BackgroundBAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia.ObjectivesTo assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A.Patients/MethodsThis 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses.ResultsBAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ∼ 19 h (vs. ∼ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed.ConclusionsThis phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

No abstract

Idiopathic thrombotic thrombocytopenic purpura (TTP) is caused by the production of autoantibodies against the Von Willebrand factor cleaving enzyme. This provides a rationale for the use of rituximab in this disease. We report a retrospective review of 12 patients treated with rituximab for TTP refractory to plasma exchange. Eleven patients were treated during initial presentation, and one patient was treated for recurrent relapse. Ten patients responded to treatment. Median time to response after first dose of rituximab was 10 days (5-32). Of the 11 patients treated during initial presentation, nine remain free of relapse after a median follow-up of 57+ months (1+-79+). Two patients died during initial treatment. One patient was lost to follow-up 1 month after achieving complete response. The patient treated for recurrent disease during second relapse remained disease free for 2years, relapsed and was treated again with rituximab, and was in remission for 22 months. She relapsed again, was retreated, and has now been in remission for 21+ months. We conclude that rituximab is an useful addition to plasma exchange treatment in TTP, but its exact role and dosing need to be verified in prospective studies.

Gossypol is a lipid soluble polyphenolic compound isolated from cotton seed oil which has been previously shown to have antiproliferative activity in vitro against a variety of human solid tumor cell lines. It has been extensively tested in clinical trials as a male contraceptive agent and found to be well tolerated. Its mechanism of action is thought to be inhibition of cellular energy metabolism. It inhibits glycolysis through inhibition of LDH isoenzyme type 5, and it inhibits mitochondrial oxidative phosphorylation and electron transport. We tested the in vitro antiproliferative effect of gossypol against four well characterized human glioma cell lines, HS 683, U373, U87 and U138, and one rat glioma cell line, C6, using the colorimetric Microculture Tetrazolium Assay (MTT). Cytotoxicity was found to be concentration and time dependent and increased with incubation times up to 8 days. The relative sensitivity of the glioma cell lines to gossypol at 48 hour incubation correlated with their respective LDH isoenzyme profiles, with the more sensitive cell lines expressing increased cathodal LDH isoenzymes (LDH5). The in vitro cytotoxicity of gossypol to these CNS tumor lines was compared to the other non central nervous system solid tumor cell lines which had been previously reported as being sensitive to gossypol, including SW-13 (adrenal), MCF-7 (breast), T47-D (breast), and HeLa (cervical). Additional lines tested included SK-MEL-3 (melanoma), Colo 201 (colon) and BRW, a line established in our laboratory from a patient with a Primitive Neuroectodermal tumor. C6, HS 683, and BRW had similar IC50s as the sensitive solid tumor cell lines. U373, U87 and U138 had significantly less sensitivity at 48 hours. There was greater cytotoxicity and no significant differences in the IC50s between any of cell lines at 8 day incubations. Additionally, we tested the cytotoxicity of gossypol against BRW in vivo, using the nude mouse xenograft model. Gossypol, given at a dose of 30 mg/kg per day five days a week for four weeks orally via gavage, was found to decrease the mean tumor weight of treated xenografts by more than 50% as compared to untreated xenografts. These findings suggest that gossypol has potential for further study as an agent for the treatment of primary CNS malignancies.

Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.