Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma (GLYRad)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02364206
Recruitment Status : Completed
First Posted : February 18, 2015
Last Update Posted : August 14, 2019
Sponsor:
Collaborators:
National Cancer Institute, France
ARC Foundation for Cancer Research
Information provided by (Responsible Party):
Centre Jean Perrin

Brief Summary:

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

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Primary Completion Date : August 2019
Actual Study Completion Date : August 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 .

Drug: LY2228820
Other Name: ralimetinib

Drug: Temozolomide
Other Name: TMZ

Radiation: radiotherapy



Primary Outcome Measures :
  1. 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.

  2. 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 ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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

  3. Overall Survival [ Time Frame: from the first dose of LY2228820 to death, up to 24 months ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. Pharmacokinetic of LY2228820 and TMZ (AUC0-12h) [ Time Frame: D7 Week 0, D28 Week 3, D35 Week 4 ]
  8. 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)

  9. Validated biomarker of glioblastoma (MGMT, IDH1 (isocitrate dehydrogenase 1), pTEN (phosphatase and tensin homolog), p53) [ Time Frame: baseline ]
    on tumor



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newly diagnosed and histologically confirmed glioblastoma
  • Recursive partitioning analysis (RPA) class III or IV
  • Age > or = 18 years and < 75 years of age
  • Life expectancy > or = 6 months
  • Patient must have at least 1 formalin fixed paraffin embedded tumor tissue block representative of glioblastoma available for pathology central review and biomarker exploration
  • Adequate hematologic (absolute neutrophil count (ANC) > or = 1.5 x 109/L, platelet count > or = 100 x 109/L, hemoglobin > or = 10 g/dL ), renal (creatinine > or = 1.25 x ULN ), and hepatic function (total bilirubin < or = 1.5 x ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < or = 2.5 x ULN)
  • Patients who were receiving corticosteroids had to receive a stable or decreasing dose for at least 14 days before enrollment
  • Patients must be able to swallow and retain oral medication
  • Women must have a negative serum pregnancy test less than 7 days prior to the first dose of study drug
  • Both men and women of reproductive potential agree to use approved contraception during the study and for 6 months after discontinuation of study treatment.
  • Willing and able to comply with the protocol as judged by the investigator
  • Patients must provide written consent

Exclusion Criteria:

  • Any prior chemotherapy (including carmustine-containing wafers) or immunotherapy (including vaccine therapy )
  • Any prior radiotherapy to the brain
  • Any contraindication to temozolomide listed in the local label
  • Have had, in the judgment of the investigator, a major bowel resection that would alter oral drug absorption
  • Have a diagnosis of inflammatory bowel disease (Crohn's disease or ulcerative colitis)
  • Have previously completed or withdrawn from this study or any other study investigating LY2228820
  • Are receiving, in the judgment of the investigator, concurrent administration of immunosuppressive therapy
  • Diarrhea of any cause CTCAE > or = grade 2
  • Current or recent (within 30 days of enrollment) treatment with another investigational drug or participation in another investigational study
  • History of other malignancy within 5 years prior enrollment except for basal cell carcinoma of the skin or carcinoma in situ of the cervix
  • Pregnant or nursing (lactating) woman, or fertile women unwilling or unable to use effective means of contraception
  • Psychiatric illness / social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance / pill diary

Information from the National Library of Medicine

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


Locations
Layout table for location information
France
CHU Amiens Sud-Salouel
Amiens, France
Institut Bergonié
Bordeaux, France
Centre François Baclesse
Caen, France
Centre Jean Perrin
Clermont-Ferrand, France
Centre Georges François Leclerc
Dijon, France
Centre Paul Strauss
Strasbourg, France
Sponsors and Collaborators
Centre Jean Perrin
National Cancer Institute, France
ARC Foundation for Cancer Research
Investigators
Layout table for investigator information
Principal Investigator: Xavier DURANDO, Pr Centre Jean Perrin

Layout table for additonal information
Responsible Party: Centre Jean Perrin
ClinicalTrials.gov Identifier: NCT02364206     History of Changes
Other Study ID Numbers: 2013-005442-11
First Posted: February 18, 2015    Key Record Dates
Last Update Posted: August 14, 2019
Last Verified: August 2019
Keywords provided by Centre Jean Perrin:
newly diagnosed glioblastoma
p38 MAPK inhibitor
temozolomide
radiotherapy
Additional relevant MeSH terms:
Layout table for MeSH terms
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents