PurposeWe conducted a phase I/II study to evaluate durvalumab (D; anti-PD-L1) in combination with tremelimumab (T; anti–cytotoxic T-lymphocyte antigen 4) in pediatric patients with relapsed/refractory solid tumors.Patients and methodsThe dose-finding phase (phase I) assessed the safety and pharmacokinetics of D+T at two dose levels to determine the recommended phase II dose (RP2D). The primary endpoint for the dose-expansion phase (phase II) was antitumor activity (by Response Evaluation Criteria in Solid Tumors v1.1) at the RP2D. Assessment of circulating cells reflecting immune cell activation was a secondary endpoint.ResultsBased on safety and pharmacokinetic data in the dose-finding phase (n = 29), the adult-equivalent RP2D was determined as D (30 mg/kg) + T (1 mg/kg). In the dose-expansion phase, 21 patients (sarcoma, n = 11; solid tumors, n = 10) were treated at the RP2D. Of patients with sarcoma, none achieved an objective response and one had stable disease ≥7 weeks. Of the patients with solid tumors, one (chordoma) had a confirmed partial response (10.8 months duration) and one (renal cell carcinoma) had stable disease ≥7 weeks. Treatment-related adverse events occurred in 76% of patients (19% as grade 3 or 4). No adverse events leading to death were reported. Across both phases treatment with D+T resulted in an increase in CD4+Ki67+ T cells.ConclusionsD (30 mg/kg) + T (1 mg/kg) had limited antitumor activity in this pediatric population; however, the safety profile was manageable and consistent with the known safety profile in adult patients, with no new safety concerns identified.Clinical trial registrationClinicalTrials.gov, identifier NCT03837899; EudraCT, identifier 2018-003118-42.

[This corrects the article DOI: 10.3389/fonc.2026.1680081.].

Viral infections and seasonality are linked with trends in new pediatric leukemia and lymphoma cases. The COVID-19 pandemic disrupted this norm, and subsequently the international medical community observed a decrease in new diagnoses of hematologic cancers in children. However, this was not the trend observed at Cohen Children’s Medical Center where, despite examining fifteen months during the COVID-19 pandemic, we did not see a statistically significant decrease in monthly cases. Rather, cases remained constant as compared to pre-COVID-19 periods. This warrants further study at a multi-institutional level to investigate the association between COVID-19 and rates of pediatric leukemia and lymphoma.

BACKGROUND:High-grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole is an anti-helminthic benzimidazole that has demonstrated efficacy in numerous in vitro cancer models, and is able to cross the blood-brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of mebendazole in combination with bevacizumab and irinotecan in children and young adults with HGG.OBJECTIVE:To determine the maximally tolerated dose of mebendazole when given in combination with bevacizumab and irinotecan in children with HGG; to describe the progression-free survival (PFS) and overall survival (OS) for this group.DESIGN/METHOD:Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of mebendazole in combination with bevacizumab (10 mg/kg/dose) and irinotecan (150 mg/m2 /dose). Subjects were eligible upfront after completion of radiation or at the time of progression. Mebendazole was taken orally twice per day continuously, and bevacizumab and irinotecan were given intravenously on Days 1 and 15 of 28-day cycles.RESULTS:Between 2015 and 2020, 10 subjects were enrolled at mebendazole doses of 50 mg/kg/day (n = 3), 100 mg/kg/day (n = 4), and 200 mg/kg/day (n = 3). One subject assigned to 100 mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, one subject had anaplastic astrocytoma, and one subject had a spinal HGG. All subjects received radiation. There were no dose-limiting toxicities. The most frequent G3/4 adverse events were neutropenia (n = 3) and lymphopenia (n = 4). The overall response rate was 33%, with two subjects achieving a partial response and one subject achieving a complete response sustained for 10 months. The mean PFS and OS from the start of study treatment were 4.7 and 11.4 months, respectively.CONCLUSION:Mebendazole was safe and well tolerated when administered with bevacizumab and irinotecan at doses up to 200 mg/kg/day. Further studies are needed to determine the efficacy of this treatment.

TPS10068 Background: Survival for high-risk neuroblastoma (NBL) remains poor with over 50% of patients experiencing disease relapse. The addition of dinutuximab (DIN) and granulocyte macrophage colony-stimulating factor (GM-CSF) to irinotecan (IRN) and temozolomide (TMZ) in patients with first relapse achieved an overall response rate of 42% in the study ANBL1221 1 and is now standard of care. However, there remains a significant unmet need to improve outcomes for children with relapsed/refractory NBL. Deregulation of the Cyclin D/cyclin-dependent kinase (CDK) 4 & 6 pathway has been observed in NBL, rendering CDK4 & 6 inhibition logical to explore. Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor approved to treat breast cancer. JPCS (NCT04238819) is designed to assess the pharmacokinetics, safety, and tolerability of abemaciclib added to standard treatment regimens for relapsed/refractory pediatric solid tumors. Part A defined the recommended phase 2 dose (RP2D) of abemaciclib in combination with IRN and TMZ. In Part C, the addition of DIN + GM-CSF to the JPCS Part A regimen will be evaluated. The co-primary objectives of Part C are to determine the RP2D and to estimate the anti-tumor activity of abemaciclib added to the ANBL1221 chemoimmunotherapy backbone in patients with first relapse/refractory NBL. Methods: JPCS Part C is a two-stage, non-randomized, open-label, Phase 1b/2 study for patients < 21 years of age with first relapse/refractory NBL. Stage 1 aims to identify the maximum tolerated dose (MTD) of abemaciclib at a starting dose of 55 mg/m 2 combined with DIN, GM-CSF, IRN and TMZ using a 3+3 design. One dose de-escalation (30 mg/m 2 ) will be possible if the starting dose is not tolerated. Further tolerability and initial anti-tumor activity will be evaluated in an expansion cohort at the MTD. Up to 11 evaluable patients will enroll in Stage 1 at the MTD; the MTD will be declared the RP2D if adequate safety and tolerability are observed and ≥6 patients achieve minimal response or better per International Neuroblastoma Response Criteria (INRC). Following determination of the RP2D, Stage 2 will enroll 35 patients. If ≥26 of 46 total patients achieve an INRC minimum response or better, further investigation of this regimen could be warranted. As of 31 Jan 2023, Part C is open for enrollment at one site (US) and additional sites are being evaluated. References: Mody et al. J Clin Oncol. 2020;38(19):2160-2169. Clinical trial information: NCT04238819 .

High-risk neuroblastoma is a highly aggressive solid tumor that most commonly presents in early childhood. Advances in treatment through decades of clinical trials and research have led to improved outcomes. This review provides an overview of the current state of treatment for high-risk neuroblastoma.

Background: Bosutinib is a second-generation Tyrosine Kinase Inhibitor (TKI), approved for adults with Chronic Myeloid Leukemia (CML), and tested for the first time in children in this phase I/II trial, sponsored by Erasmus Medical Center and the Children’s Oncology Group, and funded by Pfizer Inc. The phase I arm established the recommended phase 2 dose (RP2D) in resistant/intolerant (R/I) pediatric patients at 400 mg/m2 QD (max 600 mg/day), based on safety and target exposure as defined in adults. Extrapolation from safety and PK data in R/I children and target exposure from adults established the RP2D for newly diagnosed (ND) patients at 300 mg/m2 QD (max 500 mg/day). Aims: We present updated safety and efficacy results of bosutinib in R/I pediatric patients with CML treated at the RP2D in the phase I and II portion of the study, as well as efficacy data in ND patients. Methods: R/I and ND patients (as per ELN2013 criteria), aged 1-18 years with chronic phase CML, without evidence for organ toxicities, were enrolled. Main exclusion criteria included known T315I or V299L BCR-ABL1 mutations, use of proton pump inhibitors and CYP3A inducers/inhibitors. Due to the rarity of CML in children, the sample size was not based on formal calculations: a total of 60 patients needed to be enrolled in this phase I/II combined study per regulatory authorities’ requirements. Results: Thirteen R/I patients received the RP2D of which 11 were in phase I. Median age was 15 (range: 6-17) years, sex M:F ratio 8:5. Twelve patients were resistant and 1 intolerant to prior therapy with 5 patients having received ≥2 previous TKIs. Seven were reported in Complete Cytogenetic Response (CCyR) at baseline including 2 with Major Molecular Response (MMR). Ten patients received the capped dose of 600 mg/day. Median follow-up was 11 (range 1-25) months. At the RP2D, one patient experienced a DLT in phase I (transaminase and bilirubin increase and rash). Gastrointestinal (GI) and skin toxicities were the most common; namely 12/13 (92%) with diarrhea, of which 2 (17%) were grade 3/4, and 8/13 (62%) with skin rash, of which 1 (13%) was grade 3/4. At time of dataset lock (February 14, 2023), 11/13 (84.6%) R/I patients achieved/maintained CCyR, and 7/13 (53.8%) MMR, as best response. One patient who achieved CCyR on treatment lost the response after 12 months, while all patients which entered the study with either CCyR or MMR maintained the response. Of the 5 patients not in CCyR at baseline, 4 (80%, 95%CI: 28-99%) achieved CCyR and 1 had no response data available (on treatment for <1 month). Of the 10 patients not in MMR at baseline, 5 (50%, 95%CI: 19-81%) achieved MMR on study (2 had no response data available, on treatment for <3 months). Median time to response was 3 months for CCyR and 8 months for MMR. Two patients permanently discontinued the drug due to toxicities (one rash, one persistent GI toxicity and fatigue), three due to insufficient response. In phase II, 24 ND patients were enrolled: sex M:F ratio 15:9, median age 13 (range: 5-17) years. The median follow-up was 14 (range: 0.9-31) months. Cumulative incidence of CCyR was 77% (47%-91%) and 88.3% (95%CI 55%-98%) at 6 and 12 months respectively, and for MMR it was 23% (95%CI 7%-46%) and 30% (95%CI 10%-54%). Three patients permanently discontinued bosutinib due to intolerance four due to unsatisfactory response with 17 still on treatment at time of dataset lock. Summary/Conclusion: Bosutinib at the RP2D was well-tolerated and its preliminary efficacy in R/I and ND pediatric patients seems comparable to that recorded in adult patients treated with the same drug and in line with other second generation TKIs. Keywords: Pediatric, Chronic myeloid leukemia, Clinical trial

Background. The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. Methods. We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. Results. Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Conclusions. Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

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SUCCESSFUL USE OF CRUSHED FORMULATION OF DABRAFENIB AND TRAMETINIB IN A PEDIATRIC GLIONEURAL TUMORTania Mamdouhi1, Anshul Vagrecha2, Alan A. Johnson1,3, Carolyn Fein Levy1,2, Mark Atlas 1,2, Julie I. Krystal 1,2 1 Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY2 Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children’s Medical Center, New Hyde Park, NY3 Department of Radiology, Division of Neuroradiology, Long Island Jewish Medical Center, New Hyde Park, NYCorresponding Author : Julie Krystal. Cohen Children’s Medical Center, 269- 01 76th Avenue, Suite 255, New Hyde Park, NY 11040. Jkrystal12@northwell.edu. Phone 718-470-3460. Fax 718-343-4642.Tables: 0Figures: 1Supporting Information Files : 0Short running title: Use of crushed formulation of dabrafenib and trametinibKeywords : Dabrafenib, Trametinib, BRAF, crushedData Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Olaratumab is a monoclonal antibody that specifically binds to platelet‐derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21‐day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high‐dose ifosfamide by investigator choice for subsequent 21‐day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A‐C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose‐limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma‐glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment‐emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

Abstract INTRODUCTION Diffuse intrinsic pontine glioma (DIPG) is an aggressive and fatal pediatric brain tumor. Due to its difficult anatomic location and infiltrative nature, DIPGs are not surgically resectable and more than 90% of children die within two years of diagnosis. Historically, standard of care has consisted of clinical and radiological diagnosis followed by palliative radiation for symptomatic relief. Although tumor biopsy is not necessary for diagnosis, there is debate as to whether the procedure provides benefits that outweighs its risk. Recent studies have proposed that biopsy-driven molecular characterization of these tumors can inform prognosis and identify potential treatment targets that could lead to clinical breakthroughs. METHODS This study was a retrospective chart review of 26 patients treated for a DIPG diagnosis between July 1998 and July 2019 at Cohen Children’s Medical Center. We compared outcomes of biopsied vs. non-biopsied DIPG patients through quantitative data analyzing the number and types of treatment given. We analyzed post-surgical data regarding safety of DIPG biopsies which were performed by optical stereotactic needle biopsy or robot-assisted stereotactic biopsy procedures. RESULTS There were no permanent biopsy complications in any patient and biopsy did not delay treatment as average hospital stay was 1.5 days. All biopsies collected sufficient material for next generation sequencing analysis and revealed targetable mutations for available clinical trial therapies. 67% of patients were subsequently enrolled in clinical trials, 75% of which required biopsy results for enrollment. MGMT promoter methylation assay results in all tested DIPG biopsy cases indicated resistance to temozolomide, the most common treatment agent given to non-biopsied patients. CONCLUSION Biopsy of DIPG tumors is a safe and accurate procedure that does not delay treatment and identifies molecular targets for individualized therapy. The role of biopsy in DIPG patients allows for molecular characterization of DIPG tumors which informs and increases treatment options.