Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies.

Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST

Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas

Background RAS is dysregulated in neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs). The activity of tipifarnib, which blocks RAS signaling by inhibiting its farnesylation, was tested in children and young adults with NF1 and progressive PNs. Methods Patients aged 3–25 years with NF1-related PNs and imaging evidence of tumor progression were randomized in a double-blinded fashion to receive tipifarnib (200 mg/m2 orally every 12 h) or placebo (phase A) and crossed over to the opposite treatment arm at the time of tumor progression (phase B). PN volumes were measured with MRI, and progression was defined as ≥20% volume increase. Time to progression (TTP) in phase A was the primary endpoint, and the trial was powered to detect whether tipifarnib doubled TTP compared with placebo. Toxicity, response, and quality of life were also monitored. Results Sixty-two patients were enrolled. Tipifarnib and placebo were well tolerated. On phase A, the median TTP was 10.6 months on the placebo arm and 19.2 months on the tipifarnib arm (P = .12; 1-sided). Quality of life improved significantly compared with baseline on the tipifarnib arm but not on the placebo arm. Volumetric tumor measurement detected tumor progression earlier than conventional 2-dimensional (WHO) and 1-dimensional (RECIST) methods. Conclusions Tipifarnib was well tolerated but did not significantly prolong TTP of PNs compared with placebo. The randomized, flexible crossover design and volumetric PN assessment provided a feasible and efficient means of assessing the efficacy of tipifarnib. The placebo arm serves as an historical control group for phase 2 single-arm trials directed at progressive PNs

Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis:A potential model for rare diseases

Background Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.Methods Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts.Results The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF.Conclusions These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials