The Alliance AMBUSH Trial: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Anita Mahajan.

Medulloblastoma, the most common embryonal tumor in children, can also arise in older patients. 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.

  • medulloblastoma
  • sonic hedgehog
  • sonidegib
  • pineal parenchymal tumor
  • clinical trial
  • radiotherapy
  • targeted therapy

1. Introduction

Medulloblastoma (MB) is the most common malignant brain tumor of childhood, yet it accounts for only 1% of adult brain tumors [1,2][1][2]. Despite this low incidence, 30% of all medulloblastoma cases are diagnosed in individuals between age 15 and 39, patients who often have limited access to clinical trials.
After complete staging evaluation patients are found to either average- or high-risk groups. Patients with average-risk disease have neither residual disease (i.e., <1.5cm2) nor metastatic disease, (i.e., M0). All others are staged into the high-risk group. In addition, 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. Currently, based on several multi-institutional trials, pediatric patients with average-risk and high-risk MB have an estimated 5-year overall survival of 85% and 50–75%, respectively [3,4,5,6,7,8][3][4][5][6][7][8].
Unfortunately, due to the low incidence of the disease adult MB treatment paradigms have been challenging to establish. Pediatric data have been extrapolated to the older population, but concerns exist regarding the differences in tumor biology and treatment tolerance. Adult MB may represent a different biological spectrum than children, but many characteristics are also shared thus there is uncertainty of the validity of paradigms from the pediatric experience in an older population [9,10,11,12][9][10][11][12].
Over the last 10 years MB has become recognized as a heterogeneous disease with important biologic, molecular and clinical risk factors. The basic subgroups are Wingless/Integrated-activated (WNT), Sonic Hedgehog-activated (SHH), Group 3 and Group 4, each with a characteristic age spectrum and disease outcome [13,14,15,16][13][14][15][16].
The Alliance for Clinical Trial in Oncology group is planning 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), A072001. This will be a comprehensive trial that includes all patients 18 and older with medulloblastoma or pineal embryonal tumors divided into three cohorts: (1) average-risk non-SHH-MB, (2) average-risk SHH-MB, and (3) high-risk MB or pineal embryonal tumors. All eligible 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.

2. Classification of Medulloblastoma

The 2021 WHO classification for MB requires distinction of SHH- and WNT MB from non-WNT/non-SHH tumors. Pediatric MB paradigms now incorporate biologic in addition to clinical prognostic factors with the following goals: (1) toxicity reduction for very low risk disease (WNT+, M0) by reduction in RT dose to the CSI and the primary site, (2) improved tumor control strategies for patients with high-risk disease (metastatic disease, anaplastic MB, myc amplification, Group 3 and 4 or non WNT/SHH) using high dose chemotherapy and/or varying systemic agents. NCT00392327, NCT01878617, and NCT02724579).

3. Rationale to Include Non-SHH-MB, High-Risk MB, and Pineal Tumors

The intent of this unique trial is to leverage the opportunity and gain knowledge on all other populations of adult/AYA patients with MB (non-SHH and/or high risk) and pineal embryonal tumors since the treatment platform for all these subgroups is like the one proposed for the randomized group. Brandes et al., reported on 36 adult patients, 11 of whom had M+ disease, treated over a 12-year span. Herein, the PFS for adult patients was similar to similarly staged pediatric patients with high-risk disease having a poorer outcome [12]. Herrlinger et al., reported on a retrospective study of 36 adult patients treated over 22 years with MB and supratentorial primitive neuroectodermal tumors and noted that chemotherapy appeared to prolong survival [23][17]. The authors concluded more study was required and future efforts may build on this experience with the addition of new knowledge from ongoing and completed pediatric trials.
Because the natural history and treatment paradigms for pineal parenchymal tumors of intermediate differentiation (PPTID) vary from poorly/undifferentiated pineal parenchymal tumors, patients with PPTID will not be eligible [24][18]. Patients with non-SHH-MB, high-risk MB or pineal embryonal tumors will be enrolled on non-randomized arms and treated in a prescribed manner to determine objective outcomes since robust prospective data are not available for these patients. All patients with pineal region embryonal tumors will undergo full molecular characterization to establish prospective information for future analysis.
Non-randomized study objectives for this group will be to characterize clinical outcomes for pineal embryonal tumors and high-risk MB with comprehensive radiotherapy followed by adjuvant chemotherapy in a prospective trial setting. Further, in this rare disease setting of adult MB and pineal embryonal tumors patients, establishing a prospectively and rigorously collected set of data on a cohort treated with the current standard of care facilitates its potential use as external or ‘synthetic’ controls when evaluating experimental regimens in this same rare disease setting.

4. Backbone of AMBUSH Therapeutic Strategy

4.1. Surgery

Surgical intervention for posterior fossa tumors is important to re-establish CSF flow when there is obstructive hydrocephalus, to provide tissue diagnosis, and to decompress in the setting of mass effect. It has been noted in several MB studies that a complete resection has prognostic implication [8,25,26][8][19][20]. Herein, the degree of resection will be used for cohort assignment, where those with residual tumor greater than 1.5 cm2 on cross sectional measurement will be assigned to the high-risk arm. The degree of resection will be evaluated as an independent factor on disease outcomes including local recurrence and disease control. We will also assess for drop metastases along the spinal axis to further stratify eligibility and survival outcomes.

4.2. Radiotherapy

After studying post mortem MB failure patterns, Paterson and Farr recommended irradiating the brain and spinal cord in one undivided volume in the 1940s [27][21]. Their publication in 1953 reported the outcomes of 22 children and five adults in whom 65% had 3-year overall survival (OS). Craniospinal irradiation (CSI) has become part of the standard of care for treatment of MB with curative intent. The CSI dose in this early study was 3000–3500 roentgen to the spine and a maximum of 5000 roentgen to the cerebellum, with the limit set by tolerance of the normal tissues. Of note, a pediatric study (POG8631/CCG923) randomized pediatric patients with average risk MB to radiation therapy alone of 23.4 Gy CSI vs. 36 Gy CSI, both with a posterior fossa boost to 54 Gy, and reported an 8-year event-free survival (EFS) of 52% vs. 67%, respectively [8]. The standard CSI dose for average risk MB CSI remained 36 Gy when used without chemotherapy. Currently for patients 18 years and younger with average-risk disease, 23.4 Gy CSI with adjuvant chemotherapy is the standard of care with similar outcomes to 36Gy CSI without chemotherapy.
In adults, data for the use of lower dose CSI with chemotherapy is limited. Friedrich et al. reported a 4-year EFS of 68% and 4-year OS of 89% with no difference between 23.4 Gy CSI (n = 9) and 35.2 Gy CSI (n = 47) on the HIT 2000 prospective observational study [28][22]. Massimino et al., reported on 44 adults with non-metastatic MB treated at two European centers treated with <36 Gy CSI and chemotherapy. Thirty-six patients received 23.4 Gy CSI and eight patients had 30.6 Gy CSI in addition to a posterior fossa boost and chemotherapy based on pediatric protocols at each institution. The 5- and 10-year progression-free survival (PFS) was 82.2% and 78.5%, respectively. The OS rates were 89% and 75.2% at 5 and 10 years [26][20]. Similarly, Majd et al., published a large retrospective single institution study of adult MB in which 16 of 53 patients with standard-risk MB received <30 Gy CSI and no difference in outcome was noted [29][23].
A transition from a boost to the entire posterior fossa to a conformal boost of the primary site surgical bed has taken place as more conformal radiotherapy techniques have become available. The benefit has been lower dose to the cochlea, brainstem, spinal cord, and supratentorial brain. Michalski et al., reported the results of COG ACNS 0331 that randomized 464 children with average-risk MB to whole posterior fossa vs. involved field boosts with 5-year EFS 80.5% vs. 82.5%, respectively [7].
Based on these data and the investigators pooled experiences, 23.4 Gy CSI followed by a 30.6 Gy boost to the primary site will be used for all patients with average-risk disease. For all high-risk patients, the CSI dose will be 36 Gy followed by boost (s) to the primary (54 Gy) and metastatic (45–54 Gy) sites. All patients will receive adjuvant chemotherapy and high-risk patients will receive concurrent vincristine during CSI.

4.3. Chemotherapy

Adults do not tolerate chemotherapy as well as children as noted by several groups. Adult patients experience prolonged neutropenia, increased neuropathy, and require dose modifications or chemotherapy cessation due to toxicities [28,30,31][22][24][25]. There is no agreement on the optimal chemotherapy regimen for medulloblastoma in adults. The proposed regimen using cisplatin, vincristine, and cyclophosphamide is the result of an in-depth discussion within the neuro-oncology committee of Alliance that represents most major academic centers in the US and the NCI Connect adult MB workshop [11]. 

4.4. Targeted Therapy

The Hedgehog (Hh) pathway is essential in embryonic development and tumorigenesis. SHH is an extracellular Hh protein that is involved in nervous system development. The normal SHH pathway includes transmembrane protein, PTCH which constitutively inhibits SMO, another transmembrane protein, from internalization. If SHH binds with PTCH then, PTCH and SMO are internalized, resulting in decoupling of GLI (glioma-associated oncogene) from SUFU (negative regulator suppressor of fused). GLI then triggers transcription of hedgehog factors involved with growth. PTCH or SMO mutations can result in unopposed Hh pathway activation resulting in unregulated growth [32,33][26][27].

5. Trial Design

The overall schema of the AMBUSH trial is shown in Figure 1. Patients will be registered and the diagnosis of either MB or pineal parenchymal tumor will be confirmed by initial central pathology review. Following full clinical review, immunohistochemistry, DNA sequencing, copy number assessment, and genome-wide DNA methylation studies, patients will be assigned to either cohort 1 or 2 and their eligibility for randomization will be determined. Cohort 1 will receive CSI 23.4 Gy CSI followed by a tumor bed boost, whereas the higher-risk cohort 2 will receive CSI 36 Gy. Only patients with average-risk SHH-MB will be randomized to sonidegib or placebo as maintenance after completing chemotherapy.
/media/item_content/202201/61e61408041ffcancers-14-00414-g001.png
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.
While the nonrandomized arms will be analyzed in a descriptive manner, the primary analysis will be on those average-risk SHH-MB patients randomized to SHH pathway inhibition versus placebo. Here, this study design will provide 80% power to detect a true hazard ratio of 0.45 for PFS (corresponding to 5-year PFS rate of 70% vs. 85%), with a one-sided Type I error constraint of 0.10 and an interim analysis for futility conducted after 50% of expected events are observed.

6. Objectives

The primary objective is to evaluate the ability of SHH pathway inhibition maintenance therapy to improve progression-free survival (PFS), compared to placebo, in average risk patients with SHH-MB. Secondary objectives will include evaluating PFS in average-risk non-SHH-MB patients, high-risk MB, and pineal embryonal tumor patients with the aim to describe other clinical outcomes in these less-common subtypes.

7. Accrual Goal

A total of 108 patients will be accrued for randomization to the average-risk SHH-MB arm. The other groups will be open to accrual for the full duration of accrual to the randomized arms. It is estimated that a total of 20–40 patients will be registered to each of the non-randomized arms.

8. Translational Research

This trial presents a unique and highly valuable opportunity to understand the full spectrum of patient-centered outcomes, disease correlatives and treatment related morbidities. Patients will undergo specific evaluations at baseline and subsequent visits to facilitate a greater understanding of patient-centered outcomes. The planned tests and observations are summarized in Table 1.
Table 1. Baseline and subsequent tests and observations for patients enrolled on the AMBUSH Study.

Test or Observation

Baseline

Weekly during RT

Prior to Chemo

Chemo × 4 Cycles

Pre Sonidegib/Placebo

Monthly

Annually Post Completions

Approximate Wk,

Wk 0 = RT start

Wk

Wk

Wk

Wk

Wk

Wk

Wk 52

−4 to 2

0 to 6

9 to 10

10 to 26

26 to 30

30 to 82

Tests and Observations

History and Physical

pre RT

x

x

x

x

each visit

x

Weight (each visit)

pre RT

x

x

prn

x

x

x

Hearing

x

    

x

x

  

y 1, 3, 5

Vision

x

      

x

  

y 1, 3, 5

CompNeurocog

x

          

y 1, 3, 5

Short Neurocog

x

      

x

  

x

x

x

x

x

QOL/PRO-CTCAE

x

x

x

x

x

  

y 1, 3, 5

Laboratory Studies

CBC

pre RT

x

x

x

x

x

x

x

x

x

x

Blood Chemistries

x

  

x

prn

x

x

x

x

x

x

x

Endocrine

x

      

x

  

y 1, 3, 5

Creatine Kinase

x

  

x

x

x

x

x

x

x

x

x

BUN/Creatinine

x

  

x

x (1)

x

x

x

x

x

x

x

Staging

Tumor Imaging

pre RT

  

x

post cycle 2

x

    

Research Studies

for Banking

tumor, CSF,

plasma

plasma

  

plasma

    

plasma and CSF if Recurrence

n.b. x denotes when the test or observation will be required on the protocol. Abbreviations: Wk: week; RT: radiotherapy; chemo: chemotherapy; Comp Neurocog: comprehensive neurocognitive testing; Short Neurocog: Short neurocognitive testing; QOL: quality of life; PRO: patient reported outcomes; CBC: complete blood count; BUN: blood urea nitrogen; CSF: cerebrospinal fluid; prn: as needed; y: year.

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