Abstract 5687: Development of glutathione pegylated liposomal doxorubicin (2B3-101) for the treatment of brain cancer
Authors: Gaillard Pieter J. , Gladdines Werner , Appeldoorn Chantal C.M. , Rip Jaap , Boogerd Willem J. , Beijnen Jos H. , Brandsma Dieta , van Tellingen Olaf 
Published: August 2012

Treatment options for brain cancer are limited and overall prognoses are poor. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is essentially based on the already marketed pegylated liposomal doxorubicin (Doxil), with an additional glutathione (GSH) coating to safely enhance delivery across the blood-brain barrier. In a GLP safety study 2B3-101 was administered by intravenous bolus injection on days 1, 15 and 29 to Wistar rats at 1.75, 3.5 and 7 mg/kg. Doxil (7 mg/kg), empty GSH-PEG-liposomes, and vehicle were included, resulting in 6 groups (10 animals/sex/group). Additional animals were allowed 4 weeks of recovery or were used for toxicokinetic analysis. From observations during the in-life part of the study, as well as after histopathological investigations, no major differences were noted between 2B3-101 and Doxil at 7 mg/kg q14dx3. No treatment-related changes in the brain were observed neither after repeated 2B3-101 exposure, nor after treatment with empty GSH-PEG liposomes. In addition, 2B3-101 did not result in doxorubicin-related toxicity in heart tissue. After 1st and 3rd administration of 7 mg/kg, plasma AUC values were 10-44% higher for Doxil when compared to 2B3-101, while C0 values were considered similar for both drug substances. Apparent half-lives for Doxil were 36.1 and 32.6 hours in males and females after the 3rd administration, respectively. For 2B3-101 these values were slightly shorter at 30.0 and 28.8 hours in males and females, respectively. The doxorubicin brain/plasma ratio showed retention of both 2B3-101 and Doxil after repeated doses, where 2B3-101 resulted in significantly higher doxorubicin retention in the brain 2 weeks after the 3rd administration (p&lt;0.02). A modified Irwin test in male Wistar rats (n=8 per group) showed no neurobehavioral effects and no effects of 2B3-101 on body temperature after administration of 1.75 mg/kg, 3.5 mg/kg and 7 mg/kg. Also, empty GSH-PEG liposomes and Doxil did not result in neurobehavioral effects and effects on body temperature. Efficacy of GMP grade 2B3-101 at the maximum tolerated dose was confirmed in mice with intracranial U87 xenografts; compared to saline 10 mg/kg q4dx4 and 18 mg/kg q8dx2 showed a survival benefit of up to 60%, where 18 mg/kg q8dx2 seemed superior. In addition, in mice carrying subcutaneous MDA-MB-231 xenografts it was shown that 10 mg/kg q4dx3 2B3-101 and Doxil both produced significant anti-tumor activity, were well tolerated, and gave similar weight loss profiles. In conclusion, the therapeutic benefit and predictable safety profile of clinical-scale 2B3-101 was successfully demonstrated in preclinical studies. A clinical trial to determine the safety, tolerability and pharmacokinetics of 2B3-101 in patients with solid tumors and brain metastases or recurrent malignant glioma was initiated in June 2011.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5687. doi:1538-7445.AM2012-5687