Antibody impregnated shunt
Paclitaxel releasing cardiac stents
Ethylene/ vinyl acetate
Poly[bis(p-carboxyphenoxy propane-sebacic acid) Fatty acid dimmer-sebacic acid Poly(lactide-co-glycolide) Polyethyleneglycol
sulphate-coated microspheres Polydimethyl-siloxane
Yes Yes Yes
Glaucoma Malignant glioma
Ocusert (EVA with Pilocarpine) Gliadel (PCPP-SA with Carmustine)
Risperal Consta (PLG with Risperidone)
Adagen (PEG with adenosine deaminase)
Oncaspar (PEG with L-aspraginase) Arestin (minocycline with microspheres) Rifampin and Clindamycin impregnated shunts
Paclitaxel-Eluting Coronary Stent System
BCNU could persist in the adjacent parenchyma when delivered locally.
The next step was to test the efficacy of BCNU-polymers against a rat intracranial glioma model. Studies by Tamargo et al., consistently showed that local delivery of BCNU by polymer led to significant prolongation of survival in animals with malignant glioma when compared to systemic administration of BCNU or empty polymer . Toxicity studies performed with BCNU-polymers in primates were well tolerated, and concurrent external beam radiotherapy did not result in any additional toxi-cities . With the preclinical studies addressing the biocompatibility, biodistribution, toxicity, and efficacy of BCNU-loaded PCPP:SA polymer in place, translation into the clinical field was the next step.
Surgical Implantation of Gliadel®
Patients undergo a craniotomy for maximum resection of tumor. After removal of the tumor, up to eight discs are applied to the resection cavity surface. Sheets of oxidized regenerated cellulose (Surgicel, Johnson and Johnson, New Brunswick, NJ, USA) are used to secure the polymers against the brain (Fig. 19.4).
Clinical Trials Leading to Approval of Gliadel® by the FDA (Table 19.2)
The first clinical trial assessing the safety of 20:80 PCPP:SA BCNU-loaded polymer was a multicenter
Phase I-II clinical trial in 1987 [63,64]. The study included 21 patients who were presented with recurrent malignant glioma. Enrollment criteria limited patients to those presenting with recurrent malignant gliomas that had previously undergone surgical debulking and in whom standard therapy had failed. Other inclusion criteria included: an indication for re-operation, a unilateral single tumor focus with greater than or equal to 1 cm3 of enhancing volume on MRI or CT, completion of external beam radiotherapy, a Karnofsky Performance Scale (KPS) score greater than or equal to 60, and no exposure to nitrosureas during the 6 weeks prior to polymer implantation. In this study, three different doses of BCNU loaded in PCPP:SA polymer were tested: 1.93, 3.85 and 6.35% w/w. No evidence of systemic toxicity and no signs of neurological deterioration were seen in the treatment arms. The median survival of treated patients was 46 weeks after polymer implantation and 87 weeks after initial diagnosis. This Phase I-II trial demonstrated that implanted BCNU-PCPP:SA polymer was well tolerated by patients.
On the basis of earlier studies, a Phase III multi-centered, prospective, randomized, double-blinded, and placebo controlled clinical trial was initiated . This study investigated the efficacy of 3.8 per cent BCNU-PCPP:SA polymer for the treatment of recurrent gliomas in 222 patients from 27 medical centers in the United States and Canada. The selection criteria were similar to those in the Phase I-II study with the additional provision that chemotherapy was not permitted 4 weeks pre-operatively and use of nitros-ureas were not allowed for 6 weeks prior to polymer
Number of patients
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