A Safety Study of Fingolimod With Radiation and Temozolomide in Newly Diagnosed High Grade Glioma
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.
Inclusion Criteria:

 -  Gender: Male and Female

 -  Age: Patients must be at least 18 years of age.

 -  Race: Minorities will be recruited. No exclusion to this study will be based on race.

 -  Patients must have histologically confirmed high grade astrocytoma, WHO grade III or
 IV, by pathology.

 -  Patients' proposed post-operative treatment plan must include standard focal brain
 irradiation and temozolomide.

 -  Patients must have a Karnofsky Performance Status > 60 % (i.e. the patient must be
 able to care for himself/herself with occasional help from others).

 -  Patients must have normal bone marrow function, with a baseline total lymphocyte count
 > 1000.

 -  Patients must be able to provide informed consent.

 -  Glucocorticoid use is allowed.

 -  Women of childbearing potential should use effective contraception during and for two
 months after stopping fingolimod.

 Exclusion Criteria:

 -  Patients must not have received prior radiation therapy, chemotherapy, immunotherapy,
 therapy with biologic agents or hormonal therapy for their brain tumor.

 -  Patients must not have recent (within six months) occurrence of myocardial infarction,
 unstable angina, stroke, transient ischemic attack, decompensated heart failure
 requiring hospitalization, or Class III/IV heart failure.

 -  Patients must not have history of or presence of Mobitz Type II 2nd degree or 3rd
 degree atrioventricular block or sick sinus syndrome, unless patient has a pacemaker.

 -  Patients must not have baseline QTc interval > 500 ms.

 -  Patients must not be on treatment with Class Ia or Class III antiarrhythmic drugs.

 -  Patients must not have a history of macular edema, uveitis or diabetes mellitus.

 -  Patients must not have elevated liver transaminase levels. Adequate liver function is
 defined as total bilirubin < 1.5 times upper limit of normal, SGPT (ALT) < 5 times
 upper limit of normal and serum albumin > 2 g/dL.

 -  Patients must not have an active infection.

 -  Patients with known HIV will be excluded.

 -  Patients with collagen vascular disease are excluded.

 -  Patients taking immunosuppressive medications (other than dexamethasone) will be
 excluded.