Clinical Trials Register

Summary
EudraCT Number:	2016-001132-36
Sponsor's Protocol Code Number:	GOIRC-03-2016
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-02-09
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

2016-001132-36

A.3

Full title of the trial

A double-blind, placebo controlled, randomized multicenter Phase II Study evaluating Gemcitabine with or without Ramucirumab as II line treatment for advanced malignant pleural mesothelioma

Studio di Fase II randomizzato, doppio cieco con placebo, multicentrico, di confronto con Gemcitabina in associazione a Ramucirumab verso Gemcitabina+
placebo, nel trattamento di seconda linea del mesotelioma pleurico maligno

A.3.1

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

Clinical Study to assess the efficacy of Ramucirumab with gemcitabina in the treatment of malignant pleural mesothelioma

Sperimentazione per valutare l'efficacia di Ramucirumab in aggiunta a gemcitabina nel trattamento del mesotelioma pleurico maligno

A.3.2

Name or abbreviated title of the trial where available

RAMES

A.4.1

Sponsor's protocol code number

GOIRC-03-2016

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	GRUPPO ONCOLOGICO ITALIANO DI RICERCA CLINICA (GOIRC)
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	Eli Lilly
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	Pharmaceutical Development and Services srl
B.5.2	Functional name of contact point	Servizio Informazione sulla Sperime
B.5.3	Address:
B.5.3.1	Street Address	via dei Pratoni, 16
B.5.3.2	Town/ city	Scandicci
B.5.3.3	Post code	50018
B.5.3.4	Country	Italy
B.5.4	Telephone number	0557224179
B.5.5	Fax number	0557227014
B.5.6	E-mail	edimartino@pharmades.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	CYRAMZA - 10 MG/ML- CONCENTRATO PER SOLUZIONE PER INFUSIONE- USO ENDOVENOSO- FLACONCINO (VETRO) 10 ML- 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	ELI LILLY NEDERLAND BV
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	CYRAMZA
D.3.2	Product code	[CYRAMZA]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ramucirumab
D.3.9.2	Current sponsor code	goirc-03-16
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

diffuse malignant pleural mesethelioma

mesotelioma pleurico avanzato maligno

E.1.1.1

Medical condition in easily understood language

tumor that arises from cells of the mesothelium of the chest

tumore che nasce dalle cellule del mesotelio del torace

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

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the efficacy of ramucirumab10 mg/kg plus gemcitabine versus gemcitabine with placebo, in terms of OS

valutare l'efficacia di ramucirumab 10 mg/kg più gemcitabina versus gemcitabina con placebo, in termini di sopravvivenza totale

E.2.2

Secondary objectives of the trial

Evaluate the efficacy of ramucirumab 10 mg/kg plus gemcitabine versus gemcitabine with placebo, in terms of PFS;
Safety and tolerability
· Objective response rate
· Disease control rate
· Predictive molecular markers
· Quality life

valutare l'efficacia di ramucirumab 10 mg/kg più gemcitabina versus gemcitabina con placebo, in termini di tempo sopravvivenza senza progressione di malattia;
safety e tollerabilità
percentuale di risposta obiettiva
percentuale di controllo della malattia
marcatori molecolari predittivi
qualità di vita

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. The patient has a histopathologically or cytologically confirmed diagnosis of malignant pleural mesothelioma. 2. The patient has documented disease progression during or within 4 months after the last dose of first-line chemotherapy for metastatic disease, or during or within 6 months after the last dose of neoadjuvant or adjuvant therapy. 3. The patient received combination chemotherapy prior to disease progression. 4. The patient has metastatic disease or locally advanced disease that is measurable, or nonmeasurable but evaluable, by radiological imaging[…]. 5. The patient has an ECOG performance status of 0-2. 6. The patient has adequate organ function, including: a. Total bilirubin ¿1.5×the upper limit of institutional normal (ULN) and ALT and AST¿3 × ULN. b. Serum creatinine ¿1.5 × ULN. c. Urinary protein is <2+ on dipstick or routine urinalysis. d. Absolute neutrophil count ¿1.5 × 109/L, platelets¿100×109/L, and hemoglobin ¿9 g/dL. e. INR¿1.5×ULN and partial thromboplastin time ¿5 seconds above ULN, unless the patient is receiving anticoagulation therapy. 7. The patient is at least 18 years old. 8. The patient has provided written informed consent prior to any study-specific procedures and is amenable to compliance with protocol schedules and testing. 9. The patient has an estimated life expectancy of ¿12 weeks in the judgment of the investigator. 10. The patient has resolution to Grade ¿1 by CTCAE. 11. The patient, if male, is sterile or agrees to use a reliable method of birth control and to not donate sperm during the study and for at least 12 weeks following the last dose of study treatment. 12. The patient, if female, is surgically sterile, is postmenopausal, or agrees to use a highly effective method of birth control during the study and for 12 weeks following the last dose of study treatment. 13. The patient, if female and of child-bearing potential, must have a negative serum or urine pregnancy test within 7 days prior to randomization.

1. pazienti con confermata diagnosi istologica e patologica di mesetelioma pleurico maligno. 2. Paziente con documentata progressione di malattia durante o entro i 4 mesi dopo l’ultima dose di chemioterapia di prima linea per malattia per metastasi, o durante o entro 6 mesi dopo l’ultima dose di neoadiuvante o terapia adiuvante. 3. Paziente che ha ricevuto una combinazione di chemioterapia prima della progressione della malattia. 4. Paziente con metastasi o malattia localmente avanzata che è misurabile, o non misurabile ma valutabile, con immagini radiologiche […]. 5. Paziente con ECOG performance status di 0-2. 6. Paziente con adeguata funzione di organi, incluso: Totale bilirubina ¿1.5×ULN e ALT e AST¿3 × ULN. b. Serum creatinina ¿1.5 × ULN. c. proteina urinaria è <2+ con dipstick o esame delle urine di routine. d. conta dei neutrofili assoluta ¿1.5 × 109/L, piastrine¿100×109/L, e emoglobina ¿9 g/dL. e. INR¿1.5×ULN and tempo parziale di tromboplastine ¿5 secondi sopra ULN, a meno che il paziente non stia ricevendo una terapia con anticoagulante. 7.patiente di almeno 18 anni. 8. Paziente che ha fornito il consenso informato scritto prima dell’inzio delle procedure dello studio e è capace di rispettare la compliance al protocollo. 9. Pazienti con una stimata attesa di vita ¿12 settimane a giudizio dello sperimentatore. 10. Pazienti con grado ¿1 di CTCAE. 11. Paziente, se maschio, è sterile o in accordo ad utilizzare un affidabile metodo di contraccezione e a non donare lo sperma durante lo studio o almeno nelle 12 settimana successive all’ultima dose di trattamento. 12. Il paziente, se femmina, è sterile chirurgicamente, o in postmenopausa, o in accordo ad utilizzare un affidabile metodo di contraccezione durante lo studio o almeno nelle 12 settimana successive all’ultima dose di trattamento. 13. Il paziente, se femmina e in potenziale allattamento, deve avere test di gravidanza sierico o urinario negativo entro 7 giorni prima della randomizzazione.

E.4

Principal exclusion criteria

1. The patient has cancer with histology other than mesothelioma. 2. The patient is receiving chronic therapy with any of the following within 7 days prior to randomization: a. NSAIDs; b. other anti-platelet agents. Aspirin use at doses up to 325 mg/day is permitted. 3. The patient received radiotherapy within 14 days prior to randomization. 4. The patient received >1 line of prior therapy for the treatment MPM. 5. The patient received previous treatment with agents targeting the VEGF/VEGF Receptor 2 signaling pathway, including previous exposure to ramucirumab. 6. The patient has documented brain metastases, leptomeningeal disease, or uncontrolled spinal cord compression. 7. The patient has a significant bleeding disorder or vasculitis or had a Grade ¿3 bleeding episode within 12 weeks prior to randomization. 8. The patient experienced any arterial thromboembolic event (ATE), including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization. 9. The patient has symptomatic congestive heart failure or symptomatic or poorly controlled cardiac arrhythmia. 10. The patient has uncontrolled hypertension, prior to initiating study treatment, despite antihypertensive intervention. 11. The patient underwent major surgery within 28 days prior to randomization or central venous access device placement within 7 days prior to randomization. The patient has a serious or nonhealing wound, ulcer or bone fracture within 28 days prior to enrollment. 12. The patient has selective or planned major surgery to be performed during the course of clinical trial. 13. The patient has a history of gastrointestinal perforation or fistula within 6 months prior to randomization. 14. The patient has a history of inflammatory bowel disease or Crohn’s disease requiring medical ¿12 months prior to randomization. 15. The patient has an acute or subacute bowel obstruction or history of chronic diarrhea that is considered clinically significant in the opinion of the investigator. 16. The patient has either of the following: a. cirrhosis at a level of Child-Pugh B. b. cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. 17. The patient has known allergy or hypersensitivity to any components of study treatment. 18. The patient received any previous investigational therapy within 4 half –lives of the investigational agent prior to randomization. 19. The patient has a serious illness or medical condition including, but not limited to, the following: a. known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness b. active or uncontrolled clinically serious infection. 20. The patient is pregnant or breast-feeding. 21. The patient has a concurrent active malignancy.

1. paziente con cancro con l'istologia differente da mesotelioma. 2. paziente che riceve terapia cronica entro 7 giorni prima della randomizzazione con uno dei seguenti: a. FANS; b. altri agenti anti-piastrinici. Aspirina utilizzare a dosi fino a 325 mg / die è permesso. 3. Il paziente ha ricevuto radioterapia entro 14 giorni prima della randomizzazione. 4. Il paziente ha ricevuto più di 1 trattamento di prima linea preventiva per il trattamento MPM. 5. Il paziente ha ricevuto un precedente trattamento con agenti con target il recettore VEGF / VEGF Receptor 2, tra cui una precedente esposizione a ramucirumab. 6. Il paziente ha documentate metastasi cerebrali, malattie leptomeningea, o non controllata compressione del midollo spinale. 7. Il paziente ha un disturbo della coagulazione significativo o vasculite o ha avuto un episodio di sanguinamento di grado ¿3 entro 12 settimane prima della randomizzazione. 8. Il paziente ha avuto episodi tromboembolici arteriosi (ATE), tra cui l'infarto del miocardio, angina instabile, accidente cerebrovascolare o attacco ischemico transitorio, entro 6 mesi prima della randomizzazione. 9. Il paziente ha sintomi di insufficienza cardiaca congestizia o sintomatica o aritmia cardiaca scarsamente controllato. 10. Il paziente ha incontrollata ipertensione, prima di iniziare il trattamento in studio, nonostante l'intervento antiipertensivo. 11. Il paziente è stato sottoposto a chirurgia maggiore entro 28 giorni prima della randomizzazione o collocamento di dispositivo di accesso venoso centrale entro 7 giorni prima randomizzazione. Il paziente ha una seria non guarita: ferita, ulcera o frattura ossea entro 28 giorni prima dell'arruolamento. 12. Il paziente deve eseguire una chirurgia maggiore selettiva o pianificata nel corso della sperimentazione clinica. 13. Il paziente ha una storia di perforazione gastrointestinale o fistole entro 6 mesi prima della randomizzazione. 14. Il paziente ha una storia di malattia infiammatoria intestinale o morbo di Crohn ¿12 mesi prima della randomizzazione. 15. Il paziente ha una occlusione intestinale acuta o subacuta o storia di diarrea cronica che è considerato clinicamente significativo a giudizio dello sperimentatore. 16. Il paziente ha subito una delle seguenti operazioni: a. cirrosi ad un livello di Child-Pugh B. b. cirrosi (qualsiasi grado) e una storia di encefalopatia epatica o ascite derivanti da cirrosi clinicamente significativa. 17. Il paziente ha allergie o ipersensibilità conosciute a qualsiasi componente del trattamento dello studio. 18. Il paziente ha ricevuto una precedente terapia sperimentale entro 4 half -lives del farmaco sperimentale prima della randomizzazione. 19. Il paziente ha una grave malattia o condizione medica compresi: a. nota l'infezione da virus dell'immunodeficienza umana o immunodeficienza acquisita. b. infezioni clinicamente seria attiva o non controllata. 20. Il paziente è in stato di gravidanza o in allattamento. 21. Il paziente ha un tumore maligno attivo concorrente

E.5 End points

E.5.1

Primary end point(s)

Overall survival, as determined by investigator assessment per RECIST 1.1

sopravvivenza totale, determinata dallo sperimentatore secondo i criteri RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

the date of randomization to the date of death from any
cause or the last date the patient was known to be alive

dalla data di randomizzazione alla data di morte per ogni causa o la data nota il cui il paziente è ancora vivo.

E.5.2

Secondary end point(s)

Progression Free Survival, as determined by investigator assessment per RECIST 1.1; The safety endpoints evaluated will include but are not limited to the following:
· TEAEs, AESIs, SAEs, and hospitalizations
· Clinical laboratory tests, vital signs, and physical examinations
· ORR
· DCR
· polymorphisms assoceted with ramucirumab response;
-evaluation of circulating pro-angiogenic factors in response to ramucirumab treatment;
· Survey

Sopravvivenza libera da progressione di malattia, determinata dallo sperimentatore secondo i criteri RECIST1.1; safety endpoint:
-TEAEs, AESIs, SAEs,e ospedalizzazione
-test clinici di laboratorio, segni vitali, esame fisico
- ORR
- DCR
-polimorfismo associato alla risposta di ramucirumab
- valutazione di fattori pro-angiogenesi circolanti in risposta al trattamento con ramucirumab,
-sopravvivenza

E.5.2.1

Timepoint(s) of evaluation of this end point

from the date of randomization to the date of radiographic documentation of progression (as defined by RECIST v1.1) or the date of death due to
any cause, whichever is earlier.; from the date to entered in the study until the end of the study

dalla data di randomizzazione alla data di progressione documentata radiografica mente ( come definito dai criteri RECIST 1.1) o la data di morte dovuta a qualsiasi causa, ; dalla data di entrata nello studio fino alla fine dello studio

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

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

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

Information not present in EudraCT

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

E.8.9.2

In all countries concerned by the trial years

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:

120

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

160

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

160

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)

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

2016-10-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-09-21

P. End of Trial
P.	End of Trial Status	Ongoing

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