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AIM There is a crucial need for pharmacokinetic (PK) data of oral vinorelbine (VNR) in pediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS A multicentric, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumors, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The Influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg.m-2 dose level, were 472 L.h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (p = 0.004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among pediatric patients.

Purpose. Some high-risk medulloblastomas (HR-MB) do not respond to induction chemotherapy, with either post-induction stable (SD) or progressive disease (PD). To date, there is no consensus regarding their optimal management. Methods. A retrospective, multicentre study of non-responder HR-MB patients treated according to the PNET HR+5 protocol (NCT00936156) between 01/01/2009 and 31/12/2018. After two courses of etoposide and carboplatin induction chemotherapy, patients with SD or PD were analyzed. Based on the clinician’s decision, the PNET HR+5 protocol was either pursued with tandem high-dose chemotherapy (HDCT) and craniospinal irradiation (CSI) (continuation group) or it was modified (switched group). Results. Forty-nine patients were identified. After induction, 37 patients had SD and 12 had PD. The outcomes were significantly better for the SD group: the 5-y PFS and OS were 52% (95% confidence interval [95% CI] 35-67) and 70% (95% CI 51-83), respectively, in the SD group and 17% (95% CI 3-41) and 13% (95% CI 1-40), respectively, in the PD group (p < 0.0001). The PNET HR+5 strategy was pursued for 3 patients in the PD group, of whom only one survived. In the SD group, it was pursued for 24 patients. The 5-y PFS and the OS were 78% (95% CI 54-90) in the continuation group and 0% and 56% (95% CI 23-79), respectively, in the switched group. In the SD group, multivariate analysis revealed that MYC amplification, molecular group 3, and a switched strategy were independent prognostic factors for progression. Conclusion. Patients with post-induction SD may benefit from HDCT and CSI, whereas improvement of the way patients with early PD are treated will require new therapeutic approaches.

Background: AcSé-ESMART is a proof-of-concept, phase I/II platform trial designed to explore targeted agents in a molecularly enriched pediatric population. WEE1 plays a role in DNA repair and cell cycle control and is overexpressed in pediatric cancers. Adavosertib combinations resulted in enhanced antitumor activity compared to single agent in neuroblastoma, rhabdomyosarcoma, medulloblastoma and high-grade glioma in vivo models. The efficacy and safety of the adavosertib-carboplatin combination has been established in adults with focus on TP53 mutated ovarian cancer. Arm C of AcSé-ESMART applied this regimen to children with advanced malignancies enriched for alterations in TP53, DNA repair/replication stress and cell cycle control. Methods: Adavosertib was administered orally, twice daily on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle. Dose finding used the continuous reassessment method starting at adavosertib 100 mg/m2/dose and carboplatin AUC 5. Pharmacokinetic (PK) and retrospective molecular bioinformatic analysis was performed. Results: Twenty patients (median age: 14.0 years, range 3.4-23.5) were included, 18 received a total of 69 cycles. Seven dose-limiting toxicities (DLTs) were observed leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4. All patients with DLT had thrombocytopenia grade 3/4 requiring transfusions for >7 days and/or neutropenia grade 4 for >7 days. Main overall treatment-related toxicities were hematologic and gastrointestinal. Based on the identified DLT risk, no recommended Phase 2 dose was defined. PK analysis demonstrated equivalent adavosertib exposure in children to that in adults and both doses (75 and 100 mg/m2) achieved the cell kill target. Two patients with neuroblastoma achieved partial response (PR), one with medulloblastoma unconfirmed PR, and five had stable disease (SD) >4 cycles. Patients with PR/SD >4 cycles were considered as clinical benefit (CB) for retrospective molecular analysis. There was no correlation between TP53 genomic alteration alone and response. However, 7 of 8 patients with CB but none of the 10 patients without CB had 1 to 3 genomic alterations in the DNA repair (BRCA2 mutation, 11q loss containing ATM, MRE11A, CHEK1), cell cycle control/replication stress (CCNE1 amplification, RB1 mutation/loss, SETD2 mutation/loss) and RAS pathway (KRAS mutation and amplification, NF1 loss, PTPN11 mutation) in their tumor. Conclusions: Adavosertib combined with carboplatin exhibited significant hematologic toxicity. Activity signals and identified potential molecular biomarkers suggest further combination studies with less hematotoxic DNA damaging therapy in molecularly enriched pediatric cancers. Citation Format: Susanne A. Gatz, Anne C. Harttrampf, Caroline Brard, Francisco J. Bautista, Nicolas André, Samuel Abbou, Jonathan Rubino, Windy Rondof, Marc Deloger, Marc Rübsam, Daniel Hübschmann, Lynley V. Marshall, Souad Nebchi, Isabelle Aerts, Estelle Thebaud, Emilie De Carli, Anne-Sophie Defachelles, Xavier Paoletti, Robert Godin, Kowser Miah, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the WEE1 inhibitor adavosertib in combination with carboplatin in children with advanced malignancies: arm C of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT087.

Background: AcSé-ESMART is a proof-of-concept, phase I/II, platform trial, designed to explore targeted agents in a molecularly enriched relapsed/refractory pediatric population. Arm D was evaluating the PARP inhibitor (PARPi) olaparib (ola) in combination with irinotecan (iri). In contrast to other PARPi/chemotherapy combination studies, we opted for a prolonged course of PARPi and low dose irinotecan as sensitizer. The Phase I part previously established the recommended Phase II dose (RP2D) (Gatz ASCO 2019). This is the report of the Phase II part of the trial assessing the activity in two separate expansion cohorts: cohort 1: homologous recombination repair defect (HRD) and cohort 2: Ewing sarcoma (ES). Methods: Ola was administered orally twice daily at 90 mg/m2 on Days 1 to 10 and iri intravenously at 20 mg/m2 on Days 4 to 8 of a 21-day cycle. Activity assessment followed a Minimax Simon 2-stage design. Each cohort was to progress to the second stage (additional 9 patients) if 2 or more confirmed responses were observed in the first 16 patients. Patients treated in the Phase I part at the RP2D were counting towards the respective expansion cohorts. Results: Seventy patients (median age: 14 years, range 5-23) were included in the whole study, 67 received treatment; 27 patients were treated in the dose escalation part, including 10 at the RP2D (8 in cohort 1 and 2 in cohort 2). Both cohorts passed the 1st stage and a total of 24 and 26 patients were recruited to cohort 1 and 2, respectively. Main diagnoses in cohort 1 were sarcoma (n=10), brain tumor (n=9), neuroblastoma (n=4). In cohort 1, 15 of 24 patients were considered enriched based on molecular alteration at relapse (ATM n=6; BRCA1 n=2; DNA signature 3 n=3; FANCD2, CHEK2, FANCA, ATRX all n=1); all patients in cohort 2 had presence of a ES fusion (ESWR1::FLI1 n=22; EWSR1::ERG n=4). Median number of treatment cycles were 2, range 1;51 in cohort 1 and 1;32+ in cohort 2. In cohort 1, 3 patients had a partial response (PR) (pinealoblastoma, neuroblastoma, choroid plexus carcinoma; treated with 12, 51, 25 cycles), 1 patient an unconfirmed PR (rhabdomyosarcoma, 6 cycles) and 7 patients stable disease (SD) (2 prolonged with 6 and 8 cycles). In cohort 2, 1 patient had a complete response (10 cycles) and 1 a PR (32+ cycles), 7 patients had SD (3 prolonged with 6, 10, 16 cycles). Molecular enrichment did not predict response. Retrospective correlative analysis of the molecular profiling data and tumor tissue expression analysis are ongoing to identify predictive biomarkers for PARPi combination trials and data will be presented. Conclusions: Encouraging clinical benefit was observed with the protracted ola-iri schedule in a subset of patients. Current molecular hypothesis is insufficient for patient selection and better biomarkers are needed. Citation Format: Susanne A. Gatz, Pablo Berlanga, Baptiste Archambaud, Yassine Bouchoucha, Nicolas André, Nadege Corradini, Windy Rondof, Jonathan Rubino, Souad Nebchi, Antonin Marchais, Estelle Thebaud, Alba Rubio San Simón, Natasha K. van Eijkelenburg, Lynley V. Marshall, Anne-Sophie Defachelles, Adela Canyete, Stephane Ducassou, Guy Makin, Michela Casanova, Emilie De Carli, Arnaud Petit, Gwenael Le Teuff, Xavier Paoletti, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the PARP inhibitor olaparib in combination with irinotecan in children with advanced malignancies: arm D of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT088.

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

https://assets.researchsquare.com/files/rs-1034556/v1/4d1cede0-420b-4f61-9e10-8812e21c6fb6.pdf?c=1650446671; International audience; Introduction : At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort.Methods : We reviewed the files from children

Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients.We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/mA three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (VBeyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.

BACKGROUND: HIT-SKK protocol is used for the treatment of low risk medulloblastomas in young children with the aim of eliminating cranial irradiation and its long-term side effects, in particular neuropsychological (NP) sequelae. This therapy includes IV and intraventricular (ITV) methotrexate (MTX) potentially responsible for leukoencephalopathy (LE) and neurocognitive disorders.The objectives are to describe the risk factors and the course of LE, and to investigate its impact on long-term neurocognitive and behavioural outcome. METHODS: A French retrospective, multicenter study including 35 children under 5 years of age, treated between 2009 and 2017, with a median follow up of 72 months. All follow-up MRIs including assessment of the severity of the LE (Fazekas and CTCAE grading) and all NP evaluations were centrally rewieved. RESULTS: 25/34 evaluable patients presented a LE during follow up, in a median delay of 2 months (1 - 17 months) after the start of chemotherapy. Grade 2 and 3 abnormalities were correlated with higher cumulative dose of ITV -MTX (p=0,01). Full Scale IQ (FSIQ) and Wechsler indexes were in the average or low average of the reference population. FSIQ was deficient in 7/20 evaluable patients. Processing speed (PSI) was the most frequently impaired neurocognitive domain: 9/20 patients with borderline or very low score, all having received a significantly higher cumulative dose of ITV-MTX (p=0,04). A decrease in overall NP scores was observed in patients for whom grade 2 or 3 LE persisted at the end of follow-up with an average FSIQ estimated at 82.1 (SD 16.9) versus 94.2 (SD 20.6). This decrease was significant for PSI (p=0,049). LE and neurocognitive impairments were not correlated with a younger age at diagnosis. CONCLUSION: This study confirmed the responsibility of MTX, and in particular ITV-MTX therapy in the onset and, most often, persistence of LE and its association with neurocognitive disorders.

International audience; Aim: Arms E and F of the AcSé-ESMART phase I/II platform trial aimed to define the recommended dose and preliminary activity of the dual mTORC1/2 inhibitor vistusertib as monotherapy and with topotecan-temozolomide in a molecularly enriched population of paediatric patients with relapsed/refractory malignancies. In addition, we evaluated genetic phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian (or mechanistic) target of rapamycin (mTOR) pathway alterations across the Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial (NCT02613962). Experimental design and results: Four patients were treated in arm E and 10 in arm F with a median age of 14.3 years. Main diagnoses were glioma and sarcoma. Dose escalation was performed as per the continuous reassessment method, expansion in an Ensign design. The vistusertib single agent administered at 75 mg/m2 twice a day (BID) on 2 days/week and vistusertib 30 mg/m2 BID on 3 days/week combined with temozolomide 100 mg/m2/day and topotecan 0.50 mg/m2/day on the first 5 days of each 4-week cycle were safe. Treatment was well tolerated with the main toxicity being haematological. Pharmacokinetics indicates equivalent exposure in children compared with adults. Neither tumour response nor prolonged stabilisation was observed, including in the 12 patients whose tumours exhibited PI3K/AKT/mTOR pathway alterations. Advanced profiling across relapsed/refractory paediatric cancers of the MAPPYACTS cohort shows genetic alterations associated with this pathway in 28.0% of patients, with 10.5% carrying mutations in the core pathway genes. Conclusions: Vistusertib was well tolerated in paediatric patients. Study arms were terminated because of the absence of tumour responses and insufficient target engagement of vistusertib observed in adult trials. Targeting the PI3K/AKT/mTOR pathway remains a therapeutic avenue to be explored in paediatric patients. Clinical trial identifier: NCT2813135.

Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.

10006 Background: Access to innovative anticancer therapies for children, adolescents and young adults within clinical trials in France is steadily increasing in the last years. However, current clinical trials portfolios are still inadequate and thus pediatric hemato-oncologists regularly prescribe innovative medicines outside their marketing authorization, and/or experimental drugs through compassionate use. Methods: The Secured Access to innovative medicines for CHildren with cAncer (SACHA) is a French prospective observational study developed by the French Society of Pediatric Oncology (SFCE) with Gustave Roussy as the legal sponsor to prospectively collect real-world safety and activity data of innovative therapies administered to patients ≤ 25 years-old with pediatric malignancies (solid tumor or leukemia) or other related conditions, either on compassionate use of experimental drugs or off-label use of anti-cancer medicines that have been first approved in adults after 2007. Prior to SACHA inclusion, multicenter tumor board discussion defining best available therapeutic options for each patient with a relapsed malignancy is mandatory. Results: The SACHA study opened in March 2020 and by February 2022, 283 patients have been included from 29/31 SFCE recruiting centers; median age: 11.0 years (range: 0.3-24.4). Main cancer types were central nervous system (CNS) tumors (47%), followed by non-CNS tumors (40%) and leukemias (13%). Innovative therapies prescribed in > 10 patients with reported objective response rate (ORR) and related CTCAE v.5 grade ≥2 clinical and/or grade ≥3 biological adverse drug reactions (ADRs) are described in Table. Conclusions: SACHA confirms the feasibility of this type of prospective real word registry, with a high participation of French centers. Based on this French experience, the Innovative Therapies for Children with Cancer (ITCC) consortium is currently developing a “SACHA International Project” to be opened in ITCC and collaborating countries. [Table: see text]

PURPOSE AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) and ribociclib 175 mg/m2 once a day and everolimus 2.5 mg/m2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.

Background High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5. Methods All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). Results Fifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated. Conclusions This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.

For the brain tumor committee of SFCE (Societe ́ Française des Cancers de l’Enfant). Objective: Therapeutic approach favors chemotherapy as the first-line-treatment in progressing OPG. There are few data on long term endocrine outcomes of aggressive OPG treated by upfront chemotherapy. Our main objective was to describe the long-term endocrine sequelae in these patients and to identify potential early predictors of the endocrine involvement. Subjects and methods: Children diagnosed with OPG at an age younger than 16 years from the French multicentric BBSFOP registry were included. They were treated with upfront chemotherapy according to the BB-SFOP protocol in France between June 1990 and December 2004, and subsequent treatment (second-line chemotherapy, surgery, radiotherapy) was used depending on tumor progression. They underwent a late evaluation with clinical and biological assessment between January 2011 and March 2016. Results: One hundred and two patients were included in our study. The mean age at tumor diagnosis was 3.3±0.3 years. The mean time of follow-up was 13.9±3.7 years. A history of precocious puberty was present in 36% of the subjects. At least one endocrine deficiency was present in 93% of the subjects (GHD 74%, TSH deficiency 57%, ACTH deficiency 36%, hypogonadotropism 33%, gonadic deficiency 30%, diabetes insipidus 15%; inappropriate AVP secretion 7%). 37% of males and 39% of females were overweight or obese. Mean adult height, reached in 51 subjects, was -1.2±1.3 SDS in males, and -0.7±1.4 SDS in females. Chemotherapy only was protective from pituitary deficiencies (odds ratio 0.19 to 0.37, P < 0.05). NF1 was protective from TSH and ACTH deficiencies (odds ratio 0.25 to 0.35, P < 0.05). Tumor volume on diagnostic MRI was not predictive of pituitary deficiencies. Gonadic deficiency was significantly more frequent in males than females (46,5% vs 12.2%, P < 0.05), and associated with chemotherapy only (OR 3.2, P < 0.05) and NF1 (OR 4.8, P < 0.05). Overweight/Obesity was associated with ACTH deficiency (OR 5, P < 0.05).Conclusion: Obesity and late endocrine dysfunction were frequent in subjects treated by upfront chemotherapy for aggressive OPG during childhood. However, chemotherapy only, when possible, was protective from pituitary involvement.

Background New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. Methods This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). Results Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7–29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9–23.7), and the disease control rate was 85.3% (95% CI, 68.9–95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2–53.67). Conclusions Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

BACKGROUND Preclinical data support the activity of celecoxib and fluvastatin in high grade (HGG) and low grade gliomas (LGG). A Phase I study was designed to evaluate this combination in children with refractory/relapsed glioma. AIM: To assess the safety, pharmacokinetics (PK), maximum tolerated dose, Recommended Dose for Phase II (RDP2). METHOD: Multicenter phase I trial, including patients aged 6 to 21 year old. Fluvastatin starting dose was 2 mg/kg/day, 14/28 days, with fixed dose of celecoxib (200–800 mg /day). Four dose levels of fluvastatin (2, 4, 6, 8 mg/kg/day) were evaluated. A Continual Reassessment Method was used for dose escalation. Dose-limiting toxicities (DLT) were determined on the 1st cycle. PK samples were obtained at D1 and D14 of cycle 1, pre-dose of cycle 2. RESULTS 20 patients were enrolled with a median age of 12 years (5.9–19). They previously received a median of 3 (1–7) lines of treatment. Ten patients were treated for LGG and 10 for HGG, receiving a median of 3.5 cycles (1–21). Patients with LGG received a median of 9 cycles (1–21). Among the 17 patients evaluable for DLT, 2 DLTs were reported: 1 grade 3 maculo-papular rash (4 mg/kg), and 1 grade 4 increase of CPK (6 mg/kg). The RP2D of fluvastatin is 6 mg/kg/day. CONCLUSION In children with refractory/relapsed glioma, the RDP2 of fluvastatin associated with celecoxib is 6 mg/kg/day. This combination is well tolerated encouraging a phase 2 study in LGG.

PURPOSE To assess the 3-year EFS rate of children younger than 5 years of age with high-risk medulloblastoma (MB) treated according to the prospective multicenter trial HR MB-5. PATIENTS AND METHODS After surgery, all children received 2 cycles of Etoposide- Carboplatine. If partial (PR) or complete response (CR) was achieved after induction chemotherapy, children received 2 courses of thiotepa (600mg/m²) with stem cell rescue. For patients in CR after high-dose chemotherapy, they received one course of Cyclophosphamide – Busilvex with stem cell rescue (Phase I part). The others patients (not in PR after induction or in CR after thiotepa) were treated with 2 cycles of Temozolomide-Irinotecan followed by age-adapted craniospinal irradiation and maintenance treatment. RESULTS 28 children (2 to 4 years; median: 3.0 years) were enrolled. Group 3 MB were most common (57%). The response rate to Etoposide-Carboplatine was 60.7%. Among 20 patients treated with Thiotepa, 13 children were in CR and received Cyclophosphamide – Busilvex without radiotherapy. Out of them, 9 patients (45%) are alive in CR without craniospinal irradiation (median follow-up 5 years). Among 15 patients treated with radiotherapy, 8 patients are alive (median follow-up 3.8 years). The study was prematurely stopped for an excess of events. The median follow-up was 4 years (range 1.5 - 6.1). The 3-year EFS and OS were 42.3% [25.9 - 60.6] and 71.3% [52.7 - 84.7], respectively. CONCLUSIONS This risk-adapted strategy did not improve EFS in young children with high-risk MB. However, the study shows that good responders to chemotherapy can be cured without recourse to irradiation.

Diffuse gliomas represent the most common primary central nervous system (CNS) tumors in adults and children alike. Glioblastoma is the most frequent and malignant form of diffuse glioma with a median overall survival of 15 months despite aggressive treatments. New therapeutic approaches are needed to prolong survival in this always fatal disease. The CNS has been considered for a long time as an immune privileged organ, in part because of the existence of the blood-brain barrier. Nonetheless, immunotherapy is a novel approach in the therapeutic management of glioma patients, which has shown promising results in several clinical trials, especially in the adult population. Vaccination, with or without dendritic cells, blockade of the immune checkpoints, and adoptive T cell transfer are the most studied modalities of diffuse glioma immunotherapy. The future most likely resides in combinatorial approaches, with administration of conventional treatments (surgery, radiochemotherapy) and immunotherapy following yet to determine schedules.

BACKGROUND & METHODS. The BIOlogical MEdicines for DIPG Eradication (BIOMEDE) trial is a randomized multi-arm multi-stage program (drop-the-loser adaptive design). The first trial was an open-label phase-II trial comparing three drugs (everolimus, dasatinib, erlotinib) combined with irradiation, allocated according to the presence of their specific targets. All patients underwent a biopsy at diagnosis to confirm the DIPG molecularly and establish the expression of pre-specified biomarkers. Patient samples were explored by WES with a sequencing depth average >100X for the tumor and >60X for the blood. RESULTS. Unsupervised clustering of copy-number-variations (CNV) identified 4 groups corresponding to a new stratification of DIPG: cluster 1 (n=42) with high CNV, cluster 2 (n=23) with chromosome 1q + chromosome 2 gains, cluster 3 (n=9) with low CNV and cluster 4 (n=21) with isolated 1q gain. Clusters 1 had higher hazard-ratio for death than the others (mean HR 1.959, range 1.054–3.643, p< 0.0001, adjusted Cox model). Extensive structural rearrangements/chromotrypsis were significantly more frequent in TP53-mutated samples. Indeed, when stratiftying patients in 4 groups based on type of histone H3 mutated at K27 and the presence of a TP53 pathway alteration the subgroup with TP53 altered pathway had a significantly higher hazard-ratio for death than the others (mean HR 3.450, p=0.0017, adjusted Cox model). Additional drug targets were identified, especially in the DNA repair machinery that could be exploited for new targeted therapies. CONCLUSION. WES at diagnosis was feasible in most patients and brings new prognostic and theranostic informations. This allows a better patients stratification and the development of personalized medicine in DIPG.

We report herein the case of a 17-year-old female who presented with intracranial hypertension and diplopia. Magnetic resonance imaging showed a large left cystic and solid temporoparietal lesion, associated with an infiltrating lesion of the brainstem, hypointense in T1 and hyperintense in FLAIR sequences, without enhancement after injection of gadolinium. Complete resection of the parietal mass and biopsy of the brainstem lesion were performed. Histopathological analysis of the parietal mass showed glioblastoma (WHO grade IV) with no IDH1/2 or H3.3/H3.1 gene mutation detected by Sanger sequencing. Immunohistochemistry found the expression of the proteins of mismatch repair system. Whole exome and RNA sequencing identified a BRAF-V600E mutation. The brainstem lesion was a diffuse midline glioma, H3K27M-mutant (grade IV) according to the 2016 WHO classification. Pan-genomic SNP arrays of the 2 tumors showed distinct genetic alterations. The parietal glioblastoma displayed complex genomic alterations whereas the brainstem glioma harbored chromosome 7q gain, chromosome 9p and 10 losses, and RB, TP53 and CDKN2A homozygous deletions. The patient was treated by concomitant radiochemotherapy (according to Stupp protocol). After 12 cycles of temozolomide, there was complete remission persistant in the parietal lobe. The brainstem tumor was stable but progressed after 3 months of temozolomide discontinuation. Treatment with mTOR inhibitors was initiated. At 21-month follow-up, the patient remains with few symptoms. No predisposition syndrome was identified in the patient or her family. Concurrent glioblastomas with distinct driver gene mutations are exceptional.

International audience; PURPOSE: Presence of metastases in newly diagnosed pediatric posterior fossa tumors (PFT) is not a rare situation, but optimal treatment of associated hydrocephalus in these children has remained undetermined. METHODS: Twenty-nine children treated between January 2005 and December 2015 for a metastatic PFT associated with hydrocephalus constituted the study cohort. Patients were divided into three groups: ventriculoperitoneal shunt (VPS), endoscopic third ventriculostomy (ETV), and temporary ventricular drainage before or during tumor resection (PVD). RESULTS: There were 4 VPS, 18 ETV, and 7 PVD. The global incidence of CSF diversion failure was 52%. No case of dysfunction or dissemination of metastatic cells occurred in the VPS group. Recurrence of hydrocephalus occurred in 55% of the ETV group. Presence of multiple macroscopic metastases and CSF metastatic cells after tumor surgery was associated with ETV failure. Fifty-seven percent of the children in the PVD group were reoperated after an average time of 53 days. Specific oncologic treatment was initiated earlier in the VPS group (11 days) compared to ETV (27 days) and PVD (23 days) groups. CONCLUSIONS: ETV should be avoided in cases of multiple macroscopic metastases, and children who underwent ETV must be followed carefully when metastatic cells are present in CSF after tumor surgery. External ventricular drainage before or during surgical removal should not be considered as a final option to treat hydrocephalus. VPS remains a safe alternative in this situation and allows an early specific oncologic treatment.

The main treatment for majority of pediatric brain tumors relies on surgery. In postoperative period, patients require monitoring in a pediatric intensive care unit (PICU). In this study, we analyzed the incidence of postoperative neurological complications and the outcome of neurological impairment in individual patients. Our retrospective single-center study concerned all patients who were admitted to the PICU of the University Hospital of Angers between 2002 and 2008, after brain tumor resection. Population, perioperative data, and outcome through the stay in PICU have been analyzed. We reported 117 neurosurgical procedures. Majority of children (85.3%) were affected by neurological deficit before surgery: cranial nerve palsy and cerebellar syndrome were the most frequent impairment. In the first 2 days, neurological symptoms improved for 27 patients (23.7%), especially in children with preoperative cerebellar syndrome, convulsions, or endocrine disorders. Mean length of stay in PICU was correlated with the severity of neurological impairment (p = 0.006). Five children presented a transient mutism after surgery for infratentorial tumors (n = 5/54, 9.2%). Eight spontaneous cerebral spinal fluid leaks occurred precociously after surgery, and neurological infections complicated half of them. Neurological infections occurred in 12 patients (ten meningitis, one ventriculitis, and one brain abscess). One patient died after surgery. All these complications and their risk factors have to be systematically searched for in order to decrease postoperative morbidity of brain tumors in children. They justify neurosurgeons and anesthesiologists specialized in these pathologies.

Among pediatric malignancies, medulloblastoma (MB) is one of the most common malignant tumors of the CNS. In the past few years, thanks to a multidisciplinary approach including surgery, chemo- and radiation therapy, survival has significantly improved. Despite that, a third of patients still have a low chance of being cured and long-term survivors experience severe treatment-related sequelae. MBs are usually classified according to a clinical risk stratification, based on histological features, age at diagnosis, extent of tumor resection and presence or absence of metastases. However, these clinical variables have recently been reported to be poor for defining risk-related disease. Retrospective studies have identified histological or biological factors that have distinct roles in prognosis. As several pathways have been discovered to be involved in MB pathogenesis, they should be taken into account to more accurately stratify patients and their treatment and to develop innovative therapies.

Magnetic resonance (MR) images from children with optic pathway glioma (OPG) are complex. We initiated this study to evaluate the accuracy of MR imaging (MRI) interpretation and to propose a simple and reproducible imaging classification for MRI. We randomly selected 140 MRIs from among 510 MRIs performed on 104 children diagnosed with OPG in France from 1990 to 2004. These images were reviewed independently by three radiologists (F.T., 15 years of experience in neuroradiology; D.L., 25 years of experience in pediatric radiology; and J.L., 3 years of experience in radiology) using a classification derived from the Dodge and modified Dodge classifications. Intra- and interobserver reliabilities were assessed using the Bland–Altman method and the kappa coefficient. These reviews allowed the definition of reliable criteria for MRI interpretation. The reviews showed intraobserver variability and large discrepancies among the three radiologists (kappa coefficient varying from 0.11 to 1). These variabilities were too large for the interpretation to be considered reproducible over time or among observers. A consensual analysis, taking into account all observed variabilities, allowed the development of a definitive interpretation protocol. Using this revised protocol, we observed consistent intra- and interobserver results (kappa coefficient varying from 0.56 to 1). The mean interobserver difference for the solid portion of the tumor with contrast enhancement was 0.8 cm3 (limits of agreement = −16 to 17). We propose simple and precise rules for improving the accuracy and reliability of MRI interpretation for children with OPG. Further studies will be necessary to investigate the possible prognostic value of this approach.

10555Background: Chemotherapy (CT) is frequently used as first adjuvant treatment for low-grade gliomas (LGG) when surgery cannot be completed. Relapses are frequent and new rescue regimens are nee...

10007 Background: To assess the 3-year progression-free survival (PFS) rate of patients with newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET)...