Diagnosed Diffuse Intrinsic Pontine Glioma Research Articles

A Phase 1 Study of Intravenous EGFR-ErbituxEDVsMIT in Children with Solid or CNS Tumours Expressing Epidermal Growth Factor Receptor.

Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV. To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (EEDVsMit) in children with recurrent / refractory solid or CNS tumours expressing EGFR. Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent EEDVsMit. Thirty-seven patients' tumours were screened for EGFR expression. EEDVsMit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 108 EEDVsMit per dose and escalated to 5×109 EEDVsMit per dose. EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, EEDVsMit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response. EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response. NCT02687386.

Upfront Biology-Guided Therapy in Diffuse Intrinsic Pontine Glioma: Therapeutic, Molecular, and Biomarker Outcomes from PNOC003.

PNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Patients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN). Of 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome. Upfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.

EPCT-06. Phase I study of ribociclib and everolimus post-radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): Updated report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

BACKGROUND: Dual inhibition of CDK4/6 and mTOR in DIPG and pediatric HGG has strong biologic rationale, given prevalent genetic alterations resulting in upregulated cell cycle and PI3K/mTOR pathways in these diseases, as well as non-overlapping agent toxicities. This study sought to evaluate safety/tolerability and determine the recommended phase 2 dose (RP2D) of ribociclib and everolimus among children with newly diagnosed DIPG and HGG post-radiotherapy. METHODS: Patients were enrolled according to a Rolling-6 design and received oral ribociclib and everolimus once daily for 21 and 28 days, respectively, starting 2-4 weeks post-completion of radiotherapy. All HGG and biopsied DIPG patients were screened for RB protein presence by immunohistochemistry. Pharmacokinetics and survival data were analyzed. RESULTS: Nineteen patients enrolled (median age: 8 years [range: 2-18]). Three patients enrolled at each of dose levels 1 and 2 without dose-limiting toxicities (DLTs). Thirteen patients enrolled at dose level 3, with one patient experiencing a DLT (grade 3 infection). One patient came off therapy prior to cycle 9 due to cardiac toxicity. The most common grade 3/4 toxicities were neutropenia (33%), leucopenia (17%), and lymphopenia (11%). Steady-state everolimus exposures in combination were 1.9±0.9-fold higher than single-agent administration. Median overall survival (OS) for 15 patients with DIPG was 13.9 months, with 12-, 24-, and 36-month OS of 53.3%, 38.9%, and 38.9%. Median event-free survival for four patients with HGG was 10.5 months. Among patients with tumor molecular profiling, two longer survivors (OS: 20, >37 months) had evidence of cell cycle upregulation with CDKN2A/B deletion and CDK4 overexpression identified. CONCLUSIONS: The combination of ribociclib and everolimus was well-tolerated post-radiotherapy in children with newly diagnosed DIPG and HGG, with a RP2D of ribociclib 170 mg/m2 days 1-21 and everolimus 1.5 mg/m2 days 1-28. Results will inform a molecularly-guided phase II study currently underway to evaluate efficacy.

EPCT-05. Phase Ib study of unesbulin (PTC596) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.

EPCT-04. RESULTS OF A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 WITH RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

BackgroundA Phase 1, single center study is ongoing to evaluate the conditionally replicative oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by radiotherapy (RT) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG). MethodsPatients 1–18 years with newly diagnosed DIPG with no prior treatment, Lansky/Karnofsky performance score ≥ 70, and adequate organ function were enrolled. A tumor biopsy was performed followed by a single intratumoral injection of 1e10-5e10 virus particles (vp) DNX-2401. Conventional radiotherapy was initiated within 1 month of DNX-2401 administration. ResultsEnrolled subjects (n=12) had a median age of 9 (range 3–18) and performance scores of 90–100 (n=4; 33%) or 70–80 (n=8; 67%). As part of a dose escalation design, subjects were treated with 1e10 vp (n=4) or 5e10 vp DNX-2401 (n=8), which was then followed by standard RT in 11 of 12 subjects (92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. Adverse events (AEs) have been primarily mild to moderate and consistent with underlying disease. The most commonly reported AEs (≥ 5 subjects), regardless of study drug relationship, include headache, asthenia, vomiting, anemia, leukocytosis, and fever. Two SAEs have been reported including grade 3 lymphopenia and grade 3 abdominal pain. Tumor reductions have been observed and efficacy evaluations are ongoing. As of 09Dec2020, 12-month survival (OS-12) was 71% and 4 of 12 patients had survived > 20 months. Four subjects continue to be followed for survival. Correlative analysis of tumor biopsy and peripheral samples is ongoing. ConclusionsDNX-2401 followed by RT can be safely administered to pediatric subjects with newly diagnosed DIPG; clinical activity and preliminary survival are encouraging.

Phase I study using crenolanib to target PDGFR kinase in children and young adults with newly diagnosed DIPG or recurrent high-grade glioma, including DIPG.

BackgroundPlatelet-derived growth factor receptor (PDGFR) signaling has been directly implicated in pediatric high-grade gliomagenesis. This study evaluated the safety and tolerability of crenolanib, a potent, selective inhibitor of PDGFR-mediated phosphorylation, in pediatric patients with high-grade glioma (HGG).MethodsWe used a rolling-6 design to study the maximum tolerated dose (MTD) of once-daily crenolanib administered during and after focal radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (stratum A) or with recurrent/progressive HGG (stratum B). Pharmacokinetics were studied during the first cycle at the first dose and at steady state (day 28). Alterations in PDGFRA were assessed by Sanger or exome sequencing and interphase fluorescence in situ hybridization or single nucleotide polymorphism arrays.ResultsFifty evaluable patients were enrolled in the 2 strata, and an MTD of 170 mg/m2 was established for both. Dose-limiting toxicities were primarily liver enzyme elevations and hematologic count suppression in both strata. Crenolanib AUC0–48h and CMAX did not differ significantly for crushed versus whole-tablet administration. Overall, PDGFRA alterations were observed in 25% and 30% of patients in stratum A and B, respectively. Neither crenolanib therapy duration nor survival outcomes differed significantly by PDGFRA status, and overall survival of stratum A was similar to that of historical controls.ConclusionsChildren tolerate crenolanib well at doses slightly higher than the established MTD in adults, with a toxicity spectrum generally similar to that in adults. Studies evaluating intratumoral PDGFR pathway inhibition in biomarker-enriched patients are needed to evaluate further the clinical utility of crenolanib in this population.

IMMU-31. PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINE COMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLY DIAGNOSED HLA-A2+ H3.3K27M DIFFUSE MIDLINE GLIOMAS (DMG)

OBJECTIVETo assess safety and efficacy within a multi-center trial the H3.3K27M specific peptide vaccine with poly-ICLC in HLA-A02.01+ patients diagnosed with H3.3K27M+ DMGs.METHODSAfter focal radiation therapy, participants 3–21 years of age were enrolled into two strata. Stratum A: newly diagnosed diffuse intrinsic pontine glioma (DIPG); Stratum B: other DMGs. H3.3K27M vaccine was administered with poly-ICLC IM every 3 weeks for 8 doses followed by every 6 weeks for a total of 96 weeks. Immuno-monitoring of peripheral blood mononuclear cell (PBMC) and imaging occurred every 3 months. Modified iRANO criteria were applied. PBMC samples were evaluated by mass cytometry.RESULTSFrom November 2016 until March 2019, 19 eligible patients (median age 11, range 5–17 yrs; 53 % female) were enrolled in Stratum A and 10 eligible patients (median age 13, range 7–18 yrs; 60 % female) in Stratum B. Treatment was well tolerated (7 grade 3; 0 grade 4 related toxicities). Median number of vaccines per participant was 6 (range 1–11). Overall survival at 12 months was 40% (95% CI 22–73%) for Stratum A and 39% (95% CI 16–93%) for Stratum B. Among the 19 subjects with longitudinal immune cell assessments, 7 exhibited an expansion of K27M-reactive CD8+ effector memory T-cells correlating with prolonged survival (p=0.028).CONCLUSIONH3.3K27M specific vaccine in combination with poly-ICLC is well tolerated. CyTOF-based immune monitoring of PBMCs facilitates sensitive high-throughput analysis. Further investigation is warranted to determine if this may be predictive of clinical outcomes.

A phase I trial of lenalidomide and radiotherapy in children with diffuse intrinsic pontine gliomas or high-grade gliomas

This study was performed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the immunomodulatory agent, lenalidomide, when administered daily during 6weeks of radiation therapy to children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) PATIENTS & METHODS: Children and young adults < 22years of age with newly diagnosed disease and no prior chemotherapy or radiation therapy were eligible. Children with HGG were required to have an inoperable or incompletely resected tumor. Eligible patients received standard radiation therapy to a prescription dose of 54-59.4Gy, with concurrent administration of lenalidomide daily during radiation therapy in a standard 3 + 3 Phase I dose escalation design. Following completion of radiation therapy, patients had a 2-week break followed by maintenance lenalidomide at 116mg/m2/day × 21days of a 28-day cycle. Twenty-nine patients (age range 4-19years) were enrolled; 24 were evaluable for dose finding (DIPG, n = 13; HGG, n = 11). The MTD was not reached at doses of lenalidomide up to 116mg/m2/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression. The RP2D of lenalidomide administered daily during radiation therapy is 116mg/m2/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.

PDCT-06. PHASE 1 STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH H3 K27M-MUTANT HIGH GRADE GLIOMA OR NEWLY DIAGNOSED DIPG

The imipridone ONC201 is the first selective antagonist of DRD2 for clinical oncology. Several Phase 1, Phase 1/2 and Phase 2 studies in patients with advanced cancers have established the single agent recommended Phase 2 dose (RP2D) of 625mg ONC201 administered orally once a week in adults. ONC201 induces p53-independent apoptosis in newly diagnosed and recurrent high-grade glioma in vitro, ex vivo and in vivo. Furthermore, radiographic regressions in adult recurrent H3 K27M-mutant glioblastoma patients in response to single agent ONC201 have been reported. Based on this adult experience and complementary preclinical results demonstrating the increased susceptibility of H3 K27M-mutant gliomas to ONC201, we initiated the first Phase 1 pediatric clinical trial of ONC201 January 30, 2018. This trial will determine the safety and RP2D of ONC201 in pediatric post-radiation H3 K27M-mutant glioma patients as a single agent and in newly diagnosed diffuse intrinsic pontine glioma (DIPG) patients in combination with radiation ({type:clinical-trial,attrs:{text:NCT03416530,term_id:NCT03416530}}NCT03416530). Patients without known H3 K27M-mutation status by a CLIA-lab can enroll with commitment to post-term biopsy. This is a multicenter, open-label, 2 arm, dose-escalation and dose-expansion study. Ten children with H3 K27M-mutant gliomas ages 5–18 years have been treated post-radiation: 3 at dose level 1; 3 at dose level 2; 4 as part of the dose expansion cohort on dose level 2. Patients have received 2–12 doses (median= 5). The ONC201 has been tolerated very well. Grade III/IV events include: decreased neutrophil count grade III (n=1) spontaneously resolved without dose modification and elevated AST grade III (n=1) returned to grade II after holding 1 dose. Additional safety data as well as pharmacokinetics, pharmacodynamics, and progression-free survival results from this trial will be reported.

Corrigendum: Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

[This corrects the article on p. 127 in vol. 8, PMID: 29755954.].

Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy). Nine patients with newly diagnosed DIPG met enrollment criteria. Autologous dendritic cell vaccines (ADCV) were prepared from monocytes obtained by leukapheresis. Five ADCV doses were administered intradermally during induction phase. In the absence of tumor progression, patients received three boosts of tumor lysate every 3 months during the maintenance phase. Vaccine fabrication was feasible in all patients included in the study. Non-specific KLH (9/9 patients) and specific (8/9 patients) antitumor response was identified by immunologic studies in peripheral blood mononuclear cells (PBMC). Immunological responses were also confirmed in the T lymphocytes isolated from the cerebrospinal fluid (CSF) of two patients. Vaccine administration resulted safe in all patients treated with this schema. These preliminary results demonstrate that ADCV preparation is feasible, safe, and generate a DIPG-specific immune response detected in PBMC and CSF. This strategy shows a promising backbone for future schemas of combination IT.

A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

The purpose of this phase I/II, open-label, single-arm trial is to investigate the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Six doses of weekly gemcitabine were administered intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy. Successive cohorts received increasing doses of 140, 175 and 200 mg/m2 gemcitabine, respectively, following a 3 + 3 dose-escalation schedule without expansion cohort. Dose-limiting toxicities (DLT) were monitored during treatment period. Clinical response was assessed using predefined case report forms and radiological response was assessed using the modified RANO criteria. Quality of life (QoL) was assessed using PedsQL questionnaires. Between June 2012 and December 2016, nine patients were enrolled. Treatment was well tolerated, and no DLTs were observed up to the maximum dose of 200 mg/m2. All patients experienced reduction of tumor-related symptoms. QoL tended to improve during treatment. PFS and MOS were 4.8 months (95% CI 4.0–5.7) and 8.7 months (95% CI 7.0–10.4). Classifying patients according to the recently developed DIPG survival prediction model, intermediate risk patients (n = 4), showed a PFS and MOS of 6.4 and 12.4 months, respectively, versus a PFS and MOS of 4.5 and 8.1 months, respectively, in high risk patient (n = 5). Gemcitabine up to 200 mg/m2/once weekly, added to radiotherapy, is safe and well tolerated in children with newly diagnosed DIPG. PFS and MOS were not significantly different from literature.

Phase II study of nimotuzumab and radiotherapy in children and adolescents with newly diagnosed diffuse intrinsic pontine gliomas (DIPG).

10061 Background: DIPG are amongst the most challenging tumors to treat in childhood with no drug proven to be effective. Standard of care remains focal radiotherapy alone however, rapid disease pr...

A phase I/II clinical trial of veliparib (ABT-888) and radiation followed by maintenance therapy with veliparib and temozolomide in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG): A Pediatric Brain Tumor Consortium Interim Report of Phase I Study.

10053 Background: We report the results of the dose escalation component of a phase 1/2 trial in children with newly diagnosed DIPG designed to determine the maximum tolerated dose (MTD) and toxici...

Time to rethink the unthinkable: upfront biopsy of children with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

Pediatric Blood & CancerVolume 62, Issue 1 p. 3-4 Highlight Time to rethink the unthinkable: Upfront biopsy of children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) Mark W. Kieran MD, PhD, Corresponding Author Mark W. Kieran MD, PhD Dana-Farber Cancer Institute and Boston Children's Hospital, Pediatric Neuro-Oncology, Harvard Medical School, Boston, Massachusetts Correspondence to: Mark W. Kieran, Dana-Farber Cancer Institute and Boston Children's Hospital, Pediatric Neuro-Oncology, Harvard Medical School, 450 Brookline Avenue, Rm D-3154, Boston 02215, MA. E-mail: mark_kieran@dfci.harvard.eduSearch for more papers by this author Mark W. Kieran MD, PhD, Corresponding Author Mark W. Kieran MD, PhD Dana-Farber Cancer Institute and Boston Children's Hospital, Pediatric Neuro-Oncology, Harvard Medical School, Boston, Massachusetts Correspondence to: Mark W. Kieran, Dana-Farber Cancer Institute and Boston Children's Hospital, Pediatric Neuro-Oncology, Harvard Medical School, 450 Brookline Avenue, Rm D-3154, Boston 02215, MA. E-mail: mark_kieran@dfci.harvard.eduSearch for more papers by this author First published: 04 October 2014 https://doi.org/10.1002/pbc.25266Citations: 23 Conflict of interest: Nothing to declare. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume62, Issue1January 2015Pages 3-4 RelatedInformation

First-in-pediatrics phase I study of crenolanib besylate (CP-868,596-26) administered during and after radiation therapy (RT) in newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent high-grade glioma (HGG).

10064 Background: Children diagnosed with DIPG have a median survival of less than one year despite RT, the primary modality of therapy. PDGF pathway activation has been noted in tumor analyzed fro...

Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG. Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m(2) once daily) and dasatinib (65 and 85 mg/m(2) twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated. Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs. The MTD of vandetanib and dasatinib in combination was 65 mg/m(2) for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer.

Magnetic resonance imaging is the preferred method to assess treatment-related skeletal changes in children with brain tumors

To evaluate the growing skeleton for potential altered skeletalgenesis associated with antiangiogenesis therapy. Knee radiographs and magnetic resonance imaging (MRI) were prospectively obtained on patients enrolled on two consecutive clinical trials using vandetanib, a potent oral (VEGF receptor 2) VEGFR-2 inhibitor alone or combined with dasatinib, a multiple tyrosine kinase inhibitor, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Fifty-nine patients (32 females) underwent 119 MRIs; 51 patients underwent 89 radiographs of the knees. The median age at enrollment was 6.2 years (range, 2.4-17.6 years). The dose of vandetanib ranged from 50 to 145 mg/m(2) /day. The median treatment duration was 205 days. Only two patients have not experienced disease progression after 18 and 60 months from diagnosis. MRI identified clinically significant premature physeal fusion in both knees of one patient, focal physeal thickening in one, osteonecrosis in eight patients (present at enrollment in one), and bony spicules crossing the physis in two patients (bilateral in one). MRI follow-up period averaged 5.3 months (range, 0-25.5 months; median, 3.5 months). Radiographs delineated normally fused physes in two patients but no cases of premature physeal fusion, osteonecrosis or bony spicules. As MRI provided greater information than radiographs, and thus would be a more sensitive test to assess skeletalgenesis in pediatric patients.

MR Imaging Assessment of Tumor Perfusion and 3D Segmented Volume at Baseline, during Treatment, and at Tumor Progression in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

DIPG is among the most devastating brain tumors in children, necessitating the development of novel treatment strategies and advanced imaging markers such as perfusion to adequately monitor clinical trials. This study investigated tumor perfusion and 3D segmented tumor volume as predictive markers for outcome in children with newly diagnosed DIPG. Imaging data were assessed at baseline, during, and after RT, and every other month thereafter until tumor progression for 35 patients (ages 2-16 years) with newly diagnosed DIPG enrolled in the phase I clinical study, NCT00472017. Patients were treated with conformal RT and vandetanib, a vascular endothelial growth factor receptor 2 inhibitor. Tumor perfusion increased and tumor volume decreased during combined RT and vandetanib therapy. These changes slowly diminished in follow-up scans until tumor progression. However, increased tumor perfusion and decreased tumor volume during combined therapy were associated with longer PFS. Apart from a longer OS for patients who showed elevated tumor perfusion after RT, there was no association for tumor volume and other perfusion variables with OS. Our results suggest that tumor perfusion may be a useful predictive marker for the assessment of treatment response and tumor progression in children with DIPG treated with both RT and vandetanib. The assessment of tumor perfusion yields valuable information about tumor microvascular status and its response to therapy, which may help better understand the biology of DIPGs and monitor novel treatment strategies in future clinical trials.

Hypofractionation vs Conventional Radiation Therapy for Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Matched-Cohort Analysis

Despite conventional radiation therapy, 54 Gy in single doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most children with diffuse intrinsic pontine glioma (DIPG) will die within 1 year after diagnosis. To reduce patient burden, we investigated the role of hypofractionation radiation therapy given over 3 to 4 weeks. A 1:1 matched-cohort analysis with conventional radiation therapy was performed to assess response and survival. Twenty-seven children, aged 3 to 14, were treated according to 1 of 2 hypofractionation regimens over 3 to 4 weeks (39/3 Gy, n=16 or 44.8/2.8 Gy, n=11). All patients had symptoms for ≤3 months, ≥2 signs of the neurologic triad (cranial nerve deficit, ataxia, long tract signs), and characteristic features of DIPG on magnetic resonance imaging. Twenty-seven patients fulfilling the same diagnostic criteria and receiving at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort analysis. With hypofractionation radiation therapy, the overall survival at 6, 9, and 12 months was 74%, 44%, and 22%, respectively. Progression-free survival at 3, 6, and 9 months was 77%, 43%, and 12%, respectively. Temporary discontinuation of steroids was observed in 21 of 27 (78%) patients. No significant difference in median overall survival (9.0 vs 9.4 months; P=.84) and time to progression (5.0 vs 7.6 months; P=.24) was observed between hypofractionation vs conventional radiation therapy, respectively. For patients with newly diagnosed DIPG, a hypofractionation regimen, given over 3 to 4 weeks, offers equal overall survival with less treatment burden compared with a conventional regimen of 6 weeks.