Clinical trial NCT02364206: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adult Glioblastoma
Keywords: newly diagnosed glioblastoma
p38 MAPK inhibitor
temozolomide
radiotherapy
Lead sponsor: Centre Jean Perrin
Sponsor class: OTHER
Collaborators: name: National Cancer Institute, France
name: ARC Foundation for Cancer Research
First posted: 2015-02-18
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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)


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

Primary outcomes:
measure: maximum tolerated dose (MTD) (phase I) of LY2228820 in combination with TMZ and radiotherapy during chemoradiotherapy period
timeFrame: from D1 Week 0 (first dose of LY2228820) to D63 Week 8.
measure: 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
timeFrame: 6 months from the first dose of LY2228820
Secondary outcomes:
measure: Safety profile according to NCI Common Toxicity Criteria for Adverse Effect (CTCAE) criteria version 4.03.
timeFrame: from baseline to 30 days after treatment (concomitant and adjuvant treatment) (week 35)
measure: PFS
timeFrame: from the first dose of LY2228820 to disease progression or death for any reason, up to 24 months
measure: Overall Survival
timeFrame: from the first dose of LY2228820 to death, up to 24 months
measure: 12-month PFS rate defined as the rate of patients who not presented a progression at 12 months from the first dose of LY2228820
timeFrame: 12 months from the first dose of LY2228820
measure: Objective response rate according to RANO criteria for patients with incomplete resection or only biopsy
timeFrame: from the first dose of LY2228820 to treatment completion
measure: The neurologic status evaluated by clinical assessment and Mini-Mental State Examination (MMSE) and evaluation of corticosteroid dosage
timeFrame: from baseline to progression, up to 24 months
measure: Pharmacokinetic of LY2228820 and TMZ (AUC0-12h)
timeFrame: D7 Week 0, D28 Week 3, D35 Week 4
measure: MAPKAPK-2 activation
timeFrame: baseline (tumor) D1 D7 week 0, D28 Week 3, D35 Week 4 (PBMCs)
measure: Validated biomarker of glioblastoma (MGMT, IDH1 (isocitrate dehydrogenase 1), pTEN (phosphatase and tensin homolog), p53)
timeFrame: baseline
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens Sud-Salouel
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Strasbourg
country: France
facility: Centre Paul Strauss
Study officials:
affiliation: Centre Jean Perrin
name: Xavier DURANDO, Pr
role: PRINCIPAL_INVESTIGATOR
References: