| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced and relapsed germ cell tumors |
| Neoplasie germinali in fase metastatica ricadute o in progressione dopo trattamento chemioterapico di seconda o terza linea. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Germ cell Tumor |
| Neoplasie germinali in fase metastatica ricadute o in progressione dopo trattamento chemioterapico di seconda o terza linea. |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10068971 |
| E.1.2 | Term | Germ cell cancer metastatic |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the activity and efficacy of durvalumab and durvalumab+tremelimumab in a population of extensively pre-treated patients with GCT. |
| Valutare l¿attivit¿ di un programma di trattamento di salvataggio che prevede la somministrazione di durvalumab o di durvalumab + tremelimumab fino a progressione di malattia. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of the study drug.
To evaluate the Quality of Life changes during treatment.
To evaluate the ability of metabolic imaging (by 18Fluoodeoxyglucose positron emission tomography [18FDG-PET/CT]) to evaluate th activity of the study drug(s).
|
| Valutare la sicurezza e la tollerabilit¿ del trattamento, la qualit¿ della vita e l'efficacia della PET per valutare l'attivit¿ dei farmaci in studio. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics
Version: 01
Date: 15/03/2016
Title: An open label, randomized, phase 2 study of the anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, alone or in combination with Tremelimumab, in patients with advanced and relapsed germ cell tumors
Objectives: Integrating immunologic and genomic assessments and identifying the profile of patients who are more likely to attain a durable clinical benefit from the investigated treatments.
Pharmacogenomics
Version: 01
Date: 15/03/2016
Title: An open label, randomized, phase 2 study of the anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, alone or in combination with Tremelimumab, in patients with advanced and relapsed germ cell tumors
Objectives: expression profiling of tumor and/or tumor infiltrating immune cells, identification of immunogenic neo-antigens which potentially could promote anti-tumour T-cell response upon treatment, association of mutational load with objective tumor response.
Life quality
Version: 01
Date: 15/03/2016
Title: An open label, randomized, phase 2 study of the anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, alone or in combination with Tremelimumab, in patients with advanced and relapsed germ cell tumors
Objectives: To evaluate the Quality of Life changes diring treatment.
|
Farmacogenetica
Versione: 01
Data: 15/03/2016
Titolo: Studio in aperto, randomizzato, di fase 2 con l¿anticorpo anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, da solo o in combinazione con Tremelimumab, in pazienti con neoplasie germinali avanzate e ricadute alla chemioterapia
Obiettivi: Ad integrazione dello studio principale ¿ prevista anche una componente traslazionale relativa a biomarkers circolanti e ad analisi su tessuto. Tra i biomarkers circolanti, intendiamo valutare attraverso test di citofluorimetria una serie di citochine e altri fattori potenzialmente in relazione all¿attivit¿ di durvalumab e/o tremelimumab.
Sul tessuto, verr¿ valutata in immunoistochimica l¿espressione di PD-L1 al fine di ipotizzare un eventuale arricchimento e prosecuzione dell¿arruolamento su popolazioni di soggetti selezionati, secondo gli assunti descritti nei metodi statistici
Farmacogenomica
Versione: 01
Data: 15/03/2016
Titolo: Studio in aperto, randomizzato, di fase 2 con l¿anticorpo anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, da solo o in combinazione con Tremelimumab, in pazienti con neoplasie germinali avanzate e ricadute alla chemioterapia
Obiettivi: Ricerca del profilo di espressione delle cellule tumorali o dell'infiltrato tumorale ed identificazione degli antigeni immunogenici che potenzialmente potrebbero promuovere la risposta anti tumorale delle cellule T . Valutare l'associazione del carico mutazionale rispetto la risposta tumorale
Qualita' della vita
Versione: 01
Data: 15/03/2016
Titolo: Studio in aperto, randomizzato, di fase 2 con l¿anticorpo anti-Programmed Death-Ligand 1 (PD-L1) Durvalumab, da solo o in combinazione con Tremelimumab, in pazienti con neoplasie germinali avanzate e ricadute alla chemioterapia
Obiettivi: Valutare la qualit¿ della vita durante il trattamento con questionario ESAS
|
|
| E.3 | Principal inclusion criteria |
1. Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Age > 18 years at time of study entry
3. Male or female gender
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Life expectancy of > 12 weeks
6. Adequate normal organ and marrow function
7. Histological or clinical diagnosis of GCT.
8. Availability of archival tumor samples for local assessment (by immunohistochemistry) of PD-L1 expression.
9. Either gonadal or extragonadal tumor primary.
10. Failure of =2 prior chemotherapy regimens for metastatic disease (1-2 cycles PEB or 1 cycle carboplatin AUC7 given in the adjuvant setting for clinical stage I disease will not be counted as prior lines).
11. Failure of high-dose chemotherapy will be allowed.
12. Brain metastases: patients who present with brain metastases as the sole site of disease relapse/progression are not allowed to enter the study. Otherwise, patients with metastatic disease including brain metastases will be allowed provided that they have been irradiated, are stable from at least 4 weeks, and a wash-out period from steroids has occurred (28 days).
13. Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: =60 years old and no menses for ¿1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
14. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
|
• Età = 18 anni.
• Sesso maschile o femminile.
• Eastern Cooperative Oncology Group (ECOG) Performance Status < 2.
• Ricaduta/Progressione dopo almeno 2 linee di trattamento chemioterapico cisplatino-contenente. Tale condizione è definita come un incremento o una persistente positività di uno o più marcatori tumorali o da un incremento numerico e/o dimensionale di localizzazioni vitali non teratomatose di malattia.
• E’ ammesso un precedente trattamento chemioterapico ad alte dosi costituito da un singolo o multipli cicli di chemioterapia seguiti da reinfusione di progenitori emopoietici autologhi.
• Diagnosi istologica e/o clinica di neoplasia germinale (del testicolo o extragonadica).
• Adeguata funzionalità midollare e d’organo.
• Consenso informato scritto
|
|
| E.4 | Principal exclusion criteria |
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
3. Participation in another clinical study with an investigational product during the last 3 months
4. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
5. History of another primary malignancy except for:
• Malignancy treated with curative intent and with no known active disease =5 years before the first dose of study drug and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
6. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) =28 days prior to the first dose of study drug
7. Mean QT interval corrected for heart rate (QTc) =470 ms
8. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
9. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.
10. Any prior Grade =3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
11. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
12. Active or prior documented inflammatory bowel disease
13. History of primary immunodeficiency
14. History of allogeneic organ transplant
15. History of hypersensitivity to durvalumab or any excipient
16. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
17. Known history of previous clinical diagnosis of tuberculosis and active tuberculosis.
18. History of leptomeningeal carcinomatosis
19. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
22. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids.
23. Subjects with uncontrolled seizures.
24. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period.
25. Known allergy or hypersensitivity to IP or any excipient.
|
• Co-morbidità ed assunzione cronica di farmaci che compromettono l’esecuzione in sicurezza del trattamento con immunoterapici.
• Infezioni gravi in atto (di grado > 2 NCI-CTC versione 4.03).
• Pazienti con ricaduta tardiva (definita come recidiva di malattia dopo 2 anni dal termine del trattamento chemioterapico) e con malattia radicalmente resecabile. Viceversa, i pazienti con malattia non radicalmente operabile possono essere candidabili allo studio, dopo discussione collegiale.
• Neoplasie precedenti o concomitanti differenti da quella in trattamento fatta eccezione per il carcinoma basocellulare o per ogni precedente neoplasia diagnosticata e curata almento 5 anni prima dell’ingresso nello studio.
• Ogni condizione medica, psichiatrica o dipendenza che può compromettere l’osservanza delle indicazioni previste nello studio.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete response plus partial response with negative marker |
| tasso di risposte maggiori ( risposte complete e risposte parziali con marcatore negativizzato) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Safety ( based on CTCAE v 4.03 ); PD-L1 expression and response /PFS/OS; PFS; OS; quality of life asessment |
| ¿ Incidenza, natura e severit¿ di eventi avversi correlati al trattamento in studio, definiti in base ai Common Terminology Criteria for Adverse Events (CTCAE) v4.03.; Espressione di PD-L1 e risposta/PFS/OS (vedi ricerca traslazionale).; Sopravvivenza libera da malattia; sopravvivenza globale; Valutazione della qualit¿ della vita |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 42 months; at the end of study; 3 months; at 6 months; at the end of the study |
| 42 mesi; fine studio; 3 mesi; 6 mesi; a fine studio |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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