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 |
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E.1.1.1 | Medical condition in easily understood language |
Patients with recurrent malignant lymphomas |
Patienten met terugkerende kwaardaardige lympomen |
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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) |
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E.1.3 | Condition being studied is a rare disease | No |
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. |
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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. |
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E.2.3 | Trial contains a sub-study | No |
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). |
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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 |
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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). |
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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
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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 |
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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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |