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Dimethyl Fumarate, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

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ClinicalTrials.gov Identifier: NCT02337426
Recruitment Status : Completed
First Posted : January 13, 2015
Last Update Posted : June 28, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
This phase 1 trial studies the side effects and best dose of dimethyl fumarate when given together with temozolomide and radiation therapy(RT) in treating patients with newly diagnosed glioblastoma multiforme (GBM). Dimethyl fumarate may help radiation therapy work better by making tumor cells more sensitive to the radiation therapy. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving dimethyl fumarate with temozolomide and radiation therapy may work better in treating glioblastoma multiforme.

Condition or disease Intervention/treatment Phase
Adult Brain Glioblastoma Adult Giant Cell Glioblastoma Adult Gliosarcoma Drug: Dimethyl Fumarate Drug: Temozolomide Radiation: Radiation Therapy Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of dimethyl fumarate (DMF) when combined with standard concurrent temozolomide and RT in subjects with newly diagnosed glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

I. To evaluate the safety, tolerance, and toxicity of DMF when combined with standard concurrent temozolomide and RT in subjects with newly diagnosed GBM.

II. To obtain a preliminary estimate of the efficacy of DMF when combined with standard concurrent temozolomide and RT in subjects with newly diagnosed GBM.

OUTLINE: This is a dose-escalation study of dimethyl fumarate.

CONCOMITANT THERAPY: Between 21 days (3 weeks) and 42 days (6 weeks) following the last surgical procedure, patients receive temozolomide orally (PO) once daily (QD) for 42-49 days and dimethyl fumarate PO twice daily (BID) or thrice daily (TID) continuously. Patients also undergo radiation therapy 5 days a week over 6 weeks for a total of 30 fractions.

MAINTENANCE THERAPY: Patients continue to receive dimethyl fumarate PO BID or TID continuously. Four weeks after completing concomitant temozolomide and radiation therapy, patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 2 months thereafter.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Dimethyl Fumarate, Temozolomide, and Radiation Therapy in Glioblastoma Multiforme
Actual Study Start Date : February 13, 2015
Actual Primary Completion Date : November 8, 2016
Actual Study Completion Date : November 9, 2017


Arm Intervention/treatment
Experimental: Treatment (dimethyl fumarate, temozolomide, radiation therapy)

CONCOMITANT THERAPY: Between 21 days (3 weeks) and 42 days (6 weeks) following the last surgical procedure, patients receive temozolomide PO QD for 42-49 days and dimethyl fumarate PO BID or TID continuously. Patients also undergo radiation therapy 5 days a week over 6 weeks for a total of 30 fractions

MAINTENANCE THERAPY: Patients continue to receive dimethyl fumarate PO BID or TID continuously. Four weeks after completing concomitant temozolomide and radiation therapy, patients also receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Drug: Dimethyl Fumarate
Given PO
Other Name: Fumaric Acid, Dimethyl Ester

Drug: Temozolomide
Given PO
Other Name: TMZ

Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • Irradiation
  • RT




Primary Outcome Measures :
  1. RP2D for DMF when combined with concurrent temozolomide and radiotherapy determined by the incidence of dose limiting toxicities (DLTs) graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: Up to 6 weeks ]
    Subjects' treatment dosing level, dose modification, DLTs, and evaluability for DLTs and response will be listed and summarized by basic descriptive statistics (such as frequency and proportion).


Secondary Outcome Measures :
  1. Incidence of adverse events graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of treatment ]
    Subjects' demographics, adverse events, serious adverse events, and treatment status will be listed and summarized by descriptive statistics (such as frequency, proportion, mean, standard deviation, median, and range).

  2. Progression free survival (PFS) [ Time Frame: Time from registration to time of symptomatic and/or radiographic progression or death, whichever occurs first, assessed up to 2 years ]
    The Kaplan-Meier method will be conducted to describe PFS, and median PFS will be estimated, along with 95% confidence intervals. A Cox regression model may be used to model the PFS and adjusting for any effects of potential clinical characteristics.

  3. Overall survival (OS) [ Time Frame: Time from registration until death from any cause, assessed up to 2 years ]
    The Kaplan-Meier method will be conducted to describe OS, and median OS will be estimated, along with 95% confidence intervals. A Cox regression model may be used to model the OS and adjusting for any effects of potential clinical characteristics.

  4. Response rate assessed as per the Response Assessment in Neuro-oncology for magnetic resonance imaging scans or Macdonald criteria for computed tomography scans [ Time Frame: Up to 2 years ]
    The clinical response rate will be calculated for each cohort, along with their corresponding 95% confidence intervals. Logistic regression may be used to model the rate by adjusting potential clinical characteristics (such as age, gender, and tumor grade). Mean and standard deviation of duration of response (overall response, complete response, and stable disease, respectively), along with its 95% confidence interval, will be estimated based on the method proposed by Ellis et al. via the exponential distribution.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histopathologically proven diagnosis of glioblastoma or gliosarcoma (World Health Organization [WHO] grade IV) following either a surgical resection or biopsy
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Subjects must have recovered from surgery or biopsy before study registration
  • Therapy must begin between 21 days (3 weeks) and 42 days (6 weeks) after the most recent brain tumor surgery(resection or biopsy)
  • Documentation of steroid doses 10-14 days prior to study registration and stable or decreasing steroid dose over the week prior to registration
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 100,000/mm^3 (untransfused)
  • Hemoglobin >= 10 g/dL (the use of transfusion or other intervention to achieve hemoglobin >= 10 g/dL is acceptable)
  • Creatinine =< 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance > 45 mL/min
  • Total bilirubin =< 1.5 x ULN for the laboratory (total bilirubin criteria may be waived if a subject has documented Gilbert's syndrome)
  • Aspartate aminotransferase (AST) =< 3 x ULN for the laboratory
  • Alanine aminotransferase (ALT) =< 3 x ULN for the laboratory
  • Women of childbearing potential and male subjects must practice adequate contraception
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Prior invasive malignancy (except for non-melanoma skin cancer) unless disease free for >= 3 years
  • Recurrent malignant gliomas
  • Metastases detected below the tentorium or beyond the cranial vault
  • Prior chemotherapy or radiation therapy (RT) for the diagnosis of GBM or for cancers of the head and neck
  • Clinically significant cardiac disease, including major cardiac dysfunction, such as uncontrolled angina, clinical congestive heart failure with New York Heart Association (NYHA) class III or IV, ventricular arrhythmias requiring anti-arrhythmic therapy
  • Pregnant or lactating women
  • History of allergic reactions or intolerance to any of the required agents on the study
  • History of hypersensitivity to dacarbazine
  • Any treatment for GBM, other than surgery or anti-epileptic therapy, within 30 days prior to study treatment initiation
  • Other condition(s) that in the opinion of the investigator might compromise the objectives of the study or increase patient risk

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02337426


Locations
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United States, Virginia
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Virginia Commonwealth University
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mark G Malkin, MD Massey Cancer Center

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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT02337426     History of Changes
Other Study ID Numbers: MCC-13-09950
NCI-2014-02619 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
HM20003022
MCC-13-09950 ( Other Identifier: Virginia Commonwealth University/Massey Cancer Center )
P30CA016059 ( U.S. NIH Grant/Contract )
First Posted: January 13, 2015    Key Record Dates
Last Update Posted: June 28, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dimethyl Fumarate
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs