First in Human Clinical Trial of a Metalloporphyrin Dual Radioprotectant and Radiosensitizer, BMX-001, in Newly Diagnosed High-Grade Glioma Undergoing Concurrent Chemoradiation

3619 Background: ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that has demonstrated promising activity in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 in recurrent H3 K27M-mutant glioma patients . The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients as well tolerated and biologically active. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center trial for pediatric H3 K27M-mutant glioma or non-biopsied DIPG employed a 3+3 dose-escalation and dose-expansion design with 6 arms. Arms A and E, which have completed accrual, determined the RP2D of ONC201 using oral capsule and liquid formulations in post-radiation pediatric H3 K27M-mutant glioma patients ONC201, respectively. Arm B aims to determine the RP2D for ONC201 in combination with radiotherapy in patients with newly diagnosed DIPG. Arms C and D aim to measure intratumoral ONC201 concentrations in midline glioma patients and the impact of ONC201 on H3 K27M DNA levels in CSF, respectively. Arm F was recently opened to study ONC201 as a single agent in patients with progressive H3 K27M-mutant tumors (excluding DIPG and spinal cord tumors) following radiotherapy. After determining the RP2D, a dose-expansion cohort will evaluate the safety, radiographic response, and activity of ONC201. Results: An RP2D of weekly 625mg ONC201 scaled by body weight as a capsule or in liquid formulation was established in the primary endpoints of arms A, B and E alone or in combination with radiation, without incidence of dose-limiting toxicity (DLT). Pharmacokinetic profiles were similar to those observed in adults (T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL), with similar exposure across body weights. Conclusions: ONC201 was well tolerated without DLTs at the same adult RP2D scaled by body weight as monotherapy or in combination with radiotherapy in pediatric H3 K27M-mutant glioma patients. Further investigation of ONC201 to treat H3 K27M-mutant glioma and DIPG is warranted. Clinical trial information: NCT03416530 .

Download Full-text

Alpha-type-1 Polarized Dendritic Cell-based Vaccination in Newly Diagnosed High-grade Glioma: A Phase II Clinical Trial

Anticancer Research ◽

10.21873/anticanres.14669 ◽

2020 ◽

Vol 40 (11) ◽

pp. 6473-6484

Author(s):

KOICHI MITSUYA ◽

YASUTO AKIYAMA ◽

AKIRA IIZUKA ◽

HARUO MIYATA ◽

SHOICHI DEGUCHI ◽

...

Keyword(s):

Clinical Trial ◽

Dendritic Cell ◽

Phase Ii ◽

High Grade Glioma ◽

Phase Ii Clinical Trial ◽

High Grade ◽

Newly Diagnosed ◽

Alpha Type

Download Full-text

Dabrafenib With Trametinib After Radiation Therapy in Treating Patients With Newly-Diagnosed BRAF V600-Mutant High-Grade Glioma

Case Medical Research ◽

10.31525/ct1-nct03919071 ◽

2019 ◽

Author(s):

Keyword(s):

Radiation Therapy ◽

High Grade Glioma ◽

High Grade ◽

Newly Diagnosed

Download Full-text

Direct medical costs of treatment in newly-diagnosed high-grade glioma among commercially insured US patients

Journal of Medical Economics ◽

10.1080/13696998.2017.1364258 ◽

2017 ◽

Vol 20 (12) ◽

pp. 1237-1243 ◽

Cited By ~ 3

Author(s):

Shan Jiang ◽

Kala Hill ◽

Dipen Patel ◽

A. Reginald Waldeck ◽

Marc Botteman ◽

...

Keyword(s):

High Grade Glioma ◽

Medical Costs ◽

High Grade ◽

Newly Diagnosed ◽

Direct Medical Costs ◽

Costs Of Treatment

Download Full-text

DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG

Neuro-Oncology ◽

10.1093/neuonc/noaa222.097 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii297-iii297

Author(s):

Sharon Gardner ◽

Rohinton Tarapore ◽

Jeffrey Allen ◽

Wafik Zaky ◽

Yazmin Odia ◽

...

Keyword(s):

Clinical Trial ◽

Body Weight ◽

Phase I ◽

Single Agent ◽

High Grade Glioma ◽

Newly Diagnosed ◽

Liquid Formulation ◽

Open Label ◽

Dismal Prognosis ◽

Expansion Cohort

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

Download Full-text

Central neurotoxicity of standard treatment in patients with newly-diagnosed high-grade glioma: a prospective longitudinal study

Journal of Neuro-Oncology ◽

10.1007/s11060-013-1310-4 ◽

2013 ◽

Vol 116 (2) ◽

pp. 387-394 ◽

Cited By ~ 22

Author(s):

F. E. Froklage ◽

L. J. Oosterbaan ◽

E. M. Sizoo ◽

M. de Groot ◽

I. Bosma ◽

...

Keyword(s):

Longitudinal Study ◽

Standard Treatment ◽

High Grade Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Prospective Longitudinal Study ◽

Central Neurotoxicity ◽

Prospective Longitudinal

Download Full-text

AT-46 * VORINOSTAT AND BEVACIZUMAB FOR RECURRENT HIGH-GRADE GLIOMA: INTERIM ANALYSIS OF A PHASE II CLINICAL TRIAL

Neuro-Oncology ◽

10.1093/neuonc/nou237.45 ◽

2014 ◽

Vol 16 (suppl 5) ◽

pp. v18-v18

Author(s):

K. Peters ◽

D. Reardon ◽

D. Randazzo ◽

S. Dutton ◽

A. Edwards ◽

...

Keyword(s):

Clinical Trial ◽

Phase Ii ◽

Interim Analysis ◽

High Grade Glioma ◽

Phase Ii Clinical Trial ◽

High Grade

Download Full-text

NCOG-14. REAL-WORLD RETROSPECTIVE ANALYSIS OF TUMOR TREATING FIELDS IN THE TREATMENT OF HIGH-GRADE GLIOMA BASED ON CHINESE POPULATION

Neuro-Oncology ◽

10.1093/neuonc/noab196.605 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi154-vi155

Author(s):

Lingchao Chen ◽

Junrui Chen ◽

Kun Song ◽

Jingtao Nie ◽

Dongxiao Zhuang ◽

...

Keyword(s):

Retrospective Analysis ◽

Real World ◽

Chinese Population ◽

Adverse Reactions ◽

High Grade Glioma ◽

High Grade ◽

Newly Diagnosed ◽

Efficacy Data ◽

Tumor Treating Fields ◽

Recurrent Gbm

Abstract OBJECTIVES Tumor Treating Fields (TTFields) has been approved for the treatment of newly diagnosed and relapsed glioblastoma（GBM）in China in 2020. Only few TTFields data in Asia patients were reported. This retrospective analysis is aimed at investigating the efficacy, safety and the potential relationship with biomarkers of TTFields treatment in the real-world clinical practice of the Chinese glioma population. METHODS High-grade glioma patients who were under TTFields treatment from May 2019 to May 2021 in Shanghai Huashan Hospital were analyzed, including baseline data, efficacy data and incidence of adverse events. RESULTS Eighty-two patients (median age 51.0 [26.0 - 47.0] years) with high-grade glioma were enrolled, including 60 newly diagnosed GBM, 16 recurrent GBM, and 6 WHO grade III gliomas. The median time was 9.9 (4.6-15.7) months for follow-ups, median time for TTFields treatment was 4.3(1.1-20.35) months. The median compliance rate was 90% (40%-97%). For newly diagnosed GBM (n=60) and recurrent GBM (n=16), the 6-month PFS rate were 78.4% (95%CI: 63.9-87.6) and 46.7% (95%CI: 21.2- 67.8) respectively. The 10-month OS rate were 86.3% (95%CI: 69.6- 94.2) and 60.0% (95%CI: 12.6- 88.2) respectively. The 6-month PFS rate in the IDHw/TERTm population was 69.9% (95%CI: 45.9-84.9) and 78.3% (95%CI: 46.5-92.5) in the IDHw/TERTw patients with newly diagnosed GBM. 59(72%) patients had skin-related adverse reactions, and majority are grade 1-2 (grade 1-2, 69.5%; grade 3, 2.5%). CONCLUSIONS This is the 1st retrospective analysis done using TTFields in the treatment of high-grade gliomas in the Chinese population with the largest sample size. From our short follow up, TTFields appears good efficacy among GBM patients. The incidence of skin adverse reactions is higher comparable to published data, but mainly consisted of grade1-2. Long-term efficacy data need to be further followed-up.

Download Full-text