291 pubs · 27,076 cites · h-index 87
PURPOSE Identification of discrete risk groups remains a high priority for patients with Ewing sarcoma (EWS). We sought to prospectively validate circulating tumor DNA (ctDNA) as a prognostic factor and develop clinical-molecular risk groups. METHODS We conducted a prospective investigator-initiated biology study for patients with localized EWS (LEOPARD) and embedded ctDNA analysis into the North American frontline metastatic study AEWS1221. Eligible patients were younger than 50 years with newly diagnosed EWS. All patients provided a baseline blood sample for analysis, which was subjected to ultralow-pass whole-genome sequencing and hybrid capture panel sequencing for ctDNA quantification, fusion detection, and characterization of STAG2 and TP53 alterations. Serial ctDNA sequencing was conducted on a subset of patients in each study. We tested for associations between ctDNA burden and secondary genomic events, and clinical features and outcomes. RESULTS One hundred forty patients with localized disease and 255 with metastatic disease provided evaluable pretreatment samples for ctDNA analysis. Elevated baseline ctDNA was associated with stage, tumor size, primary site, indeterminate pulmonary nodules, and metastatic pattern. Elevated pretreatment ctDNA burden was associated with inferior outcomes in patients with localized (n = 140, hazard ratio [HR] = 2.36, P = .032) and metastatic disease (n = 255, HR = 2.15, P = .001). Patients with metastatic disease and TP53 variants and/or persistent on-therapy ctDNA had dismal outcomes. Patients with localized disease, low ctDNA, small tumors, and favorable genomics had no events and constitute a novel low-risk group. Among patients with metastatic disease, those with lung-only disease, low ctDNA, and favorable genomics represent an intermediate-risk group. CONCLUSION This study prospectively validates pretreatment ctDNA burden as prognostic in EWS. Risk groups that integrate ctDNA burden with clinical-molecular features differentiate patients with low-, intermediate-, and high-risk disease.
Retrospective study shows efficacy of Topotecan with Dinutuximab in relapsed neuroblastoma, indicating promising outcomes for prior chemoimmunotherapy patients.
BACKGROUND: Displaced medial epicondyle fractures are among the most controversial injuries in children, with increasing trends towards surgical fixation despite little supporting evidence. Approximately half of affected children undergo surgical fixation, while others receive non-surgical care. The SCIENCE trial aimed to determine whether surgical fixation to restore the position of the bone provides superior functional outcomes and is cost-effective compared with non-surgical care. METHODS: We conducted a pragmatic multicentre, randomised, superiority trial across 59 hospitals in the UK, Australia, and New Zealand. Recruiting sites were secondary or tertiary care hospitals providing acute paediatric trauma care. Eligible participants were aged 7-15 years with a displaced medial epicondyle fracture and patients were excluded if the injury occurred more than 2 weeks prior, they had a medial epicondyle fragment that was incarcerated (trapped) within the joint, the injury was part of a complex elbow fracture (ie, extending into the joint), or there were additional fractured bones outside of the elbow. Participants were randomly assigned (1:1) to either surgical fixation or non-surgical care using a web-based randomisation software from Oxford Clinical Trials Research Unit, with minimisation (including a random element) stratified by centre and elbow dislocation status at presentation. Participants and their parents and carers could not be masked to treatment. Surgical fixation was performed under general anaesthesia and involved a surgical incision, restoration of the anatomical alignment, and fixing the fragment, typically with a screw or wires. Non-surgical care involved immobilisation of the elbow at approximately 90° of flexion using a cast, splint, or sling. Both groups were allowed mobilisation as pain allowed, although cast immobilisation beyond 4 weeks was discouraged. The primary outcome was upper limb function at 12 months, measured using the Patient Report Outcomes Measurement System (PROMIS) Upper Extremity Score for Children in the intention-to-treat population, which included all participants in the groups to which they were randomly assigned, irrespective of treatment received. Complications and serious adverse events were summarised in a safety (as-treated) population defined by treatment received. A within-trial economic evaluation was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time period. The trial was registered with ISRCTN, ISRCTN16619778; recruitment is complete and extended follow-up to age 16 years is ongoing. FINDINGS: Between June 10, 2019, and Sept 22, 2023, 647 patients from 59 sites met the inclusion criteria. 146 patients were excluded (64 due to the injury being more than 2 weeks old and 24 because the epicondyle fragment was incarcerated within the joint), 161 families of children meeting the eligibility criteria declined to participate, and for five patients there was no clinician equipoise. 335 participants were randomly assigned to an intervention (166 to the non-surgical care group and 168 to the surgical fixation group) and one was immediately excluded due to a randomisation error. Primary outcome data were collected from 285 (85%) participants. 170 (51%) participants were female and 164 (49%) were male. Mean participant age at baseline was 11·7 years (SD 2·3). At 12 months post-randomisation, the PROMIS Upper Extremity score was 53·1 (SD 7·8) in the non-surgical care group and 54·3 (5·7) in the surgical fixation group (mean treatment difference, 1·57 [95% CI -0·01 to 3·14; p=0·052]). This estimate of treatment effect was below the clinically important difference specified (4 points), supporting the conclusion that a clinically important effect is unlikely. Additional episodes of surgery, either planned or related to complications, occurred in 24 participants in the surgical group and three in the non-surgical group. Among the 150 participants who underwent surgical fixation, there were 14 intraoperative complications from 13 (9%) participants, and seven participants had a postoperative complication (5% participants) each requiring surgery. Routine screw or wire removal was undertaken in a further 17 (11%) participants. From the 184 participants in the non-surgical group, there were five complications among four (2%) participants, three (2%) of which required additional surgery. The mean per patient cost from the NHS and Personal Social Services perspective was £2435 (95% CI 1812 to 3057) more for participants in the surgical fixation group with a mean per patient quality-adjusted life year difference of -0·008 (95% CI -0·039 to 0·024). The probability that surgical fixation is cost-effective at the £20 000 or £30 000 per quality-adjusted life year willingness-to-pay threshold was 0%. INTERPRETATION: The SCIENCE trial demonstrates that surgical fixation offers no clinical benefit and is not cost-effective compared with non-surgical care, while exposing children to avoidable surgical risks. These findings suggest that non-surgical care should be adopted as the default management strategy for these injuries, regardless of initial elbow dislocation status.
Phase I trial established MTD of nab-paclitaxel with gemcitabine in children with solid tumors, indicating critical toxicity levels.
Analysis reveals lower event-free survival and overall survival in mixed biology toddlers with unfavorable biologic features, suggesting urgent trial inclusion is needed.
Analysis highlights improved survival rates in pediatric cancer through clinical trials, suggesting a need for more pediatric-specific data.
PURPOSE We conducted a phase I trial to determine the safety, tolerability, and preliminary antitumor activity of 131 I-metaiodobenzylguanidine (MIBG) combined with the anti-GD2 antibody dinutuximab with or without the histone deacetylase inhibitor vorinostat in patients with relapsed/refractory neuroblastoma (rNBL). METHODS In part A, patients with MIBG-avid rNBL received MIBG intravenously (IV) on day 1 at 12, 15, or 18 mCi/kg per the rolling six design and dinutuximab (17.5 mg/m 2 once daily) IV on days 8-11 and 29-32 and granulocyte-macrophage colony-stimulating factor (250 mcg/m 2 once daily) subcutaneously on days 8-17 and 29-38. Autologous stem cells were infused on day 15. In part B, vorinostat at 180 mg/m 2 once daily was given orally on days 0-13 in combination with the part A recommended phase II dose (RP2D). Patients could receive two courses. RESULTS Forty-five eligible patients enrolled, of whom 31 were evaluable. The median age was 7.5 (range, 2.9-24.1) years. For part A (n = 19), no dose-limiting toxicities (DLTs) occurred across all dose levels and courses, establishing the RP2D of MIBG to be 18 mCi/kg. In part B (n = 12), 1 DLT (grade 3 hypokalemia) occurred during course 1, and 3 of 11 patients who received a second course experienced DLT: grade 3 ALT increase, grade 4 hypoxia and grade 5 pneumonitis, and grade 3 fatigue. The best overall response rate (BORR; complete response [CR] + partial response [PR]) on part A was 42% with a CR/PR/minor response (MR) rate of 46%, and 19% progressive disease (PD) rate. For part B, the BORR was 42% with a CR/PR/MR rate of 75% and 0% PD rate. CONCLUSION MIBG combined with dinutuximab was well tolerated with encouraging antitumor activity. Vorinostat added to this combination may augment responses in this heavily pretreated patient population.
Failure of osseointegration and periprosthetic fractures are common complications of total wrist arthroplasty. A recent increase in the incidence of the latter is hypothesized to be a result of using larger implants to avoid the former. In this mixed-methods, case–control study of the Motec® arthroplasty, six cases of failure of osseointegration were compared with eight periprosthetic fractures and 14 controls without either problem. Compared with the controls, periprosthetic fractures occurred in younger patients with better bone health and a narrower medullary diameter of the middle finger metacarpal, in which a narrow medullary isthmus was widened to facilitate screw insertion. Failure of osseointegration occurred in older patients with wider metacarpal diameters. It can, however, also occur with over-reaming in younger patients and is more common with off-axis screw insertion. The results of this study suggest that periprosthetic fracture and failure of osseointegration may be opposite ends of a spectrum, with successful osseointegration in between. Both complications should be avoidable with careful surgical technique. Level of evidence: III
INTRODUCTION: The COVID-19 pandemic onset had a global debilitating impact on individuals and on burgeoning careers. In 2021, the Children's Oncology Group Young Investigators Committee, Young SIOP (International Society of Paediatric Oncology) Network, and Young SIOPE (European Society for Paediatric Oncology) co-sponsored a survey to explore the impacts of the first year of the pandemic on early-career pediatric oncology professionals with respect to working practices, productivity, professional and career development, personal wellbeing, and changing childcare needs. METHODS: The survey comprised demographic, multiple-choice, and free-text questions, and was distributed via email and social media with English, French, and Spanish versions available. Descriptive statistics and chi-square tests were used to compare quantitative data by self-designated gender and country of origin. Qualitative data were described using content analysis. RESULTS: Professionals (N = 499, 26.3% male, 77.2% MDs) in 48 countries (77.6% high income) responded in English (79.4%), Spanish (12.4%), and French (8.2%). Respondents had difficulty obtaining and keeping jobs (26.9%), worsened overall academic productivity (50.7%, with higher rates among bench scientists, p < 0.01), and decreased career opportunities (40.9%). Childcare challenges impacted 56.7% of respondents and was felt more negatively among women (p = 0.008) and in high-income settings (p < 0.0001). Qualitative data (n = 300) highlighted these differences were often attributable to diminished professional/personal boundaries and impacted their personal wellbeing. CONCLUSION: The COVID-19 pandemic significantly impacted early-career academic and clinical professionals working in pediatric oncology, with unique challenges noted among those with childcare responsibilities. Career disruptions that resulted from the pandemic should be considered and mitigated by governing bodies and hiring institutions.
BACKGROUND: Cyclin-dependent kinases 4 and 6 (CDK 4/6) control cell cycle progression through phosphorylation of Rb. Tumor tissue studies in diffuse intrinsic pontine glioma (DIPG) demonstrate frequent alterations in cell cycle regulatory proteins, including CDK 4/6, and infrequent deletions in Rb1. Preclinical DIPG studies have demonstrated prolonged survival when CDK 4/6 inhibition is added to radiation therapy (RT) compared to RT alone. Abemaciclib is a selective and potent, orally bioavailable small molecule CDK 4/6 inhibitor that crosses the blood brain barrier. We conducted a Phase 1 trial to determine the maximum tolerated dose (MTD) of abemaciclib administered concurrently with RT, and to describe the toxicity and pharmacokinetic (PK) profile, in patients with newly diagnosed DIPG. METHODS: Patients 2-25 years of age with newly diagnosed DIPG were eligible. A CDK 4/6 pathway alteration was not required, and patients with known RB1 mutations were excluded. Abemaciclib was administered orally twice daily on days 1-28 of a 28-day cycle. Four dose levels (DLs) were evaluated using a rolling-six design: 75 (DL0), 100 (DL1), 130 (DL2), and 170 (DL3) mg/m2/dose. Abemaciclib started concurrently with RT and was continued as maintenance after completion of RT until the patient experienced progression or unacceptable toxicity. The 6-week duration of RT (54 Gy in 30 fractions) constituted the dose-limiting toxicity (DLT) evaluation period. The PKs of abemaciclib were evaluated at serial timepoints. RESULTS: Median age of the 22 enrolled patients was 7.1 years (range: 2.6 - 20.1). Eleven (50%) patients were biopsied; 10 were histologically defined as H3K27M mutant diffuse midline glioma. In seventeen DLT-evaluable patients, there was 1 DLT during the DLT evaluation period, grade 3 nausea that occurred on DL3. There were 5 DLTs during maintenance: 3 episodes of prolonged grade 3 neutropenia (DL1=1 and DL2=2) and one episode of grade 4 neutropenia (DL0), and grade 3 weight loss (DL3). The predominant abemaciclib-related toxicities were low-grade and hematologic in nature, including leukopenia (80%), lymphopenia (70%), neutropenia (65%), diarrhea (60%), anemia (50%), and nausea (45%). PK analysis demonstrated that abemaciclib exposure increased with increasing dose. The apparent clearance (CL/F) increased with increasing weight/body surface area, and there was extensive variability in exposure across doses and weight ranges. Mean abemaciclib trough concentrations achieved the target associated with preclinical and clinical efficacy (200 ng/mL) at the 130 and 170 mg/m2 dose levels. The median progression-free survival for all patients was 7.5 months (range: 3.0-21.3) and median overall survival was 12.4 months (range: 2.6-29.0); 2 (10%) patients survived > 24 months. CONCLUSIONS: The MTD of abemaciclib administered concurrently with RT to pediatric patients with newly diagnosed DIPG was 170 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly low-grade hematologic toxicity and diarrhea. Citation Format: Thomas Cash, Dolly Aguilera, Zhulin He, Melissa Schink, Amanda Sykes, Celine Pitou, Erin Connelly, Bree Eaton, Natia Esiashvili, Ross Mangum, Margaret E. Macy, Robert C. Castellino, Jason Fangusaro, Tobey J. MacDonald, Cynthia Wetmore, Lindsey Hoffman. A phase 1 study of abemaciclib, a CDK 4/6 inhibitor, with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B065.
Background Children with neuroblastoma receiving I‐131 metaiodobenzylguanidine (MIBG) therapy require sedation‐analgesia for strict radiation safety precautions during MIBG infusion and clearance. We evaluated the sedation‐analgesia trends of patients undergoing MIBG therapy using the Pediatric Health Information System (PHIS) database. Materials and methods Retrospective data from 476 patient encounters from the PHIS from 2010 to 2019. Results Total 240/476 (50.45%) children evaluated were under 6 years of age. Compared to 2010, in 2018 there was a decrease in benzodiazepine infusion use (60% vs. 40%, p < .04), as well as a decrease in use of opiate infusion (35% vs. 25%, p < .001). Compared to 2010, in 2018 we report an increase in the use of ketamine (from 5% to 10%, p < .002), as well as an increase in dexmedetomidine use (0% vs. 30%, p < .001). Dexmedetomidine was the most used medication in the 0–3 years age group compared to children older than 3 years of age (14.19% vs. 5.80%, p < .001). Opiate was the most used medication in children greater than 3 years compared to the 0–3‐year age group (36.23 vs. 23.87, p < .05). Conclusion Using PHIS data, we discovered considerable variability in the medications used for sedation in patients undergoing MIBG therapy. Although benzodiazepines and opioids were the most used agents, there was a trend toward decreasing use of benzodiazepines and opioids in these patients. Furthermore, there has been an increasing trend in the use of dexmedetomidine and ketamine.
11510 Background: Prior retrospective analyses demonstrated that elevated pre-treatment ctDNA was associated with poor outcomes in newly diagnosed localized osteosarcoma. The primary objective of the LEOPARD study (Liquid biopsy in Ewing sarcoma and osteosarcoma as a prognostic and response diagnostic) was to determine whether patients with detectable pre-treatment ctDNA have an inferior event-free survival (EFS) compared to patients with undetectable ctDNA. Methods: The LEOPARD study is a prospective multicenter ctDNA study for patients with bone sarcomas. Patients enrolled through 12 primary study sites, or provided samples after enrolling on the Children’s Oncology Group Project EveryChild (ABTR18B1-Q). Eligible patients were 1-50 years of age at enrollment, had unresected, high-grade, localized, non-pelvic osteosarcoma and were to receive standard chemotherapy (primary centers only). We utilized a validated ctDNA assay, ultra-low pass whole genome sequencing (ULP-WGS), for ctDNA quantification based on tumor aneuploidy (limit of detection 3%). We compared EFS according to baseline ctDNA burden using two pre-specified cut points (detectable/undetectable [≥3%] and ~median [≥5%]. We planned 113 patients for 80% power to detect a difference in 2-year EFS of ~20% or greater for patients with detectable baseline ctDNA (2-year EFS: 68%) vs undetectable ctDNA (2-year EFS: 87%; one-sided log-rank test; ⍺ =0.05). Results: From 10/1/17 to 3/3/23, 138 patients with osteosarcoma met eligibility and enrolled (67 - primary study centers; 71 - ABTR18B1-Q). 133 patients had an evaluable pre-treatment ctDNA measurement. Median age was 14.2 years (range: 4.2-30.3) and 50% of patients were male. At diagnosis, 63% had detectable ctDNA [median: 5.3% (range: 0-43.1)]. Age, sex, race, ethnicity, and tumor size were not associated with a difference in ctDNA burden. Baseline detectable ctDNA burden (≥3%) was associated with an increased risk of EFS-event (relapse/progression, second malignant neoplasm, death) compared to undetectable ctDNA (2-year EFS: 56% [95% CI 45-68%] vs. 88% [95% CI 78-98%]; P< 0.0001; Table). A similar pattern was seen using a cut point of ≥5% (53% [95% CI 41-67%] vs. 83% [95% CI 74-94%], P< 0.0001). Conclusions: These findings validate prior data associating baseline ctDNA detection with inferior EFS in patients with localized osteosarcoma and identify the first prospectively validated molecular biomarker in this disease. Baseline ctDNA burden is now positioned for implementation into upcoming therapeutic trials of risk-stratified therapy in localized osteosarcoma. [Table: see text]
The ReMotion wrist replacement has good short- to medium-term survival with an acceptable complication profile as we previously reported in a cohort of patients with rheumatoid arthritis. We now report the long-term results of the same cohort and details of explant analysis of revisions undertaken for aseptic loosening. A total of 16 wrists were reviewed. Seven prostheses remain in situ with no obvious signs of wear or radiological loosening at a mean follow-up of 15.5 years. Three wrists had been revised: one for infection and two for aseptic loosening. Five patients (six wrists) died 2–9 years after operation from unrelated causes. Explant analysis demonstrated relatively minor wear compared with the published results of the Universal-2 prosthesis. We hypothesize that this may be explained by differences in polyethylene sterilization and prosthetic design. The ReMotion wrist replacement has favourable long-term results in patients with rheumatoid arthritis with a 16-year survival rate of 78%–86%. Level of evidence: IV
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.
Background 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitors (statins) can inhibit tumor proliferation, angiogenesis, and restore apoptosis in preclinical pediatric solid tumor models. We conducted a phase 1 trial to determine the maximum tolerated dose (MTD) of simvastatin with topotecan and cyclophosphamide in children with relapsed/refractory solid and central nervous system (CNS) tumors. Methods Simvastatin was administered orally twice daily on days 1–21, with topotecan and cyclophosphamide intravenously on days 1–5 of a 21‐day cycle. Four simvastatin dose levels (DLs) were planned, 140 (DL1), 180 (DL2), 225 (DL3), 290 (DL4) mg/m2/dose, with a de‐escalation DL of 100 mg/m2/dose (DL0) if needed. Pharmacokinetic and pharmacodynamic analyses were performed during cycle 1. Results The median age of 14 eligible patients was 11.5 years (range: 1–23). The most common diagnoses were neuroblastoma (N = 4) and Ewing sarcoma (N = 3). Eleven dose‐limiting toxicity (DLT)‐evaluable patients received a median of four cycles (range: 1–6). There were three cycle 1 DLTs: one each grade 3 diarrhea and grade 4 creatine phosphokinase (CPK) elevations at DL1, and one grade 4 CPK elevation at DL0. All patients experienced at least one grade 3/4 hematologic toxicity. Best overall response was partial response in one patient with Ewing sarcoma (DL0) and stable disease for four or more cycles in four patients. Simvastatin exposure increased with higher doses and may have correlated with toxicity. Plasma interleukin 6 (IL‐6) concentrations (N = 6) showed sustained IL‐6 reductions with decrease to normal values by day 21 in all patients, indicating potential on‐target effects. Conclusions The MTD of simvastatin with topotecan and cyclophosphamide was determined to be 100 mg/m2/dose.
BACKGROUND: Infections cause significant treatment-related morbidity during pediatric acute lymphoblastic leukemia/lymphoma (ALL/LLy) therapy. Fevers during periods without severe neutropenia are common, but etiologies are not well-described. This study sought to describe the bloodstream infection (BSI) and non-BSI risk in children undergoing therapy for ALL/LLy. METHODS: Demographic and clinical data were abstracted for febrile episodes without severe neutropenia at two children's hospitals. Treatment courses were stratified by intensity. Multivariate logistic regression evaluated characteristics associated with infection. RESULTS: There were 1591 febrile episodes experienced by 524 patients. Of these, 536 (34%) episodes had ≥1 infection; BSI occurred in 30 (1.9%) episodes. No BSIs occurred in episodes with a recent procedural sedation or cytarabine exposure. Presence of hypotension, chills/rigors, higher temperature, and infant phenotype were independently associated with BSI (p < .05). Of the 572 non-BSIs, the most common was upper respiratory infection (URI) (n = 381, 67%). Compared to episodes without infection, URI symptoms, higher temperature, absolute neutrophil count 500-999/μl, and evaluation during a low-intensity treatment course were more likely to be associated with a non-BSI (p < .05) and inpatient status was less likely to be associated with a non-BSI (p < .05). CONCLUSIONS: The BSI rate in pediatric patients with ALL/LLy and fever without severe neutropenia is low, but one-third of the time, patients have a non-BSI. Future research should test if the need for empiric antibiotics can be tailored based on the associations identified in this study.
Approximately half of patients receiving I/T/DIN/GM-CSF for relapsed HRNB had objective responses. Patients with initial SD were unlikely to have an objective response, but > 1 of 3 patients with MR/PR on first evaluation ultimately had complete response. I/T/DIN/GM-CSF was associated with extended PFS in responders both during and after discontinuation of treatment. This study establishes a new comparator for response and survival in patients with relapsed HRNB.
PURPOSE: Profiling of pediatric cancers through deep sequencing of large gene panels and whole exomes is rapidly being adopted in many clinical settings. However, the most impactful approach to genomic profiling of pediatric cancers remains to be defined. METHODS: We conducted a prospective precision medicine trial, using whole-exome sequencing of tumor and germline tissue and whole-transcriptome sequencing (RNA Seq) of tumor tissue to characterize the mutational landscape of 127 tumors from 126 unique patients across the spectrum of pediatric brain tumors, hematologic malignancies, and extracranial solid tumors. RESULTS: We identified somatic tumor alterations in 121/127 (95.3%) tumor samples and identified cancer predisposition syndromes on the basis of known pathogenic or likely pathogenic germline mutations in cancer predisposition genes in 9/126 patients (7.1%). Additionally, we developed a novel scoring system for measuring the impact of tumor and germline sequencing, encompassing therapeutically relevant genomic alterations, cancer-related germline findings, recommendations for treatment, and refinement of risk stratification or prognosis. At least one impactful finding from the genomic results was identified in 108/127 (85%) samples sequenced. A recommendation to consider a targeted agent was provided for 82/126 (65.1%) patients. Twenty patients ultimately received therapy with a molecularly targeted agent, representing 24% of those who received a targeted agent recommendation and 16% of the total cohort. CONCLUSION: Paired tumor/normal whole-exome sequencing and tumor RNA Seq of de novo or relapsed/refractory tumors was feasible and clinically impactful in high-risk pediatric cancer patients.
Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.
Background Prexasertib (LY2606368) is a novel, second‐generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum‐tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors. Methods Prexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28‐day cycle. Four dose levels, 80, 100, 125, and 150 mg/m 2 , were evaluated using a rolling‐six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity. Results Thirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2‐20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose‐limiting toxicities. Common cycle 1, drug‐related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80‐150 mg/m 2 dose range. Conclusions Although the MTD of prexasertib was not defined by this study, 150 mg/m 2 administered i.v. on days 1 and 15 of a 28‐day cycle was determined to be the RP2D.