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

• ClinicalTrials.gov Identifier: NCT00887146
• Recruitment Status: Recruiting
• First Posted: April 23, 2009
• Last Update Posted: April 9, 2024
• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); European Organisation for Research and Treatment Center (EORTC); Canadian Cancer Trials Group
• Information provided by (Responsible Party): Alliance for Clinical Trials in Oncology

Tracking Information

• First Submitted Date: April 22, 2009
• First Posted Date: April 23, 2009
• Last Update Posted Date: April 9, 2024
• Actual Study Start Date: September 2009
• Estimated Primary Completion Date: October 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 9, 2018)

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 ]

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.

Original Primary Outcome Measures (submitted: April 22, 2009)

• Overall survival
• Time to event (i.e., clinical progression, neurocognitive progression, and radiographic progression)

Current Secondary Outcome Measures (submitted: January 9, 2018)

• 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 ]
  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.
• 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 ]
  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.
• Overall survival [ Time Frame: Time from study registration to time of death due to any cause, assessed up to 16 years ]
  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.
• Objective tumor response defined as a complete response or partial response [ Time Frame: Up to 16 years ]
  Summarized for each arm and compared between the arms using the Chi square test.
• Treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 16 years ]
  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.

Original Secondary Outcome Measures (submitted: April 22, 2009)

• Progression-free survival at 6, 12, and 24 months
• Objective tumor response
• Treatment-related adverse events according to NCI CTCAE v.3
• Interphase fusion of the CEP1 probe and a 19p12 probe to detect the t(1:19) in paraffin-embedded tumor sections by FISH
• Associations between clinical outcomes (survival, progression-free survival, and objective response) and MGMT methylation status
• Additional known prognostic markers, including but not limited to PTEN, EGFR, EGFRvIII, p53, and any additional markers which are known or are identified during the course of this study that are considered relevant by the study investigators and thei ...

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Brain and Central Nervous System Tumors

Intervention

• Drug: concomitant temozolomide (TMZ)
  75 mg/m^2, orally daily
• Radiation: radiotherapy
• Drug: procarbazine
  Days 8-21: 60 mg/m^2 orally
• Drug: adjuvant temozolomide (TMZ)
  150 or 200 mg/m^2 orally
• Drug: CCNU
  Day 1: 110 mg/m^2 orally
• Drug: vincristine
  Days 8 and 29: 1.4 mg/m^2 IV

Study Arms

• Experimental: Arm A (RT, procarbazine, lomustine, vincristine)
  Patients 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.
  Interventions:

  • Radiation: radiotherapy
  • Drug: procarbazine
  • Drug: CCNU
  • Drug: vincristine
• Experimental: Arm B (RT, temozolomide)
  Patients 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.
  Interventions:

  • Drug: concomitant temozolomide (TMZ)
  • Radiation: radiotherapy
  • Drug: adjuvant temozolomide (TMZ)

Publications *

• Cerhan JH, Anderson SK, Butts AM, Porter AB, Jaeckle K, Galanis E, Brown PD. Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from the Alliance for Clinical Trials in Oncology. Neurooncol Pract. 2019 Jul;6(4):283-288. doi: 10.1093/nop/npy048. Epub 2018 Nov 24.
• Drappatz J, Lieberman F. Chemotherapy of Oligodendrogliomas. Prog Neurol Surg. 2018;31:152-161. doi: 10.1159/000467376. Epub 2018 Jan 25.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 18, 2015): 360
• Original Estimated Enrollment (submitted: April 22, 2009): 488
• Estimated Study Completion Date: October 2025
• Estimated Primary Completion Date: October 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Kurt Jaeckle, MD; 904-953-7102

• Listed Location Countries: Austria, Belgium, Canada, France, Netherlands, United States
• Removed Location Countries: Germany, Switzerland

Administrative Information

• NCT Number: NCT00887146
• Other Study ID Numbers: N0577; NCI-2011-01915 ( Registry Identifier: CTRP (Clinical Trials Reporting System) ); EORTC-26081-22086; EudraCT-2008-007295-14; CDR0000640442 ( Registry Identifier: PDQ (Physician Data Query) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alliance for Clinical Trials in Oncology
• Original Responsible Party: Not Provided
• Current Study Sponsor: Alliance for Clinical Trials in Oncology
• Original Study Sponsor: North Central Cancer Treatment Group

Collaborators

• National Cancer Institute (NCI)
• European Organisation for Research and Treatment Center (EORTC)
• Canadian Cancer Trials Group

Investigators

• Study Chair: Kurt Jaeckle, MD; Mayo Clinic

• PRS Account: Alliance for Clinical Trials in Oncology
• Verification Date: April 2024