Abstract
Simple SummaryMedulloblastoma, the most common embryonal tumor in children, can also arise in older patients. Clinical studies in children with medulloblastoma have increased our understanding of molecular pathways and improved treatment strategies. We now know that medulloblastoma has at least four subtypes and each maybe best suited to specific therapies. The sonic hedgehog (SHH) pathway is altered in a significant proportion of older patients with medulloblastoma. The Alliance for Clinical Trials in Oncology cooperative group is developing the AMBUSH trial: Comprehensive Management of Adolescent and Young Adult (AYA) and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors With A Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). The trial gives treatment directions for all patients and randomizes patients with average risk SHH-activated medulloblastoma to maintenance sonidegib, a hedgehog signaling pathway inhibitor, or placebo. This trial will establish a baseline for future trial comparison and investigate the benefit of a novel targeted agent.Unlike medulloblastoma (MB) in children, robust prospective trials have not taken place for older patients due to the low incidence of MB in adults and adolescent and young adults (AYA). Current MB treatment paradigms for older patients have been extrapolated from the pediatric experience even though questions exist about the applicability of these approaches. Clinical and molecular classification of MB now provides better prognostication and is being incorporated in pediatric therapeutic trials. It has been established that genomic alterations leading to activation of the sonic hedgehog (SHH) pathway occur in approximately 60% of MB in patients over the age of 16 years. Within this cohort, protein patched homolog (PTCH) and smoothened (SMO) mutations are commonly found. Among patients whose tumors harbor the SHH molecular signature, it is estimated that over 80% of patients could respond to SHH pathway inhibitors. Given the advances in the understanding of molecular subgroups and the lack of robust clinical data for adult/AYA MB, the Alliance for Clinical Trial in Oncology group developed the AMBUSH trial: Comprehensive Management of AYA and Adult Patients with Medulloblastoma or Pineal Embryonal Tumors with a Randomized Placebo Controlled Phase II Focusing on Sonic Hedgehog Pathway Inhibition in SHH Subgroup Patients (Adult & Adolescent MedulloBlastoma Using Sonic Hedgehog Trial). This trial will enroll patients 18 years of age or older with MB (any molecular subgroup and risk stratification) or pineal embryonal tumor. Patients will be assigned to one of three cohorts: (1) average risk non-SHH-MB, (2) average risk SHH-MB, and (3) high risk MB or pineal embryonal tumors. All patients will receive protocol-directed comprehensive treatment with radiation therapy and chemotherapy. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year.
Highlights
Medulloblastoma (MB) is the most common malignant brain tumor of childhood, yet it accounts for only 1% of adult brain tumors [1,2]
There is no agreement on the optimal chemotherapy regimen for medulloblastoma in adults; chemotherapy regimens frequently used in clinical trials for average- and high-risk disease are summarized in Tables 1 and 2
The primary objective in the AMBUSH trial will be to evaluate the use of sonidegib, a SMO inhibitor randomized to placebo as maintenance after completion of Craniospinal irradiation (CSI) and chemotherapy in patients with average-risk sonic hedgehog (SHH)-MB, who represent an enriched population of MB with SHH pathway mutations at the level or upstream of SMO
Summary
Medulloblastoma (MB) is the most common malignant brain tumor of childhood, yet it accounts for only 1% of adult brain tumors [1,2]. All others are staged into the high-risk group It has been noted the presence of anaplasia or MYC amplification even with a complete resection and M0 disease are associated with poorer outcomes. These patients are often assigned to the high-risk group. Patients with SHH-MB in cohort 1 will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year This protocol once completed will provide robust guidance for the management of medulloblastoma and pineal embryonal tumors in the non-pediatric population
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