Collaborations with Solid Tumor Committees (Table 2):
ANBL0532: High-risk neuroblastoma outcomes have improved from
<10% to 40-50% as intensity of treatment
increased.18 Current multi-modal treatment includes a
complex sequence of multi-agent chemotherapy, surgery, high dose
chemotherapy followed by autologous HCT consolidation, post-HCT
radiation, and finally several cycles of biologic and immune therapies.
Intensification of the treatment with tandem autologous HCT further
improved outcomes in pilot studies.19, 20 ANBL0532
tested this approach in a randomized trial of single (n=179) vs tandem
(n=176) HCT. Patients randomized to single HCT received conditioning
with standard dose carboplatin-etoposide-melphalan (CEM). Patients in
the tandem HCT group received cyclophosphamide and thiotepa for the
first HCT followed by dose reduced CEM for the second HCT after
hematopoietic and organ recovery. Three year EFS from the time of
randomization was superior for tandem over single HCT (62% vs 48%,
p=0.006) without more toxicity and thus established a new standard of
care.21 The current COG protocol, ANBL1531, uses
tandem HCT consolidation and tests the hypothesis that therapeutic131I-meta-iodobenzylguanidine
(131I-MIBG) during induction will improve outcomes.
ANBL1531 also tested whether a single HCT using dose-intensive
Busulfan-Melphalan (Bu-Mel) would be as safe and effective as the tandem
HCT approach based on encouraging results.22, 23However, the Bu-Mel arm was inferior to tandem HCT on interim analysis
and closed in December 2020. ANLB1531 should complete enrollment in
2023.
ACNS0333: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare,
highly aggressive brain cancer typically diagnosed in infants and
toddlers with exceptionally poor survival rates <10%.
ACNS0333, the first cooperative group trial for AT/RT, utilized dose
intensification including two induction cycles of vincristine, high dose
methotrexate, etoposide, cyclophosphamide and cisplatin followed by
three sequential cycles of high dose, sub-ablative carboplatin and
thiotepa supported by autologous HCT (to hasten marrow recovery and
shorten the interval between courses) and then consolidation with
involved field radiation. Four-year EFS was higher for study patients
(n=68) than historic controls (35% vs 6%, p<0.0005) without
any treatment-related deaths or secondary malignancies despite high
rates of hematologic and infectious toxicities. Relapse was the major
cause for treatment failure.24 Patients with AT/RT
have biallelic alterations of the SMARCB1 gene that decreases
SMARCB1 protein expression and results in EZH2 overexpression. A phase
1b trial showed that tazemetostat, an oral EZH2 inhibitor, induced
responses in relapsed AT/RT.25 ACNS2232 is study in
development to test whether the addition of tazemetostat to the ACNS0333
schema followed by tazemetostat maintenance therapy decreases relapse.