Neurofibrosarcoma study with WGS data on dbGaP (41 participants)

phs004388 — SARC031: A Phase 2 Trial of Selumetinib and Sirolimus for Patients with    Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors    (MPNST)

<p>Combined <a href="https://www.ncbi.nlm.nih.gov/gene/2475">mTOR </a>and <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/5609/">MEK </a>inhibition, critical components of the <a href="https://www.ncbi.nlm.nih.gov/gene/3845">RAS </a>effector pathway underlying the pathogenesis of <a href="https://www.ncbi.nlm.nih.gov/datasets/gene/4763/">NF1</a>-related tumors, caused regression in a malignant peripheral nerve sheath tumors (MPNST) transgenic mouse model. The primary objective of this multi-institutional open label Simon 2 stage phase 2 study of the MEK inhibitor selumetinib and the mTOR inhibitor sirolimus was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Patients ≥12 years with histologically confirmed MPNST received selumetinib 50mg twice daily and sirolimus 4mg once daily after a cycle 1 day 1 loading dose of 12mg, in continuous 28-day cycles. 21 evaluable patients (7F; median age 41 y (range 16-72), 14 with NF1) that were heavily pretreated with advanced disease enrolled at 5 participating sites. </p><p>Clinical benefit was observed in only 1/7 in stage 1 and 1/14 in stage 2. The median number of cycles was 2 (range 1-6). Most common adverse events (AEs) related to investigational agents were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18FDG-PET scan performed during cycle 1 demonstrated partial metabolic responses in 5 patients (24%) but did not correlate with initial RECIST responses post cycle 2. Interestingly, the cfDNA were able to detect MPNST with the potential to be a biomarker of response. The combination was safe with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. </p>

SARC031: A Phase 2 Trial of Selumetinib and Sirolimus for Patients with    Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors    (MPNST)