| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PATIENTS WITH ADVANCED MALIGNANT PLEURAL MESOTHELIOMA |
| pazienti affetti da mesotelioma pleurico maligno avanzato |
|
| E.1.1.1 | Medical condition in easily understood language |
| PATIENTS WITH ADVANCED MALIGNANT PLEURAL MESOTHELIOMA |
| pazienti affetti da mesotelioma pleurico maligno avanzato |
|
| 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 | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10051930 |
| E.1.2 | Term | Mesothelioma malignancy unspecified |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 whether pembrolizumab, alone or given to patients receiving standard chemotherapy, improves progression free survival in malignant pleural mesothelioma (MPM) compared to standard chemotherapy. |
Valutare se pembrolizumab in monoterapia o in combinazione con la chemioterapia
standard prolunga la sopravvivenza libera da progressione (progression-free survival,
PFS) rispetto alla chemioterapia standard nel trattamento di prima linea di pazienti affetti
da mesotelioma pleurico maligno (MPM) avanzato. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the tolerability of pembrolizumab, alone or given to patients receiving standard chemotherapy.
• To assess antitumour activity of pembrolizumab, alone or given to patients receiving standard chemotherapy including response rate and overall survival.
• To evaluate quality of life effects of pembrolizumab, alone or given to patients receiving standard chemotherapy. |
· Valutare la tollerabilità di pembrolizumab in monoterapia o in combinazione con la
chemioterapia
· Valutare l’attività antitumorale di pembrolizumab in monoterapia o in combinazione con
la chemioterapia, in termini di tasso di risposte obiettive e sopravvivenza globale
· Valutare l’impatto sulla qualità di vita, misurata mediante EORTC C30 + LC13, di
pembrolizumab in monoterapia o in combinazione con la chemioterapia |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligibility Criteria
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. Questions about eligibility criteria should be addressed prior to randomization.
The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards used to ensure that patients who enter this study are medically appropriate candidates for this therapy. For the safety of the patients, as well as to ensure that the results of this study can be useful for making treatment decisions regarding other patients with similar diseases, it is important that no exceptions be made to these criteria for admission to the study.
Patients must fulfill all of the following criteria to be eligible for admission to the study:
4.1.1 Patients must have histologically confirmed malignant pleural mesothelioma. Patients must be eligible to receive standard chemotherapy with pemetrexed and cisplatin and have no contraindications to standard chemotherapy.
4.1.2 Patients must have unresectable advanced and/or metastatic disease, incurable by standard therapies.
4.1.3 All patients must have a cellular tumour block from their primary or metastatic tumour available and consent to release the block/recently cut slides for correlative analyses (See Section 11.0) and the centre/pathologist must have agreed to the submission of the specimen(s).
4.1.4 Presence of radiologically documented disease. At least one site of disease must be unidimensionally measurable* by mRECIST or RECIST 1.1 (see Section 8.0) as follows:
CT scan (with slice thickness of = 5 mm) = 10 mm ¿ longest diameter
Physical exam (using calipers) = 10 mm
Lymph nodes by CT scan = 15 mm ¿ measured in short axis
Pleural rind as defined by Byrne et al [Byrne 2004].
* Consult CCTG if the patient does not have a measurable pleural rind; if RECIST 1.1 is used rather than mRECIST pleura is considered a non-target lesion and the patient may not be eligible.
All radiology studies must be performed within 21 days prior to registration (exception: within 28 days if negative).
4.1.5 Age = 18 years.
4.1.6 ECOG performance status 0 or 1.
4.1.7 Previous Therapy
Cytotoxic Chemotherapy:
• Patients must not have received prior chemotherapy for any stage of advanced/metastatic disease.
• Patients who received previous (neo)adjuvant cisplatin-based systemic chemotherapy must have received the last dose of chemotherapy at least 12 months before registration. Please contact CCTG PRIOR to randomization for such patients.
Other Anti-Cancer Therapy:
• Patients may not have received targeted small molecule therapy, immunotherapies and viral therapies, biologic therapies and angiogenesis inhibitors for advanced/metastatic disease, or any prior immunotherapy for any stage of disease.
Radiation:
Patients may have had prior radiation therapy, but NOT to the thorax unless clear disease progression has been demonstrated and confirmed with CCTG. A minimum of 28 days must have elapsed between the end of radiotherapy and registration onto the study. Radiation must have involved < 30% of functioning bone marrow and there must be measurable disease outside the previously irradiated area (patients whose sole site of disease (for example pleural rind) is in a previously irradiated area are ineligible UNLESS there is evidence of progression, or new lesions have been documented, in the irradiated field). (Exceptions may be made however, for low dose, palliative radiotherapy – Please contact CCTG PRIOR to randomization if the patient has received prior thoracic radiation. Patients must have recovered from any acute toxic effects from radiation prior to registration.
Previous Surgery:
Previous major surgery is permitted provided that it has been at least 28 days prior to patient registration and that wound healing has occurred. |
1. Pazienti con diagnosi istologica di mesotelioma pleurico maligno, candidati alla chemioterapia standard con pemetrexed e cisplatino, senza controindicazioni alla chemioterapia standard
2. Malattia avanzata e/o metastatica, incurabile con le terapie standard
3. Disponibilità di un campione di tessuto tumorale (blocchetto paraffinato o vetrini allestiti
recentemente) derivante da primitivo o metastasi (NB: il consenso da parte del
paziente alla raccolta e all’uso del campione tumorale per gli studi correlativi e la
disponibilità del centro partecipante e/o del patologo all’invio, sono obbligatori per la
partecipazione allo studio)
4. Evidenza di malattia documentata radiologicamente e almeno una lesione target
secondo RECIST 1.1. Gli esami radiologici devono essere eseguiti entro i 21 giorni
precedenti la registrazione (entro 28 giorni solo se negativi).
5. Età =18 anni
6. Performance status ECOG 0 o 1.
7. Correlati alle terapia precedenti:
o Chemioterapia citotossica:
* Nessuna chemioterapia precedente per la malattia avanzata e/o
metastatica
* Almeno 12 mesi trascorsi dall’ultima dosa di chemioterapia per i pazienti
che avessero ricevuto una chemioterapia con cisplatino (neo)adiuvante.
Si prega di contattare il CCTG PRIMA della randomizzazione
o Altre terapie anti-tumorali:
* Nessun precedente trattamento con piccole molecole, terapie virali o
biologiche, o farmaci antiangiogenici per la malattia avanzata
* Nessuna precedente immunoterapia per qualsiasi stadio di malattia.
o Radioterapia:
* Almeno 28 giorni trascorsi dall’ultima seduta di radioterapia per i pazienti
che avessero ricevuto una radioterapia precedente, purché la
radioterapia abbia coinvolto < 30% del midollo funzionante, qualunque
tossicità acuta da radioterapia sia risolta e vi sia malattia misurabile
secondo m RECIST o RECIST1.1. al di fuori dell’area irradiata (i pazienti con unica
sede di malattia in un’area irradiata sono ineleggibili, a meno che non vi
sia evidenza di progressione o siano comparse nuove lesioni nell’aria
irradiata)La precedente radioterapia toracica non è ammessa, tranne che non vi sia stata una chiara progressione di malattia documentata e confermata dal CCTG. Si prega di contattare il CCTG PRIMA della randomizzazione per i pazienti che hanno ricevuto trattamento radioterapico sul torace.
* La radioterapia palliativa a base dosi può essere ammessa (in caso di
dubbi contattare il promotore)
o Chirurgia:
* Precedenti procedure di chirurgia maggiore sono ammesse purché siano
trascorsi almeno 28 giorni dall’intervento e le ferite siano rimarginate
8. Parametri di laboratorio (valutati nei 7 giorni precedenti la randomizzazione)
o Emocromo
* Neutrofili = 1.5 x 109/L
* Piastrine = 100 x 109/L
* Emoglobina = 9 g/dL
o Chimica clinica
* Bilirubina = 1.5 x LSN (limite superiore di normalità)
IND.227: Studio randomizzato di fase 2 con pembrolizumab in pazienti affetti da
mesotelioma pleurico maligno avanzato
IND.227
Version n.0
Apr 19th, 2016
4
* AST e ALT = 2.5 x LSN
* Creatinina sierica < 1.25 x LSN o clearance della creatinina = 50 mL/mim
9. Consenso informato scritto
10. Disponibilità ad aderire alle procedure dello studio e a garantire il follow-up (i pazienti
dovranno essere trattati e seguiti presso i centri partecipanti che li hanno registrati e
pertanto dovranno essere considerati dei ragionevoli limiti geografici, ad esempio una
distanza non superiore ad 1 e ½ ore di distanza in auto)
11. Possibilità di iniziare la terapia dello studio entro 2 giorni dalla randomizzazione
12. Uso di contraccezione ritenuta efficace per gli uomini e per le donne potenzialmente
fertili (vedi protocollo 4.1.12)
13. Disponibilità a rispondere ai questionari di valutazione della qualità di vita (NB: Il
questionario basale deve essere completato alla registrazione e comunque prima di
iniziare il trattamento in studio). |
|
| E.4 | Principal exclusion criteria |
Patients who fulfill any of the following criteria are not eligible for admission to the study:
1.Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at doses more than 10 mg prednisone or 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 3 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
3. Must not have received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.
4. Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
5. Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction ( including cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects) or who have had unstable angina congestive heart failure or myocardial infarction within the previous year. Patients with a significant cardiac history, this includes hypertension, even if controlled, should have a LVEF = 50%.
6. Patients with a history of other malignancies requiring concurrent anticancer therapy.
7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or any of the other chemotherapy agents.
8. Patients receiving concurrent treatment with other anti-cancer therapy or other investigational anti-cancer agents.
9. Patients with serious illness or medical condition that would not permit the patient to be managed according to the protocol including, but not limited to:
• History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements.
• Active infection requiring systemic therapy; (including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) [note: testing in asymptomatic patients is not required] or tuberculosis).
• Known history of, or any evidence of active, non-infectious pneumonitis.
• Any other medical conditions that might be aggravated by treatment.
• Serious or non-healing wound, ulcer, or bone fracture.
10 Patients with evidence of interstitial lung disease.
11. Pregnant or lactating women. (N.B.: All women of childbearing potential must have a negative pregnancy test within 72 hours prior to registration). |
1. Diagnosi di immunodeficienza o terapia sistemica in corso con corticosteroidi (dosi
> 10 mg di prednisone o equivalenti), o qualsiasi altra terapia immunosoppressiva,
nei 7 giorni precedenti la prima dose del trattamento in studio
2. Malattia autoimmune attiva che abbia richiesto un trattamento sistemico negli ultimi
3 anni (ad esempio con DMARDs, corticosteroidi, immunosoppressori). La terapia
sostitutiva (es. levotiroxina, insulina, corticosteroidi a dosi fisiologiche per
insufficienza surrenalica o ipofisaria) NON è da considerarsi una terapia sistemica.
3. Somministrazione di un vaccino vivo nei 30 giorni precedenti l’inizio del trattamento
in studio (i vaccini per l’influenza stagionale sono generalmente vaccini inattivati,
pertanto sono ammessi)
4. Presenza di metastasi cerebrali sintomatiche note o meningite carcinomatosa
(pazienti con metastasi cerebrali precedentemente trattate sono eleggibili purché
siano stabili, cioè asintomatici e senza evidenza radiologica di progressione nelle 4
settimane precedenti l’inizio del trattamento in studio, e non siano in terapia con
steroidi da almeno 7 giorni prima dell’inizio del trattamento)
5. Storia di patologie cardiovascolari non trattate o non controllate e/o disfunzione cardiovascolare sintomatica che comprendono aritmie ventricolari che richiedono terapia, storia di difetti di conduzione atrioventricolare di secondo e terzo grado o angina instabile, scompenso cardiaco o infarto del miocardio negli anni precedenti. I pazienti con una storia di patologie cardiovascolari, inclusa l’ipertensione, anche se controllate, devono avere una frazione di eiezione del ventricolo sinistro = 50% per essere considerati eleggibili
6. Diagnosi di altra neoplasia maligna che richieda una terapia antitumorale
concomitante
7. Storia di reazioni allergiche a composti con composizione chimica o biologica simile
a pembrolizumab o a uno dei farmaci chemioterapici in studio
8. Qualunque altro trattamento concomitante con farmaci antitumorali o altri farmaci
sperimentali
9. Qualunque altra patologia o condizione clinica grave che possa compromettere la
gestione del paziente secondo le procedure dello studio, ad esempio:
o Storia di disturbi neurologici o psichiatrici che potrebbero compromettere la
capacità di fornire un consenso informato o di aderire alle procedure dello studioo Infezioni in atto che richiedano una terapia sistemica (inclusi pazienti affetti da
epatite B o C attiva, pazienti affetti da HIV e da tubercolosi) (NB: non è
necessario lo screening per HIV in pazienti non sintomatici)
o Storia o evidenza attuale di polmonite non infettiva
o Ferite, ulcere o fratture ossee severe o non guarite
10.Pazienti con evidenza di malattia interstiziale polmonare
11. Gravidanza o allattamento (le donne potenzialmente fertili dovranno avere un test
di gravidanza negativo eseguito nelle 72 ore precedenti la registrazione) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| progression free survival (PFS) |
| sopravvivenza libera da progressione(PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumour Imaging (Chest/upper abdomen CT scan; other scans as necessary to document disease): Every 6 weeks for 3 assessments then every 12 weeks/4 weeks after completion of protocol therapy/3 monthly follow-up
(only required for pts without confirmed PD and ongoing toxicities 1)/6 monthly follow-up
(required for all patients with confirmed PD) |
La risposta deve essere valutata mediante ripetizione di una TC torace e addome con
m.d.c. ogni 6 settimane fino alla 18a settimana, ogni 12 settimane successivamente fino al
termine del trattamento, 4 settimane dopo il completamento del trattamento, e ogni 12
settimane successivamente fino a progressione o recidiva. |
|
| E.5.2 | Secondary end point(s) |
| objective answer |
| Risposta obiettiva |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumour Imaging (Chest/upper abdomen CT scan; other scans as necessary to document disease): Every 6 weeks for 3 assessments then every 12 weeks/4 weeks after completion of protocol therapy/3 monthly follow-up
(only required for pts without confirmed PD and ongoing toxicities 1)/6 monthly follow-up
(required for all patients with confirmed PD) |
| La risposta deve essere valutata mediante ripetizione di una TC torace e addome con m.d.c. ogni 6 settimane fino alla 18a settimana, ogni 12 settimane successivamente fino al termine del trattamento, 4 settimane dopo il completamento del trattamento, e ogni 12 settimane successivamente fino a progressione o recidiva |
|
| 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) | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 22 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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