Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Dose-Escalated Photon IMRT or Proton Beam Radiation Therapy Versus Standard-Dose Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by NRG Oncology
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
Information provided by (Responsible Party):
NRG Oncology
ClinicalTrials.gov Identifier:
NCT02179086
First received: June 27, 2014
Last updated: August 17, 2016
Last verified: August 2016
  Purpose
This randomized phase II trial studies how well dose-escalated photon intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy works compared with standard-dose radiation therapy when given with temozolomide in patients with newly diagnosed glioblastoma. Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells and shrink tumors. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as temozolomide, may make tumor cells more sensitive to radiation therapy. It is not yet known whether dose-escalated photon IMRT or proton beam radiation therapy is more effective than standard-dose radiation therapy with temozolomide in treating glioblastoma.

Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Radiation: 3-dimensional conformal radiation therapy
Radiation: intensity-modulated radiation therapy
Radiation: photon beam radiation therapy
Radiation: proton beam radiation therapy
Drug: temozolomide
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation With Concomitant and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma

Resource links provided by NLM:


Further study details as provided by NRG Oncology:

Primary Outcome Measures:
  • Overall survival (OS) compared between dose-escalated and -intensified photon IMRT or proton beam therapy with concomitant and adjuvant temozolomide and the standard-dose photon irradiation with concomitant and adjuvant temozolomide [ Time Frame: Date of randomization to the date of death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    OS rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in a stratified log-rank test, consistent with the stratified randomization. The OS rates by MGMT, recursive partitioning analysis (RPA) class and other prognostic factors will be estimated by Kaplan-Meier methods and compared using the log-rank test. Multivariate analyses with the Cox proportional hazard model for OS will be performed to assess the treatment effect adjusting for patient-specific risk factors.


Secondary Outcome Measures:
  • OS when compared between dose-escalated and -intensified photon IMRT to dose-escalated and -intensified proton beam therapy [ Time Frame: Date of randomization to the date of death, assessed up to 5 years ] [ Designated as safety issue: No ]
    If the instrumental variable assumptions hold, OS rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in the log-rank test.

  • Progression-free survival (PFS) [ Time Frame: Date of randomization to the date of progression or death, assessed up to 5 years ] [ Designated as safety issue: No ]
    PFS rates will be estimated using the Kaplan-Meier method and comparisons between treatment arms will be made in the same manner as for OS.

  • Incidence of treatment-related toxicity, as measured by the Common Terminology Criteria for Adverse Events version 4 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Differences in observed severities of toxicities (grade 3+) between groups will be estimated using an exact binomial distribution together with 95% confidence interval. The difference between the 2 groups will be tested using a chi square test. If the instrumental variable assumptions hold the experimental arms will also be compared.

  • Change in perceived cognitive function, as measured by M.D. Anderson Symptom Inventory Brain Tumor [ Time Frame: Baseline to up to 60 weeks ] [ Designated as safety issue: No ]
    The change from baseline to each follow-up time point for the perceived cognitive symptom severity score will each be compared using a t-test with alpha=0.05, or Wilcoxon test if the data is not normally distributed, between treatment arms within each group. If the instrumental variable assumptions hold and the perceived cognitive function is significantly different within both groups, a test will be performed to compare between the 2 experimental arms.

  • Change in neurocognitive function, as measured by Hopkins' Verbal Learning Test-Revised, Trail Making Test Parts A and B, and Controlled Oral Word Association Test [ Time Frame: Baseline to up to 60 weeks ] [ Designated as safety issue: No ]
    The change from baseline to each follow-up time point for the perceived Clinical Trial Battery (CTB) composite score will each be compared using a t-test with alpha=0.05, or Wilcoxon test if the data is not normally distributed, between treatment arms within each group. If the instrumental variable assumptions hold and the CTB composite score is significantly different within both groups, a test will be performed to compare between the 2 experimental arms.

  • Change in CD4 lymphopenia count [ Time Frame: Baseline to up to 5 years ] [ Designated as safety issue: No ]
    The change from baseline to the completion of radiation will be compared between the control and experimental arms in each group using a t-test. If the instrumental variable assumptions hold, then it will be compared between the experimental arms. A repeated measures analysis, using a mixed effects model, will be used to assess the change of CD4 lymphopenia across time. CD4 count at 2 months after beginning therapy (dichotomized at 200) was shown to be prognostic of OS. This will be assessed here based on the CD4 count at the completion of chemoradiation which matches best to 2-months.

  • Use of magnetic resonance diffusion and perfusion imaging to differentiate between tumor progression and pseudo-progression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Retrospective analysis will be performed to evaluate and refine the method and the threshold cut-off point determined from our previous single institute data set to determine progression using the first one-third of the patient data collected in this trial. If the initial analysis supports our preliminary results with sufficient high sensitivity and specificity, e.g., 80% specificity and 90% sensitivity or higher, results will be validated using the remaining two-thirds of the imaging data.


Estimated Enrollment: 576
Study Start Date: November 2014
Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A1 (control)

Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT QD, 5 days a week for 23 fractions plus a boost of 7 additional fractions.

In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Radiation: 3-dimensional conformal radiation therapy
Undergo standard-dose 3D-CRT
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: intensity-modulated radiation therapy
Undergo standard-dose IMRT
Other Name: IMRT
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (photon IMRT)

Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions.

In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Radiation: photon beam radiation therapy
Undergo dose-escalated and -intensified photon IMRT
Radiation: intensity-modulated radiation therapy
Undergo dose-escalated and -intensified photon IMRT
Other Name: IMRT
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: laboratory biomarker analysis
Correlative studies
Active Comparator: Arm A2 (control)

Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1.

In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Radiation: 3-dimensional conformal radiation therapy
Undergo standard-dose 3D-CRT
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: intensity-modulated radiation therapy
Undergo standard-dose IMRT
Other Name: IMRT
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm C (proton beam radiation therapy)

Patients undergo dose-escalated and -intensified proton beam therapy QD, 5 days a week for a total of 30 fractions.

In all treatment arms, patients receive temozolomide PO QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Radiation: proton beam radiation therapy
Undergo dose-escalated and -intensified proton beam radiation therapy
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: laboratory biomarker analysis
Correlative studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRIOR TO STEP 1 REGISTRATION
  • A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial
  • The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)
  • Patients must provide study-specific informed consent prior to step 1 registration
  • PRIOR TO STEP 2 REGISTRATION
  • Histologically proven diagnosis of glioblastoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration
  • Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient quantity for analysis of O6-methylguanin-DNA-methyltransferase (MGMT) status

    • Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present
    • Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed
  • History/physical examination within 14 days prior to step 2 registration
  • The patient must have recovered from effects of surgery, postoperative infection, and other complications within 14 days prior to step 2 registration
  • Documentation of steroid doses within 14 days prior to step 2 registration
  • Karnofsky performance status >= 70 within 14 days prior to step 2 registration
  • Age >= 18
  • Absolute neutrophil count (ANC) >= 1,800 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin >= 10.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin (Hgb) >= 10.0 g/dl is acceptable)
  • Bilirubin =< 1.5 upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
  • CD4 lymphocyte count within 14 days prior to step 2 registration
  • Negative serum pregnancy test obtained for females of child-bearing potential within 14 days prior to step 2 registration

Exclusion Criteria:

  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease-free for a minimum of 3 years; (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
  • Recurrent or multifocal malignant gliomas
  • Any site of distant disease (for example, drop metastases from the GBM tumor site)
  • Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide)
  • Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted
  • Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields
  • Severe, active co-morbidity, defined as follows:

    • Unstable angina at step 2 registration
    • Transmural myocardial infarction within the last 6 months prior to step 2 registration
    • Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 14 days prior to step 2 registration
    • New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration
    • Serious and inadequately controlled arrhythmia at step 2 registration
    • Serious or non-healing wound, ulcer or bone fracture or history of abdominal fistula, intra-abdominal abscess requiring major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for surgical resection
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for coagulation parameters are not required for entry into this protocol
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration
    • Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol
    • Any other severe immunocompromised condition
    • Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
    • End-stage renal disease (ie, on dialysis or dialysis has been recommended)
    • Any other major medical illnesses or psychiatric treatments that in the investigator's opinion will prevent administration or completion of protocol therapy
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
  • Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration
  • Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02179086

  Show 176 Study Locations
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Radiation Therapy Oncology Group
Investigators
Principal Investigator: Minesh Mehta NRG Oncology
  More Information

Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT02179086     History of Changes
Obsolete Identifiers: NCT02163135
Other Study ID Numbers: NRG-BN001  NCI-2014-01072  NRG-BN001  NRG-BN001  U10CA180868 
Study First Received: June 27, 2014
Last Updated: August 17, 2016
Health Authority: United States: Food and Drug Administration

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
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 23, 2016