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.