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

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ClinicalTrials.gov Identifier: NCT02227901
Recruitment Status : Completed
First Posted : August 28, 2014
Last Update Posted : December 23, 2014
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of tipifarnib when given together with radiation therapy and temozolomide in treating patients with newly diagnosed glioblastoma multiforme. Tipifarnib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x rays to kill tumor cells. 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. Giving tipifarnib together with radiation therapy and temozolomide may be a better way to treat glioblastoma multiforme.

Condition or disease Intervention/treatment Phase
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Drug: Tipifarnib Radiation: External Beam Radiation Therapy Drug: Temozolomide Other: Laboratory Biomarker Analysis Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. Establish maximum tolerated dose (MTD) for tipifarnib (R115777) in combination with temozolomide with radiation in patients not on enzyme-inducing anti-epileptic drugs (EIAEDs).

II. To define the safety of R115777 in combination with temozolomide with radiation in this patient population.

III. To assess for evidence of antitumor activity in this patient population.

OUTLINE: This is a dose-escalation study of tipifarnib.

TIPIFARNIB: Patients receive tipifarnib orally (PO) twice daily (BID) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

CONCURRENT CHEMOTHERAPY DURING RADIATION THERAPY: Within 5-9 days after starting tipifarnib, patients undergo external beam radiation therapy (EBRT) daily and receive temozolomide PO daily for 6 weeks.

POST-RADIATION CHEMOTHERAPY: Beginning at week 10 post-radiation therapy, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for 1 year or 12 complete courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of R115777 With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme
Study Start Date : September 2002
Actual Primary Completion Date : June 2007
Actual Study Completion Date : April 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (tipifarnib, EBRT, temozolomide)

TIPIFARNIB: Patients receive tipifarnib PO BID on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

CONCURRENT CHEMOTHERAPY DURING RADIATION THERAPY: Within 5-9 days after starting tipifarnib, patients undergo EBRT daily and receive temozolomide PO daily for 6 weeks.

POST-RADIATION CHEMOTHERAPY: Beginning at week 10 post-radiation therapy, patients receive temozolomide PO on days 1-5. Treatment repeats every 28 days for 1 year or 12 complete courses in the absence of disease progression or unacceptable toxicity.

Drug: Tipifarnib
Given PO
Other Names:
  • R115777
  • Zarnestra

Radiation: External Beam Radiation Therapy
Undergo EBRT
Other Names:
  • Definitive Radiation Therapy
  • EBRT
  • External Beam RT

Drug: Temozolomide
Given PO
Other Name: TMZ

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) of tipifarnib, graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 [ Time Frame: At week 10 ]
    Safety variables will be summarized by descriptive statistics.

  2. MTD of tipifarnib, defined as the dose level at which 0 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to week 10 ]
    Safety variables will be summarized by descriptive statistics.


Secondary Outcome Measures :
  1. Incidence of adverse events of tipifarnib in combination with EBRT and temozolomide, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 5 years ]
    Safety variables will be summarized by descriptive statistics. Adverse events that occur will be reported for each dose level and described in terms of incidence and severity. Parameters will be described based on the CTCAE severity grading. Distribution by CTCAE severity grade (when applicable) and clinical relevance will be given.

  2. Anti-tumor activity of tipifarnib [ Time Frame: Up to 5 years ]
    A descriptive analysis of evidence of antitumor activity will be provided based on clinical, radiographic, and biologic assessments of efficacy.



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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:

  • Patients will have histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS)
  • Diagnosis will have been established by biopsy or resection within 4 weeks prior to registration
  • Patients must not have received previous radiotherapy to the brain
  • Patients must not have received cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy directed against the brain tumor; patients who received Gliadel wafers will be excluded; patients may have received or be receiving corticosteroids, non-EIAEDs, analgesics, and other drugs to treat symptoms or prevent complications
  • Cranial magnetic resonance imaging (MRI) or contrast computed tomography (CT) must have been performed within 21days of study entry; the use of MRI rather than CT is preferred; the same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement; if the surgical procedure was a resection, cranial MRI or contrast CT performed with 96 hours of resection is preferred but not required; patients without measurable or assessable disease are eligible
  • Patients must have a plan to begin partial brain radiotherapy within 5-9 days after beginning R115777, and within 35 days (5 weeks) of the surgical procedure that established the diagnosis; radiotherapy must be given at the Radiation Oncology Department of the registering Adult Brain Tumor Consortium (ABTC) institution; radiotherapy must be given by external beam to a partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to the tumor of 60.0 Gy; stereotactic radiosurgery and brachytherapy will not be allowed
  • Patients must be willing to forego other drug therapy against the tumor while being treated with R115777 and temozolomide
  • All patients must sign an informed consent indicating that they are aware of the investigational nature of this study; patients must sign an authorization for the release of their protected health information; patients must be registered with the Adult Brain Tumor Consortium Central Office (ABTC CO) prior to treatment with study drug
  • A life expectancy > 8 weeks
  • Patients must have a Karnofsky performance status of >= 60
  • White blood cells (WBC) >= 3,000/ul
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count of >= 100,000/mm^3
  • Hemoglobin >= 10 gm/dl
  • Bone marrow function tests must be performed within 14 days prior to registration
  • Eligibility level for hemoglobin may be reached by transfusion
  • Serum glutamic oxaloacetic transaminase (SGOT) < 2 times upper limit of normal (ULN) and the test must be performed within 14 days prior to registration; if above the institutional upper limit of normal but < 2 times institutional upper limit of normal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient
  • Bilirubin < 2 times ULN and the test must be performed within 14 days prior to registration; if above the institutional upper limit of normal but < 2 times institutional upper limit of normal, the decision to initiate temozolomide treatment should carefully consider the benefits and risks for the individual patient
  • Creatinine < 1.5 mg/dL before starting therapy and the test must be performed within 14 days prior to registration
  • Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy; patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism
  • Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible
  • No exclusion to this study will be based on race; minorities will actively be recruited to participate
  • Patients must not have active infection
  • Women must not be pregnant or breast-feeding, and women with reproductive potential must practice adequate contraception
  • Patients must not be on chronic Coumadin therapy for prior medical problems (e.g. cardiac valve prophylaxis); this is due to a presumed interaction with Coumadin and ZARNESTRA leading to a significant increase in international normalized ratio (INR); patients who develop or have recently developed a deep venous thrombosis or pulmonary embolism who are on or will take Coumadin will be allowed to participate; however, the investigator should be prepared to monitor patients INR closely

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): NCT02227901


Locations
United States, California
Ronald Reagan UCLA Medical Center
Los Angeles, California, United States, 90095
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Timothy Cloughesy National Cancer Institute (NCI)

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02227901     History of Changes
Other Study ID Numbers: NCI-2014-01809
NCI-2014-01809 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI-03-C-0189
NABTC-0202
NABTC02-02 ( Other Identifier: Adult Brain Tumor Consortium )
NABTC-02-02 ( Other Identifier: CTEP )
U01CA062399 ( U.S. NIH Grant/Contract )
First Posted: August 28, 2014    Key Record Dates
Last Update Posted: December 23, 2014
Last Verified: September 2014

Additional relevant MeSH terms:
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
Dacarbazine
Tipifarnib
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents