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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02490930
Recruitment Status : Completed
First Posted : July 7, 2015
Last Update Posted : September 13, 2017
Sponsor:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information
First Submitted Date  ICMJE July 2, 2015
First Posted Date  ICMJE July 7, 2015
Last Update Posted Date September 13, 2017
Actual Study Start Date  ICMJE July 2015
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 2, 2015)
Incidence of severe infection attributable to fingolimod-induced lymphopenia [ Time Frame: 4 months ]
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)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 2, 2015)
Total lymphocyte counts (TLC) [ Time Frame: 4 months ]
Total lymphocyte counts (TLC) for study participants compared to TLC for historical control
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Safety Study of Fingolimod With Radiation and Temozolomide in Newly Diagnosed High Grade Glioma
Official Title  ICMJE A Safety Study of Fingolimod With Radiation and Temozolomide in Newly Diagnosed High Grade Glioma
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Glioblastoma
  • Anaplastic Astrocytoma
Intervention  ICMJE Drug: Fingolimod
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.
Other Name: Gilenya
Study Arms  ICMJE Experimental: Experimental
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. Fingolimod will be administered at 0.5 mg every day for the first two weeks. Beginning the third week, they will take fingolimod on Monday, Wednesday and Friday until the end of radiotherapy or until the 28th dose, whichever comes first.
Intervention: Drug: Fingolimod
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 2, 2015)
5
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE September 2017
Actual Primary Completion Date September 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02490930
Other Study ID Numbers  ICMJE J14168
IRB00055036 ( Other Identifier: JHMIRB )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study Sponsor  ICMJE Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Stuart Grossman, MD Johns Hopkins University
PRS Account Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP