Background Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide (I/T) has activity in these patients, and the toxicity profile of I/T makes it an excellent backbone for study of new agents. Temsirolimus (TEM) and dinutuximab (DIN) were selected for testing with I/T in subjects with relapsed or refractory neuroblastoma. Methods Children’s Oncology Group (COG) ANBL1221, a randomised Phase II selection design trial, compared response and toxicity in subjects treated with I/T and either temsirolimus (I/T/TEM) or dinutuximab with granulocyte-macrophage colony stimulating factor (I/T/DIN). Patients were eligible at first relapse/progression or first designation of refractory disease, provided organ function requirements were met. Patients had to have histologic verification of neuroblastoma and/or demonstration of tumour cells in bone marrow with increased urinary catecholamines at diagnosis. Patients were eligible at first designation of relapse (defined as recurrence after response to treatment), or first designation of refractory disease (defined as inadequate response to treatment that included at least 4 cycles of ≥2 chemotherapeutic agents, including an alkylator and a platinum-containing compound. Patients previously treated for refractory or relapsed disease were ineligible. Computer-based randomisation with sequence generation defined by permuted block randomisation, with blocks of size 2, was used to assign patients 1:1 to I/T/TEM or I/T/DIN. Randomisation was stratified to ensure equal distribution of disease category (measurable vs. evaluable), prior exposure to anti-GD2 antibody therapy, and tumour MYCN amplification status. Patients on both regimens received oral temozolomide (100 mg/m2/dose) and intravenous (IV) irinotecan (50 mg/m2/dose) on days 1–5 of 21-day cycles. TEM (35 mg/m2/dose IV) was given on days 1 and 8. DIN (17·5 or 25 mg/m2/day IV) was administered on days 2–5. The primary endpoint was objective (complete or partial) response; responses were centrally reviewed by an independent panel of radiologists. Response was analysed on an intent-to-treat basis. Toxicity was assessed in all participants who received at least one dose of protocol therapy. Follow up of the initial cohort is ongoing. This study is registered at ClinicalTrials.gov (NCT01767194). Findings Thirty-five eligible subjects were enrolled from February 22, 2013-March 23, 2015. Median age was 5.7 years (range 2·1–16·2 years; interquartile range (IQR) 4·5–9·1 years). Among 18 subjects randomised to I/T/TEM, 1 PR was observed (5·6%, 95% confidence interval (CI): [0·0%, 16·1%]). Among 17 patients randomised to I/T/DIN, 9 (53%, 95% CI: [29·2%, 76·7%]) had objective responses (4 PR, 5 CR), including responses in 5/10 patients with relapsed/progressive disease and 4/7 with refractory disease. I/T/DIN met protocol-defined criteria for selection as the combination meriting further study. The most common ≥Grade 3 toxicities among I/T/TEM patients were neutropenia ...

The objective of this study was prospectively to investigate the health-related quality of life (HRQOL) of 80 pediatric recipients of allo-SCT for malignant and non-malignant diseases. The PedsQL 4.0 was used to assess self-reported physical, emotional and social functioning of children X5 years old once, pre-allo-SCT and on days þ 100, þ 180, þ 365 and þ 730. Emotional and social functioning was stable pre-to-post-allo-SCT and comparable to the normative sample (P40.05), and physical functioning was 17 points lower pre-allo-SCT (Pp0.01) with improved scores equivalent to the norms by day þ 730. Lower physical scores were reflected by 50-54% of children reporting difficulties with movement, strength, pain and fatigue. At baseline, children ages 5-7 reported lower social functioning (Po0.05) and patients with non-malignant disease reported better physical functioning (Po0.05). Emotional functioning in ages 8-12 improved over time (Po0.05). More than 50% of the participants were minority and their HRQOL was similar to non-minority participants. Physical functioning significantly improved for recipients of reduced-toxicity conditioning (Pp0.01), significantly worsened for patients with chronic GVHD (cGVHD; Po0.05), and significantly decreased in recipients of matched-unrelated donor transplant who developed cGVHD (Po0.05). Multidisciplinary efforts are necessary to identify and support pediatric patients' physical needs to improve functional outcomes.

The identification of germline pathogenic variants in young adult cancer patients is especially critical given risk of second primary cancers, need for appropriate long-term surveillance, potential reproductive implications, and cascade testing of at-risk family members. We sought to determine the prevalence of germline susceptibility in cancer patients, age 18-39, across diverse solid tumor phenotypes. A total of 1201 cases, diagnosed between ages 18-39 were prospectively ascertained from 2015-2019 under a human subjects-approved protocol that provided result transmission of germline analysis. A next-generation sequencing panel consisting of up to 88 genes previously implicated in cancer predisposition (MSK-IMPACT) was utilized. Based on SEER data, we refined our population of young cancer patients into those with 1) early-onset cancer (EO-CA), defined as cancer wherein age 39 is >1 standard deviation (STD) below the mean age of diagnosis for that cancer type and 2) young-adult cancer (YA-CA), defined as cancer wherein age 39 is <1 STD below the mean age at cancer diagnosis. Among EO-CA (n=877) cases, the most common cancers included colorectal, breast, kidney, pancreas, and ovarian cancer, while among YA-CAs (n=324), the most frequent diagnoses were sarcoma, brain, testicular and thyroid cancer. Germline prevalence of likely pathogenic or pathogenic variants (PV) was 21% in the EO-CA versus 13% in YA-CA patients (p=0.002), with an enrichment of high- and moderate-penetrance PVs in the EO-CA cohort (15% vs 10%; p=0.01). Among EO-CAs, the most commonly mutated genes were BRCA2, BRCA1, CHEK2 and ATM, with pancreas, breast, and kidney cancer harboring the highest rates of germline PVs. In contrast, in the YA-CA cohort, TP53 and SDHA mutations predominated. Among YA-CA patients with sarcoma, the 18.1% mutation prevalence was similar to the prevalence in EO-CAs. Matched tumor analyses assessing biallelic inactivation is on-going and will be presented. Among young adults with early-onset phenotypes of malignancies typically presenting at later ages, the increased prevalence of germline PVs supports a role for genetic testing irrespective of tumor type. Citation Format: Zsofia K. Stadler, Anna Maio, Angelika Padunan, Yelena Kemel, Erin Salo-Mullen, Margaret Sheehan, Kimeisha Belanfanti, Prince R. Tejada, Ozge Birsoy, Diana Mandelker, Liying Zhang, Jesse Galle, Darren Feldman, Laura Boucai, Julia Glade Bender, Anna Piotrowski, Carol Aghajanian, Karen A. Cadoo, Maria I. Carlo, Michael Walsh, Yelena Janjigian, Eileen O'Reilly, Lisa M. DeAngelis, David B. Solit, Barry Taylor, Andrea Cercek, William Tap, Mark E. Robson, Michael F. Berger, Kenneth Offit, Luis A. Diaz. Germline mutation prevalence in young adults with cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1122.

Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children.Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations.There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors.However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults.Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous systemepenetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation.This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

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