Randomized phase 2 trial of the combination of vincristine and irinotecan with or without temozolomide, in children and adults with refractory or relapsed rhabdomyosarcoma (RMS).

Abstract

10000 Background: Vincristine with Irinotecan (VI) is effective in patients with relapsed RMS but outcomes remain poor. The addition of temozolomide to VI (VIT) is attractive owing to different resistance mechanisms and distinct toxicity profiles. Methods: The VIT-0910 trial, an EpSSG-ITCC randomized phase 2 trial, evaluated efficacy and safety of VI and VIT in patients (pts) aged 0.5-50 years with relapsed/refractory RMS. Pts received Vincristine 1.5 mg/m2 d1, d8, Irinotecan 50mg/m2 d1-d5 +/- Temozolomide 125 mg/m² d1-d5 (150 mg/m² from cycle 2 if no toxicity > grade 2); 21-day cycles were given until progression/unacceptable toxicity. The primary endpoint was centrally reviewed objective response rate (ORR) after 2 cycles (primary lesion, WHO response criteria: metastatic sites, RECIST 1.1 ). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events (NCI-CTCAE v4). Initially a Simon 2-stage design was used to analyse separately 40 pts/arm. After amendment, the trial sample size was increased to 120, and a comparison between arms, adjusted for confounding factors, was added to the statistical plan. Results: 120 pts (60 VIT, 60 VI) were recruited in 37 European centers from 03/2012-04/2018. Median age was 11 years (0.75-46), 89% pts relapsed RMS. ORR was 24/55 (44%) for VIT vs 18/58 (31%) for VI; adjusted odds ratio =0.50, 95%CI, 0.22-1.12, p=0.09. The VIT arm achieved significantly better PFS (adjusted Hazard Ratio (HR)=0.65, 95%Cl, 0.43-0.97, p=0.036) and OS (HR=0.53, 95%CI, 0.33-0.83, p=0.005) compared to VI. PFS and OS results were similar when only relapsed patients were included. Adverse events ≥ grade 3 were more frequent in VIT compared to VI, but only hematological toxicity was significantly increased (81% for VIT, 59% for VI, odds ratio=1.36, 95%CI, 1.06-1.76, P=0.02). Conclusions: The addition of temozolomide to VI improves PFS and OS of pts with relapsed/refractory RMS. VIT is now standard treatment for relapsed RMS in Europe. Clinical trial information: NCT01355445.