| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin |
| Mesotelioma pleurico maligno avanzato o metastatico con iperespressione di mesotelina |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic malignant pleural mesothelioma |
| Mesotelioma pleurico maligno avanzato o metastatico |
|
| 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 | 10027406 |
| E.1.2 | Term | Mesothelioma |
| 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 |
| Test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) |
| ¿ Testare la superiorit¿ della monoterapia con anetumab ravtansine rispetto alla vinorelbina nella sopravvivenza libera da progressione (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
¿ Test overall survival
¿ Evaluate patient-reported outcomes ¿ symptom burden and healthrelated
quality of life (QoL)
¿ Evaluate other indicators of treatment efficacy
¿ Evaluate safety
The other objectives of this study are to evaluate the:
¿ Pharmacokinetics and immunogenicity
¿ Biomarkers |
¿ Testare la sopravvivenza globale (OS)
¿ Valutare gli effetti riferiti dal paziente (Patent-Reported Outcomes = ROs) ¿ l¿impatto dei sintomi e la qualit¿ della vita relativa alla salute (QoL)
¿ Valutare altri indicatori dell¿efficacia del trattamento (indicatori della risposta tumorale)
¿ Valutare la tossicit¿ del farmaco
Gli altri obiettivi di questo studio sono quelli di valutare:
¿ Le farmacocinetiche (PKs)
¿ L¿immunogenicit¿
¿ I biomarcatori
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent for full study.
2. Histological documentation of MPM overexpressing mesothelin at the
moderate and stronger level in at least 30% of tumor cells as
determined by centrally performed IHC
Note: Patients with a sarcomatoid histology are not expected to have
mesothelin overexpression and should not be enrolled in the study.
3. Unresectable locally advanced or metastatic MPM after progression on
1st line treatment with platinum in combination with pemetrexed. Last
dose of previous therapy must be at least 28 days before start of study
treatment.
Note: Patients progressed on 1st line treatment with platinum plus
pemetrexed in combination bevacizumab are allowed
4. Patients must have at least 1 measurable lesion according to mRECIST
for mesothelioma i.e. pleural lesion(s) measured using mRECIST or
extra-pleural lesion(s) measurable per RECIST 1.1. This will be
confirmed by central review of images before the patient can be
randomized into the study.
Note: In case the only site of disease was previously treated with
radiotherapy, there should be evidence of unequivocal PD in this site:
measurable pleural disease should be assessed on a contrast enhanced
CT/MRI done at the minimum 4 weeks after the end of radiotherapy and
compared with previous imaging; unequivocal progression should be
judged by the investigator as per mRECIST per MPM
5. Age = 18 years (age limit may be higher if legally required in a
country e.g. in Japan adult age is considered > 20 years)
6. ECOG PS of 0 or 1
7. Life expectancy of at least 3 months
8. Women of childbearing potential (WOCBP) and men must agree to use
adequate contraception from signing of the ICF for full study until at
least 4 months after the last study drug administration. Men being
treated with vinorelbine are advised not to father a child during and up
to 6 months after treatment; for all male patients, prior to treatment
with either study drug, advice should be sought for conserving sperm
due to the chance of irreversible infertility as a consequence of
treatment (22).The investigator or a designated associate is requested
to advise the patient how to achieve an adequate birth control. Highly
effective (failure rate of less than 1% per year) contraception methods
(23) include: (...)
9. Adequate bone marrow, liver and renal function as assessed by the
following laboratory requirements conducted within 7 days before
starting study treatment:
• Total bilirubin < 1.5 x the upper limit of normal (ULN). Documented
Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6
mg/dL).
• ALT and AST < 3 x ULN (< 5 x ULN for patients with liver involvement
of their cancer).
• ALP limit < 2.5 x ULN (< 5 x ULN for patients with liver involvement of
their cancer).
• Amylase and lipase < 1.5 x ULN.
• Serum creatinine < 1.5 x ULN
• Glomerular filtration rate (GFR) = 30 mL/min/1.73 m2 according to
the Modification of Diet in Renal Disease (MDRD) abbreviated formula
• Adequate coagulation, as assessed by the following laboratory test
results:
o International normalized ratio (INR) or prothrombin time (PT) < 1.5 x
ULN (CTCAE Grade < 1) o Partial thromboplastin time (PTT) or activated PTT (aPTT) < 1.5 x ULN
(CTCAE Grade < 1)
Note: Patients on anti-coagulation therapy will be allowed to participate
if INR / PT and PTT / aPTT test results are compatible with the
acceptable benefit-risk ratio at the investigator's discretion
• Platelet (PLT) count > 100000/mm3 , without PLT transfusion within 3
weeks before the start of study treatment
• Hemoglobin (Hb) > 9 g/dL, without blood transfusion or erythropoietin
within 6 weeks before the start of study treatment
• Absolute neutrophil count (ANC) > 1500/mm3, without biologic
response modifiers, such as G-CSF, within 6 weeks before the start of
study treatment
10. Left ventricular ejection fraction (LVEF) = 50% of the lower limit of
normal (LLN) according to local institution ranges of normality. |
II seguenti criteri di inclusione devono essere soddisfatti al momento della randomizzazione ed al C1D1 se non diversamente specificato.
1. Consenso informato scritto per lo studio completo.
2. Diagnosi istologica di MPM che iperesprime la mesotelina a livello moderato e forte in almeno il 30% delle cellule tumorali, come da test immunoistochimico eseguito presso il laboratorio centralizzato.
3. MPM non resecabile localmente avanzato o metastatico dopo progressione inequivocabile, confermato localmente, al trattamento di prima linea con platino (sia cis- che carbo-platino) in associazione con pemetrexed. L’ultima dose della terapia precedente deve essere di almeno 28 giorni, quale sia più breve, prima dell’inizio del trattamento in studio.
Nota: Sono ammessi i pazienti in progressione a trattamento di prima linea con platino più pemetrexed in combinazione con bevacizumab (13).
4. I pazienti devono avere almeno una lesione misurabile secondo i criteri mRECIST per il mesotelioma (specificato in appendice 16.3 del protocollo),es. lesione (i) dela pleura misurata usando mRECIST o lesione (i) extra pleura misurabili per RECIST 1.1. Questo sarà confermato dalla revisione centralizzata delle immagini prima della randomizzazione.
5. PS secondoECOG di 0 o 1 (specificato nell’Appendice 16.1 del protocollo)
6. Aspettativa di vita di almeno 3 mesi.
7. Le donne in età fertile (acronimo in inglese di “Women Of ChildBearing Potential = WOCBP) e gli uomini in età fertile devono accettare di praticare un’adeguata contraccezione: cfr. protocollo
8. Adeguata funzionalità midollare, epatica e renale in base ai seguenti test di laboratorio eseguiti entro 7 giorni prima di iniziare il trattamento in studio:
cfr protocollo
9. Frazione di eiezione del ventricolo sinistro(acronimo in inglese di Left Ventricle Ejection Fraction)(LVEF) =50% o del limite inferiore di norma (LLN) secondo i valori di normalità dell’Istituto. |
|
| E.4 | Principal exclusion criteria |
1. Previous assignment to treatment during this study. Patients
permanently withdrawn from study participation will not be allowed to
re-enter the study.
2. Previous (within 5 drug half-lifes – if drug half-life in subjects is
known – or 28 days, whichever is shorther, before the start of study
treatment) or concomitant participation in another clinical study with
investigational medicinal product(s).
3. Close affiliation with the investigational site; e.g. a close relative of
the investigator, dependent person (e.g. employee or student of the
investigational site).
4. More than 1 previous systemic anti-cancer therapy line for MPM (even
if therapy used as neoadjuvant or adjuvant treatment).
Note: Patients pre-treated with systemic therapy other than platinum,
pemetrexed, bevacizumab (e.g. other cytotoxic drugs, immunotherapy,
targeted therapy, hormonal therapy, or any other experimental or
approved therapy or device) are not to be enrolled.
5. Patients with corneal epitheliopathy or any eye disorder that may
predispose the patients to this condition at the discretion of the
investigator in consultation with the ophthalmologist/optometrist.
Note: Low grades of superficial punctate keratitis, within the range seen
in the normal population, should not lead to the exclusion of the patient.
6. Previous or concurrent cancer that is distinct in primary site or
histology from mesothelioma within 5 years before randomization.
Exceptions: curatively treated
• Cervical cancer in situ.
• Non-melanoma skin cancer.
• Superficial bladder tumors [Ta (Non-invasive tumor), Tis (Carcinoma in
situ) and T1 (Tumor invades lamina propria)].
7. Major surgery, open biopsy or significant traumatic injury within 28
days before the start of study treatment.
8. Pregnant or breast-feeding patients. WOCBP must have a serum
pregnancy test performed a maximum of 7 days before the start of study
treatment, and a negative result must be documented before the start of
study treatment.
9. Pre-existing cardiac conditions as outlined below:
• Congestive heart failure > New York Heart Association (NYHA) class 2
• Unstable angina (angina symptoms at rest), new-onset angina (begun
within the last 3 months). Myocardial infarction less than 6 months
before the start of study treatment.
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers
or digoxin are permitted).
10. Clinically significant uncontrolled hypertension (systolic bloodpressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal
medical management).
11. Arterial thrombotic or embolic events such as cerebrovascular
accident (including transient ischemic attacks), or venous pulmonary
embolism within 6 months before the start of study treatment; venous
thrombotic events as deep vein thrombosis within 3 months before the
start of study treatment.
12. Ongoing or active infection (bacterial, fungal, or viral) of NCI-CTCAE
version 4.03 Grade > 2.
13. Known history of human immunodeficiency virus (HIV) infection.
14. Known history of chronic hepatitis B or C.
15. Patients with seizure disorder requiring medication.
16. Brain metastases or meningeal tumors or other metastases in the
central nervous system (CNS). Patients with neurological symptoms
must undergo a contrast CT scan or MRI of the brain and/or other areas
of the CNS as applicable within 28 days before the start of study
treatment to exclude metastastic disease in the CNS.
17. History of organ allograft, stem cells or bone marrow transplant.
18. Patients with evidence or history of bleeding diathesis. Any
hemorrhage or bleeding event > CTCAE Grade 3 within 4 weeks before
the start of study treatment.
19. Non-healing wound, ulcer, or bone fracture.
20. Renal failure requiring peritoneal or hemodialysis.
For following criteria see Protocol |
Verranno esclusi i pazienti che soddisfino i seguenti criteri al momento della randomizzazione ed al C1D1:
1. Precedente assegnazione al trattamento durante questo studio. Ai pazienti esclusi permanentemente dalla partecipazione allo studio non sarà consentito di rientrare nello studio.
2. Partecipazione precedente (entro 5 emivite del farmaco – se è nota l’emivita del farmaco nei soggetti – o 28 giorni, qualunque sia più breve, prima dell’inizio del trattamento in studio) o partecipazione concomitante ad un altro studio clinico con il(i) farmaco(i) sperimentale(i) (IMP[i]).
3. Stretta affiliazione con la sede della sperimentazione; ad esempio un parente stretto dello sperimentatore, un dipendente (ad esempio un impiegato o uno studente della sede della sperimentazione).
4. More than 1 previous systemic anti-cancer therapy line for MPM (even if therapy used as neoadjuvant or adjuvant treatment).
Note: Patients pre-treated with systemic therapy other than platinum, pemetrexed, bevacizumab (e.g. other cytotoxic drugs, immunotherapy,targeted therapy, hormonal therapy, or any other experimental or approved therapy or device) are not to be enrolled.
5. Patients with corneal epitheliopathy or any eye disorder that may predispose the patients to this condition at the discretion of the investigator in consultation with the ophthalmologist/optometrist.
6. Tumore precedente o concomitante che sia diverso nella sede e nell’istologia dal mesotelioma pleurico entro 5 anni prima della randomizzazione.
Eccezioni: pazienti trattati a scopo curativo
• Tumore cervicale in situ.
• Tumore cutaneo diverso dalmelanoma.
• Tumori superficiali della vescica (tumore non-invasivo [Ta], Carcinoma in situ [Tis] e Tumore che invade la lamina propria [T1]).
7. Interventi di chirurgia maggiore, biopsia in aperto o trauma significativo entro 28 giorni prima dell’inizio del trattamento in studio.
8. Pazienti incinte o che allattino al seno. Le donne in età fertile devono sottoporsi ad un test di gravidanza sul siero eseguito massimo 7 giorni prima dell’inizio del trattamento in studio e con risultato negativo documentato prima dell’inizio del trattamento in studio.
9. Patologie cardiache pre-esistenti come:
• Insufficienza cardiaca congestizia = classe 2 secondo la New York Heart Association (NYHA) (specificato nell’Appendice 16.2 del Protocollo).
• Angina instabile (sintomi a riposo), angina di nuova insorgenza (iniziata entro gli ultimi 3 mesi). Infarto miocardico meno di 6 mesi prima dell’inizio del trattamento in studio.
• Aritmie cardiache che richiedano una terapia anti-aritmica (i beta-bloccanti o la digossina sono permessi).
10. Ipertensione clinicamente significativa non controllata (pressione sistolica> 150 mmHg o pressione diastolica > 90 mmHg nonostante trattamento medico ottimale).
11. Eventi arteriosi trombotici od embolici come accidente cerebrovascolare (comprendente attacchi ischemici transitori) od embolia polmonare venosa entro 6 mesi dall’inizio del trattamento in studio; eventi venosi trombotici come trombosi venosa profonda entro 3 mesi prima dell’inizio del trattamento in studio.
12. Infezione in corso o attiva (batterica, fungina o virale) di NCI-CTCAE versione 4.03 Grado > 2.
13. Anamnesi nota di infezione da parte del virus dell’immunodeficienza umana (HIV).
14. Storia di epatite B o C cronica.
15. Pazienti con disturbo convulsivo che richiedano un trattamento farmacologico.
16. Brain metastases or meningeal tumors or other metastases in the central nervous system (CNS). Patients with neurological symptoms must undergo a contrast CT scan or MRI of the brain and/or other areas of the CNS as applicable within 28 days before the start of study treatment to exclude metastastic disease in the CNS.
17. Anamnesi di trapianto d’organo, cellule staminali o trapianto di midollo osseo.
for following criteria see Protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is progression free survival. |
| PFS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assuming median PFS of 3.6 months under vinorelbine treatment and constant hazards and a 2:1 treatment:comparator randomization, a 100% prolongation of PFS in the anetumabravtansine arm in comparison to the comparator arm can be detected at a 1-sided significance level of 0.0125 with 90% power, with a single-stage trial with approximately 117 PFS events (hazard ratio 0.5). Assuming a maximum accrual rate of 10.5 patients/month (17.5 patients/month screened with 40% overall screening failure rate) with 8-month linear accrual ramp-up,and a 2.7%/month dropout (loss to follow-up and unevaluable for tumorassessment) rate,183 patients be will accrued in approximately 20.4 months and reach endpoint maturation of117 events in approximately 23.9 months. |
Sopravvivenza libera da progressione (PFS), definita come il tempo dalla randomizzazione fno alla progressione della malattia (secondo i criteri mRECIST per il MPM, per la lettura centralizzata delle immagini in cieco) o alla morte
|
|
| E.5.2 | Secondary end point(s) |
| The secondary endpoint is overall survival. |
| OS (overall survival) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assuming true median OS of 9.6 months under vinorelbine treatment and constant hazards, a60% prolongation of true OS (median 15.4 months) in the anetumab ravtansine arm incomparison to the comparator arm (median 9.6 months) can be detectedwith an overall 73%power and an overall 1-sided significance level of 0.025 (hazard ratio 0.625), with a 2-stagegroup sequential test with a total of 135 events. |
| Sopravvivenza Totale |
|
| 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 | Yes |
| 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 | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| 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 | 3 |
| 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 | 3 |
| 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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