Clinical Trials Register

Summary
EudraCT Number:	2017-000200-23
Sponsor's Protocol Code Number:	2017-BN-001
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-04-06
Trial results	View 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

Belgium - FPS Health-DGM

A.2

EudraCT number

2017-000200-23

A.3

Full title of the trial

Phase II clinical trial on the combination of avelumab and axitinib for the treatment of patients with recurrent glioblastoma

A.3.1

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

Phase II clinical trial on the combination of avelumab and axitinib for the treatment of patients with recurrent glioblastoma

A.3.2

Name or abbreviated title of the trial where available

GliAvAx

A.4.1

Sponsor's protocol code number

2017-BN-001

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	UZ Brussel
B.1.3.4	Country	Belgium
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	UZ Brussel
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UZ Brussel
B.5.2	Functional name of contact point	Bart Neyns
B.5.3	Address:
B.5.3.1	Street Address	Laarbeeklaan 101
B.5.3.2	Town/ city	Jette
B.5.3.3	Post code	1090
B.5.3.4	Country	Belgium
B.5.4	Telephone number	003224775447
B.5.5	Fax number	00322477 5460
B.5.6	E-mail	bart.neyns@uzbrussel.be

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	InlytaTM,
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Inlyta
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AXITINIB
D.3.9.1	CAS number	319460-85-0.
D.3.9.2	Current sponsor code	AG013736
D.3.9.3	Other descriptive name	Inlyta
D.3.9.4	EV Substance Code	SUB25427
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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.IMP: 2
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	No
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	Avelumab
D.3.2	Product code	MSB0010718C
D.3.4	Pharmaceutical form	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	AVELUMAB
D.3.9.1	CAS number	1537032-82-8
D.3.9.2	Current sponsor code	MSB0010718C
D.3.9.4	EV Substance Code	SUB180078
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	20
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)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
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

recurrent glioblastoma

E.1.1.1

Medical condition in easily understood language

recurrent glioblastoma (brain tumor)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
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.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10018336
E.1.2	Term	Glioblastoma
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 estimate the anti-tumor effect of combination therapy with avelumab and axitinib in patienst with recurrent/progressive glioblastoma following prior therapy with surgery, radiation therapy and temozolomide (on both strata seperatly)

E.2.2

Secondary objectives of the trial

• To document the safety of a combination of avelumab with axitinib in patients with recurrent glioblastoma The incidence of unacceptable treatment related adverse events will be graded according to the CTCAEv4.0)
• Treatment disposition for avelumab and axitinib
• Corticosteroid use
• Tumor response according to the iRANO criteria
• Estimate survival (PFS, and OS) by Kaplan-Meier estimates
• Assess the neuro-cognitive function (by Cogstate computer based neurocognitive assessment), psycho-emotional wellbeing and HR-QOL
• Assess physical activity level by continuous activity tracking using an activity tracking device (e.g. Garmin Vivofit device)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Diagnosis:
•Histologically confirmed diagnosis of World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma);
•Documentation of recurrent (or progressive according to RNAO criteria) glioblastoma following prior treatment with surgery (resection or biopsy), radiation therapy and temozolomide chemotherapy;
•A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 15 unstained slides (10 minimum) obtained from an archival FFPE tumor tissue block will be required.
•Presence of a measurable tumor lesion that is characterized by gadolinium enhancement on T1-MRI of the brain (with a shortest diameter of >5 mm) and enhanced lesion to normal brain uptake on FET-PET imaging of the brain;
•If first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field.
•An interval of >28 days and full recovery (ie, no ongoing safety issues) from surgical resection and an interval of >4 weeks after the last administration of any other treatment for glioblastoma.
2.Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative, as allowed by local guidance/practice) has been informed of all pertinent aspects of the study.
3.Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
4.Age 18 years.
5.Estimated life expectancy of at least 3 months.
6.Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
7.No evidence of pre-existing uncontrolled hypertension as documented by 2 baseline blood pressure (BP) readings taken at least 1 hour apart. The baseline systolic BP readings must be 140 mm Hg, and the baseline diastolic BP readings must be 90 mm Hg. Use of antihypertensive medications to control BP is allowed.
8.Adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c. Hemoglobin 9 g/dL (may have been transfused).
9.Adequate renal function, including:
a.Estimated creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault (CG) equation;
b.Urinary protein <2+ by urine dipstick. If dipstick is 2+, then 24-hour urinary protein <2 g per 24 hours.
10.Adequate liver function, including:
a.Total serum bilirubin 1.5 x upper limit of normal (ULN);
b.AST and ALT 2.5 x ULN.
11.Serum pregnancy test (for females of childbearing potential) negative at screening.
12.Male patients able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use 2 highly effective methods of contraception throughout the study and for at least 90 days after the last dose of assigned treatment.

E.4

Principal exclusion criteria

1.Any of the following prior cancer therapies:
•Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways;
•Prior therapy with axitinib as well as any prior therapies with other VEGF pathway inhibitors (including bevacizumab)
2.Participation in other therapeutic studies within 4 weeks prior to enrollment in the current study
3.Persisting toxicity related to prior therapy NCI CTCAE v4.03 Grade >1; however, sensory neuropathy Grade ≤2 is acceptable
4.Current or prior use of immunosuppressive medication within 7 days prior to enrollment, except for steroid treatment needed to palliate glioblastoma associated neurological symptoms and intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
5.No treatment with enzyme inducing anti-epileptic drugs (EIAED) during and at least 14 days before the administration of axitinib
6.Known severe hypersensitivity reactions to monoclonal antibodies (Grade >3), any history of anaphylaxis
7.Known prior or suspected hypersensitivity to study drugs or any component in their formulations
8.Diagnosis of any other malignancy within 5 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for treatment intervention (eg, surgery, radiation or castration)
9.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
10.Gastrointestinal abnormalities including:
•Inability to take oral medication;
•Requirement for intravenous alimentation;
•Prior surgical procedures affecting absorption including total gastric resection;
•Treatment for active peptic ulcer disease in the past 6 months;
•Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically significant hematemesis, hematochezia or melena
•Malabsorption syndromes
11.Active infection requiring systemic therapy
12.Diagnosis of prior immunodeficiency or organ transplant requiring immunosuppressive therapy, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
13.Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or chronic infection
14.Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines (for example, inactivated influenza vaccines)
15.Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed
16.Evidence of inadequate wound healing (including dehiscence of the craniotomy scar)
17.Grade 3 hemorrhage within 4 weeks of patient enrollment
18.Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack
19.Any of the following in the previous 6 months: deep vein thrombosis or symptomatic pulmonary embolism
20.Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus extending to the heart
21.Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4/5 inhibitors,
23.Pregnant female patients, breastfeeding female patients.
24.Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, uncontrolled asthma, and pneumonitis or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

E.5 End points

E.5.1

Primary end point(s)

The percentage of patients who are alive and free-from confirmed tumor progression at 6-month (24 weeks) following the date of randomisation (6-month PFS%)

E.5.1.1

Timepoint(s) of evaluation of this end point

at 6-months

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

Continuously during the study

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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

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

confirmed progression of disease, unacceptable toxicity, the patient’s refusal to continue study treatment, or death of the patient

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

Depending on the patients general condition and previous treatments, the best available care will be given

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

2017-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-09-16

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