scholarly journals PDCT-04. PHASE 1 TRIAL OF WEE1 KINASE INHIBITOR AZD1775 COMBINED WITH RADIATION THERAPY FOR CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP PHASE 1 PILOT CONSORTIUM (ADVL1217)

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi201-vi201
Author(s):  
Sabine Mueller ◽  
Xiaodong Yang ◽  
Sharmistha Pal ◽  
Ralph Ermioian ◽  
Elizabeth Fox ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Pontine Glioma ◽  
Phase 1 Trial ◽  
Wee1 Kinase

CTIM-08. SAFETY, EFFICACY, AND SURVIVAL RESULTS FROM A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWED BY STANDARD OF CARE RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi50-vi51
Author(s):  
Jaime Gállego Pérez-Larraya ◽  
Marc Garcia-Moure ◽  
Ana Patiño-García ◽  
Marisol González-Huarriz ◽  
Jasper Van der Lugt ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Oncolytic Adenovirus ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Serious Adverse Events ◽  
Tumor Biopsy ◽  
Grade 3

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is the most lethal pediatric brain tumor. Median overall survival (OS) with standard of care radiation therapy (RT) is approximately 8-10 months and 2-year survival is < 10%. A Phase 1 single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT for DIPG. METHODS Newly-diagnosed DIPG patients 1-18 years old received a tumor biopsy through the cerebellar peduncle followed by intratumoral injection of 1e10 – 5e10 vp DNX-2401 and conventional RT 1-3 weeks later. RESULTS Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 years (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone 3 K27M mutations were identified in 10 subjects, including H3F3A (n=8), HIST2H3C (n=1), and HIST1H3B (n=1); 1 subject was H3 wildtype (n=1). TP53 mutations were identified in 5 subjects (42%). DNX-2401 was administered followed by RT (n=11; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported adverse events (≥ 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three serious adverse events were reported including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) responses per RAPNO criteria. As of the data cutoff, median OS is 19.7 months and OS-24 is 32% with follow-up ongoing for 3 subjects (26.9, 25.6, 13.7 months). CONCLUSIONS DNX-2401 followed by RT can be safely administered to DIPG. Survival outcomes are encouraging, thus warranting further evaluation in a Phase 2 study.

Phase I/II study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM) or gliosarcoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12511-12511 ◽  
Author(s):  
N. A. Butowski ◽  
K. Lamborn ◽  
S. Chang ◽  
D. Thornton ◽  
R. DeBoer ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Primary Objective ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Current Standard Treatment ◽  
Newly Diagnosed Glioblastoma ◽  
Endothelial Growth Factor

12511 Background: Enzastaurin is a potent, selective, oral serine/threonine kinase inhibitor of PKCβ, an enzyme activated by vascular endothelial growth factor (VEGF). VEGF is upregulated in most cases of GBM, producing significant angiogenesis. This study combines the anti-angiogenic properties of enzastaurin with the current standard treatment of radiation therapy (RT) and cytotoxic chemotherapy (temozolomide; TMZ). Methods: A Phase 1/2 study of enzastaurin with TMZ during and following RT is ongoing in patients with newly diagnosed GBM. Two doses of enzastaurin will be evaluated during Phase 1. The first 6 patients will received 250 mg of enzastaurin daily. If no more than one patient experiences a dose-limiting toxicity (DLT) during RT and the first adjuvant cycle, an additional 6 patients will receive an escalated dose of 500 mg daily. The dose established in Phase 1 will be administered to 60 patients in Phase 2. The primary objective of Phase 2 is to determine the efficacy of enzastaurin as measured by overall survival. Multiple pharmacokinetic (PK) and pharmacodynamic (PD) endpoints will be evaluated using perfusion imaging and plasma biomarkers. Relevant growth factors and pathways will be analyzed in primary tumor tissue from each patient. Results: Since September 06, 6 patients have completed RT with concurrent enzastaurin (250 mg) and TMZ. None of these patients has experienced a DLT to date. It is expected that an additional 6 patients will be enrolled in January 07 and Phase 2 will start in May 2007. Conclusions: Enzastaurin with concurrent RT and TMZ appears safe. Final Phase 1 safety results and preliminary PK and PD data will be presented. [Table: see text]

A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

2020 ◽  
Vol 149 (3) ◽  
pp. 511-522
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Trent R. Hummel ◽  
Lionel M. L. Chow ◽  
Ralph Salloum ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma

scholarly journals Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial

2018 ◽  
Vol 19 (8) ◽  
pp. 1040-1050 ◽  
Author(s):  
Mark M Souweidane ◽  
Kim Kramer ◽  
Neeta Pandit-Taskar ◽  
Zhiping Zhou ◽  
Sofia Haque ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Single Centre ◽  
Convection Enhanced Delivery ◽  
Phase 1 Trial

scholarly journals PDCT-16. A PHASE I STUDY OF SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WITH TEMSIROLIMUS IN CHILDREN WITH NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi186-vi187
Author(s):  
Soumen Khatua ◽  
Joya Chandra ◽  
Vidya Gopalakrishnan ◽  
Leena Ketonen ◽  
Michael Johnson ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Dose Escalation ◽  
Survival Data ◽  
Progressive Disease ◽  
Maximum Tolerated Dose ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Phase Ii Studies

Abstract Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. Thus targeting these pathways with mTOR inhibitors could hold promise. Genomic and epigenetic insights have shown the role of histone deacetylase (HDAC) in these tumors. Both temsirolimus (mTOR inhibitor) and SAHA (HDAC inhibitor) are well described in pediatric clinical trials with an established maximum tolerated dose (MTD) for phase II studies. This is the first ongoing phase I multi-targeted therapeutic study, in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules (NCT02420613 currently recruiting). Patients with a performance score of 50 or greater, with newly diagnosed (Stratum I), or progressive (stratum II) DIPG will be eligible. Biopsy is not mandatory. A standard 3 + 3 design is being used for this study. 1 dose escalation and 2 dose de-escalations are permitted beyond the starting dose level. In stratum I patients receive radiation therapy concurrently with vorinostat on the days of radiation, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if they do not have progressive disease. In stratum II patients receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if they do not have progressive disease. Correlative studies evaluating histone acetylation, phosphorylated 70S6K and Akt are being performed. Currently 5 patients have been enrolled, and the study is at the dose escalation level with no dose limiting toxicity (DLT) seen so far. Safety, adverse effects, biological correlatives, and clinical outcomes will be reported once study is completed.

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