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

• ClinicalTrials.gov Identifier: NCT02364206
• Recruitment Status: Completed
• First Posted: February 18, 2015
• Last Update Posted: August 14, 2019
• Sponsor: Centre Jean Perrin
• Collaborators: National Cancer Institute, France; ARC Foundation for Cancer Research
• Information provided by (Responsible Party): Centre Jean Perrin

Tracking Information

• First Submitted Date: February 4, 2015
• First Posted Date: February 18, 2015
• Last Update Posted Date: August 14, 2019
• Actual Study Start Date: June 8, 2015
• Actual Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2015)

• 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 ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 10, 2016)

• 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

Original Secondary Outcome Measures (submitted: February 10, 2015)

• 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 ]
  desease 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 tensine homolog), p53) [ Time Frame: baseline ]
  on tumor

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma
• Official Title: Phase I/II Study of LY2228820 With Radiotherapy Plus Concomitant TMZ in the Treatment of Newly Diagnosed Glioblastoma

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)

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Adult Glioblastoma

Intervention

• Drug: LY2228820
  Other Name: ralimetinib
• Drug: Temozolomide
  Other Name: TMZ
• Radiation: radiotherapy

Study Arms

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 .

Interventions:

• Drug: LY2228820
• Drug: Temozolomide
• Radiation: radiotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 9, 2018): 18
• Original Estimated Enrollment (submitted: February 10, 2015): 50
• Actual Study Completion Date: August 2019
• Actual Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02364206
• Other Study ID Numbers: 2013-005442-11
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Centre Jean Perrin
• Original Responsible Party: Same as current
• Current Study Sponsor: Centre Jean Perrin
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute, France
• ARC Foundation for Cancer Research

Investigators

• Principal Investigator: Xavier DURANDO, Pr; Centre Jean Perrin

• PRS Account: Centre Jean Perrin
• Verification Date: August 2019