Clinical Trials /

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

NCT02179086

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NRG-BN001
  • SECONDARY ID: NCI-2014-01072
  • SECONDARY ID: NRG-BN001
  • SECONDARY ID: NRG-BN001
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT02179086
  • NCT ALIAS: NCT02163135

Conditions

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma

Interventions

DrugSynonymsArms
temozolomideSCH 52365, Temodal, Temodar, TMZArm A1 (control)

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using
      a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and
      adjuvant temozolomide improves overall survival, as compared to standard-dose photon
      irradiation with concomitant and adjuvant temozolomide.

      SECONDARY OBJECTIVES:

      I. To indirectly compare dose-escalated and -intensified photon IMRT to dose-escalated and
      -intensified proton beam therapy in terms of overall survival.

      II. To indirectly compare and record toxicities of dose-escalated and -intensified photon
      IMRT versus dose-escalated and -intensified proton beam therapy and directly compare the
      toxicities of these approaches versus standard-dose photon irradiation on the backbone of
      concomitant and adjuvant temozolomide.

      III. To indirectly determine if dose-escalated and -intensified proton beam therapy with
      concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as
      compared to dose-escalated and -intensified photon IMRT, and to directly compare symptom
      burden with these approaches versus standard-dose photon irradiation on the backbone of
      concomitant and adjuvant temozolomide.

      IV. To indirectly determine if dose-escalated and -intensified proton beam therapy with
      concomitant and adjuvant temozolomide improves neurocognitive function, as compared to
      dose-escalated and -intensified photon IMRT, and to directly compare neurocognitive function
      with these approaches versus standard-dose photon irradiation on the backbone of concomitant
      and adjuvant temozolomide.

      TERTIARY OBJECTIVES:

      I. Tissue banking for future translational science projects that will be determined based on
      the state of the science at the time the primary endpoint is reported and will be submitted
      to National Cancer Institute (NCI) for review and approval.

      II. To prospectively compare cluster of differentiation (CD)4 lymphopenia between
      dose-escalated and intensified proton beam therapy, dose-escalated and -intensified photon
      IMRT, and standard-dose photon irradiation.

      III. To explore the most appropriate and clinically relevant technological parameters to
      ensure quality and effectiveness throughout radiation therapy processes, including imaging,
      simulation, patient immobilization, target and critical structure definition, treatment
      planning, image guidance and delivery.

        -  To establish feasibility and clinical relevancy of quality assurance guidelines.

        -  To evaluate efficacy of quality assurance tools.

      OUTLINE: Patients are assigned to 1 of 2 groups depending on enrolling institution. Within
      each group, patients will be randomized 1:2 in favor of the experimental arms.

      GROUP I (PHOTON IMRT CENTERS): Patients are randomized to 1 of 2 treatment arms.

      ARM A1: Patients undergo standard-dose photon irradiation using 3-dimensional conformal
      radiation therapy (3D-CRT) or IMRT once daily (QD), 5 days a week for 23 fractions plus a
      boost of 7 additional fractions.

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

      GROUP II (PROTON CENTERS): Patients are randomized to 1 of 2 treatment arms.

      ARM A2: Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1.

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

      In all treatment arms, patients receive temozolomide orally (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.

      After completion of study treatment, patients are followed up every 3 months for 1 year,
      every 4 months for 1 year, and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A1 (control)Active ComparatorPatients 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.
  • temozolomide
Arm B (photon IMRT)ExperimentalPatients 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.
  • temozolomide
Arm A2 (control)Active ComparatorPatients 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.
  • temozolomide
Arm C (proton beam radiation therapy)ExperimentalPatients 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.
  • temozolomide

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:Date of randomization to the date of progression or death, assessed up to 5 years
Safety Issue:
Description: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.
Measure:Incidence of treatment-related toxicity, as measured by the Common Terminology Criteria for Adverse Events version 4
Time Frame:Up to 5 years
Safety Issue:
Description: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.
Measure:Change in perceived cognitive function, as measured by M.D. Anderson Symptom Inventory Brain Tumor
Time Frame:Baseline to up to 60 weeks
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Change in CD4 lymphopenia count
Time Frame:Baseline to up to 5 years
Safety Issue:
Description: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.
Measure:Use of magnetic resonance diffusion and perfusion imaging to differentiate between tumor progression and pseudo-progression
Time Frame:Up to 5 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NRG Oncology

Last Updated

August 17, 2016