Clinical Trials Register

Summary
EudraCT Number:	2017-003511-20
Sponsor's Protocol Code Number:	201700599
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-09-26
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

Netherlands - Competent Authority

A.2

EudraCT number

2017-003511-20

A.3

Full title of the trial

Molecular imaging of zirconium-89-labeled atezolizumab in high-risk diffuse large B-cell lymphoma prior to atezolizumab treatment

Moleculaire beeldvorming middels Zirkonium-89-gelabeled Atezolizumab als een instrument om de biodistributie van atezolizumab in hoog risico diffuus grootcellig B-cellymfoom te onderzoeken

A.3.1

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

Imaging with a radioactively-labeled antibody against PDL-1 in patients with lymphoma

Beeldvorming met een radioactief gelabelde antilichaam gericht tegen PDL-1 in patienten met lymfoom

A.3.2

Name or abbreviated title of the trial where available

PDL1 imaging in DLBCL

A.4.1

Sponsor's protocol code number

201700599

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	HOVON Foundation
B.1.3.4	Country	Netherlands
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	Hoffman la Roche
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus MC, HOVON Data Center
B.5.2	Functional name of contact point	HOVON Data Center (EE2155)
B.5.3	Address:
B.5.3.1	Street Address	Wytemaweg 80
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015 CN
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31107041560
B.5.5	Fax number	+31107041028
B.5.6	E-mail	hdc@erasmusmc.nl

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	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	89ZR-N-SUCDF-ATEZOLIZUMAB
D.3.2	Product code	89ZR-N-SUCDF-MPDL3280A
D.3.4	Pharmaceutical form	Solution for injection
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	ATEZOLIZUMAB
D.3.9.3	Other descriptive name	MPDL3208
D.3.9.4	EV Substance Code	SUB178312
D.3.10	Strength
D.3.10.1	Concentration unit	MBq megabecquerel(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	37
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)	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	Yes
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

Diffuse large B-cell Lymphoma

Diffuus grootcellig B-cellymfoom

E.1.1.1

Medical condition in easily understood language

Diffuse large B-cell Lymphoma

Diffuus grootcellig B-cellymfoom

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10012819
E.1.2	Term	Diffuse large B-cell lymphomas
E.1.2	System Organ Class	100000004851

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	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10012820
E.1.2	Term	Diffuse large B-cell lymphoma NOS
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 biodistribution of 89Zr-atezolizumab in patients with high risk DLBCL at diagnosis.

E.2.2

Secondary objectives of the trial

• Assess the heterogeneity of 89Zr-atezolizumab tumor uptake in high-risk DLBCL before R-CHOP
• Correlate 89Zr-atezolizumab biodistribution with PD-L1 expression on tumor cells and cells in the micro-environment as assessed by immunohistochemistry on archival tumor biopsies, soluble PD-L1 measurements and PD-L1 RNA expression
• Evaluate 89Zr-atezolizumab biodistribution in metabolic complete remission following R-CHOP and assess the relation with minimal residual disease
• Assess the 89Zr-atezolizumab biodistribution at relapse after treatment with atezolizumab for patients treated in the HOVON 151 trial
• Correlate 89Zr-atezolizumab tumor uptake dynamics and biodistribution to potential adverse reactions of atezolizumab treatment for patients treated in the HOVON 151 trial
• Establish the baseline characteristics for the T-cell and NK-cell repertoire and dynamics induced by R-CHOP
• Establish the baseline characteristics for the microbiome and the dynamics induced by R-CHOP

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to receive information on the dynamics induced by R-CHOP, patients should preferably be included before standard R-CHOP therapy (at Part A). Alternatively, patients who are eligible can also be included after having achieved complete remission with standard R-CHOP therapy (i.e. at Part B).

Inclusion criteria
• Age 18-75 (inclusive) years
• Patients with a confirmed histologic diagnosis of diffuse large B-cell lymphoma (DLBCL-NOS) based upon a representative histology specimen according to the WHO classification, revision 2016 (see appendix A)
• Ann Arbor stages II-IV (see appendix B)
• WHO performance status 0 – 1 (see appendix E)
• IPI ≥ 3 at diagnosis (see appendix C)
• Negative pregnancy test at study entry
• Patient is willing and able use adequate contraception during and until 5 months after the last protocol treatment.
• Written informed consent
• Patient is capable of giving a written informed consent

E.4

Principal exclusion criteria

Diagnosis
• All histopathological diagnoses other than DLBCL-NOS according to the WHO classification, revision 2016 (see appendix A), including:
- High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations
- Testicular large B-cell lymphoma
- Primary mediastinal B cell lymphoma
- Transformed indolent lymphoma
- Post-transplant lymphoproliferative disorder

Organ dysfunction
• Clinical signs of severe pulmonary dysfunction
• Clinical signs of heart failure (NYHA classification II-IV)
• Symptomatic coronary artery disease or cardiac arrhythmias not well controlled with medication.
• Myocardial infarction during the last 6 months
• Significant renal dysfunction (serum creatinine ≥ 150 umol/l or clearance ≤ 30ml/min
Creatinine clearance may be calculated by Cockcroft –Gault formula:
CrCl = (140 - age [in years]) x weight [kg] (x 0.85 for females) /
(0.815 x serum creatinine [μmol/L])
• Inadequate hematological function: hemoglobin < 5.5 mmol/L ANC < 1.0x10^9/L or platelets < 75x10^9 /L
• Spontaneous INR > 1.5, aPTT >33
• Significant hepatic dysfunction (total bilirubin ≥ 1.5x upper limit of normal (ULN) or transaminases ≥ 2.5 x ULN), unless related to Gilberts syndrome.
• Clinical signs of severe cerebral dysfunction
• Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs
• Major surgery within the last 4 weeks

Known or suspected infection
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks before date of registration. Suspected active or latent tuberculosis needs to be confirmed by positive interferon gamma (IFN-γ) release assay
• Patients known to be HIV-positive
• Active chronic hepatitis B or C infection
• Administration of a live, attenuated vaccine within 4 weeks before date of registration or anticipation that such a live attenuated vaccine will be required during the study and for a period of 5 months after discontinuation of atezolizumab.

Auto-immune
• Any active or history of documented autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
The following exceptions are allowed: Patients with autoimmune-related hypothyroidism or type 1 diabetes mellitus who are on stable treatment.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening.
• Patients with uncontrolled asthma or allergy, requiring systemic steroid treatment
• Regular treatment with corticosteroids within the 4 weeks prior to date of registration, unless administered for indications other than NHL at a dose equivalent to < 30 mg/day prednisone/prednisolone.

General
• Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
• Current participation in another clinical trial interfering with this trial
• History of active cancer during the past 5 years, except basal cell carcinoma of the skin or stage 0 cervical carcinoma
• Life expectancy < 6 months
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Prior treatment
• Prior treatment with atezolizumab, or anti PD-1 or PDL-1 antibodies.
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4 therapeutic antibodies.
• Treatment with systemic immunostimulatory agents (including but not limited to IFN, interleukin [IL]-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to date of registration.
• Treatment with systemic immunosuppressive medications, including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents within 2 weeks prior to date of registration; inhaled corticosteroids and mineralocorticoids are allowed.

E.5 End points

E.5.1

Primary end point(s)

• Description of 89Zr-atezolizumab biodistribution in DLBCL by measuring standardized uptake value (SUV) on the 89Zr-atezolizumab-PET scans

E.5.1.1

Timepoint(s) of evaluation of this end point

Data analysis will be performed on an ongoing basis after every patient

E.5.2

Secondary end point(s)

• Tumor and immune cell PD-L1 expression analysis in an archival pre-treatment biopsy, will be correlated to 89Zr-atezolizumab tumor uptake, evaluated by measuring standardized uptake value (SUV) on the 89Zr-atezolizumab-PET
• Correlation analysis of tumor 89Zr-atezolizumab uptake, evaluated by measuring standardized uptake value (SUV) and sPD-L1 levels in patient serum, assessed using ELISA
• Correlation analysis of tumor 89Zr-atezolizumab uptake, evaluated by assessing immune signature by GEP
• Correlation analysis of 89Zr-atezolizumab uptake and MRD status
• Correlation analysis between 89Zr-atezolizumab off-target uptake and atezolizumab toxicity
• Analysis of predictive value of 89Zr-atezolizumab imaging in high-risk DLBCL patients

Exploratory study endpoints:
• Establish baseline characteristics and dynamics for T-cell repertoire and microbiome after R-CHOP

E.5.2.1

Timepoint(s) of evaluation of this end point

Data analysis will be performed on an ongoing basis after every patient

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

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

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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

The end of this study is marked by the last study procedure, i.e. the last 89Zr-atezolizumab-PET scan. Patients eligible for atezolizumab treatment will be followed up for 5 years according to HOVON 151 protocol.
Patients, who participated in the imaging trial and who are not eligible for atezolizumab treatment, will be followed 28±3 days (after tracer injection), or until the last (serious) adverse event related to the tracer or unlabeled atezolizumab administration has resolved.

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

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Patients who are participating in the 89Zr-atezolizumab imaging study are eligible for participation in the HOVON 151 study which aims at increasing disease free survival via consolidation therapy with atezolizumab.

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

2018-09-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-30

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

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