Clinical Trials Register

Summary
EudraCT Number:	2014-004395-28
Sponsor's Protocol Code Number:	MANTRA
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2014-10-30
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-004395-28

A.3

Full title of the trial

Phase II randomized study of maintenance regorafenib vs placebo in no progression patients after first-line platinum and fluoropyrimidines based chemotherapy in HER2 negative locally advanced/metastatic gastric or gastroesophagel junction cancer.

Studio randomizzato, di fase II, per la valutazione dell’efficacia di Regorafenib vs Placebo in pazienti con adenocarcinoma gastrico o adenocarcinoma della giunzione gastro-esofagea, HER2-negativo localmente avanzato/metastatico non in progressione di malattia dopo chemioterapia di prima linea contenente fluoro pirimidine o fluorofolati in associazione a composti del platino.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Regorafenib vs placebo as maintenance therapy in no progression patients after first-line platinum and fluoropyrimidines based chemotherapy in HER2 negative locally advanced/metastatic gastric or gastroesophagel junction cancer.

Regorafenib vs placebo come terapia di mantenimento dopo una prima linea contenente fluoro pirimidine o fluorofolati in associazione a composti del platino in pazienti con adenocarcinoma gastrico o della giunzione gastro-esofagea HER2 negativo localmente avanzato o metastatico in risposta o stabilità di malattia.

A.3.2

Name or abbreviated title of the trial where available

MANTRA Study

Protocollo MANTRA

A.4.1

Sponsor's protocol code number

MANTRA

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Azienda Ospedaliero-Universitaria di Parma
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	BAYER
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UOC di Oncologia Medica, Azienda Ospedaliero-Universitaria di Parma
B.5.2	Functional name of contact point	Ufficio Sperimentazioni Cliniche
B.5.3	Address:
B.5.3.1	Street Address	Via Gramsci 14
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43126
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390521702682
B.5.5	Fax number	00390521995448
B.5.6	E-mail	rcamisa@ao.pr.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Stivarga
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Farma AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Regorafenib
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	REGORAFENIB
D.3.9.1	CAS number	755037-03-7
D.3.9.3	Other descriptive name	REGORAFENIB
D.3.9.4	EV Substance Code	SUB73090
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	40
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

HER2 negative locally advanced/metastatic gastric or gastroesophagel junction cancer.

Adenocarcinoma gastrico o adenocarcinoma della giunzione gastro-esofagea, HER2-negativo localmente avanzato/metastatico

E.1.1.1

Medical condition in easily understood language

HER2 negative locally advanced/metastatic gastric or gastroesophagel junction cancer.

Adenocarcinoma gastrico o adenocarcinoma della giunzione gastro-esofagea, HER2-negativo localmente avanzato/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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10063916
E.1.2	Term	Metastatic gastric cancer
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

PFS-progression free survival

PFS-sopravvivenza libera da progressione

E.2.2

Secondary objectives of the trial

OS-overall survival, safety, RR-response rate, quality of life

OS-sopravvivenza globale, tollerabilità, RR-tasso di risposte obiettive, qualità della 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

Evaluation of serum biomarkers (e-NOS)

Valutazione dei biomarcatori (e-NOS)

E.3

Principal inclusion criteria

Male of female ≥ 18 years of age
Have an Eastern Cooperative Oncology Group performance status of 0 or 1
Diagnosis of histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction
HER2 negative gastric or gastroesophagel junction cancer ( ICH 0, IHC 1+, IHC + FISH -)
CR/PR/SD after first-line platinum compound and Fluoropyrimidines based chemotherapy
Measurable disease according to RECIST 1.1 criteria
Normal bone marrow, liver, renal functionality
Written informed consent
Negative pregnacy test within 7 days before treatment start

Maschi e femmine di età ≥ 18 anni
Eastern Cooperative Oncology Group performance status 0-1
Diagnosi istologica di adenocarcinoma gastrico o della giunzione gastro-esofagea
Negatività di HER2 (ICH 0, IHC 1+, IHC + FISH -)
Pazienti non in progressione di malattia dopo chemioterapia di prima linea contenente fluoro pirimidina o fluorofolati in associazione a composti del platino
Malattia misurabile secondo i criteri RECIST 1.1
Adeguata funzionalità midollare, epatica, renale
Consenso informato scritto prima dell’inizio di ogni procedura dello studio
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

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)
Have used biologic response modifiers, such as G-CSF, within 3 weeks of study entry
Have had prior treatment with regorafenib or any other VEGFR-targeting kinase inhibitor.
Completed their last dose of chemotherapy more than 8 weeks, whichever came later, prior to randomization.
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, non melanoma skin cancer, or superficial bladder tumors classified as noninvasive tumor (Ta), carcinoma in situ (Tis), or tumor invades lamina propria (T1).
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.
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 oxaliplatin-induced neurotoxicity ≤ Grade 2 and hemoglobin ≥ 9 g/dL as per inclusion criteria.
Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment.
Are pregnant.
Are breastfeeding.
Are unable to swallow oral tablets (crushing of study treatment tablets is not allowed).
Have congestive heart failure classified as New York Heart Association Class 2 or higher
Have had unstable angina (angina symptoms at rest) or new-onset angina  3 months prior to screening.
Have had a myocardial infarction  6 months prior to initiation of study treatment.
Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin.
Have uncontrolled hypertension (systolic blood pressure [SBP]  140 mmHg or diastolic blood pressure [DBP]  90 mmHg) despite optimal medical management.
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.
Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0).
Have a known history of human immunodeficiency virus infection.
Have either active or chronic hepatitis B or C requiring treatment with antiviral therapy.
Have a seizure disorder requiring medication.
Have a history of organ allograft.
Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity.
Have had a hemorrhage or a bleeding event  Grade 3 (NCI-CTCAE v 4.0) within 4 weeks prior to the initiation of study treatment.
Have a nonhealing wound, ulcer, or bone fracture.
Have renal failure requiring hemodialysis or peritoneal dialysis.
Have dehydration  Grade 1 (NCI-CTCAE v 4.0).
Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained.
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).
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.
Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs.
Have any malabsorption condition.
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).
Untreated gastro-esophageus varices

Contemporanea assunzione di forti inibitori o forti induttori del citocromo P CYP3A4
Precedente assunzione (entro le 3 settimane dall’entrata in studio di modificatori della risposta (es G-CSF)
Precedente trattamento con regorafenib o altro inibitore di VEGFR
Precedente chemioterapia completata da più di 8 settimane prima della randomizzazione
Precedente o concomitante neoplasia eccetto carcinoma in situ della cervice trattato, tumore della pelle non-melanoma, tumore superficiale della vescica.
Terapia antiblastica sistemica (terapia citotossica, terapia target, immunoterapia e/o ormonoterapia) nelle 4 settimane precedenti l’inizio del trattamento in studio
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.
Chirurgia (inclusa biopsia a cielo aperto), trauma significativo entro le 4 settimane prima dell'iniziodel trattamento in studio
Gravidanza o allattamento.
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).
Difficoltà o incapacità di deglutire pastiglie/compresse
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
Pazienti che hanno avuto infarto del miocardio negli ultimi 6 mesi prima dell'inizio del trattamento dello studio
Pazienti con aritmia cardiaca che richiede l'utilizzo di terapia anti-aritmica con eccezione di farmaci beta-bloccanti o digossina.
Ipertensione non controllata
Storia di eventi trombotici o emorragici nei 6 mesi precedenti l'inizio del trattamento dello studio
Pazienti con concomitante infezione di Grado > 2
Positività nota per HIV
Pazienti con epatite B o C (attiva o cronica) che richieda trattamento con antivirali
Pazienti con storia di eventi convulsivi che richiedano trattamento
Pazienti con varici gastro-esofagee non trattate
Pazienti con malattie causino malassorbimento intestinale
Pazienti con storia o concomitante condizione clinica che porti a sanguinamento (inclusa emofilia lieve)
Pazienti che abbiano avuto un evento emorragico o sanguinamneto > Grado 3 nelle 4 settimane precedenti l'inizio del trattamento dello studio
Pazienti con persistente proteinuria > 3.5 g/24 ore misurata come rapporto proteine:creatinina in un campione di urina (> Grado 3)
Pazienti con insufficienza renale che richieda emodialisi o dialisi peritoneale.
Pazienti con malattia interstiziale del polmone sintomatica al momento della firma del consenso informato
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
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)

PFS-progression free survival

PFS-sopravvivenza libera da progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

36 months

36 mesi

E.5.2

Secondary end point(s)

OS-overall survival, safety, RR-response rate, quality of life

OS-sopravvivenza globale, tollerabilità, RR-tasso di risposte obiettive, qualità della vita

E.5.2.1

Timepoint(s) of evaluation of this end point

36 months

36 mesi

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

quality of life

qualità della vita

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

CLINICAL FOLLOW UP AS USUAL CARE

FOLLOW UP CLINICO COME DA NORMALE PRETICA CLINICA

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-12-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-17

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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