Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group

Abstract

Purpose: The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children's Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF.

Patients and methods: Patients were eligible at first relapse or first designation of refractory disease. Oral T and intravenous (IV) irinotecan were administered on days 1 to 5 of 21-day cycles. DIN was administered IV (days 2-5), and GM-CSF was administered subcutaneously (days 6-12). The primary end point was objective response, analyzed on an intent-to-treat basis per the International Neuroblastoma Response Criteria.

Results: Seventeen eligible patients were randomly assigned to I/T/DIN/GM-CSF (February 2013 to March 2015); 36 additional patients were nonrandomly assigned to I/T/DIN/GM-CSF (August 2016 to May 2017). Objective (complete or partial) responses were observed in nine (52.9%) of 17 randomly assigned patients (95% CI, 29.2% to 76.7%) and 13 (36.1%) of 36 expansion patients (95% CI, 20.4% to 51.8%). Objective responses were seen in 22 (41.5%) of 53 patients overall (95% CI, 28.2% to 54.8%); stable disease was also observed in 22 of 53. One-year progression-free and overall survival for all patients receiving I/T/DIN/GM-CSF were 67.9% ± 6.4% (95% CI, 55.4% to 80.5%) and 84.9% ± 4.9% (95% CI, 75.3% to 94.6%), respectively. Two patients did not receive protocol therapy and were evaluable for response but not toxicity. Common grade ≥ 3 toxicities were fever/infection (18 [35.3%] of 51), neutropenia (17 [33.3%] of 51), pain (15 [29.4%] of 51), and diarrhea (10 [19.6%] of 51). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Higher DIN trough levels were associated with response.

Conclusion: I/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.

Trial registration: ClinicalTrials.gov NCT01767194.

FIG 1.

Trial profile. Best response by cycle 6 was the primary end point of the trial. Patients with stable disease (SD) or better could remain in the study and receive a maximum of 17 cycles of treatment. Best response is indicated in parentheses. CR, complete response; I/T/DIN, irinotecan, temozolomide, and dintuximab; PD, progressive disease; PR, partial response.

FIG 2.

Survival by ANBL1221 cohort. (A) Progression-free survival (PFS) and (B) overall survival (OS) for patients treated in the initial (randomly assigned) cohort, expansion (nonrandomly assigned) cohort, and combined cohort.

FIG 3.

Association of dintuximab (DIN) trough level and response in patients with an available plasma sample on day 1 of cycle 2. Relationship between response (complete response [CR]/partial response [PR]; n = 20 v stable disease [SD]/progressive disease [PD]; n = 21) and median DIN level (ng/mL) measured on day 1 of cycle 2. P value calculated using the Mann-Whitney-Wilcoxon test (P < .001). Data for 40 patients are shown. One responder had a DIN level of 12,595 ng/mL (off the scale for this figure). Values for all 41 patients were included in statistical analyses.