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

NCT02490930 | Completed Early Phase 1 DMC

• 2 other identifiers: J14168IRB00055036
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Glioblastoma; Anaplastic Astrocytoma

Keywords

lymphopenia

Outcome Measures

Primary Outcomes (1)

• Incidence of severe infection attributable to fingolimod-induced lymphopenia

  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)

  4 months

Secondary Outcomes (1)

• Total lymphocyte counts (TLC)

  4 months

Study Arms (1)

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.

Drug: Fingolimod

Interventions

Fingolimod DRUG

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.

Also known as: Gilenya

Experimental

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Gender: Male and Female
• Age: Patients must be at least 18 years of age.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead

Study Sites (1)

The Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Glioblastoma; Astrocytoma; Lymphopenia

Interventions

Fingolimod Hydrochloride

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Sphingosine; Amino Alcohols; Alcohols; Organic Chemicals; Propylene Glycols; Glycols; Amines

Study Officials

• Stuart Grossman, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2015
• First Posted: July 7, 2015
• Study Start: July 1, 2015
• Primary Completion: September 1, 2017
• Study Completion: September 1, 2017
• Last Updated: September 13, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)