Clinical Trials Register

Summary
EudraCT Number:	2020-006143-26
Sponsor's Protocol Code Number:	2019/ABM/01/00062
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-02-16
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Poland - Office for Medicinal Products

A.2

EudraCT number

2020-006143-26

A.3

Full title of the trial

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).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

2019/ABM/01/00062

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Śląski Uniwersytet Medyczny w Katowicach
B.1.3.4	Country	Poland
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Agencja Badań Medycznych
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Śląski Uniwersytet Medyczny w Katowicach / Prof. Wojciech Kaspera
B.5.2	Functional name of contact point	Oddział Kliniczny Neurochirurgii
B.5.3	Address:
B.5.3.1	Street Address	pl. Medyków 1
B.5.3.2	Town/ city	Sosnowiec
B.5.3.3	Post code	41-200
B.5.3.4	Country	Poland
B.5.4	Telephone number	0048323682551
B.5.6	E-mail	wkaspera@sum.edu.pl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	KEYTRUDA 25 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	KEYTRUDA 25 mg/ml
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.4	EV Substance Code	SUB167136
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Glioblastoma Multiforme

E.1.1.1

Medical condition in easily understood language

malignant brain tumour of glial origin

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10018337
E.1.2	Term	Glioblastoma multiforme
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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).

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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):
a) Hemoglobin ≥ 9g/dL
b) Absolute Neutrophils Count (ANC) ≥1.5×10 9/L
c) White Blood Cells (WBC) count ≥3×10 9/L
d) Platelets (PTL) ≥ 100×10 9/L
e) AST/ALT ≤2.5×ULN
f) Serum creatinine (S-Cr) ≤ ULN
g) Glomerular Filtration Rate (GFR) ≥50mL/min
h) Albumin ≥ LLN
i) Bilirubin ≤ 1.5 ULN (except patients with documented Gilbert’s Syndrome, who must present adequate level of direct bilirubin)
j) 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.

E.4

Principal exclusion criteria

1. Any active concomitant malignancy, except:
a. Locally treated basal or squamous cell carcinoma
b. Cervical carcinoma in situ
c. Breast cancer in situ
d. Bladder cancer in situ
e. Low grade prostate cancer (under observation with PSA level in normal range)
2. Any previous systemic cancer treatment, including, but not limited to:
a. Radiotherapy
b. Brachytherapy for brain tumor
c. Chemotherapy
d. Carmustine wafer treatment (Gliadel®)
e. 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 less or equal to 12mg of dexamethasone equivalent; the dose of dexamethasone should be kept as low as possible throughout the whole duration of this trial)
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.

E.5 End points

E.5.1

Primary end point(s)

1. Safety and tolerability – incidence of Adverse Events (AEs) and Serious
Adverse Events (SAEs) related and unrelated with Pembrolizumab
3. Patient-Reported Outcomes to evaluate health status and Quality of Life (QoL)
instruments for patients with GBM:
 Eastern Cooperative Oncology Group (ECOG) status
 Karnofsky Performance Status (KPS)
 EORTC: QLQ-BN20 (brain), and QLQ-C30 (general cancer
questionnaire).

E.5.1.1

Timepoint(s) of evaluation of this end point

will be assessed using CTCAE/ICD10. The QoL will be measured with EORTC – QLQ-C30 and EORTC-QLQ-BN20 scale as well as ECOG status and Karnofsky Performance Scale (KPS).

E.5.2

Secondary end point(s)

Clinical endpoints – response in tumor burden - progression-free survival
(PFS), objective response rate (ORR), disease control rate (DCR, time-toprogression
(TTP) and overall survival (OS). Serial evaluation of tumor
burden/tumor growth is assessed according to Response Assessment in Neuro-
Oncology (RANO) and the modified RANO for immune-based therapeutics
(iRANO). Regardless of the number of imaging techniques used, at least one
specific technique should be consistent for each patient during the entire study
period with measurements done initially every 3 months during treatment period
and then every 6 months after completion of immuno- and chemo-radiotherapy (in
accordance with SoC), through 3 years of clinical follow up:
 Progression-free survival (PFS), defined as the time from initial tumor
resection to the first occurrence of progression/relapse or death from any
cause, whichever occurs first. PFS will be calculated based on disease
status evaluated by the investigator according to RANO and iRANO.
 Disease control rate (DCR), defined as the percentage of patients who
attain complete response (CR), partial response (PR) or stable disease
(SD) according to RANO.
 Objective response rate (ORR), defined as the percentage of patients who
attain complete response (CR) or partial response (PR) according to
RANO.
 Time-to-progression (TTP), defined as the time from initiation of study
treatment to disease progression/relapse
 OS, defined as the proportion of patients remaining alive from initial
tumor resection through 3-years of clinical follow-up from EOT.

E.5.2.1

Timepoint(s) of evaluation of this end point

Clinical Efficacy Assessment will be based on tumor measurements assessed in accordance with RANO criteria. The same technique ( [MRI] scan) should be used for the disease assessment at screening period and throughout the study. The standard assessments will be performed at: screening, every 3 months during post-surgery treatment period and every 6 months up to three years of follow up. Patients treated with immunotherapy who have disease progression (PD) within first 6 months of treatment RANO will be allowed to continue treatment if clinically stable.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard treatment with chemo-radiotherapy

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-02

P. End of Trial
P.	End of Trial Status	Ongoing

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