Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme (SEJ)
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|ClinicalTrials.gov Identifier: NCT03047473|
Recruitment Status : Recruiting
First Posted : February 9, 2017
Last Update Posted : February 6, 2019
|First Submitted Date ICMJE||January 31, 2017|
|First Posted Date ICMJE||February 9, 2017|
|Last Update Posted Date||February 6, 2019|
|Actual Study Start Date ICMJE||March 10, 2017|
|Estimated Primary Completion Date||September 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Safety and tolerability according to emergent adverse event leading to avelumab interruption or termination [ Time Frame: over the course of the 52 weeks stsudy ]
Safety and tolerability based on avelumab related adverse events leading to permanent or transient discontinuation of avelumab Treatment related adverse events of special interest will include those of autoimmune origin (irAE). The adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT03047473 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||iRANO criteria [ Time Frame: over the course of the 52 weeks study ]
Radiological tumor response will be graded according to the Immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria by a single study radiologist based on the gadolinium enhanced brain MRI performed at the study center at baseline and at the final visit (week 52) or within 2 weeks of the end of avelumab treatment visit and evaluations of locally obtained MRI's Clinical tumor response as per the iRANO criteria will be evaluated by the principal investigator based on the protocol specified neurological exams The OS and PFS will be stratified according to MGMT status, baseline age (>50yrs), baseline Karnofsky performance score (score of 100), whether the patient had a radical tumor resection vs biopsy and according to histopathological diagnosis of primary versus secondary GBM
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures
||potential biomarkers of response [ Time Frame: over the course of the 52 weeks study ]
The correlation between OS and PFS and the prevalence of PD-L1 expression on tumor cells and microglia/macrophages within the tumor, the histological immunoscore. The correlation between OS and PFS in relation the baseline corticosteroid dose, the average daily corticosteroid dose over the whole study duration, inability because of temozolomide related tolerability issues to complete the 6 month temozolomide cycles, the change from baseline to end of study neurocognitive function as measured by the evoked potential P300 and the incidence and severity of irAE's. The change between baseline biomarker results and those obtained from biomarkers in tissue samples from patients with second surgical resection ie treatment failures
|Original Other Pre-specified Outcome Measures||Same as current|
|Brief Title ICMJE||Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme|
|Official Title ICMJE||Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme|
This is a safety and tolerability study looking at the addition of avelumab, an immune checkpoint inhibitor, to standard therapy of temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme.
All patients will be receiving active therapy. Patients will begin the avelumab within 3 weeks of finishing their radiotherapy. Avelumab will be given at a dose of 10mg/kg IV every 2 weeks concomitantly with the monthly temozolomide. Avelumab will be continued for a total of 52 weeks.
Protocol Title: Avelumab in patients with newly diagnosed Glioblastoma Multiforme
Indication: Patients with newly diagnosed Glioblastoma Multiforme
Study Type: Single center, phase 2, open label, addition of avelumab to standard therapy
To determine the safety and tolerability of avelumab administered as 10mg/kg IV q2weeks in patients receiving standard therapy for newly diagnosed GBM.
To determine the impact of the addition of avelumab at a dose of 10mg/kg IV Q2weeks in patients receiving standard therapy for newly diagnosed GBM on overall survival (OS), progression free survival (PFS) and other antitumor activity parameters according to the immunotherapy Response Assessment for Neuro-Oncology (iRANO) (1) at 52 weeks.
To explore biomarkers that could predict treatment response to avelumab such as: the tumor immunoscore, presence and extent of PD-L1 expression on tumor cells and microglia/macrophages within the tumor
To correlate the OS and PFS in relation to the change between baseline and end of study neurocognitive function as measured by the evoked potential P300 (normal), the baseline corticosteroid dose, the average daily corticosteroid dose over the whole study duration, those who for tolerability reasons do not complete the temozolomide standard 6 monthly pulses of therapy and the presence and severity of immune related adverse events (irAE's).
To assess and compare above mentioned biomarkers in tissue samples from patients with second surgical resection ie treatment failures.
To assess in this GBM population the duration of pseudoprogression and the lagtime needed for immunotherapy to become effective.
Study Design: This is a single center, phase 2, open label, add-on, single dose study in patients receiving standard therapy for newly diagnosed GBM. In total 30 patients who meet the entry criteria will be entered into the study within 3 weeks of finishing their last day of combined radiotherapy/temozolamide. Avelumab will be initiated concurrently with the initiation of the first 5 day, monthly cycle of temozolamide and continued for a total of 52 weeks.
A local pathology report will constitute adequate documentation of histology for study inclusion.
The tumor block used for diagnosis of GBM must be collected for each patient and sent for MGMT assessment (if not already done), biomarker and immunoscore analysis. The availability of these samples is mandatory for randomization into the study, and they must be sent within 2 months after patient's entry into the study for analysis.
Paraffin embedded blocks containing formalin-fixed tumor tissue representative of the glioblastoma diagnosis is the preferred sample (if available, and of sufficient quality), otherwise, a partial tumor block, or pathology material should be sent. If surgery was not performed but biopsy was performed (or if it is not possible to send FFPE tumor tissue blocks) at least 10 unstained, uncovered slides must be sent.
The study will consist of 3 different phases: a Combination Phase, a Monotherapy Phase and an Extended Safety Follow-up Phase
Combination Phase: Upon completion of the standard combination therapy of radiotherapy (total dose 60 Gy, administered as daily 2Gy fractions, 5 days/week) and temozolomide (75 mg/m2/day p.o. qd) and a treatment break of no more than 21 days, the combination phase will start. Patients will receive temozolomide and avelumab for 6 cycles of 28 days each. During the 1st cycle Temozolomide will be given the first 5 days at a dose of 150mg/m2/day p.o. In the next cycle, the temozolomide dose should be escalated to 200/mg/m2 if permitted by the patient's hematological and non-hematological toxicity profile (as per NCI-CTC AE version 3). The temozolomide dose will be adjusted according to hematological and non-hematological toxicity as per temozolomide's product monograph (appendix 4). Avelumab will be administered on day 1 and day 15 of each cycle at a dose of 10mg/kg IV. Avelumab therapy will be withheld according to the occurrence and severity of avelumab related adverse events as per table 3. Patients will continue the combination of temozolomide (150-200mg/m2 per day PO X5 days Q28days) and avelumab (at 10mg/kg dose, IV on days 1 and 15 per cycle) until 6 cycles are completed or until confirmed disease progression or unacceptable (grade 3 or higher) avelumab related toxicity occurs.
Monotherapy Phase: Upon completion of the Combination Phase or upon stopping temozolomide because of temozolomide related toxicity the patient will continue into the avelumab Monotherapy Phase. Avelumab 10mg/kg IV Q2weeks will be continued as monotherapy until a total of 52 weeks of avelumab has been received or evidence of confirmed disease progression as per the iRANO definition or unacceptable (grade 3 or higher) avelumab related toxicity has occurred.
Patients who experience irAE's may according to table 3 directives have their avelumab therapy suspended.
The use of Bevacizumab, second surgical resection or re-irradiation will not be allowed in the study and will be considered as evidence of disease progression.
Patients will be promptly informed upon confirmation of disease progression as per the new iRANO criteria. They will be offered to pursue with the avelumab therapy as per protocol or to withdraw from therapy and enter the extended safety follow up phase.
Upon completion of the Monotherapy Phase at week 52 patients will be then be offered the option of being rolled over into an open label extension study or receive commercial avelumab via a special access program.
Extended Safety Follow-up Phase:
Patients who discontinue avelumab therapy for any reason at any point in the study will be entered into an extended safety follow-up period of 90 days. Treatment will then be at the investigator or local oncologist's discretion. All subjects will be observed for the possible occurrence of delayed irAE's. Survival data and information about subsequent therapies will be collected. Tissue samples in patients undergoing second surgical resections will be obtained for further biomarker analysis.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Intervention Model Description:
single center, add on, open label, single dose, single armMasking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Glioblastoma Multiforme of Brain|
|Intervention ICMJE||Biological: avelumab
add on of avelumab 10mg/kg IV to standard therapy
|Study Arms ICMJE||Experimental: Newly diagnosed GBM
single arm, open label Addition of Avelumab to standard treatment
Intervention: Biological: avelumab
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||March 2020|
|Estimated Primary Completion Date||September 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||Canada|
|Removed Location Countries|
|NCT Number ICMJE||NCT03047473|
|Other Study ID Numbers ICMJE||CNO-006|
|Has Data Monitoring Committee||Not Provided|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Dr. Francois Jacques, Clinique Neuro-Outaouais|
|Study Sponsor ICMJE||Clinique Neuro-Outaouais|
|Collaborators ICMJE||Not Provided|
|PRS Account||Clinique Neuro-Outaouais|
|Verification Date||July 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP