Clinical Trials Register

Summary
EudraCT Number:	2021-001270-34
Sponsor's Protocol Code Number:	RIMAL1
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-04-08
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

2021-001270-34

A.3

Full title of the trial

Enhancement of immune response by combining immune checkpoint blockade and radiation in patients with
recurrent / refractory malignant lymphoma (re-directing the immune system).

Verbetering van de behandelingsresultaten van patiënten met een recidief / refractair maligne lymfoom is nodig. Immuuntherapie kan daaraan bijdragen. Inzicht in mechanismen, die het effect van de immuuntherapie beïnvloeden, is van groot belang om aangrijpingspunten te vinden, die immuuntherapie effectiever maken. Bestraling lijkt daaraan een belangrijke bijdrage te leveren.

A.3.1

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

Radio-Immunotherapy in MAlignant Lymphoma 1 (RIMAL1)

Radio-Immunotherapie bij MAligne Lymfoom 1 (RIMAL1)

A.3.2

Name or abbreviated title of the trial where available

RIMAL1

A.4.1

Sponsor's protocol code number

RIMAL1

A.5.4

Other Identifiers

Name:

ABR

Number:

75774

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	Radboud University Medical Centre
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	Radboudumc
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Radboud University Medical Centre
B.5.2	Functional name of contact point	Projectleader
B.5.3	Address:
B.5.3.1	Street Address	Geert Grooteplein zuid 10
B.5.3.2	Town/ city	Nijmegen
B.5.3.3	Post code	6525GA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031243686456

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	Opdivo
D.2.1.1.2	Name of the Marketing Authorisation holder	European Commission
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	Opdivo
D.3.2	Product code	EMEA/H/C/003985
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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	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	Yes
D.2.1.1.1	Trade name	KEYTRUDA
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
D.3.2	Product code	EMEA/H/C/003820
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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

patients with recurrent / refractory 9p24.1 amplified malignant lymphomas
patients with recurrent / refractory malignant lymphoma without 9p24.1 amplification

Patienten met recidiverende kwaardaardige lymfomen met of zonder 9p24.1 versterking

E.1.1.1

Medical condition in easily understood language

Patients with recurrent malignant lymphomas

Patienten met terugkerende kwaardaardige lympomen

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10025310
E.1.2	Term	Lymphoma
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

Enhancement of the immune response (with Optivo or Keytruda) by radiation, and thereby treatment efficacy, in patients with recurrent / refractory malignant lymphomas treated with ICB. As a measure for immune activation, INF I and II signature alterations will be correlated with clinical response measured by standard [18F]FDG PET-CT scans and ctDNA in blood.

We willen de immuurrespons, met ICB's Optivo en Kytruda, door bestraling versterken en daarmee ook de werkzaamheid van de behandeling. Dit doen we bij patienten met een gerecidiveerd / refractiair maligne lymphoom die met ICB worden behandeld. Als maat voor immuunactivatie zullen INF I en II signanuurveranderingen gecorreleerd worden met klinische respons gemeten door een standaard FDG PET-CT scans en ctDNA in het bloed.

E.2.2

Secondary objectives of the trial

-To correlate the presence of 9p24.1 in the tumour with response to (radio-) checkpoint blockade immune therapy (CBIT).
-To investigate tumour mutational burden as a measure for tumor antigens and neo-antigens.
-To investigate the T-cell receptor repertoire as response to the increase in tumour antigens and neoantigens, and in relation to treatment.
-To investigate whether and which additional factors influence and reveal the immune response (changes in blood leukocyte subsets, functional T- and NK-cell assays, gut microbiome).
-To correlate ‘myeloid regulatory cell number and function’ with immune response as measured by [18F]FDG PET-CT scans and the amount of ctDNA.
-Comparison of therapy response of irradiated and non-irradiated lesions in the same patient (abscopal effect).
--To investigate whether re-treatment with radio-immunotherapy will undo checkpoint inhibition resistance in patients who show progression in the study protocol.

-om de aanwezigheid van 9p24.1 in de tumor te correleren met de respons op (radio-) checkpoint blockade immuuntherapie (CBIT).
-Het onderzoeken van tumormutatiebelasting als maat voor tumorantigenen en neo-antigenen.
-Het T-celreceptorrepertoire onderzoeken als reactie op de toename van tumorantigenen en neoantigenen, en in relatie tot behandeling.
-Om te onderzoeken of en welke aanvullende factoren de immuunrespons beïnvloeden en onthullen (veranderingen in subgroepen van bloedleukocyten, functionele T- en NK-celassays, darmmicrobioom).
-Het correleren van ‘aantal en functie van myeloïde regulerende cellen’ met immuunrespons zoals gemeten door [18F] FDG PET-CT-scans en de hoeveelheid ctDNA.
-Vergelijking van de therapierespons van bestraalde en niet-bestraalde laesies bij dezelfde patiënt).
- Om te onderzoeken of herbehandeling met radio-immunotherapie de resistentie tegen controlepuntinhibitie ongedaan maakt bij patiënten die progressie vertonen in het studieprotocol.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- patients with refractory / recurrent malignant lymphoma eligible for ICB therapy
- aged 18 – 75 year
- WHO score ≥2
- adequate organ function: neutrophil count, serum creatinine, ASAT, ALAT, albumin
- no prior treatment with checkpoint inhibitors
- no non-infectious pneumonitis requiring steroids
- not pregnant
- patients of childbearing/reproductive potential should use 2 birth control methods
- written informed consent

- Patiënten met een refractair / recidief maligne lymfoom die in aanmerking komen voor immuun checkpoint blokkade therapie.
- Leeftijd: 18 - 75 jaar.
- WHO score ≥ 2.
- Niet eerder behandeld met checkpoint inhibitors.
- Niet onder behandeling met steroïden in verband met niet-infectieuze pneumonitis.
- Niet zwanger.
- Gebruik van afdoende anti-conceptie (2 manieren), indien van toepassing.
- Schriftelijke toestemming (informed consent).

E.4

Principal exclusion criteria

- Not fit (mentally or physically) to undergo the proposed treatment.
- Patients with connective tissue diseases (inflammatory myopathy (polymyositis and ermatomyositis), systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, antisynthetase syndrome, rheumatoid arthritis, severe psoriasis and mixed CTDs), vasculitis (granulomatosis with polyangiitis (Wegener’s granulomatosis), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome), severe Behçet disease, Takayasu arteritis, giant cell arteritis, Buerger disease, Kawasaki disease, polyarteritis nodosa, severe immunoglobulin A (IgA) vasculitis (Henoch–Schönlein purpura), severe cutaneous vasculitis, polymyalgia rheumatica, severe cryoglobulinaemia and undifferentiated systemic vasculitis) and other autoimmune diseases (primary biliary cirrhosis, severe autoimmune hepatitis, multiple sclerosis, severe antiphospholipid syndrome, myasthenia gravis, Guillain–Barré syndrome, inflammatory bowel disease, Miller–Fisher syndrome, Vogt–Koyanagi–Harada syndrome, eosinophilic fasciitis (Shulman syndrome), relapsing polychondritis and severe autoinflammatory diseases) ( Martins et al. 2019).
- Sensory or motor peripheral neuropathy > grade 2.

- Niet in staat (zowel mentaal als fysiek) om voorgestelde behandeling te ondergaan.
- Patiënten met auto-immuun aandoeningen zoals bindweefsel aandoeningen en vasculitis.
- Sensibele en motore perifere neuropathie > graad 2

E.5 End points

E.5.1

Primary end point(s)

Enhancement of the immune response by radiation, and thereby treatment efficacy, in patients with relapsed / refractory malignant lymphomas treated with immune checkpoint inhibition. As a measure for immune activation, interferon I and II signature alterations will be correlated with clinical response using standard [18F]FDG PET-CT scans and ctDNA measurements in blood.

Versterking van de immuunrespons door bestraling, en daarmee de werkzaamheid van de immuuntherapie, bij patiënten met gerecidiveerd / refractair maligne lymfoom, die worden behandeld met immuun checkpoint blokkade. Als maat voor immuunactivering zullen interferon I en II signatuurveranderingen gecorreleerd worden met klinische respons zoals die gemeten wordt met [18F] FDG PET-CT scans en de hoeveelheid circulerend tumor-DNA (ctDNA).

E.5.1.1

Timepoint(s) of evaluation of this end point

a) Alteration / increase in interferon I and II (INF I and II) signatures in blood, measured 3 weeks after radiotherapy and after every 3 consecutive courses of ICB.
b) FDG PET-CT response 3 weeks after radiotherapy and after every 3 consecutive courses of ICB, related to the presence of 9p24.1 amplification.
c) Changes in ctDNA, based on the presence of tumour-specific somatic genomic characterizations of the lymphoma; reflecting lymphoma activity or tumour cell death, measured 3 weeks after radiotherapy and after every 3 consecutive courses of ICB.

a) verandering/ toename van de tekenen van interferon I en II in bloed, gemeten 3 weken na de radiotherapie en na elke 3 opeenvolgende ICB-kuren.
b) FDG PET-CT respons 3 weken na radiotherapie en na elke 3 opeenvolgende ICB-kuren, gerelateerd aan de aanwezigheid van 9p24.1 amplificatie
c) verandering in ctDNA, gebaseerd op de aanwezigheid van tumorspecifieke somatische genomische karateriseringen van het lymphoom, gemeten 3 weken na de radiotherapie en na elke 2 opeenvolgende ICB-uren

E.5.2

Secondary end point(s)

To correlate amplification of 9p24.1 in malignant lymphoma with response to (radio-) immune checkpoint inhibition therapy. The 9p24.1 amplification contains several genes; we focus mainly on the genes PDCD1LG1 (encoding programmed cell death 1 ligand 1) and PDCD1LG2 (encoding programmed cell death 1 ligand 2).
- To correlate tumour mutational burden with response to treatment.
- To investigate additional factors either influencing or revealing the immune response: changes in blood leukocyte subsets, T-cell receptor repertoire, functional T- and NK-cell assays, gut microbiome.
- To correlate ‘myeloid regulatory cell number and function’ with immune response as measured by [18F]FDG PET-CT scans and the amount of ctDNA.
- To compare, using [18F]FDG PET-CT scans, irradiated and non-irradiated lesions in the same patient (abscopal effect).
- To investigate whether re-treatment with radio-immune checkpoint blockade will undo checkpoint inhibition resistance in patients who show progression in the study protocol.

- Correlatie van 'amplificatie van 9p24.1 bij maligne lymfomen' met 'respons op immuun checkpoint blokkade'. De 9p24.1-amplificatie bevat verschillende genen; we richten ons voornamelijk op de genen PDCD1LG1 (coderend voor geprogrammeerde celdood 1 ligand 1) en PDCD1LG2 (coderend voor geprogrammeerde celdood 1 ligand 2) verantwoordelijk voor immuun checkpoint-resistentie.
- Correlatie van 'tumour mutational burden' met 'de respons op de behandeling'.
- Factoren onderzoeken die mede de immuunrespons beïnvloeden of onthullen: veranderingen in subgroepen van leukocyten, T-cel receptor repertoire, functionele T- en NK-cel assays, darm-microbioom.
- Correlatie van ‘aantal en de functie van myeloid regulatory cells’ met de immuunrespons, zoals gemeten met [18F] FDG PET-CT-scans en de hoeveelheid ctDNA.
- Vergelijking, met behulp van [18F] FDG PET-CT-scans, van bestraalde en niet-bestraalde laesies in dezelfde patiënt (abscopal effect).
- Onderzoeken of bestraling de resistentie, die tijdens de behandeling met immuun checkpoint blokkade kan/zal optreden, ongedaan kan maken.
- Optioneel: extra biopsie van pathologische lymfklier om immuunresponse in de tumor te correleren aan de immuunresponse in het bloe

E.5.2.1

Timepoint(s) of evaluation of this end point

3 weeks after radiotherapy and after every 3 consecutive courses of ICB

gemeten 3 weken na de radiotherapie en na elke 2 opeenvolgende ICB-uren

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

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

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

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.4.2

For a multinational trial

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-04-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-04-19

P. End of Trial
P.	End of Trial Status	Completed

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