| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| melanoma patients with regional lymph node metastases (stage III) |
| melanoom patiënten met regionale lymfeklier metastasen (stadium III) |
|
| E.1.1.1 | Medical condition in easily understood language |
| regionally metastasised skin cancer |
| regionaal gemetastaseerde huidkanker |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| 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 |
| This is an interventional study and the primary objective is the biodistribution and the immunogenicity of single and combined pDC and myDC vaccination. |
| Dit is een interventie-studie en de primaire doelstelling is de biologische verdeling en de immunogeniciteit van aparte en gecombineerde pDC en myDC vaccinaties. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are the safety, quality of life and overall survival. |
| De secundaire doelstellingen zijn de veiligheid, de kwaliteit van leven en de totale overleving. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-stage III melanoma with enlarged lymph nodes according to the 2001 AJCC criteria
- cytological or histological documented evidence of stage III melanoma
- HLA-A2.1 positive
- WHO performance status 0-1 (Karnofsky 100-70)
- life expectancy ≥3 months
- age 18-75 years
- no clinical signs or symptoms of CNS metastases
- WBC >3.0×109/l, lymphocytes >0.8×109/l, platelets >100×109/l, serum creatinine <150 µmol/l, serum bilirubin <25 µmol/l
- normal serum LDH (≤250 U/l)
- expected adequacy of follow-up
- no pregnant or lactating women
- written informed consent
- radical regional lymphnode dissection is scheduled, but not yet performed |
- histologisch bewezen maligne melanoom
- stadium III volgens AJCC criteria
- cytologisch of histologisch bewezen stadium III melanoom
- WHO performance status 0-1 (Karnofsky 100-70%)
- Levensverwachting > 3 maanden
- Leeftijd 18-70 jaar
- Geen klinische tekenen van CZS metastasen
- Normaal bloedbeeld
- Normaal serum LDH
- Redelijkerwijs mag verwacht worden dat de patient in staat is tot een geode follow-up
- Geen zwangere vrouwen of vrouwen die borstvoeding geven
- Schriftelijke informed consent
- Aangedane klieren gaan chirurgisch verwijderd worden |
|
| E.4 | Principal exclusion criteria |
- any prior chemotherapy, immunotherapy or radiotherapy is allowed if completed
more than 4 weeks prior to planned vaccination
- history of any second malignancy in the previous 5 years, with the exception of adequately treated basal cell carcinoma or carcinoma in situ of the cervix
- serious active infections, known HbsAg or HIV positive, or autoimmune diseases or organ allografts
- concomitant use of immunosuppressive drugs
- known allergy to shell fish (since it contains KLH)
- rapidly progressive symptomatic disease
- acute kidney injury or chronic severe kidney disease
- any serious clinical condition that may interfere with the safe administration of DC
- expected adequacy of follow-up
- no pregnant or lactating women
- written informed consent
- radical regional lymphnode dissection is scheduled |
- behandeld met chemotherapie, immuuntherapie of radiotherapie minder dan 4 weken voordat de vaccinatie gepland is of toxiciteit van een eerdere behandeling
- voorgeschiedenis van tweede tumor, adequaat behandeld basaal cel carcinoom, of carcinoom in situ van de cervix is acceptabel
- actieve infectie, HbsAg of HIV positief
- autoimmuun ziekte of orgaan allografts
- gebruik van immuunsuppressiva
- snelle progressieve ziekte
- een klinische aandoening die van invloed zou kunnen zijn op de veiligheid van het toedienen van dendritische cellen |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
the biodistribution and the immunogenicity of single and combined pDC and mDC vaccination.
Biodistribution and immunological responses are:
(a) The migratory capacity of blood DC in vivo.
(b) The localization of injected blood DC in dissected lymph nodes.
(c) The antitumor immune response induced with blood DC loaded with tumor-derived peptides. Immunogenicity is defined as the antitumor immune response induced in stage III melanoma patients. Therefore, immunomonitoring will be performed that includes: 1) Functional response and tetramer analysis of DTH-infiltrating T cells against tumor peptides. The occurrence and magnitude of the response will be compared. 2) Type I IFN gene expression in PBMC shortly after vaccination. The occurrence and magnitude of the type I IFN response in patients will be compared. 3) Proliferative, effector cytokine- and humoral responses to keyhole limpet hemocyanin (KLH), a immunogenic providing T cell help. |
de biodistributie en de immunogeniciteit van enkelvoudige en gecombineerde PDC en mDC vaccinatie.
Biodistributie en immunologische reacties zijn:
(a) migratie capaciteit van bloed DC in vivo.
(b) de lokalisatie van de ingespoten bloed DC in de lymfeknopen.
(c) Een immuunresponse tegen 1 van de epitopen van de vaccinatie peptiden in de lymfeknopen. Er wordt hierbij gekeken naar: 1) functionerende T cellen in de huidtest gericht tegen de eiwit stukjes van de prostaatkanker, 2) toename van afweersignalen op genniveau in de witte bloedcellen, gemeten kort na een vaccinatie en 3) proliferatie, cytokine productie en antilichaam responsen tegen KLH, een eiwit dat dient als immunogene T cell hulp. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The migratory capacity of pDC, myDC and coinjected pDC and mDC:24 hours after injection
The localization of injected blood DC in dissected lymph nodes:After surgical removal of the lymph nodes, DC and surrounding leukocytes will be analyzed
The antitumor immune response induced in melanoma patients vaccinated with blood DC
loaded with tumor-derived peptides:immunomonitoring will be peformed |
De migratie capaciteit van de pDC, mDC en coinjected pDC en mDC: 24 uur na de injectie
De lokalisatie van geinjecteerd bloed DC in verwijderde lymfeklieren: Na chirurgische verwijdering van de lymfeklieren, zullen DC en de omliggende leukocyten worden geanalyseerd
De anti-tumor immuunrespons geïnduceerd in melanoom patiënten gevaccineerd met bloed DC
beladen met tumor afgeleide peptiden: immunomonitoring zal plaatsvinden
|
|
| E.5.2 | Secondary end point(s) |
Safety, Quality of Life, and the clinical efficacy of vaccination with blood DC.
Clinical endpoint is overall survival |
Veiligheid, Kwaliteit van Leven, en de klinische werkzaamheid van de vaccinatie met bloed DC.
Klinisch eindpunt is overall survivall |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: during the whole trial
Quality of life questionnaires: every 6 weeks
Clinical efficacy: before treatment, 6 weeks after the third vaccination, and before the second round a thorough physical examination and blood tests will be performed to check for disease recurrence. Also during the second round, third round, and follow-up for 1 year this will be performed. |
Veiligheid: gedurende de hele studie
Kwaliteit van leven vragenlijsten: elke 6 weken
Klinische effectiviteit: voor start vaccinaties, 6 weken na de 3e vaccinatie en voor de tweede vaccinatieronde vindt er een uitgebreid lichamelijk onderzoek plaats inclusief laboratorium onderzoek om na te gaan of er sprake is van recidief ziekte. Ook tijdens de 2e vaccinatieronde, de 3e vaccinatieronde en gedurende het jaar follow-up daarna zal dit plaatsvinden. |
|
| 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 | Yes |
| E.6.5 | Efficacy | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| plasmacytoide denritische cellen, myeloide dendritische cellen of een combinatie van beide (4 armen) |
| plasmacytoid denritic cells, myeloid dendritic cells or a combination of these two (4 study arms) |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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
|
| LVLS |
| Laatste visite van laatste patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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