Bagatell, Rochelle

Neuroblastoma is the most common extracranial solid tumor diagnosed in children. This inaugural version of the NCCN Guidelines for Neuroblastoma provides recommendations for the diagnosis, risk classification, and treatment of neuroblastoma. The information in these guidelines was developed by the NCCN Neuroblastoma Panel, a multidisciplinary group of representatives with expertise in neuroblastoma, consisting of pediatric oncologists, radiologists, pathologists, surgeons, and radiation oncologists from NCCN Member Institutions. The evidence-based and consensus recommendations contained in the NCCN Guidelines are intended to guide clinicians in selecting the most appropriate treatments for their patients with this clinically heterogeneous disease.

11508 Background: Trabectedin(T) is a marine-derived minor groove DNA binding compound that alters transcription factor activity. Preclinical data suggests that T suppresses the oncogenic driver of ES, EWS::FLI1. This suppression requires a threshold concentration of T and is potentiated by low doses of Irinotecan(I). Preliminary clinical activity and reversal of the EWS::FLI1 transcriptome was seen in patients (pts) in the phase I portion of SARC037. Here we report the phase II results of T with I at the recommended dose in pts with relapsed/refractory ES. Methods: In this open-label multicenter study, T was given at 1 mg/m2 as a 1-h infusion on day(D)1 with I at 25 mg/m2 intravenously on D2 and D4 of a 21D cycle. Key eligibility criteria were EWS::FLI1 fusion transcript, age ≥6 years, ECOG ≤2, adequate organ function, and willing to have a research biopsy if safely accessible. The primary objective was to determine the objective response rate (ORR) assessed by RECIST v1.1. Secondary objectives were progression-free survival (PFS), duration of response (DOR), and safety. This study used a Simon two-stage design that required 4 or more responses (CR or PR) at the final analysis to establish treatment activity. Results: 18 pts enrolled from 12/2022-12/2023 across 6 sites, 8F/10M, median age 21y (9-43). Pts had a median of 3 (1-7) prior therapy lines, including I in 67% of pts. Of 16 pts evaluable for response at the cutoff date, 5 pts had a PR, and 2 pts had SD. Two pts have evaluations pending and two pts were removed for toxicity before the first evaluation. Median time to response was 2.6 months(m), 6-month PFS was 37.7% (95% CI 18.3%, 77.7%), and all responses were sustained at the time of data cutoff at 10.4+, 7.5+, 5.5+, 5.0+ and 4.6+ m. There were no G5 AEs. Most pts had molecular profiling, translocation testing, as well as ctDNA collection, quantitation, and analysis. A subset of pts had pre- and post-treatment biopsies for RNA sequencing and evaluation of the impact of drug exposure on the EWS::FLI1 transcriptome. Conclusions: T+I exhibited anti-tumor activity in heavily pretreated pts with ES and met its prespecified ORR with 5 PRs in 16 evaluable patients, all of which are ongoing at data cutoff. There were no unexpected safety signals. The combination of T given as a 1h infusion and low-dose I demonstrated meaningful clinical benefit and is worthy of further study in ES pts. Analysis of biological correlates is ongoing. Clinical trial information: NCT04067115 .

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

Abstract Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m2/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in α-fetoprotein and stable disease over three cycles. At 270 mg/m2/dose, the Cmax and areas under the plasma concentration-time curves of 17-AAG were 5,303 ± 1,591 ng/mL and 13,656 ± 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 ± 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m2/d. Non-DMSO–containing formulations may improve acceptance of this drug by children and their families.