A phase 3 randomized trial comparing temozolomide with PCV as adjuvant chemotherapy in grade 2 and 3 diffuse gliomas in adults.

Abstract

TPS2104 Background: Both Temozolomide (TMZ) and PCV are standard adjuvant chemotherapy regimens used in treatment of grade 2 gliomas with high risk features and grade 3 gliomas. The PCV regimen has a complex schedule, higher rate of adverse events (esp myelosuppression), and is difficult to administer, but has long-term data with an overall survival benefit. On the other hand,TMZ is an oral drug, with a simple dosing schedule, and fewer adverse events. Currently, there is lack of data directly comparing PCV to TMZ, there is emerging evidence to suggest that PCV may be the regimen of choice for oligodendrogliomas (ODGs). There is often debate on the choice of adjuvant chemotherapy. Hence we are conducting this study to compare TMZ with PCV in this setting. Methods: This is an ongoing phase 3, parallel-arm, non-inferiority trial. Adults with high-risk grade 2 (age ≥40 years and/or the presence of residual disease ≥1 cm after maximal safe resection) or grade 3 gliomas, are randomized 2:1 to receive TMZ or PCV after adjuvant radiation (RT). Patients receive adjuvant focal conformal radiation, with doses between 54 to 59.4 Gy at 1.8-2 Gy/fraction with conventional fractionation. In the TMZ arm, patients receive RT with concurrent TMZ 75 mg/m 2 /day (max. 49 days) followed by adjuvant TMZ 150-200 mg/m 2 for 5 of 28 days (max. 12 cycles). In the PCV arm, patients receive Procarbazine 60 mg/m 2 on days 8-21, CCNU 110 mg/m 2 on day 1 and Vincristine 1.4 mg/m 2 on days 8, 29 of a 56-day cycle (maximum 6 cycles). Adjuvant chemotherapy is started within 8 weeks of completing RT. Adverse events are recorded as per CTCAE v4.03. EORTC QLQ C-30 & QLQ BN-20 is used for quality of life (QoL) assessment. Follow up evaluation will be conducted every 3 months in the 1 st year, every 4 months in the 2 nd year, and every 6 months from the 3 rd to 5 th year, then annually. The primary endpoint of the study is Progression-Free Survival (PFS). Secondary endpoints are Overall Survival (OS), safety,compliance & QoL. Sample Size: Assuming a 3-year PFS of 70% in the PCV arm, with type 1 error of 5% (1- sided), type 2 error of 20%, with 2:1 ratio of accrual (in favor of the TMZ arm) for 10 years, with a study duration of 15 years, to show a non-inferiority by 12% for the upper limit of 95% confidence interval of the PFS with one interim analysis; the sample size estimated by group sequential design for time-to-event outcome was 216. Statistical analysis: Kaplan Meir analysis will be used to estimate the PFS & OS and log rank test will be used for comparison between two arms.Cox proportional hazard model will be constructed for calculation of hazard ratio with its 95%CI. An interim analysis will be performed at 82 events of progression. If the log rank p value for the difference in the estimated PFS of the 2 arms is ≤ 0.006 then the trial will be terminated. Otherwise the trial will continue and undergo a final analysis at 163 events of progression. Clinical trial information: CTRI/2018/07/015056.