Phase III Intergroup Study of Temozolomide Alone Versus Radiotherapy With Concomitant and Adjuvant Temozolomide Versus Radiotherapy With Adjuvant PCV Chemotherapy in Patients With 1p/19q Co-deleted Anaplastic Glioma
Rochester, Minn., Jacksonville, Fla.
Trial status: Open for Enrollment
Why is this study being done?
This research study is a Phase III clinical trial. The purpose of this study is to compare the effectiveness of radiotherapy with temozolomide followed by temozolomide chemotherapy versus radiotherapy followed by PCV chemotherapy versus temozolomide chemotherapy alone in the treatment of anaplastic glioma. Patients are stratified according to cooperative group (EORTC vs North American groups [NCCTG, RTOG, CTSU, and NCIC CTG]), age (≤ 50 years vs > 50 years), and ECOG performance score (0 or 1 vs 2). Patients are randomized to 1 of 3 treatment arms. Please see the "Arms" section below for more detailed information. The primary and secondary objectives are summarized below.
To determine whether patients who receive radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant temozolomide (RT + TMZ --> TMZ) have a marginally better progression free survival (PFS) than patients who receive radiotherapy followed by PCV chemotherapy (RT --> PCV).
1. Time to Progression - To determine whether patients who receive temozolomide (TMZ) alone have a significantly longer time to progression (neurocognitive, clinical or radiographic progression) than patients who receive radiotherapy with concomitant TMZ followed by adjuvant TMZ (RT + TMZ --> TMZ) or radiotherapy followed by PCV chemotherapy (RT --> PCV).
2. Survival Difference - Determine whether there is a difference in survival based on translocation status and MGMT promoter hypermethylation status.
3. Descriptive Comparisons of Additional Secondary Endpoints - Perform descriptive comparisons of additional secondary outcome endpoints, including overall survival, objective tumor response, prognostic factor analysis and quality of life.
4. Toxicity - Determine the toxicity of the treatment in each arm and perform descriptive comparisons.
5. Descriptive Determination of Timing of RT - Determine descriptively whether it is reasonable to delay RT in this patient cohort by documenting the time to progression and progression free survival of patients receiving temozolomide alone
6. Neurocognitive and Quality of Life (QOL) Effects - Determine the neurocognitive and QOL effects in patients treated on this protocol and correlate these results with outcome endpoints
After completion of study therapy, patients are followed every 12 weeks for 1 year, then every 4 months for 2 years and then every 6 months until progressive disease.
Who is eligible to participate?
Pre-Registration Inclusion Criteria:
Central Pathology Review Submission This review is mandatory prior to registration to confirm eligibility. Patients must be willing to submit tissue samples for mandatory central pathology review submission and deletion status determination. It should be initiated as soon after surgery as possible.
Registration Inclusion Criteria:
1. Age ≥ 18 years
2. Newly diagnosed and ≤ 3 months from surgical diagnosis
3. Histological confirmation of anaplastic glioma (oligodendroglioma, mixed, or astrocytoma [WHO grade III], as determined by pre-registration central pathology review. 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.
4. Tumor is co-deleted for 1p and 19q.
5. Surgery (partial or gross total resection or biopsy) must be performed ≥ 2 weeks prior to registration. Patient must have recovered from the effects of surgery.
6. The following laboratory values obtained ≤ 21 days prior to registration.
1. Absolute neutrophil count (ANC) ≥ 1500/mm3
2. Platelet (PLTs) count ≥ 100,000/mm3
3. Hemoglobin (Hgb) > 9.0g/dL
4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
5. Serum glutamic oxaloacetic transaminase (SGOT) aspartate transaminase (AST) ≤ 3 x ULN
6. Creatinine ≤ 1.5 x ULN
7. Negative serum or urine pregnancy test done ≤ 7 days prior to registration for women of childbearing potential only.
8. Willing and able to complete neurocognitive testing without assistance and the Quality of Life (QOL) questionnaires with or without assistance
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
10. Provide informed written consent.
11. Willing to return to enrolling institution for follow-up during the Active Monitoring Phase (ie, active treatment and observation portion of the study)
12. Mandatory Tissue Samples for Correlative Research - Patient is willing to provide tissue samples for correlative research purposes
Registration Exclusion Criteria:
1. Pregnant women, nursing women, men or women of childbearing potential who are unwilling to employ adequate contraception during this study and for up to 6 months following the completion of temozolomide treatments.
2. Received any prior surgery, radiation therapy or chemotherapy for any central nervous system (CNS) neoplasm. Note: Patients who have had a prior low grade glioma with or without surgery and who now have anaplastic glioma with no prior radiation or chemotherapy are eligible for the study.
3. 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.
4. Concomitant serious immunocompromised status (other than that related to concomitant steroids).
5. Patients known to be Human Immunodeficiency Virus (HIV) positive and currently receiving retroviral therapy. Note: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for the study.
6. 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.
7. Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
8. 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 must not be receiving other specific treatment (other than hormonal therapy) for their cancer.
9. History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
10. Recent history of hepatitis infection or treating physician determined that the patient would be at significant risk of reactivation of hepatitis.