This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 7/20/2008 The American Cancer Society (ACS) estimated the incidence of primary central nervous system (CNS) tumors in the United States as 18,400 in 2004. Glioblastoma multiforme (GBM) represents approximately 15%-20% of primary brain tumors. With median survival estimated at 12 to 18 months from the time of diagnosis, and recurrence considered nearly inevitable, the prognosis for GBM remains poor. For recurrent GBM, the treatment options are few and limited in effectiveness. Glioblastoma multiforme is one of the most highly vascularized tumors, characterized by abnormal vessel structure and unique vascular endothelial cells. This vascular hyperplasia is believed to be essential to the rapid growth of the tumor and the microenvironment in the tumor can also be abnormal, distinguished by increased interstitial pressures that may interfere with cytotoxic chemotherapy. This abnormal vasculature could also offer an avenue for intervention, however, using agents that selectively disrupt tumor vasculature. Acute vascular disruption could also enhance the value of other cytotoxic chemotherapy agents by reducing interstitial pressures within the tumor. One agent that has shown vascular disrupting activity in animal models and in a human ovarian xenograft model is MPC-6827, a new chemical entity being developed by Myriad Pharmaceuticals, Inc for the treatment of cancers that have progressed despite best standard treatment and/or which have metastasized to the central nervous system. MPC-6827 binds to the same or nearby site on ? tubulin as colchicine and paclitaxel, and inhibits microtubule assembly in a manner that is similar to that of colchicine and the vinca alkaloid drugs. Vascular disrupting agents have been established to reduce interstitial pressure in the tumor microenvironment which may increase local exposure to cytotoxic chemotherapy. Consistent with this hypothesis, MPC-6827 has shown synergistic action in combination with carboplatin in a mouse xenograft model. In mechanism of action studies, MPC-6827 bound tubulin and inhibited microtubule assembly, interfered with cell cycle G2/M phase transition and induced mitotic arrest. MPC-6827 displayed proapoptotic activity in multiple cancer cell lines and was equally cytotoxic in nondrug resistant tumor cells lines and in multidrug resistant tumor cell lines. The observation that MPC-6827 crosses the blood brain barrier (BBB) suggests the promising application of this agent in treating primary brain tumors and solid tumors, commonly metastatic to the brain, including lung cancer, breast cancer, colon cancer, and melanoma. Because of the promising antitumor activity against drug sensitive and multidrug resistant tumor cell lines, and the activity in many xenograft models, MPC-6827 is hypothesized to possess antitumor activity which complements the activity of other chemotherapeutic agents. This is an open-label, dose finding, multiple-dose study in subjects with recurring/relapsing glioblastoma multiforme. Dose levels of MPC-6827 of 2.1, 2.7 and 3.3 mg/m2 will be administered with Carboplatin to three separate cohorts, respectively. Study endpoints will include the determination of the maximum tolerated dose of MPC-6827 when given with Carboplatin, determination of dose limiting toxicities with combination therapy at MPC-6827 doses up to 3.3 mg/m2, and the evaluation of evidence of anti-tumor activity of the combination therapy in the treatment of recurrent/relapsed glioblastoma multiforme. This is an open-label, nonrandomized, dose escalation, dose finding study;therefore the statistical hypothesis testing will not be performed and analyses will be descriptive only. The sample size of 3-30 subjects is based on the need to establish the maximum tolerated dose (MTD). The evaluation of MTD will be based on data from subjects who receive at least one IV infusion of MPC-6827 and whose data are interpretable in the context of MPC-6827 specific toxicity. All subjects who receive any amount of study drug will be included in the evaluation of safety. This dose finding study is not intended to satisfy requirements in determining efficacy of MPC-6827 for the treatment of glioblastoma multiforme (GBM). No efficacy analyses are planned;however, we will be looking for any evidence of anti-tumor activity with the combination therapy. Hypotheses/Objectives : The primary objective of this dose finding study is to define the safety and tolerability (Maximum Tolerated Dose [MTD]) of MPC-6827 when administered in combination with Carboplatin in subjects with recurrent/relapsed glioblastoma multiforme. The primary hypothesis is that safety and tolerability parameters will be isolated in the instant study. The secondary objectives are: o To characterize the pharmacokinetics (PK) of MPC-6827 and Carboplatin when sequentially administered, each as a 1-hour intravenous (IV) infusion. o To observe for evidence of antitumor activity of the combination therapy in the treatment of recurrent/relapsed glioblastoma multiforme. It is hypothesized that MPC-6827 will demonstrate antitumor activity and will potentiate the cytotoxic effects of Carboplatin on recurrent GBM tumors.
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