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. ABSTRACT: This is a multicenter, Phase I trial to estimate the maximum tolerated dose and describe dose limiting toxicities of enzastaurin(LY317615) administered orally for 28 consecutive days to children and adolescents with refractory primary CNS tumors. Pharmacokinetic, imaging and biology correlative studies will be performed in all consenting patients. HYPOTHESIS: Enzastaurin will have anti-tumor activity in children and adolescents with refractory primary CNS tumors.
SPECIFIC AIMS Primary Objectives: 1. To estimate the maximum tolerated dose (MTD) and/or recommend a Phase II dose of enzastaurin administered as a once daily oral dose to children with recurrent or refractory CNS tumors who are not receiving enzyme-inducing anticonvulsants. Secondary Objectives: 1. To characterize the pharmacokinetics of enzastaurin in children when administered on this schedule. 2. To document and describe toxicities associated with enzastaurin administered on this schedule. 3. To document antitumor activity in children with recurrent or refractory CNS tumors that may be apparent in a phase I, dose escalation trial of enzastaurin. 4. To explore changes in MR perfusion and diffusion scans obtained within 15 ?? 2 days after initiation of enzastaurin therapy as compared to baseline and to correlate these changes with clinical outcome, as applicable. 4.1. Results of imaging studies will be also be combined across similar PBTC protocols to increase the power for detecting correlations among scans and with outcome. 5. To evaluate a panel of biological surrogate markers in this patient population at baseline and following enzastaurin administration. BACKGROUND AND SIGNIFICANCE:Central nervous system tumors (CNS) are the most common solid malignancy of childhood and the second most common pediatric cancer. There are approximately 2000 new childhood brain tumors diagnosed each year. There have been modest improvements in the treatment of childhood CNS tumors over the past several decades using multi-modality therapy including surgery, radiation and chemotherapy. Nevertheless, deaths caused by CNS tumors are the highest among pediatric cancers. In addition, the morbidity associated with CNS tumors and currently available therapeutic strategies may be profound with regard to physical deficits as well as neuro-psychological and neuroendocrine sequelae. Thus, new agents and treatment strategies are needed for the effective treatment of these challenging malignancies. Neovascularization is important for tumor growth and metastases and therefore chemotherapeutic agents that inhibit angiogenesis pathways are an important emerging class of agents that warrant further study and characterization in pediatric patients with malignancies. Studies of the role of angiogenesis in CNS tumors from both children and adults have shown that there is marked angiogenic activity in astrocytic as well as embryonal tumors. In some studies, the degree of angiogenesis inversely correlates with patient survival, particularly for patients with high-grade tumors. In addition, preliminary studies evaluating VEGF concentrations in the cerebrospinal fluid of patients with leptomeningeal metastasis reveal that CSF VEGF levels mirror the patient's clinical course with a marked reduction in response to therapy and an increase at relapse. This suggests that markers of angiogenesis may serve as predictors of response to therapy and outcome. Preclinical Studies: Antitumor Activity: The mechanisms involved in tumor-induced angiogenesis are complex and involve paracrine stimuli, such as vascular endothelial growth factor(VEGF), basic fibroblast growth factor (bFGF), and a variety of other cytokines. VEGF is one of the most common angiogenic factors found in tumor-induced angiogenesis. The expression of VEGF correlates with microvessel density and appears to be predictive of adverse outcome in many solid tumors, including CNS tumors. Enzastaurin, an acyclic bisindolymaleimide that is a potent selective inhibitor of protein kinase C beta &(PKCIC50 ~ 6 uM, is a novel anti-angiogenic agent that inhibits VEGF-induced angiogenesis. The Protein Kinase C (PKC) family of enzymes is serine/threonine kinases essential to the cell signal cascades effecting cellular growth, proliferation, and apoptosis. Preclinical studies of enzastaurin have demonstrated anti-angiogenic activity in endothelial cell lines, as well as in an in vivo rat model of VEGFinduced neoangiogenesis. The antitumor activity of the parent drug, enzastaurin, has been shown in xenografts from U87MG human glioblastoma cells and a variety of other solid tumors. Twice daily oral dosing of enzastaurin at 75 mg/kg significantly suppressed tumor growth at clinically achievable exposures for the parent drug. Enzastaurin and its metabolites 326020 and 485912 prevent substrate phosphorylation by competing with the enzyme?'s ATP binding site for PKC beta. Additionally these compounds, particularly 326020, act to inhibit signaling through the PI3 kinase/Akt signaling pathway. These signaling pathways promote tumor-induced angiogenesis, as well as tumor survival and proliferation. Accordingly, inhibition of the PKC and Akt signaling pathways by enzastaurin suppressed the phosphorylation of glycogen synthase kinase 3 beta, induced apoptosis and suppressed proliferation in cultured cell lines from a variety of human cancers, including gliomas. LY326020 can act as an ATP-competitive inhibitor of phophatidylinositol-dependent kinase 1 (PDK1) and p70S6. The in vitro IC50s for PK beta inhibition are approximately 5 nM. Inhibition of PKC alpha is 3- to 8-fold less potent and 10- to 20-fold less potent for PKC gamma and PKC epsilon. Animal Toxicology Chronic dosing of enzastaurin was well tolerated in rats and dogs. Enzastaurin produced an increase in hexobarbital-induced sleep time at higher doses (30 mg/kg). There were no changes in cardiovascular or respiratory function. Both enzastaurin and its metabolite produce a dose related blockade of the IKr ion channel. Minor prolongation of the QT interval was seen in dogs in one study but was not replicated in a 6-month study in dogs. Other noted events in toxicology studies were testicular atrophy, ocular cataracts and hepatobiliary toxicity, which reversed following dose reduction. Preclinical Pharmacology: Plasma pharmacokinetics in animals demonstrate reasonable oral absorption (Tmax 3-4 hours)and bioavailability. The metabolite LSN326020 appears to have a greater half-life and accumulates with daily oral dosing. Drug was widely distributed with moderate concentrations in most tissues, low to moderate concentration in the CSF and low concentration in the brain. Plasma protein binding is 97%. Data from human hepatic microsomal studies suggest inhibition of CYP3A4 and CYP2C9. Excretion is primarily through the feces and bile.
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