Clinical Trials /

Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma

NCT00887146

Description:

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 or by stopping them from dividing. It is not yet known whether giving radiation with concomitant and adjuvant temozolomide versus radiation with adjuvant PCV is more effective in treating anaplastic glioma or low grade glioma.

Related Conditions:
  • Glioma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Radiation Therapy With Concomitant and Adjuvant Temozolomide Versus Radiation Therapy With Adjuvant PCV Chemotherapy in Patients With Anaplastic Glioma or Low Grade Glioma
  • Official Title: Phase III Intergroup Study of Radiotherapy With Concomitant and Adjuvant Temozolomide Versus Radiotherapy With Adjuvant PCV Chemotherapy in Patients With 1p/19q Co-deleted Anaplastic Glioma or Low Grade Glioma

Clinical Trial IDs

  • ORG STUDY ID: N0577
  • SECONDARY ID: NCI-2011-01915
  • SECONDARY ID: EORTC-26081-22086
  • SECONDARY ID: EudraCT-2008-007295-14
  • SECONDARY ID: CDR0000640442
  • NCT ID: NCT00887146

Conditions

  • Brain and Central Nervous System Tumors

Interventions

DrugSynonymsArms
concomitant temozolomide (TMZ)Arm B (RT, temozolomide)
procarbazineArm A (RT, procarbazine, lomustine, vincristine)
adjuvant temozolomide (TMZ)Arm B (RT, temozolomide)
CCNUArm A (RT, procarbazine, lomustine, vincristine)
vincristineArm A (RT, procarbazine, lomustine, vincristine)

Purpose

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 or by stopping them from dividing. It is not yet known whether giving radiation with concomitant and adjuvant temozolomide versus radiation with adjuvant PCV is more effective in treating anaplastic glioma or low grade glioma.

Detailed Description

      This study will be a randomized phase III for patients with newly diagnosed co-deleted 1p/19q
      anaplastic glioma or high risk low grade glioma. The trial will only enroll patients with
      1p/19q co-deletion. This study includes two arms as described in the "Arms" section. A
      dynamic allocation procedure will be used to allocate an equal number of patients to
      different arms (Arms A:B = 1:1). This procedure will balance the marginal distributions of
      the stratification factors among arms. The stratification factors that will be used are
      cooperative groups (EORTC vs. all North American groups), age (≤ 50 vs. > 50), performance
      score (ECOG 0-1 vs. 2), and tumor grade (anaplastic glioma vs. low grade glioma).

      The primary goal is to determine whether patients who receive radiotherapy with concomitant
      temozolomide (TMZ) followed by adjuvant temozolomide (RT + TMZ --> TMZ) (Arm B) have a
      marginally better progression free survival (PFS) as compared with patients who receive
      radiotherapy followed by PCV chemotherapy (RT --> PCV)(Arm A).

      Secondary Goals:

        1. Time to Progression - To determine whether patients who receive (RT + TMZ --> TMZ) have
           a significantly longer time to progression (clinical or radiographic progression) as
           compared with patients who receive radiotherapy followed by adjuvant PCV chemotherapy
           (RT --> PCV).

        2. Correlation between exploratory biomarkers and survival - To determine whether there is
           a difference in survival based on t(1;19)(q10, p10) translocation status and MGMT
           promoter hypermethylation status.

        3. Descriptive Comparisons of Additional Secondary Endpoints - To perform descriptive
           comparisons of additional secondary outcome endpoints, including overall survival,
           objective tumor response, prognostic factor analysis and quality of life.

        4. Toxicity - To determine the toxicity of the treatment in each arm and perform
           descriptive comparisons.

        5. Neurocognitive and Quality of Life (QOL) Effects - To determine the neurocognitive and
           QOL effects in patients treated on this protocol and correlate these results with
           outcome endpoints.

        6. Banking of Biospecimens and Neuroimaging Studies - To store blood products (i.e.,
           plasma, DNA and buffy coat), tumor tissue and MRI/CT images for future scientific
           investigations.

      After completion of study treatment, patients are followed every 12 weeks for 1 year, then
      every 4 months for 2 years and then every 6 months until progressive disease or until the end
      of study participation.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (RT, procarbazine, lomustine, vincristine)ExperimentalPatients undergo 3D-CRT or IMRT on days 1-5 for 5-7 weeks. Patients also receive procarbazine hydrochloride PO on days 8-21, lomustine PO on day 1 and vincristine sulfate IV on days 8 and 29 of courses 3-8. Treatment repeats every 6-7 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • procarbazine
  • CCNU
  • vincristine
Arm B (RT, temozolomide)ExperimentalPatients undergo RT as in arm I and receive temozolomide PO QD on days 1-5 for 5-7 weeks. Beginning 4 weeks after completion of concurrent chemoradiotherapy, patients receive adjuvant temozolomide PO QD days 1-5. Treatment with adjuvant temozolomide repeats every 4 weeks for 6-12 courses in the absence of disease progression and unacceptable toxicity.
  • concomitant temozolomide (TMZ)
  • adjuvant temozolomide (TMZ)

Eligibility Criteria

        Pre-Registration Inclusion Criteria:

          -  United States (US) and Canadian sites:

             * This review is mandatory prior to registration to confirm eligibility; patients must
             be willing to submit tissue samples for mandatory central pathology review submission;
             it should be initiated as soon after surgery as possible

          -  Tissue must have been determined to have local 1p/9q co-deletion and IDH mutation
             prior to submission for central path review

               -  Tumor tissue must show co-deletion of chromosomes 1p and 19q; for eligibility,
                  the 1p/19q analysis results will be accepted from the local site, as determined
                  by either a locally available or reference laboratory (for US, must be Clinical
                  Laboratory Improvement Act [CLIA] certified); acceptable methods for
                  determination of 1p/19q loss include fluorescent in-situ hybridization (FISH), by
                  genomic sequencing or methylomic analyses; US and Canadian sites must send a copy
                  of the official report to the pathology coordinator and quality assurance
                  specialist (QAS)

               -  Tumor must also show evidence of IDH mutation by immunohistochemistry or genomic
                  analyses; this should be performed at the local site (US: performed in a CLIA
                  certified laboratory); the site must send a copy of the official report to the
                  pathology coordinator and QAS

        Registration Inclusion Criteria:

          -  Newly diagnosed and =< 3 months from surgical diagnosis; patients are also eligible if
             they have had a prior surgical procedure > 3 months earlier for low grade glioma, as
             long as the patient has not received prior radiation or prior chemotherapy

          -  Histological evidence of World Health Organization (WHO) grade III anaplastic glioma
             or WHO grade II low grade glioma with locally diagnosed combined 1p/19q loss and the
             presence of an either IDH1 or IDH2, both as established by a local or referenced
             laboratory qualified for the study

             * Note: mixed gliomas are eligible, regardless of the degree of astrocytic or
             oligodendrocytic predominance, as long as the tumor is also co-deleted for 1p and 19q

          -  Patients with codeleted low grade gliomas must also be considered "high risk" by
             exhibiting one or more of the following characteristics:

               -  Age >= 40 and any surgical therapy

               -  Age < 40 with prior and subtotal resection or biopsy (i.e., anything less than
                  gross total resection)

               -  Documented growth following prior surgery (NOTE: patients with prior surgery
                  cannot have received prior radiation, chemotherapy or targeted therapy)

               -  Intractable seizures

          -  Surgery (partial or gross total resection or biopsy) must be performed >= 2 weeks
             prior to registration; patient must have recovered adequately from the effects of
             surgery

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 21 days prior to
             registration

          -  Platelet (PLTs) count >= 100,000/mm^3 obtained =< 21 days prior to registration

          -  Hemoglobin (Hgb) > 9.0 g/dL obtained =< 21 days prior to registration

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) obtained =< 21 days
             prior to registration

          -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3
             x ULN obtained =< 21 days prior to registration

          -  Creatinine =< 1.5 x ULN obtained =< 21 days prior to registration

          -  Negative serum or urine pregnancy test done =< 7 days prior to registration, for women
             of childbearing potential only

          -  Willingness and ability to personally complete neurocognitive testing (without
             assistance) and willingness to complete the QOL testing, (either personally or with
             assistance)

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2

          -  Written informed consent

          -  Willingness to return to enrolling institution for follow-up during the active
             monitoring phase (that is, the active treatment and observation portion) of the
             study); patients who have been formally transferred to another active and approved
             site participating in this study would not need to return to the enrolling institution
             for this purpose

          -  Willingness to allow the provision of tissue samples for correlative research, as long
             as adequate tissues are available; patients will not be excluded from participation in
             the study, if they are willing to allow provision of tissues for the correlative
             research, but there are insufficient quantities of tissue for the correlative analyses
             (e.g., a patient otherwise eligible and willing who had biopsy only) Willingness to
             allow the provision of blood samples for correlative research; patients are not
             excluded from participation in the study, if they are willing to provide the mandatory
             biospecimens for translational/correlative research, but for logistical reasons the
             specimens(s) were not obtainable or if the volume collected was insufficient

        Registration Exclusion Criteria:

          -  The following categories are ineligible:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception or contraceptive method during this study and 6 months following
                  the completion of chemotherapy treatments

          -  History of prior radiation therapy or chemotherapy for glioma; note: patients who have
             a history of prior low grade glioma (with or without a distant history of prior
             surgery for that glioma), but who have never received prior chemotherapy or radiation
             therapy for the glioma are eligible for the study

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Concomitant serious immunocompromised status (other than that related to concomitant
             steroids) that would compromise the safety of the patient on the study

          -  Patients known to be human immunodeficiency virus (HIV) positive and currently
             receiving retroviral therapy are not eligible; note: patients known to be HIV
             positive, but without clinical evidence of an immunocompromised state, are eligible
             for the study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Receiving any other investigational agent that would be considered as a treatment for
             the primary neoplasm

          -  Other active malignancy within 5 years of registration; exceptions: non-melanotic skin
             cancer or carcinoma-in-situ of the cervix; note: if there is a history of prior
             malignancy, the patient is not eligible if they are receiving other specific treatment
             (with the exclusion of hormonal therapy or Her-2 inhibitors) for their cancer or if
             they have received prior total body irradiation which included the brain

          -  History of myocardial infarction =< 6 months, or congestive heart failure requiring
             use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

          -  Recent history of hepatitis infection or if the treating physician determined that the
             patient would be at significant risk of reactivation of hepatitis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:Time from study registration to time of tumor progression or death due to any cause, whichever comes first, assessed up to 16 years
Safety Issue:
Description:The distribution of progression free survival for Arms A and B will be estimated using the Kaplan-Meier method. The hazard ratios and median progression free survival (PFS) will be estimated with their confidence intervals. The Cox proportional hazards model will be used to assess whether the distributions of progression survival times differ with respect to treatment regimen having adjusted for all stratification factors (cooperative groups, age, and performance score). Both non-inferiority and superiority will be tested in this trial for the primary goal and no multiple-comparison adjustment will be considered.

Secondary Outcome Measures

Measure:Time to progression
Time Frame:Time from study registration to the earliest evidence of clinical progression, radiographic progression or neurocognitive progression, assessed up to 16 years
Safety Issue:
Description:Estimated by Kaplan-Meier method and analyzed by Cox regression model adjusting all stratification factors. Correlations among baseline neurocognitive test scores and progression free survival will be analyzed using Cox proportional hazards model.
Measure:Time to neurocognitive progression, assessed using the Hopkins Verbal Learning Test-Revised for Free Recall, Delayed Recall, and Delayed Recognition; the Controlled Oral Word Association test; and the Trail Making Test Part A or B
Time Frame:Time from study registration to the first cognitive failure, assessed up to 16 years
Safety Issue:
Description:Estimated by Kaplan-Meier method and analyzed by Cox regression model adjusting all stratification factors. For each test in the battery, a standard error of measurement will be used to derive the Reliable Change Index (RCI) which will be used to represent the 90% confidence interval for the difference in raw scores from baseline to follow-up assessment will be coded as 1 (deterioration), 2 (no change), and 3 (improved) according to the RCI.
Measure:Overall survival
Time Frame:Time from study registration to time of death due to any cause, assessed up to 16 years
Safety Issue:
Description:The Cox proportional hazards model will be used to assess whether the distributions of overall survival times differ with respect to treatment regimen having adjusted for all stratification factors (cooperative groups, age, and Performance Score). The distribution of overall survival for Arm A and B will be estimated using the Kaplan-Meier method. The hazard ratios and median survivals will be estimated with their 95% confidence intervals.
Measure:Objective tumor response defined as a complete response or partial response
Time Frame:Up to 16 years
Safety Issue:
Description:Summarized for each arm and compared between the arms using the Chi square test.
Measure:Treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 16 years
Safety Issue:
Description:The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. In addition, will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. Adverse events and treatment-related adverse events will be evaluated using all patients. Treatment-related adverse events will be tabulated for each arm.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Alliance for Clinical Trials in Oncology

Trial Keywords

  • adult anaplastic astrocytoma
  • adult anaplastic oligodendroglioma
  • adult mixed glioma

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