The Alliance AMBUSH Trial: Rationale and Design

Abstract

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.

Keywords: clinical trial; medulloblastoma; pineal parenchymal tumor; radiotherapy; sonic hedgehog; sonidegib; targeted therapy.

Figure 1

Overall schema of the AMBUSH trial (A072001) for patients 18 years of age at diagnosis or older with medulloblastoma or pineal embryonal tumors. * Preregister on study and begin clinical staging, RT plan preparation. Central pathology review and biomarker assays: IHC, DNA seq, CNA and clinical staging (postoperative brain MRI, spinal MRI, CSF analysis) required to assign to cohort: Cohort 1: average risk MB (non-SHH or SHH arms); Cohort 2: high risk MB or any PET. ** Final integrated pathological diagnosis including results of DNA methylation for MB subgroup confirmation (SHH vs. Non-SHH—Group 4, WNT). *** Patients receiving placebo who relapse will be allowed to crossover. Abbreviations: RT: radiotherapy; MB: medulloblastoma; IHC: immunohistochemistry; DNA seq: DNA sequencing; CNA: copy number assessment; SHH: sonic hedgehog; yo: years old; GTR: gross total resection; NTR: near total resection; M0: no metastatic disease; M1–3: any metastatic disease; CSI: craniospinal irradiation; q2wk: every other week; CIS: cisplatin; VCR: vincristine; CPM: cyclophosphamide; PS: performance status; XRT: x-ray radiotherapy; PRT: proton radiotherapy.