ACT-17 Protocol design of a matrix-type of novel clinical trial for lower-grade gliomas

Introduction: Differentiation between glioma grade 2 and 3 was performed based on histological findings. The current grade is an important prognostic factor due to its widespread use, economic efficiency, and data accumulation, but analog elements remain and the genetic marker is unknown. The concept of Lower-grade glioma including G2/3 is spreading. On the other hand, WHO grade is the criteria of clinical trials, and evidence is established for G2 with low risk and high risk, G3 alone or with G4. In Japan, JCOG 1303 and 1016 have been implemented for high-risk G2 and G3, respectively and will be finished next year. Therefore, we examined the feasibility and design of novel clinical trial for patients with grade 2/3 glioma. Method: With reference to clinical trials of high evidence level and public database registration, we researched trials, arms, and designs for each of 3 genotypes, oligodendroglioma (OD), astrocytoma IDH mutant and IDH wild (A-IDHm, A-IDHw). Results: The standard arm common to all genotypes is follow-up (EORTC22845) for G2 low-risk, and chemoradiotherapy (CRT) for G3. Standard arm for G2 high risk, depending on a genotype, is follow-up (EORTC22845), radiation alone (A-IDHm and IDHw, A-IDHw: RTOG9802 subanalysis), or PCV chemoradiotherapy (OD and A-IDHm: 9802). Furthermore, the standard arm and the test arm were replaced by the matrix-like method on each genotype. Results in the G2/3-targeted trial, there was no standard arm all in the three genotypes. In addition, there were a design of master protocols for many genotype and a design that has arms of randomization and observation. Conclusion: Applying the master protocol, the possibility of novel G2/3 target trial in which the arms existing in MATRIX form was suggested. With the improvement of the genetic analysis infrastructure, prospective observational research and a well-designed intervention research plan for each genotype are required.