Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma (GLYRad)
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|ClinicalTrials.gov Identifier: NCT02364206|
Recruitment Status : Active, not recruiting
First Posted : February 18, 2015
Last Update Posted : November 29, 2018
Glioblastomas are extremely resistant to treatment, including radiotherapy and/or chemotherapy. Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. Activation of p38 MAPK has been associated with a poor prognosis among patients with glioblastoma during the temozolomide (TMZ) era and represents a compensatory response by tumor cell to environmental stress such as radiation or chemotherapy.
LY2228820 is a potent and selective inhibitor of p38 MAPK, and reduces phosphorylation of its cellular target, MAPK-activated protein kinase 2 (MAPKAPK-2) . LY2228820 is a good candidate to target malignant glioma resistance to the gold standard treatment combining radiation and TMZ by acting on both tumor and stromal cells.
The primary objectives of this study were to determine the recommended dose of LY2228820 in combination with TMZ and radiotherapy during chemoradiotherapy period (phase I) and to estimate the 6-month progression free survival (PFS) rate of patients treated with LY2228820 when administered at the recommended dose in combination with radiotherapy and concomitant TMZ (phase II)
|Condition or disease||Intervention/treatment||Phase|
|Adult Glioblastoma||Drug: LY2228820 Drug: Temozolomide Radiation: radiotherapy||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||18 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma|
|Actual Study Start Date :||June 8, 2015|
|Estimated Primary Completion Date :||June 2019|
|Estimated Study Completion Date :||June 2019|
Experimental: LY2228820 + TMZ + Radiotherapy
addition of LY2228820 to standard radiotherapy and concomitant treatment by temozolomide (TMZ).
LY2228820 will be administered orally for two 28 day cycles, from one week before the beginning of radiotherapy, and during standard chemoradiotherapy. Three dose levels of LY2228820 will be tested.
After a 4 week break after concomitant treatment, patient were then received up to 6 cycles of adjuvant TMZ according to the standard 5-day schedule every 28 days .
Other Name: ralimetinib
Other Name: TMZ
- maximum tolerated dose (MTD) (phase I) of LY2228820 in combination with TMZ and radiotherapy during chemoradiotherapy period [ Time Frame: from D1 Week 0 (first dose of LY2228820) to D63 Week 8. ]defined as the highest dose tested in which a dose limiting toxicity (DLT) is experienced by no more than 33% of patients during chemoradiotherapy period.
- 6-month Progression Free Survival (PFS) rate (phase II) defined as the rate of patients who not presented a progression at 6 months from the first dose of LY2228820 [ Time Frame: 6 months from the first dose of LY2228820 ]
- Safety profile according to NCI Common Toxicity Criteria for Adverse Effect (CTCAE) criteria version 4.03. [ Time Frame: from baseline to 30 days after treatment (concomitant and adjuvant treatment) (week 35) ]
- PFS [ Time Frame: from the first dose of LY2228820 to disease progression or death for any reason, up to 24 months ]disease progression assessed per Response Assessment in Neuro-Oncology (RANO) criteria
- Overall Survival [ Time Frame: from the first dose of LY2228820 to death, up to 24 months ]
- 12-month PFS rate defined as the rate of patients who not presented a progression at 12 months from the first dose of LY2228820 [ Time Frame: 12 months from the first dose of LY2228820 ]
- Objective response rate according to RANO criteria for patients with incomplete resection or only biopsy [ Time Frame: from the first dose of LY2228820 to treatment completion ]
- The neurologic status evaluated by clinical assessment and Mini-Mental State Examination (MMSE) and evaluation of corticosteroid dosage [ Time Frame: from baseline to progression, up to 24 months ]
- Pharmacokinetic of LY2228820 and TMZ (AUC0-12h) [ Time Frame: D7 Week 0, D28 Week 3, D35 Week 4 ]
- MAPKAPK-2 activation [ Time Frame: baseline (tumor) D1 D7 week 0, D28 Week 3, D35 Week 4 (PBMCs) ]in tumor and stromal cells and Peripheral Blood Mononucleated Cells (PBMCs)
- Validated biomarker of glioblastoma (MGMT, IDH1 (isocitrate dehydrogenase 1), pTEN (phosphatase and tensin homolog), p53) [ Time Frame: baseline ]on tumor
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02364206
|CHU Amiens Sud-Salouel|
|Centre François Baclesse|
|Centre Jean Perrin|
|Centre Georges François Leclerc|
|Centre Paul Strauss|
|Principal Investigator:||Xavier DURANDO, Pr||Centre Jean Perrin|