mertansine and were observed for 21 days within one treatment course. Starting dose was 25 mg/m, while dose was escalated by increments of 25 mg/m. Patients who experienced a disease stabilization were eligible for further courses with bivatuzumab mertansine. Blood serum samples were taken throughout the treatment period for pharmacokinetic analysis. Twenty-four patients were treated at eight different dose levels (25-200 mg/m), seven of these patients received more than one course of bivatuzumab mertansine. Two dose-limiting toxicities occurred: one patient treated with 125 mg/m developed transient National Cancer Institute Common Toxicity Criteria grade 4 elevation of liver enzymes; another patient treated at 175 mg/m experienced National Cancer Institute Common Toxicity Criteria grade 3 vomiting. She died from renal failure, which might have been caused by deterioration of pre-existing renal insufficiency. The most common toxicities were transient and mild skin disorders in 75% of patients. As a consequence of one fatal toxic epidermal necrolysis that occurred in a study running in parallel, the clinical trials programme of bivatuzumab mertansine was discontinued. None of the patients developed antibodies against bivatuzumab mertansine. No objective responses were observed. Disease stabilization was achieved in 50% of patients independently of dose level. In conclusion, bivatuzumab mertansine targets CD44v6 and appears to stabilize heavily pretreated metastatic breast cancer that expresses CD44v6. The maximum tolerated dose could not be determined in this trial as the sponsor discontinued the clinical development of bivatuzumab mertansine.

A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results.

OBJECTIVE: In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA). METHODS: Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups. RESULTS: Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups. CONCLUSION: The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.

Safety, biodistribution, pharmacokinetics, and immunogenicity of 99mTc-labeled humanized monoclonal antibody BIWA 4 (bivatuzumab) in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: Previous studies have shown the potential of murine and chimeric anti-CD44v6 monoclonal antibodies (MAbs) for radioimmunotherapy (RIT) of head and neck squamous cell carcinoma (HNSCC). A limitation of these MAbs, however, appeared to be their immunogenicity. Therefore, humanized monoclonal antibody BIWA 4 (bivatuzumab), with an intermediate affinity for CD44v6, was recently selected. As a prelude to RIT, we evaluated the safety, tumor-targeting potential, pharmacokinetics, and immunogenicity of technetium-99m-labeled BIWA 4 in patients undergoing operations for primary HNSCC in this study. Ten patients were treated at BIWA 4 dose levels of 25 mg (n=3), 50 mg (n=4), and 100 mg (n=3). Patients received 2 mg of 750 MBq 99mTc-BIWA 4, together with 23-, 48-, and 98-mg unlabeled BIWA 4, respectively. Radioimmunoscintigraphy (RIS) was performed within 1 h and after 21 h, and patients underwent surgery at 48 h after injection. Biodistribution of 99mTc-BIWA 4 was evaluated by radioactivity measurements in blood, bone marrow, and in biopsies of a surgical specimen obtained 48 h after injection. BIWA 4 concentration in blood was assessed by ELISA and high performance liquid chromatography and related to soluble CD44v6 levels in serum samples. The development of human anti-human antibody (HAHA) responses was determined. Administration of 99mTc-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. A mean t1/2 in plasma of 54.8 +/- 11.5 h, 76.1 +/- 21.8 h, and 68.5 +/- 21.2 h was found for the 25-, 50-, and 100-mg dose group, respectively. No complex formation of BIWA 4 with soluble CD44v6 in blood was observed. RIS showed targeting of primary tumors and lymph node metastases in 8 of 10 and 1 of 5 patients, respectively. The highest tumor uptake and tumor to nontumor ratios were observed for the 50-mg dose group. Tumor uptake was 12.9 +/- 5.9, 26.2 +/- 3.1, and 15.4 +/- 1.9% of the injected dose (ID)/kg for the 25-, 50-, and 100-mg dose group, respectively, while the tumor to bone marrow ratios for these groups were 1.7 +/- 0.5, 3.2 +/- 1.1, and 2.0 +/- 0.6, respectively. CONCLUSION: 99mTc-BIWA 4 can safely be administered to patients with HNSCC, with absence of detectable HAHA responses. The 50-mg dose level showed the highest tumor uptake and tumor to nontumor ratios. These findings support the use of BIWA 4 for RIT studies in patients with HNSCC.