| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced malignant pleural mesothelioma (MPM) |
| Mesotelioma pleurico maligno (MPM) in stadio avanzato |
|
| E.1.1.1 | Medical condition in easily understood language |
| Malignant pleural mesothelioma is a rare form of cancer that affects the thin cell wall lining (or mesothelium) of lungs and chest wall, often diagnosed in people exposed to high levels of asbestos. |
| Mesotelioma pleurico maligno (MPM) in stadio 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10035605 |
| E.1.2 | Term | Pleural mesothelioma malignant advanced |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Determine effectiveness of study treatment by looking at response rate (RR), as measured by modified RECIST and RECIST 1.1 criteria (phase 2 portion), and overall survival (phase 3 portion).
Modified RECIST and RECIST 1.1 criteria were developed as standards to assess the response in patients with cancer, based on measurement of viable tumor on scans [computed tomography (CT) and magnetic resonance imaging (MRI)].
Overall survival is the percentage of people in a study or treatment group who are still alive for a certain period of time after they started treatment for a disease, such as cancer. |
L’obiettivo primario del presente studio è:
• Stabilire l’efficacia, come determinato dal tasso di risposta obiettiva (RR) misurato tramite i criteri RECIST modificati per la malattia pleurica localizzata e i criteri RECIST 1.1 per le lesioni metastatiche (sezione di fase 2), nonché la OS (sezione di fase 3).
|
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary objective - Phase 2:
-Determine the duration of response (DOR)
Key Secondary objective for Phase 3 is:
-Assess progression free survival (PFS)
Other Secondary objectives:
-Assessment of safety and tolerability of ADI-PEG 20 in combination with pemetrexed and cisplatin (standard-of-care)
-Determine the pharmacokinetics (how the body affects the drug) of ADI-PEG 20
-Determine the pharmacodynamics (how the drug affects the body) of ADI-PEG 20 in combination with pemetrexed and cisplatin
-Determine the immunogenicity of ADI-PEG 20 in combination with pemetrexed and cisplatin |
L’obiettivo secondario chiave della sezione di fase 2 dello studio è:
• Stabilire la durata della risposta (DOR)
L'obiettivo secondario chiave della sezione di fase 3 dello studio è:
• Valutare la sopravvivenza libera da progressione (PFS)
Tra gli altri obiettivi secondari di questo studio vi sono i seguenti:
• Valutare la sicurezza e la tollerabilità di ADI-PEG 20 in associazione a pemetrexed e cisplatino
• Stabilire la farmacodinamica di ADI-PEG 20 in associazione a pemetrexed e cisplatino
• Stabilire l’immunogenicità di ADI-PEG 20 in associazione a pemetrexed e cisplatino
• Stabilire la farmacocinetica di ADI-PEG 20 in associazione a pemetrexed e cisplatino |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Histologically proven not resecable MPM of biphasic or sarcomatoid histology. Biphasic MPM is defined using the World Health Organization’s international histological classification of tumors as containing an epithelial and a sarcomatoid component with each component comprising at least 10% of the tumor (Corson 2004, Allen 2005).
Naïve to prior chemotherapy or immunotherapy (i.e., this is a first-line systemic therapy study).
Measurable disease by modified RECIST criteria for MPM for local pleural disease and RECIST 1.1 criteria for metastatic lesions
ECOG performance status of 0 – 1 (Appendix C).
Predicted life expectancy of at least 12 weeks.
Age = 18 years (there is no upper age limit).
Fully recovered from any prior surgery and no major surgery within 4 weeks. Surgery for placement of vascular access devices is acceptable.
Subjects and their partners must be asked to use appropriate contraception. They must agree to use two forms of contraception or agree to refrain from intercourse for the duration of the study and for 35 days after last dose of ADI-PEG 20 or for at least six months after treatment with pemetrexed and cisplatin whichever is the longer duration. Females must not be pregnant at the start of the study, and a serum human chorionic gonadotropin (HCG) pregnancy test must be negative before entry into the study. If positive HCG pregnancy test, further evaluation to rule out pregnancy must be performed according to GCP before this patient is claimed eligible.
Informed consent must be obtained prior to study initiation.
Hemoglobin (HB) > 9.0 g/dL.
Absolute neutrophil count (ANC) > 1,500/µL.
Platelets > 75,000/µL.
Either: (i) serum bilirubin = 1.5 x upper limit of normal (ULN) or (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or alkaline phosphatase (ALP) = 3 x (ULN) unless raised due to tumor in which case up to 5 x ULN is permissible
Serum uric acid = 10 mg/dL (595 µmol/L) (with or without medication control).
Creatinine clearance = 40 mL/min (estimated, using Cockcroft and Gault formula). Cisplatin dose adjustment is recommended for subjects with a creatinine clearance between 40 and 59 mL/min (Bennis 2014) as follows: reduce cisplatin dose by 25% for clearance between 50 59.9 mL/min and by 50% for clearance between 40 – 49.9 mL/min. |
MPM non resecabile, come comprovato istologicamente, di istologia bifasica o sarcomatoide
Soggetti naïve a chemioterapia o immunoterapia
Stato di validità (performance status, PS) ECOG 0-1
Aspettativa di vita di almeno 3 mesi
Almeno 18 anni di età (non vi sono limiti per l’età massima)
Malattia misurabile tramite i criteri RECIST modificati per MPM nel caso di malattia pleurica locale, e criteri RECIST 1.1 nel caso di lesioni metastatiche
Rilascio del consenso informato per iscritto (firmato e datato) e pazienti in grado di cooperare con il trattamento e il follow-up
Adeguata funzionalità ematologica, epatica e renale |
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| E.4 | Principal exclusion criteria |
1. Radiotherapy (except for palliative reasons) the previous two weeks before.
2. Ongoing toxic manifestations of previous treatments.
3. Symptomatic brain or spinal cord metastases (patients must be stable for > 1 month post radiotherapy or surgery).
4. Major thoracic or abdominal surgery from which the patient has not yet recovered.
5. Serious infection requiring treatment with intravenous antibiotics at the time of study entrance, or an infection requiring intravenous therapy within 7 days prior.
6. Known to be serologically positive for human immunodeficiency virus (HIV). Testing to determine possible infection status is not required.
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (New York Heart Association Class III or IV), symptomatic cardiac arrhythmia, previous history of myocardial infarction (unless stable and good ejection fraction on echocardiogram) or psychiatric illness, and social situations that would limit compliance with study requirements.
8. Is a participant of, or plans to participate in, another interventional clinical study whilst taking part in this study. Participation in an observational or biomarker study would be acceptable, with prior Sponsor approval.
9. Subjects with history of another primary cancer, including co-existent second malignancy, with the exception of: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid tumor with no known active disease present in the opinion of the Investigator will not affect patient outcome.
10. Allergy to platinum salts.
11. Pregnancy or lactation.
12. Expected non-compliance.
13. Subjects who had been treated with ADI-PEG 20 previously.
14. History of seizure disorder not related to underlying cancer.
15. ECOG performance status > 2.
16. Allergy to pegylated compounds.
17. Allergy to E. coli drug products (such as GMCSF).
|
Radioterapia (salvo per ragioni palliative) nelle due settimane precedenti il trattamento dello studio
Anamnesi di cardiopatia instabile
Manifestazioni di tossicità che perdurano da trattamenti pregressi
Metastasi sintomatiche cerebrali o midollari (i pazienti devono essere stabili per > 1 mese dopo la radioterapia o l’intervento chirurgico)
Chirurgia toracica o addominale maggiore, da cui il paziente non si è ancora ripreso. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of this study is: • Determine efficacy as determined by the objective response rate (RR), measured by modified RECIST and RECIST 1.1 criteria (phase 2 portion), and OS (phase 3 portion). The goal of the phase 2 portion of the trial is to provide data to support accelerated approval by the United States Food & Drug Administration, and the goal of the phase 3 portion of the trial is to provide a confirmatory study that would be ongoing at the time of the marketing application.
|
| Determinare l'efficacia come definito dal tasso di risposta oggettiva (RR), misurata tramite i criteri RECIST modificati e RECIST 1.1 (nella Fase 2) e la sopravvivenza globale OS (nella Fase 3). L'obiettivo della porzione di Fase 2 della sperimentazione è di fornire dati per supportare l'approvazione accelerata da parte di FDA, e l'obiettivo della porzione di Fase 3 della sperimentazione è di fornire uno studio confirmatorio che sarà in corso al momento della richiesta di commercializzazione. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Scans will be performed every 6 weeks through Week 18 and during the Single Agent dosing period, scans will be every 8th weekly dose of ADI-PEG 20/placebo. Confirmatory scans are no longer required in Phase 3 (Protocol V 5).The first primary endpoint of RR will be analyzed at the interim analysis,at the end of the Phase 2 portion, after adequate response assessment of the first 176 enrolled subjects. This interim analysis will evaluate the treatment effect on RR in the ITT population The second primary endpoint of OS will be evaluated at the second interim analysis once 50% of the planned OS events for phase 3 have occurred (ie, 169 of the 338 planned OS events). This interim analysis will evaluate OS in the ITT population in an unblinded manner |
| Le valutazioni tramite immagini saranno effettuate ogni 6 settimane fino alla settimana 18 e durante il periodo di somministrazione in mono-agente ogni 8 somministrazioni settimanali di ADI-PEG 20/placebo. Non saranno richieste valutazioni confirmatorie nella Fase 3 del protocollo (PV 5). Il primo endpoint primario di RR sarà analizzato all'interim analisys, alla fine della Fase 2, dopo valutazione di adeguata risposta dei primi 176 pazienti arruolati. Questa analisi ad interim valuterà l'effetto del trattamento sulla RR nella popolazione ITT. Il secondo endpoint primario di OS sarà valutato alla seconda interim analisys quando si siano verificati l 50% degli eventi di OS per la Fase 3 (cioè 169 dei 338 OS pianificati). Questa analisi valuterà gli OS nella ITT, in aperto. |
|
| E.5.2 | Secondary end point(s) |
The key secondary objective of the phase 2 portion is:
• Determine the duration of response
The key secondary objective of the phase 3 portion is:
• Assess progression free survival (PFS)
Other secondary objectives of this study include:
• Assessment of safety and tolerability of ADI-PEG 20 in combination with pemetrexed and cisplatin
• Determine the pharmacodynamics of ADI-PEG 20 in combination with pemetrexed and cisplatin
• Determine the immunogenicity of ADI-PEG 20 in combination with pemetrexed and cisplatin
• Determine the pharmacokinetics of ADI-PEG 20 in combination with pemetrexed and cisplatin |
L'obiettivo secondario chiave della porzione di Fase 2 è:
• Determinare la durata della risposta
L'obiettivo secondario chiave della porzione di Fase 3 è:
• Valutare la sopravvivenza libera da malattia (PFS)
Altri obiettivi secondari di questo studio comprendono:
• Valutazione della sicurezza e tollerabilità di ADI-PEG 20 in combinazione con pemetrexed e cisplatino
• Determinare la farmacodinamica di ADI-PEG 20 in combinazione con pemetrexed e cisplatino
• Determinare l'immunogenicità di ADI-PEG 20 in combinazione con pemetrexed e cisplatino
• Determinare la farmacocinetica di ADI-PEG 20 in combinazione con pemetrexed e cisplatino |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary objective of the phase 2 (DOR) will be analyzed at the end of the phase 2 portion.
The key secondary objective for the phase 3 (PFS) which will be analyzed only if the analysis of OS is statistically significant at the final analysis, with alpha level of 0.05 (two-sided) using the same statistical methodologies as applied to OS.
Safety and tolerability will be monitored throughout the study by lead investigators, sponsor, and DSMB (as outlined in Charter). A complete evaluation of these and other secondary objectives will be conducted at the interim analysis and/or final analysis. |
L'obiettivo secondario della fase 2 (DOR) sarà analizzato alla fine della porzione di Fase 2
L'obiettivo secondario della Fase 3 (PFS) sarà analizzato solo se l'analisi di OS è statisticamente significativo all'analisi finale, con un livello alfa a 0,05 (due code) utilizzando lo stesso metodo statistico applicato ad OS.
Sicurezza e tollerabilità saranno monitorati durante lo studio dallo Sperimentatore principale, dallo Sponsor e dal DSMB (come delineato nel Charter). Una valutazione di questi e altri obiettivi secondari saranno effettuati all'interim analisys e/o all'analisi finale. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | 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 | 5 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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