A Safety Study of Fingolimod With Radiation and Temozolomide in Newly Diagnosed High Grade Glioma

A recent prospective multicenter study by Dr. Grossman demonstrated that 40% of patients with high grade glioma undergoing radiation and chemotherapy developed severe and persistent lymphopenia (CD4 counts \<200 cells/mm3). This lymphopenia lasted for twelve months following radiation treatment and on multivariate analysis was associated with shorter survival. Our group has data that strongly suggests that this lymphopenia is secondary to the inadvertent radiation of circulating lymphocytes as they pass through the radiation beam. Investigators propose the use of FDA approved for multiple sclerosis, fingolimod to signal lymphocytes to leave the circulation prior to the initiation of radiation. It is a functional antagonist of the sphingosine-1-phosphate receptor (S1PR) pathway and prevents lymphocyte egress from secondary lymphoid organs. Oral fingolimod will be given 1 week prior to the initiation of concurrent radiation and temozolomide and will be discontinued immediately upon completion of the six weeks of therapy. The primary objective is to evaluate if fingolimod can be safely combined with radiation and temozolomide. Secondary endpoint is total lymphocyte counts (TLC) for the proposed study participants. Investigators expect that patients receiving radiation and temozolomide plus fingolimod have a recovery of lymphocyte counts to 80% of baseline within four months, reference to historical control in which sustained lymphopenia lasted for twelve months.

Five evaluable patients with newly diagnosed high grade gliomas who will undergo standard concomitant radiation and temozolomide followed by adjuvant temozolomide will be accrued to this open-label, single arm, safety study. Oral fingolimod will be given 1 week prior to the initiation of concurrent radiation and temozolomide and will be discontinued immediately upon completion of the six weeks of therapy. The primary objective is to evaluate if fingolimod can be safely combined with radiation and temozolomide. This standard chemoradiation causes 40% of patients to develop severe lymphopenia two months after initiation of therapy. Investigators expect that when this is combined with fingolimod, virtually all patients will have severe lymphopenia two months after beginning treatment. Investigators will determine if these patients who routinely receive pneumocystis jiroveci prophylaxis develop other severe opportunistic infections that would prohibit further evaluation of this novel treatment approach. Primary endpoint is incidence of greater than or equal to Grade III infections attributable to fingolimod-induced lymphopenia defined by the NIH/NCI Common Terminology Criteria for Adverse Events (CTCAE) within four months of starting fingolimod. The secondary objective is to obtain preliminary information regarding the ability of fingolimod to reduce radiation-related lymphopenia three months after stopping fingolimod. The NIH funded Adult Brain Tumor Consortium (ABTC) followed total lymphocyte and CD4 counts in 96 patients after treatment with radiation and temozolomide. The severe lymphopenia (CD4 count less than 200/mm3) lasted for twelve months in this historical control. Secondary endpoint is total lymphocyte counts (TLC) for the proposed study participants. These will be compared with patient level data on TLC from an historical cohort obtained from the ABTC. Investigators expect that patients receiving radiation and temozolomide plus fingolimod have a recovery of lymphocyte counts to 80% of baseline within four months, reference to historical control in which sustained lymphopenia lasted for twelve months. Investigators will also obtain laboratory analysis on lymphocyte subtypes and cytokine levels (CD3, CD4, CD8, IL-7, TGF-Beta, etc.). Routine care for high grade gliomas includes weekly Heme-8 and absolute lymphocyte count. Research blood will be obtained at 2 weeks prior to chemoradiation and again at weeks 6, 10, 18, 26 and 46. Patients will be on study for approximately one year.