CTP-03. A Phase 2 study of alisertib in combination therapy for newly diagnosed Atypical Teratoid/Rhabdoid Tumor (AT/RT)- Results from SJATRT strata B and C

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Abstract BACKGROUND Atypical teratoid/rhabdoid (AT/RT) is an aggressive pediatric brain tumor, prevalent in children < 3 years(Y) of age. Though treatment with surgery, radiation and chemotherapy has improved clinical outcome, the cure rate remains suboptimal. Molecularly, AT/RT demonstrates alterations in SMARCB1 and SMARCA4 and methylation profiles sub-classify AT/RTs into AT/RT-MYC(MYC), AT/RT-SHH(SHH) and AT/RT-TYR(TYR). METHODS We conducted a phase 2 study of Aurora Kinase A inhibitor, alisertib, in combination with chemotherapy and radiotherapy (RT) in newly diagnosed AT/RT (Stratum B [B1-M0 & B2-M+]: < 36 months; Stratum C [C1-M0 & C2-M+] - ≥ 36 months). Stratum B1 patients received focal RT at ≥12 months of age and patients on stratum C1 (23.4 Gy) and C2 (36 Gy) received post-operative CSI. RESULTS 71 evaluable patients were enrolled on strata B1 (n=30), B2 (n=17), C1(n=13) and C2 (n=11). For, B1 (SHH:18, TYR:7, MYC:3, NC:2) the 3Y PFS and OS were 30.0% and 56.7%. B2 (SHH:8, TYR:7, MYC:2) had a 3Y PFS and OS of 0 and 17.6% and was closed early at PI discretion due to lack of efficacy. Stratum C1 (SHH:4, TYR:2 & MYC:6, NA:1, NC:1) the 3Y PFS and OS were 84.6% & 100.0% and for C2 (SHH:6 and MYC:3, NC:2), 63.6% was the 3Y PFS and OS. SHH patients had better PFS (p=0.036) in C2 in comparison to MYC. Strata C1 and C2 did not reach target accrual. There were no unexpected toxicities, most common grade 3 toxicities were related to myelosuppression. CONCLUSION Combination of alisertib with chemotherapy and RT was well tolerated, however, it didn’t improve survival in newly diagnosed AT/RT. The study confirms, albeit in small numbers, prior results of a higher survival for M0 patients with post-operative CSI in ≥ 36-month-old (C1). The PFS in M+ ≥ 36-month-old patients (C2) was higher with CSI than previously reported. Molecular subclass was not associated with outcome except in SHH in C2.

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