| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| glioblastoma |
| glioblastoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Glioblastoma (GBM) is a poor prognosis malignant WHO grade IV glioma. It is the most common malignant primary central nervous tumor in adults |
| Il Glioblastoma (GBM) è un glioma ad alto grado (grado IV WHO) a cattiva prognosi ed è il tumore cerebrale più frequente negli adulti. |
|
| 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 | 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Primary objectives are clinical activity and safety of the study treatment. |
| Gli obiettivi primari dello studio sono la valutazione dell’attività clinica e della sicurezza del trattamento sperimentale. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are the evaluation of the immune response in vivo, the clinical outcome and the immunological efficacy of the study treatment. A series of exploratory objectives will be also assessed on samples from patients who participate to this optional part of the trial. |
| Gli obiettivi secondari sono la valutazione della risposta immune in vivo, dell'esito clinico e la determinazione dell’efficacia immunologica del trattamento sperimentale. Verranno valutati poi una serie di obiettivi esplorativi sui pazienti che aderiranno a questa parte facoltativa dello studio. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
After signing the informed consent form for pre-screening, patient will assess the procedures to obtain sufficient leukapheretic material for the dendritic cell vaccine manufacturing and will perform the standard radiochemotherapy treatment (Stupp regimen) for the disease.
For the pre-screening phase of the study the eligibility criteria are:
1. Histologically confirmed “monofocal” glioblastoma
2. Near-complete resection (= 5 ml residual tumor volume) confirmed by “central neuroradiologist on magnetic resonance imaging (MRI) or CT scan within 72 h postoperative”
3. Karnofsky performance status (KPS) = 70% or performance status of 0 or 1 on the ECOG Performance Scale (Appendix A)
4. Be willing and able to provide written informed consent/assent for the pre-screening phase of the trial.
5. Be = 18 years of age on day of signing informed consent.
6. Life expectancy of greater than 12 weeks.
7. Patient suitable for the collection of biological material from leukapheresis: serological tests HIV, HBV, HCV, Treponema pallidum negative; normal cardiological parameters (ECG and cardiological examination); evaluation by transfusionist to exclude possible contraindications to leukapheresis.
8. Patient candidate to standard radiochemotherapy (Stupp regimen)
9. Appropriate 12-lead ECG and echocardiogram.
After pre-screening, patient will be enrolled based on subsequent Inclusion Criteria:
1. Histologically confirmed “monofocal” glioblastoma
2. The autologous surgical specimen needed for vaccine manufacturing must have been collected and sent to the Somatic Cell Therapy Lab of IRST IRCCS and must fulfil all the acceptance criteria prescribed by the GMP procedures.
3. Availability of sufficient leukapheretic material for the preparation of the vaccine product.
4. No progressive disease near-complete resection (= 5 ml residual tumor volume) confirmed by MRI after standard radiochemotherapy treatment (Stupp regimen)
5. Patients must have recovered (grade 1 or less by CTCAE 5.0) from all the events related to previous treatments.
6. Be willing and able to provide written informed consent/assent for the trial.
7. Be >= 18 years of age on day of signing informed consent.
8. Have a Karnofsky performance status (KPS) = 70% or a performance status of 0 or 1 on the ECOG Performance Scale.
9. Demonstrate adequate organ and marrow function |
Dopo aver firmato il modulo di consenso informato per il pre-screening, il paziente effettuerà le procedure per ottenere il materiale leucaferetico sufficiente per la produzione del vaccino a cellule dendritiche ed eseguirà il trattamento radiochemioterapico standard (regime Stupp) per la sua malattia.
Per la fase di pre-screening dello studio i criteri di eleggibilità sono:
1. Glioblastoma “monofocale” confermato istologicamente
2. Resezione quasi completa (= 5 ml di volume residuo del tumore) confermata dal "neuroradiologo che ha effettuato la risonanza magnetica (MRI) o la TAC entro 72 ore dopo l'intervento chirurgico"
3. Karnofsky Performance status (KPS) = 70% o ECOG performance status 0 o 1 ECOG
4. Paziente disponibili e in grado di fornire un consenso informato scritto / l'assenso per la fase di pre-screening dello studio
5. Età = 18 anni il giorno della firma del consenso informato.
6. Aspettativa di vita superiore a 12 settimane.
7. Paziente idoneo alla raccolta di materiale biologico da leucaferesi: test sierologici HIV, HBV, HCV, Treponema pallidum negativi; parametri cardiologici normali (ECG e visita cardiologica); valutazione da parte di un trasfusionista per escludere possibili controindicazioni alla leucaferesi.
8. Paziente candidato alla radiochemioterapia standard (regime Stupp)
9. 12-lead ECG ed ecocardiogramma nella norma
Dopo il pre-screening, i pazienti saranno arruolati in base ai seguenti criteri di inclusione:
1. Conferma istologica di glioblastoma “monofocale”
2. Malattia non in progressione (= 5 ml di residuo di malattia) confermata da RMN dopo il trattamento standard radiochemioterapico (regime Stupp)
3. Il materiale tumorale asportato deve essere inviato alla Cell Factory IRST e deve rispettare tutti i criteri di accettazione previsti dalle procedure GMP.
4. Disponibilità di sufficiente materiale leucaferetico per l’allestimento del prodotto vaccinico.
5. I pazienti devono aver recuperato (grado 1 o inferiore, secondo CTCAE 5.0) da tutti gli eventi avversi relativi ai trattamenti precedenti.
6. Paziente disposto ed in grado di fornire il consenso informato scritto / l'assenso per la partecipazione allo studio
7. Età >= 18 anni al momento della firma del consenso informato
8. Karnofsky performance status (KPS) = 70% o Performance status di 0 o 1 secondo ECOG.
9. Adeguata funzionalità d'organo e midollare. |
|
| E.4 | Principal exclusion criteria |
1. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy > 10 mg prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
2. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Previous treatment with a cancer vaccine
5. Other known malignant neoplastic diseases in the patient’s medical history with a disease-free interval of less than 5 years, except basal or squamous cell carcinoma of the skin and in situ carcinoma of the cervix uteri treated with radical surgery.
6. Any known history of or is positivity of any serologic marker indicative of infection by Treponema pallidum, hepatitis B virus (HBsAg, HBsAb, HBcAB), hepatitis C virus (HCVAb, HCV RNA quantitative), human immunodeficiency virus (HIV), whether actual or previous.
7. Has received a live vaccine within 30 days of planned start of study therapy. |
1. Paziente con patologia autoimmune o che necessita di terapia immunosoppressiva (> 10 mg prednisone o equivalenti) o che ha eseguito terapia immunosoppressiva nei 7 gg precedenti.
2. Paziente con patologia autoimmune attiva che ha richiesto un trattamento sistemico negli ultimi 2 anni. Le terapie sostitutive (es. L-Tiroxina, Insulina o cortone acetato per l’insufficienza surrenalica o ipofisaria) non rientrano in questa categoria.
3. Paziente con storia nota di tubercolosi attiva
4. Trattamenti precedenti con vaccini anti-tumorali
5. Storia nei 5 anni precedenti di neoplasie maligne ad eccezione del basalioma, ca. squamoso della cute o della cervice trattati con chirurgia radicale.
6. Storia nota o positività sierologica che indichi infezione in atto per: Treponema pallidum, Epatite B (HBsAg, HBsAb, HBcAB), epatite C (HCVAb, HCV RNA quantitative), immunodeficienza acquisita (HIV).
7. Paziente che ha ricevuto una vaccinazione con virus vivi o attenuati nei 30 giorni precedenti l’entrata in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Progression free survival (PFS), measured as the proportion of patients without progression of disease at three months from leukapheresis.
- Proportion of patients experienced grade 3 or higher adverse events related to the study treatment |
- Proporzione di pazienti liberi da progressione a 3 mesi dalla data della leucaferesi
- Proporzione di pazienti che sviluppano tossicità di grado 3-4 correlata al trattamento sperimentale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| about 55 months |
| circa 55 mesi |
|
| E.5.2 | Secondary end point(s) |
| Evaluation of the prognostic role of a positive DTH test after at least four vaccine administrations; Overall survival (OS); Immunological efficacy: ability to enhance the proportion of circulating immune effectors specific for tumor antigens; evaluation of the persistence of an anti-tumor immune response; determination of plasma levels of a panel of inflammatory cytokines and pro-angiogenic factors; evaluation of the prognostic and predictive role of tumor antigen expression in tumor tissue; analysis of the prognostic and predictive role of immune cells in the peripheral blood and in the tumor microenvironment; Explorative endpoint (optional participation for patients): HLA class I and II characterization of patients |
| Valutazione del ruolo prognostico della positività del test in vivo DTH dopo almeno 4 vaccini; Sopravvivenza globale (OS); Efficacia immunologica, intesa come: capacità di aumentare la percentuale di effettori immunologici circolanti specifici per gli antigeni tumorali; valutazione della persistenza di una risposta immunitaria antitumorale; determinazione dei livelli plasmatici di un gruppo di citochine infiammatorie e fattori pro-angiogenici; determinazione del ruolo prognostico e predittivo dell'espressione dell'antigene tumorale nel tessuto tumorale; valutazione del ruolo prognostico e predittivo delle cellule immunitarie nel sangue periferico e nel microambiente tumorale; Endpoint esplorativo (partecipazione facoltativa da parte dei pazienti): caratterizzazione HLA di classe I e II dei pazienti |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| about 32 months; about 55 months; about 55 months; about 32 months |
| circa 32 mesi; circa 55 mesi; circa 55 mesi; circa 32 mesi |
|
| 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 | 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | Information not present in EudraCT |
| 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
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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