Abstract ID 129646Poster Board 407Introduction: Recurrent pediatric solid and CNS tumors pose significant challenges in pediatric oncology, resulting in considerable morbidity and mortality due to a lack of effective treatments. Dysregulation of the PI3K-Akt-mTOR pathway complex can lead to tumorigenesis and may be implicated in CNS tumors. nab-Sirolimus, also recognized as ABI-009, is a nanoparticle albumin-bound injectable form of sirolimus, a potent mTOR inhibitor. The pharmacokinetic behavior of nab-sirolimus is currently not completely elucidated in the pediatric population. Consistent with the nab-sirolimus US prescribing information and mTOR inhibitor class effects, toxicities commonly observed in the phase 1 trial of nab-sirolimus in adults (NCT00635284) included thrombocytopenia, mucositis, fatigue, rash, diarrhea, and hypertriglyceridemia. The aims of the present study were to characterize the population pharmacokinetics of nab-sirolimus in pediatric patients with relapsed/refractory solid tumors, including CNS tumors and to identify factors significantly affecting pharmacokinetic parameters. Methods:nab-Sirolimus was administered intravenously as a weekly dose on days 1 and 8 of a 21-day cycle at doses of 15, 20, and 35 mg/m2. Patients were assessed on days 1,2,4 and 8 of cycle 1 of single agent nab-sirolimus. Blood samples were collected at the following time points: at Day 1 (pre-dose, and 1, 2, 4, 8 hrs. after beginning the infusion), Day 2 (24 hrs. after beginning the Day 1 infusion), Day 4 (72 hrs. after beginning the Day 1 infusion), and Day 8 (pre-infusion) . A total of 29 pediatric patients (258 concentrations) were included in a population pharmacokinetic analysis. Non-linear mixed effect models were developed using the whole blood concentrations attained from the phase 1 clinical trial by implementing the Phoenix NLME program. Covariates that may be related to pharmacokinetics were screened using stepwise methods. The final model was validated by goodness-of-fit plots, visual predictive check, and non-parametric bootstrap. Results: A three-compartment model was selected as the best structural base model to adequately characterize nab-sirolimus pharmacokinetics. Body surface area (BSA) was the most influential factor on clearance of the central compartment, while BSA, age, sex and dose level affected the overall volume of distribution. The population estimates of clearance, and volume of distribution of the central compartment in the final model were 3.0 L/h, and 14.7 L respectively. Conclusion: The first robust population pharmacokinetic model of nab-sirolimus was successfully developed following the intravenous infusion of nab-sirolimus in pediatric patients with relapsed/refractory solid tumors, including CNS tumors. Notably, BSA emerged as a significant covariate influencing the pharmacokinetics of nab-sirolimus. This model serves as a valuable reference for guiding dose regimens in future pediatric studies involving nab-sirolimus. Keywords:nab- Sirolimus; Population Pharmacokinetics; Pediatric Oncology. This work has been supported by Mayo Clinic Cancer Center Grant Number P30 CA015083 from the National Cancer Institute (NCI), the National Institute of General Medical Sciences (NIGMS) grant T32GM 08685, AADi, The Pediatric Early Phase-Clinical Trials Network (PEP-CTN) UM1CA228823 and Cookies for Kids' Cancer.
Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores ≥20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.
BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a “hybrid morphology” in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.
ABSTRACT Background Nab ‐sirolimus (ABI‐009, nab ‐rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin‐bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose‐limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab ‐sirolimus in combination with temozolomide and irinotecan. Methods Using a rolling 6 design, Nab ‐sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab ‐sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m 2 /dose, maximum 250 mg/dose) and irinotecan (90 mg/m 2 /dose) orally, daily on D1–5. Cycle duration was 21 days. Three dose levels (DL) of Nab ‐sirolimus were investigated (DL1: 35 mg/m 2 /dose, DL‐1: 20 mg/m 2 /dose, and DL‐2: 15 mg/m 2 /dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2. Results Thirty‐three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median (range) age 12 (2–20) years and six additional patients were enrolled (four evaluable for toxicity) on a pharmacokinetic cohort. C1 or C2 DLTs were primarily thrombocytopenia including 2/5 patients at DL1, 2/6 patients at DL‐1, and 1/6 patients at DL‐2. One patient (DL1) with Ewing Sarcoma had a partial response and remained on study for 35 cycles. Rapamycin clearance was dose dependent. Irinotecan clearance and its active metabolite SN‐38 exposure were not affected by coadministration with Nab ‐sirolimus. Conclusion The MTD for Nab ‐sirolimus was 15 mg/m 2 /dose IV on D1 and D8 in combination with temozolomide 125 mg/m 2 /dose and oral irinotecan 90 mg/m 2 /dose daily for 5 days during 21D cycles. Trial Registration ClinicalTrials.gov identifier NCT02975882
PURPOSE Unlike most childhood cancers, therapy for ALL includes a prolonged maintenance phase during which children typically resume regular activities. Physicians need data regarding the persistent impact of COVID-19 in this population to help guide families after the pandemic. METHODS The Pediatric Oncology COVID-19 Case Report (POCC) collects deidentified data (sociodemographics, clinical data [cancer, COVID-19 course]) on children, adolescents, and young adults with cancer and COVID-19 from 104 US pediatric oncology institutions. The analysis presented here compares children (≤21 years) with ALL in maintenance (ALL-MTN) with all other children with cancer and COVID-19. Multivariable analyses adjust for age, race/ethnicity, insurance, absolute neutrophil count at the time of infection, vaccination, and comorbidities. RESULTS Compared with other children reported to POCC (n = 1,190), those in ALL-MTN (n = 481) were less often hospitalized (23% v 29%, P = .01) or admitted to the intensive care unit (ICU: 3% v 5%, P = .01); these findings persisted in multivariable analysis (hospitalization: odds ratio [OR], 0.7 [95% CI, 0.6 to 0.9]; ICU: OR, 0.5 [95% CI, 0.2 to 0.8]). However, cancer-directed therapy was changed more often for children in ALL-MTN (50% v 33%, P ≤ .01; OR, 2.0 [95% CI, 1.6 to 2.5[). Vaccination was an independent prognostic factor in our multivariable model, decreasing odds of hospitalization (OR, 0.7 [95% CI, 0.5 to 0.9]). CONCLUSION Children in ALL-MTN required fewer hospitalizations and ICU admissions but more therapy modifications than other children with cancer. Vaccination against COVID-19 reduced the odds of hospitalization.
Abstract Background Cancer predisposition syndromes (CPS) are caused by germline pathogenic variants that put an individual at increased risk of developing cancer throughout their lifetime. It is estimated that approximately 10‐15% of children with cancer have an underlying CPS. Although research has investigated the clinical utility of genetic testing for children diagnosed with cancer, this study aimed to gain a deeper understanding of parental attitudes toward genetic testing in this population. Procedure Attitudes toward genetic counseling and testing among parents of children diagnosed with cancer were solicited through questionnaires distributed to a pediatric cancer clinic and online support groups. Quantitative data were analyzed using descriptive statistics and chi‐square tests for association. Results The majority of participants had prior knowledge of genetic counseling (64.3%), yet most were not offered genetic counseling (59.5%). Fifty percent of parents reported interest in pursuing genetic counseling/testing and 31.0% reported uncertainty. Statistically significant associations were identified between interest in genetic counseling/testing and the child's age at diagnosis, child's sex, and participant annual income ( P < .05). Conclusions Parents of children diagnosed with cancer generally expressed interest in genetic counseling/testing; however, notable uncertainty was also reported. In light of this uncertainty, genetic counselors have an ideal skill set to engage families in their decision‐making process as they weigh the benefits and drawbacks to pursuing genetic testing among this population. Demonstrated parental receptiveness to genomic technologies supports expansion of genetics providers in pediatric oncology care.
CIC- rearranged sarcomas rarely occur in visceral organs including the kidney. The most common fusion partner with CIC is the DUX4 gene, but variant fusion partners have also been reported. Herein, we describe the clinicopathologic features and comprehensive molecular profiling of 4 cases of primary renal CIC- rearranged sarcomas. All cases occurred in females, age range 13 to 82 years and included 3 resections and 1 needle biopsy specimen. There was a tendency for development of metastatic disease predominantly to the lungs and poor disease outcome despite different treatment strategies. Histologically, variable round cell (20% to 100%), spindle cell (0% to 80%), and rhabdoid morphologies (0% to 20%) were seen. By immunohistochemistry diffuse WT1 nuclear (2 to 3+, ∼90%) labeling was present in 1 case, with cytoplasmic staining in the others (3+, 40% to 75%). CD99 was focally positive in all 4 cases (≤10%); 1 case each was diffusely positive for c-myc (2 to 3+, ∼90%) and ETV4 (3+, ∼90%); 1 case was focally positive for c-myc (2+, ∼5%) and calretinin (2+, ∼5%); and all cases were negative for cytokeratin and NKX2.2. CIC rearrangement by fluorescence in situ hybridization was present in the 3 cases tested. Comprehensive genomic profiling (CGP) of 3 cases revealed a CIC-DUX4 fusion in 2 cases, and 1 CIC-NUTM1 fusion. All 4 CIC -rearranged renal sarcomas had low mutation burden, and except HLA-A and MLL mutations lacked genomic alterations in other oncogenic drivers. Material from the needle biopsy was insufficient for CGP but that case was positive with the DUX4 immunohistochemical stain as were the 2 CIC-DUX4 tumors. In conclusion, CIC- rearranged sarcomas rarely occur in the kidney with a tendency for poor outcome and in this series we illustrate an example with CIC-NUTM1 fusion, an emerging variant, at a visceral site. Testing by fluorescence in situ hybridization or CGP is optimal to avoid missing cases that harbor variant fusion partners.
