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.

Characterization of recurrence patterns and outcomes of medulloblastoma in adults: The University of Texas MD Anderson Cancer Center experience

“…Further studies with larger combined datasets that account for molecular features and variation in treatment strategies are needed to better understand which factors are most contributory to prolonging PFS and OS in adults with medulloblastoma. With growing access to targeted therapies and chemotherapeutic clinical trials (SJMB12, NCT01878617; SJDAWN, NCT03434262; PersoMed-I, NCT04402073; and Alliance AMBUSH Trial 40 ), and surgical trials (PBTC-053, NCT03904862) specifically including adults, subsequent studies must factor in optimal combinations of treatment modalities that include new targeted and immunotherapeutic approaches at recurrence.…”

Management and Long-term Outcomes of Adults With Medulloblastoma

“…We suspect that the benefit of these management practices could not be adequately assessed given relatively minimal duration from time of diagnosis. Future studies will provide insight into possible survival impact with less long-term morbidity, including the Alliance AM-BUSH Trial 43 and PersoMed-I trial (NCT04402073). A large phase 3 trial in children (ACNS0331; NCT00085735) showed that tumor bed (involved field) was noninferior (event-free survival) to PF boost RT, supporting the use of a more targeted boost that may limit therapy-related comorbidities.…”

Adult Medulloblastoma: Updates on Current Management and Future Perspectives

“…While histopathological MB features are nearly indistinguishable from those observed in children, the distribution of molecular types is markedly different, with SHH-activated MB representing by far the most common molecular group in adults [ 35 ].…”

“…To date, whole-genome methylation profiling is considered the gold standard diagnostic method, has been obtained mainly in children while these methylation data in adults is limited [ 41 , 42 , 45 ]. Comparative studies are being added to MB clinical trials in adults to further define the optimal diagnostic approach [ 35 ].…”

“…All patients will receive protocol-directed comprehensive treatment with 23.4 Gy radiotherapy on the neuroaxis followed by a boost of 36 Gy to primary and metastatic sites and chemotherapy with cisplatin, vincristine and cyclophosphamide. Patients within the average risk SHH-subgroup will be randomized to a smoothened inhibitor or placebo as maintenance therapy for one year [ 35 ].…”