SARC006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs).

Abstract

10522 Background: MPNSTs occur in 10% of the NF1 population, and retrospective, pooled analyses have reported worse chemotherapy response for NF1 (9-18%) compared to sporadic MPNSTs (39-55%). Methods: We prospectively evaluated the objective response (OR) rate, [complete responses (CR) and partial responses (PR) WHO criteria] of children and adults with high-grade, unresectable or metastatic chemotherapy naive NF1 associated versus sporadic MPNST after 2 cycles of ifosfamide and doxorubicin (IA) followed by 2 cycles of ifosfamide and etoposide (IE) as primary endpoint. This was followed by surgery and/or radiation for local control and up to 2 more cycles of IA and IE each. Pathology was centrally confirmed. A Simon optimal two-stage design was used with a target response rate of 40% and 17 patients per stratum in the first stage. With 4+/17 ORs, enrollment was to be expanded to 37 patients per stratum, and 11+/37 ORs would be potentially consistent with a 40% OR rate. Results: Both initial stages met criteria for enrollment expansion with 4/17 PRs in NF1 and 4/12 PRs in sporadic MPNSTs, but only 1 additional PR was observed in the expanded NF1 stratum. Of the 9 PRs, 5 were first observed after 2 cycles IA, and additional 4 after 2 cycles IE. Enrollment was slower than expected and the trial was closed before full accrual. Conclusions: While the primary trial objective was not reached due to slow enrollment, with only 5/29 ORs in the NF1 stratum the desired OR rate of 11+/37 would have unlikely been met even if accrual had been completed. We observed a lower OR rate in NF1 compared to sporadic MPNSTs similar to retrospective literature reports. However, our trial was not powered to detect a difference in response rates between the two strata. In addition to PRs after both IA and IE, disease stabilization was achieved in most patients. Novel strategies including the evaluation of targeted agents in combination with chemotherapy should be considered. Clinical trial information: NCT00304083. [Table: see text]