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The Assessment of Immune Response in Newly Diagnosed Glioblastoma Patients Treated With Pembrolizumab (PIRG)

Primary Purpose

Newly Diagnosed Glioblastoma

Status
Recruiting
Phase
Phase 4
Locations
Poland
Study Type
Interventional
Intervention
Pembrolizumab
Pembrolizumab
Sponsored by
Medical University of Silesia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Newly Diagnosed Glioblastoma focused on measuring Glioblastoma, Pembrolizumab, Immunotherapy, PD-1, PD-L1

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  1. Signed Informed Consent Form
  2. Age ≥ 18 years
  3. Age ≤70 years
  4. Able to comply with the study protocol in the investigator's judgment
  5. Clinically and radiologically (contrast CT, full profile MRI - T1-weighted with or without contrast, T2-weighted, FLAIR, DWI, PWI, MR-spectroscopy) confirmed diagnosis of GBM, localized outside eloquent brain areas
  6. Resectable tumor
  7. Fully physically active ≥80 points in Karnofsky performance scale
  8. Life expectancy of at least 3 months
  9. Adequate organ function (confirmed within 1 weeks before enrollment):

    1. Hemoglobin ≥ 9g/dL
    2. Absolute Neutrophils Count (ANC) ≥1.5×109/L
    3. White Blood Cells (WBC) count ≥3×109/L
    4. Platelets (PTL) ≥ 100×109/L
    5. AST/ALT ≤2.5×ULN
    6. Serum creatinine (S-Cr) ≤ ULN
    7. Glomerular Filtration Rate (GFR) ≥50mL/min
    8. Albumin ≥ LLN
    9. Bilirubin ≤ 1.5 ULN (except patients with documented Gilbert's Syndrome, who must present adequate level of direct bilirubin)
    10. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN. (Elevation of INR and aPTT due to administration of anticoagulation drugs is not a contraindication for the enrollment. However, it must return to normal range prior to surgery).
  10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use double barrier contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 120 days after the last immuno-PET imaging.
  11. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use double barrier contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 120 days after the last immuno-PET imaging.

Exclusion criteria:

Patients who meet any of the following criteria will be excluded from study entry:

  1. Any active concomitant malignancy, except:

    1. Locally treated basal or squamous cell carcinoma
    2. Cervical carcinoma in situ
    3. Breast cancer in situ
    4. Bladder cancer in situ
    5. Low grade prostate cancer (under observation with PSA level in normal range)
  2. Any previous systemic cancer treatment, including, but not limited to:

    1. Radiotherapy
    2. Brachytherapy for brain tumor
    3. Chemotherapy
    4. Carmustine wafer treatment (Gliadel®)
    5. Any immune checkpoint inhibitor therapy or any anticancer vaccination
  3. Hypersensitivity or allergy to any substance with similar action mechanism to Pembrolizumab, Atezolizumab, Temozolomide, other monoclonal antibodies or contrast agents
  4. Any active immunosuppressive systemic therapy (except corticosteroids under 12mg)
  5. Any active autoimmune disease or systemic therapy for autoimmune disease within 2 years before enrollment
  6. History of any immunodeficiency
  7. Active infection
  8. Significant cardiovascular disease, such as New York Heart Association cardiac disease ≥ Class III, myocardial infarction within 3 months, coronary artery disease, unstable arrhythmias or unstable angina
  9. Active liver disease, hepatitis, HBV or HCV infection
  10. History of tuberculosis
  11. Any mental disorder that may affect patient's participation
  12. Any drug or psychoactive substance dependence
  13. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol
  14. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to study treatment initiation
  15. Major surgical procedure within 4 weeks prior to study enrollment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
  16. Any live vaccination within 30 days before enrollment
  17. Any active immunosuppressive systemic infection including history of human immunodeficiency virus (HIV) infection
  18. Body mass index (BMI) ≥ 35 kg/m2
  19. Pregnant or lactating or intending to become pregnant during the study - women who are not postmenopausal (postmenopausal defined as ≥ 12 months of non-drug-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 2 weeks prior to initiation of study treatment
  20. Any condition that the patient's physician determines to be detrimental to the patient participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical events.
  21. Inability to understand the local language for use of the patient QoL instruments.
  22. Tumor other than glioblastoma grade 4 IDH-wildtype, astrocytoma grade 3 or 4 IDH-mutant identified in post-surgery histopathology.
  23. Presence of 1p19q codeletion.

Sites / Locations

  • Wojciech KasperaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

No Intervention

Arm Label

Treatment arm 1

Treatment arm 2

Treatment arm 3

Arm Description

n=12 evaluable patients - neoadjuvant Pembrolizumab (2 doses, 200mg each) plus adjuvant Pembrolizumab (16 cycles q3w, 200mg each) on top of standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 of body surface area (BSA) daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 for 5 days in each 28-day cycle)

n=12 evaluable patients - neoadjuvant Pembrolizumab (2 doses, 200mg each) on top of standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 for 5 days in each 28-day cycle)

n=12 evaluable patients - standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 for 5 days in each 28-day cycle)

Outcomes

Primary Outcome Measures

Overall survival
Proportion of patients remaining alive from initial tumor resection
Progression-free survival
Time from initial tumor resection to the first occurrence of progression/relapse or death from any cause, whichever occurs first

Secondary Outcome Measures

Time-to-progression
Time from initiation of study treatment to disease progression/relapse

Full Information

First Posted
February 1, 2022
Last Updated
August 28, 2023
Sponsor
Medical University of Silesia
Collaborators
Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice
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1. Study Identification

Unique Protocol Identification Number
NCT05235737
Brief Title
The Assessment of Immune Response in Newly Diagnosed Glioblastoma Patients Treated With Pembrolizumab
Acronym
PIRG
Official Title
A Single Center, Open-Label, Randomized Study to Evaluate the Safety and Efficacy of Neoadjuvant and Adjuvant Pembrolizumab on Top of Standard Chemo-Radiotherapy (Stupp Protocol) in Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme (GBM).
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2022 (Actual)
Primary Completion Date
June 1, 2025 (Anticipated)
Study Completion Date
May 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Medical University of Silesia
Collaborators
Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No

5. Study Description

Brief Summary
To evaluate the short-term and longer-term safety, tolerability, and effectiveness of neoadjuvant and adjuvant Pembrolizumab on top of standard therapy (Stupp protocol) in patients with Glioblastoma Multiforme (GBM). Randomized comparison of safety, tolerability, and clinical efficacy of (1) neoadjuvant and adjuvant Pembrolizumab (on top of Stupp protocol, n=12 patients), (2) neoadjuvant Pembrolizumab (on top of Stupp protocol, n=12 patients), and (3) standard of care (Stupp protocol only, n=12 patients). Immuno-PET examination will be performed before and after surgery in all patients.
Detailed Description
This is an open-label, Phase IV study of Pembrolizumab employed in neoadjuvant and adjuvant setting on top of standard therapy to evaluate the short-term and long-term safety, tolerability and efficacy in disease control in Glioblastoma Multiforme (GBM) patients. The control arm will be a group of patients treated in accordance with Standard of Care (SoC). The study will include 3 treatment arms (up to n=12 evaluable patients per arm) and will be conducted at single site in Poland. Patients with GBM will be randomly assigned in 1:1:1 ratio into one of 3 treatment arms: Treatment arm 1 - n=12 evaluable patients - neoadjuvant Pembrolizumab (2 doses, 200mg each) plus adjuvant Pembrolizumab (16 cycles q3w, 200mg each) on top of standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 BSA for 5 days in each 28-day cycle) Treatment arm 2 - n=12 evaluable patients - neoadjuvant Pembrolizumab (2 doses, 200mg each) on top of standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 BSA for 5 days in each 28-day cycle) Treatment arm 3 - n=12 evaluable patients - standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 BSA for 5 days in each 28-day cycle) A pre-screening period will identify potential candidates for enrollment. Once qualified to the study patients will be randomized to one of the treatment arms. Then patients randomized to treatment arm 1 and 2 will receive first dose of neoadjuvant Pembrolizumab on day 4 and day 18 (200mg each). An immuno-PET scan for these arm 1 and 2 patients will be performed on day 29 and 30. Up to 72 hours after last immuno-PET scan all patients will undergo tumor resection. After surgery all patients will be treated in accordance with standard of care (Stupp protocol) with combined radio- and chemotherapy. Radiotherapy will consist of 60Gy over 6 weeks in daily fraction of 2Gy in Mo-Fri setting and parallel chemotherapy with Temozolomide of 75mg/m2 of BSA on a daily basis. After completion of radiotherapy the chemotherapy will continue for six cycles of 28 days with 150-200mg/m2 Temozolomide on days 1-5 of each cycle. In addition, patients randomized to arm 1 will receive 16 cycles of 21 days with Pembrolizumab treatment in adjuvant setting of 200mg/cycle. During treatment period all patients will be assessed every three months and MRI will be performed in order to evaluate disease status/response. After EOT patient's follow up period will continue for up to 3 years from initial resection with MRI assessment every 3 months. If progression/relapse is identified, patients will undergo a tumor resection or biopsy within 48 hours thereafter. All patients will then stay in follow up until the end of three years follow up period or death from any cause. The evaluation of safety, tolerability, and quality-of-life (QoL) will be based on adverse event reporting criteria (Common Terminology Criteria for Adverse Events - CTCAE/WHO Classification of Diseases - ICD10), ECOG status assessment, KPS assessment, EORTC - QLQ-C30 and EORTC-QLQ-BN20 scale. Clinical assessment will be based on Response Assessment in Neuro-Oncology (RANO). For patients treated with immunotherapy beyond onset of objective disease progression, the iRANO scale will be used within first 6 months of immunotherapy. Due to a significant risk of identifying other pathology than GBM (i.e. metastasic tumor) in post-surgery histopathology it is anticipated that up to additional 6 patients may be recruited in order to achieve planned number of evaluable patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Newly Diagnosed Glioblastoma
Keywords
Glioblastoma, Pembrolizumab, Immunotherapy, PD-1, PD-L1

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Masking Description
Open Label
Allocation
Randomized
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment arm 1
Arm Type
Active Comparator
Arm Description
n=12 evaluable patients - neoadjuvant Pembrolizumab (2 doses, 200mg each) plus adjuvant Pembrolizumab (16 cycles q3w, 200mg each) on top of standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 of body surface area (BSA) daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 for 5 days in each 28-day cycle)
Arm Title
Treatment arm 2
Arm Type
Active Comparator
Arm Description
n=12 evaluable patients - neoadjuvant Pembrolizumab (2 doses, 200mg each) on top of standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 for 5 days in each 28-day cycle)
Arm Title
Treatment arm 3
Arm Type
No Intervention
Arm Description
n=12 evaluable patients - standard chemo-radiotherapy (Stupp protocol: radiotherapy 60Gy over 6 weeks, 2 Gy per daily fraction Mo-Fri setting plus Temozolomide 75mg/m2 BSA daily during radiotherapy and six cycles post-radiotherapy of 150-200mg/m2 for 5 days in each 28-day cycle)
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Intervention Description
Adding Pembrolizumab as a neoadjuvant and adjuvant therapy to the standard of care protocol
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Intervention Description
Adding Pembrolizumab as a neoadjuvant therapy to the standard of care protocol
Primary Outcome Measure Information:
Title
Overall survival
Description
Proportion of patients remaining alive from initial tumor resection
Time Frame
3 years after initial tumor surgery
Title
Progression-free survival
Description
Time from initial tumor resection to the first occurrence of progression/relapse or death from any cause, whichever occurs first
Time Frame
3 years after initial tumor surgery
Secondary Outcome Measure Information:
Title
Time-to-progression
Description
Time from initiation of study treatment to disease progression/relapse
Time Frame
3 years after initial tumor surgery
Other Pre-specified Outcome Measures:
Title
Usability assessment of immuno-PET imaging with 89Zr-DFO-Atezolizumab for quantitative analysis of early changes in PD-L1 expression
Description
Immuno-PET scans (Standardized Uptake Values) will be correlated with the level and distribution of T cell activation markers.
Time Frame
48 hours after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Signed Informed Consent Form Age ≥ 18 years Age ≤70 years Able to comply with the study protocol in the investigator's judgment Clinically and radiologically (contrast CT, full profile MRI - T1-weighted with or without contrast, T2-weighted, FLAIR, DWI, PWI, MR-spectroscopy) confirmed diagnosis of GBM, localized outside eloquent brain areas Resectable tumor Fully physically active ≥80 points in Karnofsky performance scale Life expectancy of at least 3 months Adequate organ function (confirmed within 1 weeks before enrollment): Hemoglobin ≥ 9g/dL Absolute Neutrophils Count (ANC) ≥1.5×109/L White Blood Cells (WBC) count ≥3×109/L Platelets (PTL) ≥ 100×109/L AST/ALT ≤2.5×ULN Serum creatinine (S-Cr) ≤ ULN Glomerular Filtration Rate (GFR) ≥50mL/min Albumin ≥ LLN Bilirubin ≤ 1.5 ULN (except patients with documented Gilbert's Syndrome, who must present adequate level of direct bilirubin) International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN. (Elevation of INR and aPTT due to administration of anticoagulation drugs is not a contraindication for the enrollment. However, it must return to normal range prior to surgery). For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use double barrier contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 120 days after the last immuno-PET imaging. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use double barrier contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 120 days after the last immuno-PET imaging. Exclusion criteria: Patients who meet any of the following criteria will be excluded from study entry: Any active concomitant malignancy, except: Locally treated basal or squamous cell carcinoma Cervical carcinoma in situ Breast cancer in situ Bladder cancer in situ Low grade prostate cancer (under observation with PSA level in normal range) Any previous systemic cancer treatment, including, but not limited to: Radiotherapy Brachytherapy for brain tumor Chemotherapy Carmustine wafer treatment (Gliadel®) Any immune checkpoint inhibitor therapy or any anticancer vaccination Hypersensitivity or allergy to any substance with similar action mechanism to Pembrolizumab, Atezolizumab, Temozolomide, other monoclonal antibodies or contrast agents Any active immunosuppressive systemic therapy (except corticosteroids under 12mg) Any active autoimmune disease or systemic therapy for autoimmune disease within 2 years before enrollment History of any immunodeficiency Active infection Significant cardiovascular disease, such as New York Heart Association cardiac disease ≥ Class III, myocardial infarction within 3 months, coronary artery disease, unstable arrhythmias or unstable angina Active liver disease, hepatitis, HBV or HCV infection History of tuberculosis Any mental disorder that may affect patient's participation Any drug or psychoactive substance dependence Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to study treatment initiation Major surgical procedure within 4 weeks prior to study enrollment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis Any live vaccination within 30 days before enrollment Any active immunosuppressive systemic infection including history of human immunodeficiency virus (HIV) infection Body mass index (BMI) ≥ 35 kg/m2 Pregnant or lactating or intending to become pregnant during the study - women who are not postmenopausal (postmenopausal defined as ≥ 12 months of non-drug-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 2 weeks prior to initiation of study treatment Any condition that the patient's physician determines to be detrimental to the patient participating in this study; including any clinically important deviations from normal clinical laboratory values or concurrent medical events. Inability to understand the local language for use of the patient QoL instruments. Tumor other than glioblastoma grade 4 IDH-wildtype, astrocytoma grade 3 or 4 IDH-mutant identified in post-surgery histopathology. Presence of 1p19q codeletion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Wojciech Kaspera, Md, Phd
Phone
+48-32-3682551
Email
wkaspera@sum.edu.pl
Facility Information:
Facility Name
Wojciech Kaspera
City
Sosnowiec
State/Province
Silesian
ZIP/Postal Code
41-200
Country
Poland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Wojciech Kaspera, Phd
Phone
+48323682551
Email
wkaspera@sum.edu.pl
First Name & Middle Initial & Last Name & Degree
Wojciech Szopa
Phone
+48323682657
Email
wszopa@sum.edu.pl

12. IPD Sharing Statement

Plan to Share IPD
No
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The Assessment of Immune Response in Newly Diagnosed Glioblastoma Patients Treated With Pembrolizumab

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