The overall objective of this U01 application is to provide support for a Pharmacokinetics (PK) Center for the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. The PK Center will consist of a single site, namely, the Clinical Pharmacology Laboratory of the Massachusetts General Hospital Cancer Center. All of the physical facilities, instrumentation and staff that comprise the laboratory will be made fully available to the design and performance of PK studies during phase I and II clinical trials undertaken by the NABTT CNS Consortium.
The specific aims of the PK Center are: (1) to design PK studies for clinical trials of cancer chemotherapeutic agents in adult patients with brain cancer; (2) to establish and validate analytical methods for measuring the concentration of cancer chemotherapeutic agents and/or their metabolites in biological fluids and apply them to the analysis of PK study samples; and (3) to perform all appropriate analyses of the PK data. PK studies have assumed considerable importance in the early clinical evaluation of anticancer drugs in patients with brain tumors. The major objectives of the PK studies defined in clinical trial protocols undertaken by the Consortium typically involve: (1) determining whether supporting medications that are used extensively in this patient population, such as anticonvulsant drugs and corticosteroids, have a clinically significant affect on the PK behavior of anticancer drugs; and (2) identifying relationships between PK parameters, patient characteristics, and clinical effect data (toxicity and therapeutic response). In addition, with the emergence of relatively nontoxic, cytostatic therapies for cancer, the traditional toxicologic endpoint for phase I clinical trials may not be applicable, in which case some measure of systemic exposure to the drug may be employed as an endpoint for terminating dose escalation. The PK Center will also assume overall responsibility for the logistics and management of the PK samples obtained from clinical trials performed by the NABTT Consortium. As permitted by the accomplishment of PK projects that are directly linked to clinical trial protocols, ancillary laboratory studies may be undertaken to address pharmacologic questions that become evident during the course of clinical trials. The ultimate goal of the PK Center is to facilitate the acquisition of informative PK data, that has a direct relevance to the clinical evaluation of new chemotherapeutic agents for the treatment of brain cancer, and make the data available to clinical investigators in a timely manner.
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