Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and ...characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection.
Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m
) for 7-10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts.
Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9-20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2-17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m
for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22-53.4).
Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.
Abstract
Background
A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed ...diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series.
Methods
Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity.
Results
Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively.
Conclusion
Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG.
Trial Registration
NCT01514201
BACKGROUND
Both intensity‐modulated radiotherapy (RT) and passively scattered proton therapy have a risk of secondary malignant neoplasm (SMN) in children. To determine the influence of RT modality ...on the incidence of SMN after craniospinal irradiation (CSI), the authors compared the incidence of SMN in children who had medulloblastoma treated with either photon CSI plus an intensity‐modulated RT boost (group I) or passively scattered proton CSI plus a boost (group II).
METHODS
From 1996 to 2014, 115 children with medulloblastoma (group I, n = 63; group II, n = 52) received CSI followed by a boost to the tumor bed. Most patients had standard‐risk disease (63.5%). The median follow‐up was 12.8 years for group I and 8.7 years for group II.
RESULTS
The 5‐year and 10‐year overall survival (OS) rates were 88.8% and 85.1%, respectively, for standard‐risk patients and 63.1% and 57.3%, respectively, for high‐risk patients, with no OS difference by RT modality (P = .81). Six SMNs were identified (4 in group I, 2 in group II). The 5‐year and 10‐year SMN incidence rates were 1.0% and 6.9%, respectively (0.0% and 8.0%, respectively, in group I; 2.2% and 4.9%, respectively, in group II; P = .74). Two SMNs occurred in the clinical target volume in the brain, 2 occurred in the exit dose region from the photon spinal field, 1 occurred in the entrance path of a proton beam, and 1 occurred outside the radiation field. There were no reported cases of secondary leukemia.
CONCLUSIONS
This analysis demonstrates no difference in OS or SMN incidence between patients in groups I and II 10 years after RT.
LAY SUMMARY
One hundred fifteen children with medulloblastoma received radiotherapy (RT) with either photon craniospinal irradiation (CSI) and an intensity‐modulated RT boost (group I; n = 63) or passively scattered proton CSI and a boost (group II;, n = 52).
The majority of children had standard‐risk disease (63.5%).
The 5‐year and 10‐year overall survival rates were 88.8% and 85.1% for standard‐risk patients, respectively, and 63.1% and 57.3% for high‐risk patients, respectively, with no difference in overall survival by RT group (P = .81).
The 5‐year and 10‐year second malignant neoplasm incidence rates were 1.0% and 6.9%, respectively, with no difference in second malignant neoplasm incidence according to RT group (P = .74).
In total, 115 children with medulloblastoma who received surgery, chemotherapy, and radiotherapy (RT) with either 3‐dimensional RT followed by an intensity‐modulated boost (n = 63) or passively scattered proton therapy (n = 52) are assessed. At 10 years after RT, there are no differences in overall survival or secondary malignant neoplasms according to RT modality.
Purpose
To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or ...high‐grade glioma (HGG).
Methods
Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 μg/mL. VPA was continued post‐radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy.
Results
From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event‐free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6‐8.2) and 10.3 (7.4‐13.4) months, and estimated one‐year EFS was 12% (2%‐31%). Median EFS and OS for HGG were 9.1 (6.4‐11) and 12.1 (10‐22.1) months, and estimated one‐year EFS was 24% (7%‐45%). Four patients with glioblastoma and mismatch‐repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months.
Conclusion
Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.
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•Axon Guidance Factors are drivers of the invasive behavior of DIPG.•Neogenin is elevated in DIPG cells and patients.•Neogenin blockade strongly decrease invasion of DIPG cells.•The ...targetable receptor neogenin is an interesting therapeutic strategy for DIPG.•Netrin-1 and neogenin are identified as DIPG urinary biomarkers.
Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. ...It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM.
23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 10
cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 10
viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage.
PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times.
A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.
BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the ...oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m
once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .
Brain tumors are the leading cause of cancer-related death in children. Tazemetostat is an FDA-approved enhancer of zeste homolog (EZH2) inhibitor. To determine its role in difficult-to-treat ...pediatric brain tumors, we examined EZH2 levels in a panel of 22 PDOX models and confirmed EZH2 mRNA over-expression in 9 GBM (34.6 ± 12.7-fold) and 11 medulloblastoma models (6.2 ± 1.7 in group 3, 6.0 ± 2.4 in group 4) accompanied by elevated H3K27me3 expression. Therapeutic efficacy was evaluated in 4 models (1 GBM, 2 medulloblastomas and 1 ATRT) via systematically administered tazemetostat (250 and 400 mg/kg, gavaged, twice daily) alone and in combination with cisplatin (5 mg/kg, i.p., twice) and/or radiation (2 Gy/day × 5 days). Compared with the untreated controls, tazemetostat significantly (Pcorrected < 0.05) prolonged survival times in IC-L1115ATRT (101% at 400 mg/kg) and IC-2305GBM (32% at 250 mg/kg, 45% at 400 mg/kg) in a dose-dependent manner. The addition of tazemetostat with radiation was evaluated in 3 models, with only one IC-1078MB (group 4) showing a substantial, though not statistically significant, prolongation in survival compared to radiation treatment alone. Combining tazemetostat (250 mg/kg) with cisplatin was not superior to cisplatin alone in any model. Analysis of in vivo drug resistance detected predominance of EZH2-negative cells in the remnant PDOX tumors accompanied by decreased H3K27me2 and H3K27me3 expressions. These data supported the use of tazemetostat in a subset of pediatric brain tumors and suggests that EZH2-negative tumor cells may have caused therapy resistance and should be prioritized for the search of new therapeutic targets.
This study confirms the preservation of EZH2 overexpression in 22 patient-derived orthotopic xenograft models of pediatric brain tumors. The authors demonstrate the activity of an FDA-approved EZH2 inhibitor, tazemetostat, alone and in combination with radiation in a subset of the models, and identifies EZH2-negative cells as potential cause of therapy resistance.
BACKGROUND
Sporadic optic pathway/hypothalamic gliomas represent a unique entity within pediatric low‐grade glioma. Despite favorable survival, location makes treatment difficult and local ...progression debilitating. This study is a longitudinal assessment of visual acuity (VA) among children treated within the last 2 decades.
METHODS
Clinical characteristics were ed for patients treated from 2000 to 2018 at Texas Children's Cancer Center in Houston. Ophthalmologic data taken at 3‐ to 6‐month intervals were examined with age‐appropriate VA metrics converted to the LogMAR (logarithm of the minimum angle of resolution) scale. Kaplan‐Meier blindness‐free survival (BFS) curves, calculated as time‐to‐bilateral functional blindness (LogMAR ≥0.8 in both eyes), were calculated for patients receiving early radiation therapy (RT; upfront or as first‐line salvage treatment) or chemotherapy (CT) and evaluated using the log‐rank test.
RESULTS
Thirty‐eight patients with a median follow‐up of 8.5 years (range, 2‐17 years) were identified. Median age at diagnosis was 3 years (interquartile range, <1‐6 years). Early RT was administered in 11 patients (29%). Twenty‐seven patients (71%) were treated primarily with CT, initiated at a median age of 3.5 years (range, <1‐11 years). Eight patients in the CT group did eventually require RT secondary to VA loss and following multiple lines of CT. Median age at RT for all patients was 11 years (range, 3‐17 years). BFS rates were 81% at 5 years and 60% at 8 years for CT and 100% at 5 and 8 years for early RT (P = .017).
CONCLUSIONS
In a contemporary cohort, early RT, defined as initial or first‐line salvage therapy, was found to have superior BFS for appropriately selected patients with sporadic optic pathway/hypothalamic gliomas.
LAY SUMMARY
Children with low‐grade brain tumors of the optic pathway generally have excellent long‐term survival; however, given the location of these tumors, there can commonly be threatened vision if the tumor grows.
Although radiation is generally deferred in children on the basis of legitimate concerns regarding the effects on the developing brain, it may represent a vision‐preserving therapy for well‐selected older patients.
The treatment paradigm for pediatric optic pathway glioma has mostly shifted from using radiation therapy (RT) as the definitive therapy to favor postponement of RT for secondary and tertiary lines of systemic therapy. Despite excellent patient survival rates, long‐term vision outcomes with chemotherapy are poor. Well‐selected older patients who receive early RT as upfront or first‐line salvage therapy retain meaningful long‐term visual acuity.
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