bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-54. A COMBINED ANALYSIS OF TWO RANDOMISED STUDIES EXPLORING THE IMPACT OF EXTENDED POST-RADIATION TEMOZOLOMIDE ON SURVIVAL OUTCOMES IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Gately Lucy , Mesia Carlos , Sepúlveda Juan , del Barco Sonia , Pineda Estela , Gironés Regina , Fuster José , Hong Wei , Gill Sanjeev , Navarro Luis Miguel , Herrero Ana , Dowling Anthony , De La Peñas Ramón , Vaz Maria Angeles , Alonso Miriam , Lwin Zarnie , Harrup Rosemary , Peralta Sergio , Long Anne , Perez-Segura Pedro , Ahern Elizabeth , Garate Clara Olier , Wong Mark , Campbell Robert , Cuff Katharine , Jennens Ross , Gallego Oscar , Underhill Craig , Martinez-García María , Covela Marta , Cooper Adam , Brown Stephen , Rosenthal Mark , Torres Javier , Collins Ian M , Gibbs Peter , Balana Carmen 
Published: November 2023

Abstract

BACKGROUND
The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Stupp protocol uses 6 months, however, in routine care, it is often extended to 12 months, given its tolerability, lack of effective salvage treatments, and extended regimen in lower grade gliomas.

METHODS
GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled patients with newly diagnosed glioblastoma without progression at the end of 6 months post-radiation temozolomide. Participants were randomised in a 1:1 allocation to either six additional months (total 12 months) or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required for 80% power to detect an improvement in 6mPFS from 50% to 60%. Neither study recruited sufficient patients, so we performed a combined analysis of individual patient data.

RESULTS
205 patients were recruited: 169 in GEINO14-01 (2014–2018) and 46 in EX-TEM (2019–2022). Median follow up was 20 and 14.5 months respectively. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR 0.75, p = 0.4), nor across any subgroups including MGMT methylated. There was no significant improvement in PFS (HR 0.92, P = 0.59, median 7.8 vs 9.7 months) or OS (HR 1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required changes to treatment, with 4.5% requiring dose delay, 7.5% dose reduction and 1.5% discontinuation of temozolomide.

CONCLUSION
For patients with newly diagnosed glioblastoma, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any individual patient subset that appeared to benefit from extended treatment. Six months should remain standard of care.
CTNI-55. A MULTICENTER STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND WITH SYSTEMIC MICROBUBBLE OSCILLATORS FOR BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Ahluwalia Manmeet , McDermott Michael , Burns Terry , de Groot John , Mogilner Alon , Achrol Achal , Shah Bhavya , Bettegowda Chetan , Ozair Ahmad , Khosla Atulya , Schwartz Theodore , Sahgal Arjun , Mishra Mark , Everson Richard , Weinberg Jeffrey , Amankulor Nduka , Sporrer Justin , Cifarelli Christopher , Rezai Ali , Lipsman Nir , Woodworth Graeme F 
Published: November 2023

Abstract

BACKGROUND
Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) blood levels in due to the blood-brain barrier (BBB). Real-time image-guided low-intensity focused ultrasound (LIFU) with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM.

METHODS
LIBERATE is an ongoing, prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using 220 kHz LIFU device is performed, with real-time acoustic feedback for effective sonication. Pre- and post-procedure, phlebotomies, and MRI brain are performed. The primary study endpoint is defined, per subject, as the ratio between cfDNA levels in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% concordance between biomarker patterns in the cfDNA sample from 1-hour post-LIFU sample and tumor tissue obtained later. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours post-LIFU to determine the time of greatest yield, (3) correlation of MRI parameters related to BBBD grading and biomarkers in cfDNA from post-LIFU samples. Patient enrollment commenced in 2022, and 13 patients have been recruited by 06/09/2023. Clinical trial information: NCT05383872.
CTNI-58. UPDATED RESULTS AND MOLECULAR SUBGROUP ANALYSES FROM THE RANDOMIZED PHASE 3 MIRAGE TRIAL ON MARIZOMIB IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Roth Patrick , Gorlia Thierry , Reijneveld Jaap , de Vos Filip , Idbaih Ahmed , Frenel Jean-Sébastien , Le Rhun Emilie , Sepúlveda Juan , Perry James , Masucci G Laura , Freres Pierre , Hirte Hal , Seidel Clemens , Walenkamp Annemiek , Lukacova Slavka , Meijnders Paul , Blais Andre , Ducray Francois , Verschaeve Vincent , Nicholas Garth , Balana Carmen , Bota Daniela , Preusser Matthias , Nuyens Sarah , Dhermain Fréderic , van den Bent Martin , O’Callaghan Chris J , Vanlancker Maureen , Mason Warren , Weller Michael 
Published: November 2023

Abstract

BACKGROUND
The standard of care for patients with newly diagnosed glioblastoma includes maximum safe resection followed by radiotherapy (RT) with concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Among potential new therapeutic strategies, targeting the proteasome has been considered promising because of its implication in numerous biological processes in tumors cells. Marizomib is a novel small molecule proteasome inhibitor that crosses the blood brain barrier and showed signs of activity in recurrent glioblastoma.

METHODS
EORTC 1709/CCTG CE.8 was a randomized, controlled, multicenter, open label phase 3 superiority trial. Major inclusion criteria were histologically confirmed newly diagnosed glioblastoma, age of 18 years or older and a Karnofsky performance status (KPS) &gt; 70. Patients with tumors known to harbor an isocitrate dehydrogenase mutation were not eligible.

RESULTS
The trial was opened at 82 institutions in Europe, Canada and the US and 749 patients (of 750 planned) were randomized in a 1:1 ratio. Following a pre-planned interim analysis and a recommendation of the independent data monitoring committee, enrolment was discontinued. No significant difference in the median OS (mOS) was observed (standard arm: 17 months, marizomib arm: 16.5 months; p = 0.64; HR = 1.04). Median PFS was 6.0 vs. 6.3 months (p = 0.67; HR = 0.97). Patients with tumors harboring an unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoter had a mOS of 14.5 months in the standard therapy group and 15.1 months in the marizomib arm (p = 0.27, HR = 1.13). Among patients with an MGMT promoter-methylated tumor, median OS was 29.4 months in the marizomib arm and 25.5 months in the standard arm (p = 0.41, HR = 0.86). More CTCAE grade 3/4 treatment-emergent adverse events were noticed in the marizomib arm than in the standard arm.

CONCLUSIONS
The addition of marizomib to standard temozolomide-based radiochemotherapy was associated with more toxicity but did not confer a survival benefit in glioblastoma patients, independent of the MGMT promoter methylation status.
CTNI-59. RARE AND NOVEL KIAA1549-BRAF FUSION BREAKPOINTS PREDICT POOR CLINICAL OUTCOME FOR PATIENTS WITH RECURRENT OR PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA: PHASE II PNOC001 TRIAL RESULTS
Authors: Waszak Sebastian , Aboian Mariam , Minturn Jane , Leary Sarah , Abdelbaki Mohamed S , Goldman Stewart , Elster Jennifer , Kraya Adam , Lueder Matthew , Ramakrishnan Divya , von Reppert Marc , Liu Kevin , Resnick Adam , Solomon David , Molinaro Annette , Phillips Joanna , Prados Michael , Haas-Kogan Daphne , Mueller Sabine 
Published: November 2023

Abstract

OBJECTIVES
PNOC001 sought to estimate progression-free survival (PFS) associated with everolimus for progressive/recurrent pediatric low-grade glioma (pLGG) and to determine if activated PI3K/AKT/mTOR pathway as measured by positive phosphorylated-ribosomal protein S6 (p-RPS6) was associated with response. A secondary objective was to assess whether somatic drivers influence median PFS.

METHODS
Patients, 3-21 years of age, with recurrent/progressive pLGG received everolimus orally at 5 mg/m2 daily. Somatic drivers, when available, were associated with PFS and compared to four independent molecular pLGG cohorts with newly-diagnosed and progressive/recurrent patients.

RESULTS
From 2012 to 2019, 65 subjects enrolled [median age 9.6 years, 3.0-19.9; 46% female]; Median PFS for all-comers was 11.1 months (95%-CI 7.6-19.8, n = 64). PFS was not modulated by PI3K/AKT/mTOR pathway activation (median PFS 11.2 vs 9.4 months, P = 0.83, n = 62). BRAF alterations were identified in 67.8% (40/59) of patients. Rare/novel KIAA1549-BRAF fusion breakpoints were enriched in PNOC001 compared to newly-diagnosed pLGGs in independent cohorts (28.6% vs 2.6%, P = 1.4e-4, n = 214). In PNOC001, patients with rare/novel KIAA1549-BRAF fusion breakpoints had worse clinical outcomes than patients with common fusion breakpoints (median PFS 6.1 vs 16.7 months, P &lt; 0.05, n = 20). Rare/novel KIAA1549-BRAF fusion breakpoints were also enriched in patients with progressive/recurrent disease in independent pLGG cohorts (17.6% vs 2.6%, P = 2e-3, n = 227). Integration of BRAF alterations and DNA methylation-based tumor subtypes further revealed that rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline (14.1%) compared to infratentorial (2.0%) pilocytic astrocytomas (P = 1e-4). KIAA1549-BRAF fusion breakpoints remained risk factors for progressive/recurrent disease in PNOC001 (P = 0.05) and independent pLGG cohorts (P &lt; 0.05) after accounting for tumor location and DNA methylation subtypes.

CONCLUSIONS
Rare/novel KIAA1549-BRAF fusion breakpoints are more frequent in supratentorial midline pLGGs and define independent genomic risk factors for disease progression/recurrence. Our results indicate that future clinical trials must interrogate and define KIAA1549-BRAF fusion breakpoints for informative results and conclusions.
CTNI-61. MYCOPHENOLATE MOFETIL INHIBITS GLIOBLASTOMA PURINE METABOLISM IN HUMANS: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Umemura Yoshie , Al-Holou Wajd , Elaimy Ameer , Scott Andrew J , Leung Denise , Clarke Nathan , Kim Michelle M , Ferris Sean , Thomas Jennifer , Heth Jason , Schipper Matthew , Suresh Krithika , Lawrence Theodore , Wahl Daniel 
Published: November 2023

Abstract

BACKGROUND
Mycophenolate mofetil (MMF), a purine synthesis inhibitor, improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) is the first-in-human study to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor.

METHODS
Adult patients meeting eligibility are given MMF 500-2000 PO BID using TITE-CRM dose assignment. Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly-diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with chemoradiation and followed for 28 days for DLT1-period. During the adjuvant temozolomide (days 1-5/28-day cycle) period, MMF is given days 0-5 on a separate dose-escalation (DLT2 period = cycles 1-2). Tissues from phase-0 recurrent glioblastoma patients (N = 8) receiving MMF 500-2000mg BID one-week pre-operatively are analyzed using mass spectrometry.

RESULTS
Enhancing and non-enhancing tumor from phase 0 subjects yielded above 1 µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p = 0.009), indicating effective target engagement and inhibition of purine synthesis. No DLT has been observed with adjuvant cyclic temozolomide in phase 1 newly-diagnosed group (N = 26), nor in the recurrent-disease group (N = 18) with re-irradiation. In newly diagnosed arm, 3 subjects experienced DLT1 at 2000mg BID; grade-3 hemiparesis and cognitive disturbance, and grade-4 thrombocytopenia. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1.

CONCLUSION
MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary promising evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.
CTNI-62. INTERIM DATA ON DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA FROM THE FIRST EXPANSION ARM OF THE PHASE 1/2 GLORIA TRIAL
Authors: Giordano Frank , Layer Julian , Leonardelli Sonia , Friker Lea , Schaub Christina , Zeyen Thomas , Sperk Elena , Hambsch Peter , Oster Christoph , Grau Franziska , Paech Daniel , Müller Wolf , Pietsch Torsten , Schmeel L Christopher , Grauer Oliver , Renovanz Mirjam , Tabatabai Ghazaleh , Kebir Sied , Bisdas Sotirios , Güresir Erdem , Glas Martin , Seidel Clemens , Hölzel Michael , Herrlinger Ulrich 
Published: November 2023

Abstract

BACKGROUND
We recently reported favorable safety and preliminary efficacy signals for treatment with radiotherapy (RT), the CXCL12 neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) and bevacizumab for glioblastoma (GBM) in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report updated outcomes on dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab).

METHODS
Six patients with incompletely resected, MGMT-unmethylated GBM, ECOG≤ 2 were enrolled, receiving standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response according to modified RANO criteria (mRANO) as well as perfusion/diffusion imaging.

RESULTS
Combination treatment was well-tolerated and safe. Of all G≥2 AEs (n = 79), two G2 events (2.5%) were deemed related to NOX-A12 only. There were no dose-limiting toxicities and no treatment-related deaths. At a median follow-up of 14.6 months, one patient deceased due to distant leptomeningeal spread. Median overall survival (OS) has not yet been reached. With an overall response rate (ORR) of 83.3% under treatment, one patient achieved confirmed complete response (CR), four patients partial response (PR) and one patient stable disease (SD). The median best response under treatment was -68.9% (-53,8% to -100%) for target lesion sums and -100% (-99.9% to -100%) for non-target lesion (NTL) sums. In all three patients with NTLs at least one lesion disappeared. The median best change from baseline of the highly perfused-tumor fraction was -98.2% (-61.3% to -100%) and the median best change of the apparent diffusion coefficient was 24.9% (7.3% to 59.1%).

CONCLUSIONS
Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 for combinatory treatment with bevacizumab while demonstrating improved efficacy with deeper and longer-lasting responses and a higher ORR compared to treatment with RT and NOX-A12 only.
CTNI-65. INVESTIGATING SAFETY AND EFFICACY OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA - FIRST RESULTS OF THE PRICOTTF PHASE I/II TRIAL
Authors: Kebir Sied , Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Feldheim Jonas , Pierscianek Daniela , Proescholdt Martin , Hau Peter , Grosu Anca-Ligia , Krex Dietmar , Sure Ulrich , Scheffler Björn , Kleinschnitz Christoph , Pöttgen Christoph , Stuschke Martin , Glas Martin 
Published: November 2023

Abstract

BACKGROUND
A synergistic inhibiting effect on glioblastoma cell proliferation was reported for the combination of TTFields and radiotherapy. Based on these preclinical findings, we performed the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. Material and

METHODS
In this phase I/II trial, TTFields therapy was initiated following surgery and continued throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was allowed at recurrence. Radiotherapy was conducted with arrays applied on the patients’ scalp. Safety and tolerance are the study’s primary endpoint, determined by a selection of pre-specified treatment-limiting toxicities (TLTs).

RESULTS
A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of ≥ common toxicity criteria (CTC) grade 3 was comparable to that of established glioblastoma trials. Notably, skin toxicity of ≥ CTC grade 3 was uncommon (n = 2, 6%). No patient developed TLTs. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence &gt;23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p = 0.008).

CONCLUSION
The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
CTNI-73. ALLIANCE A071601: PHASE II TRIAL OF BRAF/MEK INHIBITION IN NEWLY DIAGNOSED PAPILLARY CRANIOPHARYNGIOMAS
Authors: Brastianos Priscilla , Twohy Erin , Geyer Susan , Gerstner Elizabeth , Kaufmann Timothy , Tabrizi Shervin , Kabat Brian , Thierauf Julia , Ruff Michael , Bota Daniela , Reardon David , Cohen Adam , de la Fuente Macarena , Lesser Glenn , Campian Jian , Agarwalla P K , Kumthekar Priya , Mann Bhupinder , Vora Shivangi , Knopp Michael , John Iafrate A , Curry William , Cahill Daniel , Shih Helen , Brown Paul , Santagata Sandro , Barker Frederick , Galanis Evanthia 
Published: November 2023

Abstract

BACKGROUND
Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation.

METHODS
Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial.

RESULTS
Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events.

CONCLUSIONS
Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.
CTNI-74. ON-TRK: A NON-INTERVENTIONAL STUDY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION SOLID TUMORS
Authors: Tabatabai Ghazaleh , Trent Jonathan , Novello Silvia , Passiglia Francesco , Burcoveanu Domnita-Ileana , Norenberg Ricarda , Laetsch Theodore 
Published: November 2023

Abstract
Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date.