| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| No progression patients after first-line platinum and fluoropyrimidines based chemotherapy in HER2 negative locally advanced/metastatic gastric or gastroesophagel junction cancer |
Adenocarcinoma gastrico o della giunzione gastroesofagea, HER2-negativo localmente
avanzato/metastatico non in progressione di malattia dopo chemioterapia di prima linea contenente fluoro pirimidina o fluorofolati in associazione a composti del platino.
|
|
| E.1.1.1 | Medical condition in easily understood language |
| No progression patients after first line chemotherapy, locally advanced/metastatic gastric or gastroesophagel junction cancer |
| Tumore maligno gastrico o della giunzione gastro-esofagea, localmente avanzato e metastatico non in peggioramento di malattia dopo un primo trattamento chemioterapico |
|
| 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 | LLT |
| E.1.2 | Classification code | 10071114 |
| E.1.2 | Term | Metastatic gastric adenocarcinoma |
| 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 |
| Progression Free Survival 1 (PFS 1) |
| Sopravvivenza Libera da Progressione 1 (PFS 1) |
|
| E.2.2 | Secondary objectives of the trial |
-Overall Survival
-Progression Free Survival 2 (PFS2)
-Safety
-Objective Response Rate
-Quality of Live |
-Sopravvivenza Globale
-Sopravvivenza Libera da Progressione 2 (PFS2)
-Tollerabilit¿
-Tasso di risposte Obiettive
-Qualit¿ di vita |
|
| 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: 2
Date: 20/01/2017
Title: Genetic profiling of Regorafenib treated gastric cancer (optional)
Objectives: The identification of genetic-molecular markers able to predict the response of patients with gastric cancer to Regorafenib. The collection of additional information on the mechanism of action of this drug.
|
Farmacogenetica
Versione: 2
Data: 20/01/2017
Titolo: Progetto di ricerca sulla valutazione di marcatori genetici e molecolari (opzionale)
Obiettivi: Valutazione di marcatori genetici e molecolari in grado di predire la risposta al trattamento con Regorafenib in pazienti affetti da tumore gastrico. Raccolta di ulteriori dati relativi al meccanismo d'azione di Regorafenib.
|
|
| E.3 | Principal inclusion criteria |
1. Male of female = 18 years of age
2. Have an Eastern Cooperative Oncology Group performance
status of 0 or 1 within 14 days prior to the initiation of study
treatment
3. Diagnosis of histologically confirmed adenocarcinoma of the
stomach or gastroesophageal junction
4. HER2 negative gastric or gastroesophagel junction cancer (
ICH 0, IHC 1+, IHC + FISH -)
5. Locally advanced/metastatic gastric or gastroesophageal
junction cancer
6. CR/PR/SD after first-line platinum compound and
Fluoropyrimidines based chemotherapy
7. Measurable disease according to RECIST 1.1 criteria
8. Have adequate bone marrow function, liver function, and
renal function
9. Understand, be willing to give consent, and sign the written
informed consent form (ICF) prior to undergoing any studyspecific
procedure.
10. If female and of childbearing potential, have a negative result
on a pregnancy test performed a maximum of 7 days before
initiation of study treatment.
|
1.Maschi e femmine di età =18 anni
2.Eastern Cooperative Oncology Group performance
status 0-1
3.Diagnosi istologica di adenocarcinoma gastrico o
della giunzione gastro-esofagea
4.Negatività di HER2 (ICH 0, IHC 1+, IHC + FISH -)
5. Adenocarcinoma gastrico o della giunzione gastroesofagea,
localmente avanzato/metastatico
6. Pazienti con risposta completa/parziale/malattia stabile dopo
chemioterapia di prima linea contenente fluoro
pirimidina o fluorofolati in associazione a composti
del platino
7.Malattia misurabile secondo i criteri RECIST 1.1
8.Adeguata funzionalità midollare, epatica, renale
9.Consenso informato scritto prima dell’inizio di ogni
procedura dello studio
10.Le donne in età fertile devono avere un test di
gravidanza (eseguito 7 giorni prima l’inizio del
trattamento) negativo.
|
|
| E.4 | Principal exclusion criteria |
1. Are taking strong cytochrome P (CYP) CYP3A4 inhibitors
(eg, clarithromycin, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir,
telithromycin, voriconazole) or strong CYP3A4 inducers (eg,
carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s
Wort)
2. Have used biologic response modifiers, such as G-CSF,
within 3 weeks of study entry
3. Have had prior treatment with regorafenib or any other
VEGFR-targeting kinase inhibitor.
4. Completed their last dose of chemotherapy more than
8 weeks, whichever came later, prior to randomization.
5. Have had prior or concurrent cancer distinct in primary site or
histology from GC or GJC within 5 years prior to
randomization EXCEPT for curatively treated cervical
cancer in situ, no-melanoma skin cancer, or superficial
bladder tumors classified as noninvasive tumor (Ta),
carcinoma in situ (Tis), or tumor invades lamina propria (T1).
6. Have had systemic anticancer therapy including cytotoxic
therapy, signal transduction inhibitors, immunotherapy,
and/or hormonal therapy within 4 weeks prior to initiation of
study treatment.
7. Have unresolved toxicity higher than National Cancer
Institute-Common Terminology for Adverse Events version
4.0 (NCI-CTCAE v 4.0) Grade 1 attributed to any prior
therapy/procedure, excluding alopecia and/or oxaliplatininduced
neurotoxicity = Grade 2 and hemoglobin = 9 g/dL as
per inclusion criteria (see Section 0).
8. Have had a major surgical procedure, open biopsy, or
significant traumatic injury within 28 days prior to initiation
of study treatment.
9. Are pregnant.
10. Are breastfeeding.
11. Are unable to swallow oral tablets (crushing of study
treatment tablets is not allowed).
12. Have congestive heart failure classified as New York Heart
Association Class 2 or higher
13. Have had unstable angina (angina symptoms at rest) or newonset
angina ¿¿3 months prior to screening.
14. Have had a myocardial infarction ¿¿6 months prior to
initiation of study treatment.
15. Have cardiac arrhythmias requiring anti-arrhythmic therapy,
with the exception of beta blockers or digoxin.
16. Have uncontrolled hypertension (systolic blood pressure
[SBP] ¿¿140 mmHg or diastolic blood pressure [DBP] ¿¿90
mmHg) despite optimal medical management.
17. Have had arterial or venous thrombotic or embolic events
such as cerebrovascular accident (including transient ischemic
attacks), deep vein thrombosis, or pulmonary embolism
within 6 months prior to the initiation of study treatment.
18. Have an ongoing infection with severity of Grade 2 or above
(NCI-CTCAE v 4.0).
19. Have a known history of human immunodeficiency virus
infection.
20. Have either active or chronic hepatitis B or C requiring
treatment with antiviral therapy.
21. Have a seizure disorder requiring medication.
22. Have a history of organ allograft.
23. Have evidence or history of any bleeding diathesis (including
mild hemophilia), irrespective of severity.
24. Have had a hemorrhage or a bleeding event ¿¿Grade 3 (NCICTCAE
v 4.0) within 4 weeks prior to the initiation of study
treatment.
25. Have a nonhealing wound, ulcer, or bone fracture.
26. Have renal failure requiring hemodialysis or peritoneal
dialysis.
27. Have dehydration ¿¿Grade 1 (NCI-CTCAE v 4.0).
28. Have interstitial lung disease with ongoing signs and
symptoms at the time informed consent is obtained.
29. Have persistent proteinuria > 3.5 g/24 hours measured by
urine protein-creatinine ratio from a random urine sample (¿
Grade 3, NCI-CTCAE v 4.0).
30. Have any other serious or unstable illness, or medical,
psychological, or social condition, that could jeopardize the
safety of the subject and/or his/her compliance with study
procedures, or may interfere with the subject’s participation in
the study or evaluation of the study results.
31. Have a known hypersensitivity to any of the study drugs,
study drug classes, or excipients in the formulation of the
study drugs.
32. Have any malabsorption condition.
33. Have a close affiliation with the investigational site (eg, be a
close relative of the investigator) or be a dependent person
(eg, be an employee or student working at the investigational
site).
34. Untreated gastro-esophageus varices
|
1.Contemporanea assunzione di forti inibitori o forti
induttori del citocromo PCYP3A4
2.Precedente assunzione (entro le 3 settimane
dall’entrata in studio di modificatori
della risposta (es G-CSF)
3.Precedente trattamento con regorafenib o altro
inibitore di VEGFR
4.Precedente chemioterapia completata da più di 4
settimane prima della randomizzazione
5.Precedente o concomitante neoplasia eccetto
carcinoma in situ della cervice trattato, tumore della
pelle non-melanoma, tumore superficiale della
vescica.
6.Terapia antiblastica sistemica (terapia citotossica,
terapia target, immunoterapia e/o ormonoterapia)
nelle 4 settimane precedenti l’inizio del trattamento
in studio
7.Tossicità > grado 1 (NCI-CTCAE v 4.0)
riconducibile a terapie/procedure precedenti, eccetto
alopecia e/o neurotossicità oxaliplatino-indotta _
grado 2 ed emoglobina _ 9 g/dL.
8.Chirurgia (inclusa biopsia a cielo aperto), trauma
significativo entro le 4 settimane prima dell'iniziodel
trattamento in studio
9.Gravidanza o allattamento.
10.Uomini o donne in età fertile che non usino
un’adeguata contraccezione (contraccettivi orali,
spirale intrauterina o metodi di barriera unitamente a
creme spermicide o sterilizzate chirurgicamente).
11.Difficoltà o incapacità di deglutire pastiglie/compresse
12.Pazienti con scompenso cardiaco in atto [New York
Heart Association (NYHA) classe II-III-IV], o con
angina instabile o progressiva o di nuova insorgenza
nei 3 mesi precedenti la firma del consenso
14.Pazienti che hanno avuto infarto del miocardio negli
ultimi 6 mesi prima dell'inizio del trattamento dello
studio
15.Pazienti con aritmia cardiaca che richiede l'utilizzo
di terapia anti-aritmica con eccezione di farmaci
beta-bloccanti o digossina.
16.Ipertensione non controllata
17.Storia di eventi trombotici o emorragici nei 6 mesi
precedenti l'inizio del trattamento dello studio
18.Pazienti con concomitante infezione di Grado > 2
19.Positività nota per HIV
20.Pazienti con epatite B o C (attiva o cronica) che
richieda trattamento con antivirali
21.Pazienti con storia di eventi convulsivi che
22.richiedano trattamento
23.Pazienti con varici gastro-esofagee non trattate
24.Pazienti con malattie causino malassorbimento
intestinale
25.Pazienti con storia o concomitante condizione
clinica che porti a sanguinamento (inclusa emofilia
lieve)
26.Pazienti che abbiano avuto un evento emorragico o
sanguinamento > Grado 3 nelle 4 settimane
precedenti l'inizio del trattamento dello studio
27.Pazienti con persistente proteinuria > 3.5 g/24 ore
misurata come rapporto proteine: creatinina in un
campione di urina (> Grado 3)
28.Pazienti con insufficienza renale che richieda
emodialisi o dialisi peritoneale.
29.Pazienti con malattia interstiziale del polmone
sintomatica al momento della firma del consenso
informato
30.Evidenza di altre malattie, disfunzioni metaboliche,
anomalie fisiche o di laboratorio che creino un
ragionevole sospetto di una malattia o condizione
contro-indicata all’uso del farmaco sperimentale o
che pongano il paziente ad alto rischio per
complicanze correlate al trattamento
31.Nota ipersensibilità a qualsiasi dei farmaci in studio
o farmaci appartenenti alla stessa classe, o agli
eccipienti utilizzati.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) in all randomized patient |
| Sopravvivenza Libera da Progressione in tutti i pazienti randomizzati |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Progression Free Survival (PFS)
Imaging studies will be performed at baseline, 8, 16, 24 and
32 weeks, and then every 12 weeks. The objective
(confirmed) response and the progression-free survival will
be assessed by RECIST criteria. Progression free survival
will be calculated for all patients from the date of
randomization until the date PD or death is first reported.
|
La rivalutazione della malattia mediante immagini
radiologiche verrà effettuata al baseline, alle
settimane 8, 16, 24, 32, quindi ogni 12 settimane; la
risposta obiettiva e la progressione verrà stabilita
secondo i criteri RECIST 1.1.
La sopravvivenza libera da progressione verrà
calcolata dalla data di randomizzazione alla data di
progressione o decesso.
|
|
| E.5.2 | Secondary end point(s) |
| Overall Survival Safety, Objective Response Rate, Quality of Live in all randomized patient; Progression Free Survival 2 (PFS2) |
| Sopravvivenza Globale -Tollerabilit¿-Tasso di risposte Obiettive-Qualit¿ di vita in tutti i pazienti randomizzati; Sopravvivenza Libera da Progressione in pazienti in seconda linea (PFS2). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From the start to the end date of patient's participation in the study ; PFS 2 will be calculated from the start of second line therapy to Progression or death |
| Dalla data di inizio alla data di fine della partecipazione del paziente nello studio; PFS 2 verr¿ calcolata dall'inizio del trattamento di seconda linea alla data di progressione o decesso. |
|
| 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 | No |
| 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 | 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) | 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 | 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 | 33 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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
|
| Follow-up period end date: LP (last patient) off study. (Estimate date: April 2019) |
| Termine periodo di follow-up: Ultimo paziente fuori dallo studio (Stima: Aprile 2019) |
|
| 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 | 29 |
| 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 | 29 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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