| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced MET-Positive Gastric, Lower Esophageal or Gastroesophageal
Junction Adenocarcinoma |
| adenocarcinoma gastrico, dell’esofago distale o della giunzione gastroesofagea (GEJ), MET-positivo, metastatico o localmente avanzato |
|
| E.1.1.1 | Medical condition in easily understood language |
Lower Esophageal and Gastroesophageal Junction Adenocarcinoma
Gastric Cancer |
| adenocarcinoma gastrico, dell’esofago distale o della giunzione gastroesofagea |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066354 |
| E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017761 |
| E.1.2 | Term | Gastric cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017766 |
| E.1.2 | Term | Gastric cancer stage IV NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017765 |
| E.1.2 | Term | Gastric cancer stage III |
| 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 determine if the treatment of rilotumumab in combination with ECX
significantly improves overall survival (OS) as compared with
rilotumumab-placebo in combination with ECX in subjects with
unresectable locally advanced or metastatic MET-positive gastric or GEJ
adenocarcinoma. |
| Stabilire se la terapia con rilotumumab in combinazione con ECX migliori in modo significativo la sopravvivenza globale (OS) rispetto al placebo in combinazione con ECX nei pazienti con adenocarcinoma gastrico o della giunzione gastroesofagea MET-positivo metastatico o localmente avanzato non resecabile. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate progression-free survival (PFS), survival rate at 12 months,
time to progression (TTP), objective response rate (ORR), disease
control rate (DCR), duration of response, time to response (TTR), safety
and immunogenicity, rilotumumab and ECX
pharmacokinetic (PK) parameters. To evaluate the impact of MET
expression levels on efficacy. |
| Valutare la sopravvivenza libera da progressione (PFS), il tasso di sopravvivenza a 12 mesi, il tempo alla progressione (TTP), il tasso di risposta obiettiva (ORR), il tasso di controllo della malattia (DCR), la durata della risposta, il tempo alla risposta (TTR), la sicurezza e immunogenicità e i parametri farmacocinetici (PK) di rilotumumab e ECX. Valutare l’impatto dei livelli di espressione di MET sull’efficacia. |
|
| 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 |
PHARMACOGENETIC:
Vers:NA
Date:2012/08/30
Title:Pharmacogenetic substudy
Objectives:These optional pharmacogenetic
analyses focus on inherited genetic variations to evaluate their possible
correlation to the disease and/or responsiveness to the therapies used
in this study.
PHARMACOKINETIC/PHARMACODYNAMIC:
Vers:NA
Date:2012/08/30
Title:Pharmacokinetic substudy
Objectives:If subjects sign the additional optional pharmacokinetic informed
consent, subjects at selected sites will participate in rilotumumab and
ECX intensive PK (IPK) sampling until approximately 12 evaluable
subjects per arm have been identified. A detailed example of dosing and
PK sampling schedule for those subjects can be found in Appendix A of
the protocol.
|
FARMACOGENETICA:
Vers:NA
Data:2012/08/30
Titolo:Sottostudio di farmacogenetica
Obiettivi:Questa farmacogenetica opzionale
si concentra su variazioni genetiche ereditarie per valutare la loro possibile correlazione con la malattia e risposta alle terapie utilizzate
in questo studio
FARMACOCINETICA/FARMACODINAMICA:
Vers:NA
Data:2012/08/30
Titolo:Sottostudio di farmacocinetica
Obiettivi:i pazienti dei centri selezionati parteciperanno ad analisi farmacocinetica intensiva di rilotumumab e ECX fino a quando non saranno identificati circa 12 pazienti. Per ulteriori informazioni si rimanda allappendice A del protocollo.
|
|
| E.3 | Principal inclusion criteria |
Disease Related
• Pathologically confirmed unresectable locally advanced or metastatic
gastric or GEJ adenocarcinoma; adenocarcinomas of the distal
esophagus within 5 cm of the GEJ are eligible
• ECOG performance status (0 or 1)
• Tumor MET-positive by IHC (fulfilling the MET IHC criteria as defined
by an investigational use only MET IHC assay) by protocol-specified
centralized testing
• Formalin fixed paraffin-embedded (FFPE) tumor tissue submission
required
• Evaluable (measurable or non-measurable) disease by RECIST 1.1
criteria
Demographic
• Men or women ≥ 18 years of age
Ethical
• Before any study-specific procedure, the appropriate written
informed consent must be obtained (Section 11.1)
Laboratory
• Adequate organ function as evidenced by the following laboratory
studies within 28 days prior to randomization:
- Hemoglobin ≥ 9 g/dL
- Absolute neutrophil count ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Creatinine clearance ≥ 60mL/minute (calculated or measured)
- Aspartate aminotransferase (AST) and alanine amino transferase (ALT)
≤ 2.5 x ULN or AST and ALT ≤ 5.0 x ULN if liver metastases are present
- Total bilirubin ≤ 1.5x ULN
General
• Able to tolerate infusions and take oral medications |
• Adenocarcinoma gastrico o della giunzione gastroesofagea, metastatico o localmente avanzato, non resecabile, con conferma istopatologica; gli adenocarcinomi dell’esofago distale entro 5 cm dalla giunzione gastroesofagea sono eleggibili
• Performance status ECOG (0 o 1)
• Tumore MET-positivo valutato mediante immunoistochimica (IHC) (che soddisfi i criteri immonoistochimici per la valutazione di MET definiti mediante un test immunoistochimico per MET ad uso esclusivamente sperimentale) secondo l’analisi centralizzata indicata dal protocollo
• Invio di un campione di tessuto tumorale fissato in formalina e incluso in paraffina (FFPE)
• Malattia valutabile (misurabile o non misurabile) in base ai criteri RECIST 1.1 |
|
| E.4 | Principal exclusion criteria |
Disease Related
• HER2-overexpressing locally advanced or metastatic gastric or GEJ
adenocarcinoma. Subjects whose tumor HER2 expression status is not
known must submit tumor samples for HER2 testing
• Previous systemic therapy (including chemotherapy, biologic,
immunotherapy, or investigational therapy) for locally advanced or
metastatic gastric or GEJ or lower esophageal (within 5 cm of GEJ)
adenocarcinoma Less than 6 months have elapsed from completion of
prior neoadjuvant or adjuvant chemotherapy or chemoradiotherapy to
randomization
• Previous treatment with anthracyclines exceeds total cumulative dose
of epirubicin of 400 mg/m2 (or equivalent thereof, if a different
anthracycline has been administered in the past)
• Subjects with ongoing toxicities from palliative radiotherapy, or who
have undergone radiotherapy to the only site of known disease, or
received palliative radiation ≤ 14 days prior to randomization. Subjects
who received palliative
radiotherapy are otherwise eligible.
• Squamous cell histology
• Subjects with resectable disease or suitable for definitive
chemoradiation
• Plans for surgical resection or definitive chemoradiation based on
response to protocol therapy
• Subjects who have persistent gastric outlet obstruction, complete
dysphagia or are dependent upon jejunostomy for feeding
• Known central nervous system metastases
• Clinically significant upper gastro-intestinal bleeding < 30 days prior to
randomization
Other Medical Conditions
• Left ventricular ejection fraction (LVEF) < 50% as determined by
either multiple gated acquisition (MUGA) scan or echocardiogram
(ECHO)
• Documented myocardial infarction or unstable/uncontrolled cardiac
disease (eg, unstable angina, severe arrhythmias, congestive heart
failure [New York Heart Association (NYHA) > Class II]) within 6 months
before randomization (Appendix E)
• Presence of peripheral edema > grade 1
• Arterial thrombosis or vascular ischemic events, such as transient
ischemic attack, cerebral infarction, within six months prior to
randomization
• Subjects with venous thromboembolic events (including deep vein
thrombosis or pulmonary emboli) within 6 months prior to
randomization
• Serious or non-healing wound
• Known positive HepBsAg (indicative of acute or chronic Hepatitis B) or
detectable Hepatitis C virus (indicative of active Hepatitis C), known
positive test for HIV
• Known peripheral neuropathy > grade 1
• Known dihydropyrimidine dehydrogenase deficiency (DPD)
• History of any medical condition including cardiovascular disease or
chronic obstructive pulmonary disease (COPD), that in the opinion of the
investigator, may increase the risks associated with study participation
or study treatments or may interfere with the conduct of the study or
interpretation of study resultsMajor surgical procedure ≤ 30 days before
randomization or not yet recovered from prior major surgery. Major
surgery is defined within this protocol as any surgical procedure that
involves general anesthesia and a significant incision (ie, larger than
what is required for placement of central venous access, percutaneous
feeding tube, or biopsy)
• Minor surgery (eg, catheter or gastrostomy tube placement) ≤14 days before randomization or not yet recovered from prior minor surgery.
Placement of central venous access device, fine needle aspiration,
thoracentesis, endoscopic biliary stent or paracentesis ≥ 1 day before
randomization is acceptable
Medications or Other Treatments
• Prior treatment with inhibitors of the MET pathway
• Recent infection requiring a course of systemic anti-infectives that was
administered within 7 days before randomization (with the exception of
uncomplicated urinary tract infection) |
• Adenocarcinoma gastrico o della giunzione gastroesofagea, metastatico o localmente avanzato, con iperespressione di HER2. I soggetti il cui stato di espressione di HER2 è ignoto dovranno fornire campioni tumorali per il test su HER2
• Precedente terapia sistemica per adenocarcinoma gastrico o della giunzione gastroesofagea metastatico o localmente avanzato
• Periodo di tempo inferiore a 6 mesi tra la conclusione del precedente trattamento chemioterapico o chemioradioterapico neoadiuvante o adiuvante e la randomizzazione
• L’eventuale precedente trattamento con antracicline non deve aver superato la dose cumulativa totale di epirubicina pari a 400 mg/m2 (o il suo equivalente, se in passato è stata somministrata un’altra antraciclina)
• Istologia di carcinoma a cellule squamose
• Frazione di eiezione ventricolare sinistra (LVEF) <50% rilevata tramite angiografia a radionuclidi (esame MUGA) o ecocardiogramma (ECHO) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| overall survival (OS) |
| overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assuming an approximate average enrollment rate of 16.8 subjects per
month with an accrual period of approximately 27 months and a dropout
rate of 5% per year, the event goal is expected to be achieved
approximately 36 months after the first subject is enrolled if the study
enrolls 450 subjects. |
Assuming an approximate average enrollment rate of 16.8 subjects per
month with an accrual period of approximately 27 months and a dropout
rate of 5% per year, the event goal is expected to be achieved
approximately 36 months after the first subject is enrolled if the study
enrolls 450 subjects. |
|
| E.5.2 | Secondary end point(s) |
•PFS, defined as the time from the date of randomization to either
disease progression (as per RECIST 1.1) or death
• Survival rate at 12 months, defined as the K-M estimate of the
proportion of subjects alive at the corresponding time point
• TTP, defined as time from the date of randomization to disease
progression (per RECIST 1.1)
• ORR, defined as the incidence rate of either CR or PR per RECIST 1.1
criteria.
• DCR, defined as the incidence rate of either a CR, PR or SD per RECIST
1.1. The stable disease classification requires subjects to have a
response of stable disease ≥ 11 weeks after the date of the first dose of
rilotumumab
• Duration of response, defined as time from the date of first response
(PR or CR) to disease progression (per RECIST 1.1) or death
• TTR, defined as time from the date of randomization to either a CR or
PR per RECIST 1.1 criteria
• OS within tertiles of MET expression levels
• Incidence of subject adverse events, laboratory abnormalities and
immunogenicity
• Rilotumumab dose exposure, dose intensity and PK parameters
• ECX dose exposure, dose intensity and PK parameters in a subset of
subjects |
• PFS, definito come il tempo intercorso tra la data di randomizzazione e la progressione della malattia (secondo RECIST 1.1) o il decesso
• Tasso di sopravvivenza a 12 mesi, definito come la stima secondo Kaplan-Meier (K-M) della percentuale di soggetti in vita al corrispondente punto temporale
• TTP, definito come il tempo intercorso tra la data di randomizzazione e la progressione della malattia (secondo RECIST 1.1)
• ORR, definito come il tasso di incidenza di una risposta completa (CR) o di una risposta parziale (PR) secondo i criteri RECIST 1.1
• DCR, definito come il tasso di incidenza di CR, PR o malattia stabile (SD) secondo RECIST 1.1 La classificazione di SD prevede che i pazienti presentino una risposta di SD ≥11 settimane dopo la data di assunzione dell’ultima dose di rilotumumab
• Durata della risposta, definita come il tempo intercorso tra la data della prima risposta (PR o CR) e la progressione di malattia (secondo RECIST 1.1) o il decesso
• TTR, definito come il tempo intercorso tra la data della randomizzazione e la CR o PR secondo i criteri RECIST 1.1
• OS nei terzili dei livelli di espressione del MET
• Incidenza di eventi avversi, anomalie di laboratorio e immunogenicità
• Esposizione a rilotumumab, intensità della dose e parametri di PK
• Esposizione a ECX, intensità della dose e parametri di PK in un sottogruppo di pazienti |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All of the secondary endpoints will be analysed at the same time as the
primary endpoint. |
| tutti gli endpoint secondari verranno analizzati allo stesso tempo come quelli primari |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health-related quality of life |
| qualità della vita correlata alla salute |
|
| 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) | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 130 |
| 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 | No |
| 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 |
| European Union |
| Australia |
| Brazil |
| Canada |
| Mexico |
| Russian Federation |
| South Africa |
| Switzerland |
| Turkey |
| Ukraine |
| 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
|
| Primary Completion: the time when the last subject is assessed or receives an intervention for the purposes of final data collection for the primary analysis. End of Trial: the time when the last subject is assessed or receives an intervention for evaluation in the study. This will be the later of the final analysis or when the last subject discontinues all protocol therapyand has had the opportunity to complete the safety follow-up visit. |
| il momento in cui l'ultimo soggetto è valutato o è valutato nello studio. |
|
| 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 | 28 |
| 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 | 32 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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