A phase 2 randomized study of chemoimmunotherapy with or without eflornithine (DFMO) in relapsed/refractory neuroblastoma: A Children’s Oncology Group (COG) report.

• DOI: 10.1200/jco.2025.43.16_suppl.10001
• Publication Date: 2025-05-28T21:06:45Z
• Authors: Margaret E. Macy; Arlene Naranjo; Fan F. Zhang; Michael Acord; Thomas Cash; Steven G. DuBois; Jennie Haunani Fo...; Kristin R. Knight; Michael D. Hogarty; Rajen Mody; Daniel A. Morgens...; Marguerite T. Parisi; Navin Pinto; C. Patrick Reynolds; Michelle E Keyel; Barry L. Shulkin; David Simon Ziegler; Rochelle Bagatell; Julie R. Park; Kelly C. Goldsmith

10001

Background: Dinutuximab, irinotecan, temozolomide and GM-CSF (DIT) is widely used in first relapsed/ refractory high-risk neuroblastoma (r/r HRNB), however <50% of patients (pts) respond. ODC1 is a key enzyme important for NB cell survival. Difluoromethylornithine (DFMO) irreversibly inhibits ODC1, suppressing polyamine biosynthesis and driving anti-NB activity. DFMO also inhibits arginase and may enhance immunotherapy in r/r NB. COG ANBL1821 was a randomized phase 2 study for pts with r/r NB that evaluated response to DIT with or without DFMO (NCT03794349). Methods: Patients with first episode of r/r NB were randomized 1:1 to DIT (Arm A) or DIT with DFMO (6750 mg/m 2 divided TID; Arm B). They were stratified by measurable/evaluable disease, MYCN status, prior anti-GD2 therapy, and prior DFMO therapy. Cycles were 21 days. On Arm B, DFMO was initially given continuously; discontinuous DFMO dosing (days 1-7 and 15-21) was instituted due to ototoxicity in the initial cohort. Objective Response Rate [(ORR); sum of complete (CR), partial (PR), and minor (MR) responses per the 2017 International Neuroblastoma Response Criteria (INRC)] was determined based on central review of imaging. Toxicities were graded per CTCAE v5.0. Results: 91 eligible and evaluable pts (44 Arm A, 47 Arm B) were randomized May 2019-Jan 2024. 28/44 (63.6%) of Arm A pts and 32/47 (68.1%) of Arm B pts had relapsed or progressive disease (RPD); the remaining pts had refractory disease. The ORR was 61.4% (27/44) for Arm A and 57.4% (27/47) for Arm B (p=0.566). On Arm A, 22/44 (50%) achieved CR or PR compared to 23/27 (48.9%) on Arm B. Response rates for pts with RPD were similar to those with refractory disease in both arms. The 1-year progression-free survival (PFS) for Arm A was 70.0±8.0% and 56.8±8.2% for Arm B. Overall survival was 87.0±5.7% and 81.4±6.3% for Arms A and B, respectively. The most common toxicities reported on both arms were hematologic and gastrointestinal. Fewer pts on Arm B (n=7) had Grade 3+ pain than on Arm A (n=15) (p=0.0326). Hearing loss was a toxicity of interest; with continuous dosing, 55.6% (5/9) of Arm B pts developed hearing loss requiring DFMO dose hold. With discontinuous dosing, hearing loss was 15.8% (6/38) on Arm B compared to 6.3% (2/32) on Arm A (p=0.275). 14/16 (87.5%) NB+ marrows were GD2+ at enrollment; loss of GD2 was not detected on persisting NB cells in on therapy marrows analyzed. Conclusions: The addition of DFMO to DIT did not improve response rates in pts with first r/r HRNB, though the response rates in both arms confirmed DIT activity in this population. The ORR to DIT is higher than previously reported, likely due to use of the 2017 INRC that includes MR in calculation of ORR. Rates of CR+PR in this trial were similar to those previously reported. DFMO was associated with an increased incidence of hearing loss which was partially mitigated by discontinuous dosing.

Clinical trial information: NCT03794349

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