Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma (GLYRad)
Primary Purpose
Adult Glioblastoma
Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
LY2228820
Temozolomide
radiotherapy
Sponsored by
About this trial
This is an interventional treatment trial for Adult Glioblastoma focused on measuring newly diagnosed glioblastoma, p38 MAPK inhibitor, temozolomide, radiotherapy
Eligibility 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- Have previously completed or withdrawn from this study or any other study investigating LY2228820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
Sites / Locations
- CHU Amiens Sud-Salouel
- Institut Bergonié
- Centre François Baclesse
- Centre Jean Perrin
- Centre Georges François Leclerc
- Centre Paul Strauss
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
LY2228820 + TMZ + Radiotherapy
Arm Description
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 .
Outcomes
Primary Outcome Measures
maximum tolerated dose (MTD) (phase I) of LY2228820 in combination with TMZ and radiotherapy during chemoradiotherapy period
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
Secondary Outcome Measures
Safety profile according to NCI Common Toxicity Criteria for Adverse Effect (CTCAE) criteria version 4.03.
PFS
disease progression assessed per Response Assessment in Neuro-Oncology (RANO) criteria
Overall Survival
12-month PFS rate defined as the rate of patients who not presented a progression at 12 months from the first dose of LY2228820
Objective response rate according to RANO criteria for patients with incomplete resection or only biopsy
The neurologic status evaluated by clinical assessment and Mini-Mental State Examination (MMSE) and evaluation of corticosteroid dosage
Pharmacokinetic of LY2228820 and TMZ (AUC0-12h)
MAPKAPK-2 activation
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)
on tumor
Full Information
NCT ID
NCT02364206
First Posted
February 4, 2015
Last Updated
August 13, 2019
Sponsor
Centre Jean Perrin
Collaborators
National Cancer Institute, France, ARC Foundation for Cancer Research
1. Study Identification
Unique Protocol Identification Number
NCT02364206
Brief Title
Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma
Acronym
GLYRad
Official Title
Phase I/II Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma
Study Type
Interventional
2. Study Status
Record Verification Date
August 2019
Overall Recruitment Status
Completed
Study Start Date
June 8, 2015 (Actual)
Primary Completion Date
August 2019 (Actual)
Study Completion Date
August 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Jean Perrin
Collaborators
National Cancer Institute, France, ARC Foundation for Cancer Research
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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)
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Glioblastoma
Keywords
newly diagnosed glioblastoma, p38 MAPK inhibitor, temozolomide, radiotherapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
LY2228820 + TMZ + Radiotherapy
Arm Type
Experimental
Arm Description
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 .
Intervention Type
Drug
Intervention Name(s)
LY2228820
Other Intervention Name(s)
ralimetinib
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
TMZ
Intervention Type
Radiation
Intervention Name(s)
radiotherapy
Primary Outcome Measure Information:
Title
maximum tolerated dose (MTD) (phase I) of LY2228820 in combination with TMZ and radiotherapy during chemoradiotherapy period
Description
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.
Time Frame
from D1 Week 0 (first dose of LY2228820) to D63 Week 8.
Title
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 Measure Information:
Title
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)
Title
PFS
Description
disease progression assessed per Response Assessment in Neuro-Oncology (RANO) criteria
Time Frame
from the first dose of LY2228820 to disease progression or death for any reason, up to 24 months
Title
Overall Survival
Time Frame
from the first dose of LY2228820 to death, up to 24 months
Title
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
Title
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
Title
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
Title
Pharmacokinetic of LY2228820 and TMZ (AUC0-12h)
Time Frame
D7 Week 0, D28 Week 3, D35 Week 4
Title
MAPKAPK-2 activation
Description
in tumor and stromal cells and Peripheral Blood Mononucleated Cells (PBMCs)
Time Frame
baseline (tumor) D1 D7 week 0, D28 Week 3, D35 Week 4 (PBMCs)
Title
Validated biomarker of glioblastoma (MGMT, IDH1 (isocitrate dehydrogenase 1), pTEN (phosphatase and tensin homolog), p53)
Description
on tumor
Time Frame
baseline
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xavier DURANDO, Pr
Organizational Affiliation
Centre Jean Perrin
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Amiens Sud-Salouel
City
Amiens
Country
France
Facility Name
Institut Bergonié
City
Bordeaux
Country
France
Facility Name
Centre François Baclesse
City
Caen
Country
France
Facility Name
Centre Jean Perrin
City
Clermont-Ferrand
Country
France
Facility Name
Centre Georges François Leclerc
City
Dijon
Country
France
Facility Name
Centre Paul Strauss
City
Strasbourg
Country
France
12. IPD Sharing Statement
Learn more about this trial
Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma
We'll reach out to this number within 24 hrs