Clinical Trials Register

Summary
EudraCT Number:	2012-000164-25
Sponsor's Protocol Code Number:	MILES-4
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:	2012-03-08
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

2012-000164-25

A.3

Full title of the trial

A factorial study comparing pemetrexed with gemcitabine and testing the efficacy of the addition of cisplatin in elderly patients with non squamous advanced, metastatic or recurrent NSCLC.

Studio multicentrico randomizzato di fase III, con disegno fattoriale, di valutazione della efficacia di pemetrexed vs. gemcitabina, e della efficacia della aggiunta del cisplatino nel trattamento dei pazienti anziani con carcinoma polmonare non a piccole cellule, ad istotipo non squamoso, in fase avanzata

A.3.1

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

A factorial study comparing pemetrexed with gemcitabine and testing the efficacy of the addition of cisplatin in elderly patients with non squamous advanced, metastatic or recurrent NSCLC.

A.3.2

Name or abbreviated title of the trial where available

MILES-4

A.4.1

Sponsor's protocol code number

MILES-4

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	ISTITUTO NAZIONALE PER LO STUDIO E LA CURA DEI TUMORI - FONDAZIONE "G. PASCALE"
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 Italia S.p.A
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	Istituto Nazionale per lo studio e la Cura dei Tumori - Napoli
B.5.2	Functional name of contact point	SC Sperimentazioni Cliniche
B.5.3	Address:
B.5.3.1	Street Address	Via Mariano semmola
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	081 5903 571
B.5.5	Fax number	081 770 29 38
B.5.6	E-mail	segreteria@usc-intnapoli.net

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	ALIMTA*1FL POLV 500MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ELI LILLY ITALIA SpA
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.3.4	Pharmaceutical form	Powder 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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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.IMP: 2
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.2.1.2	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.3.4	Pharmaceutical form	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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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.2.1.2	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.3.4	Pharmaceutical form	Powder 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	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1200
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

elderly patients with non squamous advanced, metastatic or recurrent NSCLC

pazienti anziani con carcinoma polmonare non a piccole cellule, ad istotipo non squamoso, in fase avanzata

E.1.1.1

Medical condition in easily understood language

elderly patients with non squamous advanced, metastatic or recurrent NSCLC

pazienti anziani con carcinoma polmonare non a piccole cellule, ad istotipo non squamoso, in fase avanzata

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	PT
E.1.2	Classification code	10025038
E.1.2	Term	Lung adenocarcinoma stage IV
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	10023780
E.1.2	Term	Large cell lung cancer stage IV
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

To test whether the addition of cisplatin to single agent chemotherapy (gemcitabine or pemetrexed) prolongs survival as compared to single agent chemotherapy in elderly patients with non squamous NSCLC. To test whether pemetrexed prolongs survival as compared to gemcitabine in elderly patients with non squamous NSCLC.

Valutare l’efficacia dell’aggiunta del cisplatino alla chemioterapia con agente singolo (gemcitabina o pemetrexed) in termini di prolungamento della sopravvivenza globale, in pazienti anziani con NSCLC ad istotipo non squamoso. Valutare l’efficacia del pemetrexed rispetto alla gemcitabina in termini di prolungamento della sopravvivenza globale, in pazienti anziani con NSCLC ad istotipo non squamoso

E.2.2

Secondary objectives of the trial

To compare toxicity within each planned comparison. To compare progression-free survival within each planned comparison. To compare response rate within each planned comparison. To compare quality of life within each planned comparison. To conduct exploratory analyses for the identification of prognostic and predictive factors of the efficacy of pemetrexed and cisplatin

Confrontare la tossicità in ciascuno dei 2 confronti programmati. Confrontare la sopravvivenza libera da progressione in ciascuno dei 2 confronti programmati. Confrontare la risposta obiettiva in ciascuno dei 2 confronti programmati. Confrontare la qualità di vita in ciascuno dei 2 confronti programmati. Condurre analisi esplorative per l’identificazione di fattori prognostici e fattori predittivi dell’efficacia del pemetrexed e del cisplatino.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Diagnosis of cytologically or histologically confirmed non-small cell lung cancer. · Non squamous tumor type (including those with a non-specified tumor type). · Metastatic (stage IV, both M1A or M1B) or locally advanced (stage IIIB, with metastasis to supraclavicular nodes) according to TNM VII edition. · Both patients at first diagnosis or those with disease recurrence after former surgery are eligible. · At least one target or non-target lesion according to RECIST version 1.1. · Male or female ³ 70 years of age. · ECOG PS 0 or 1. · Life expectancy of > 3 months. · Neutrophils ³ 1.5 x 109/L, platelets ³ 100 x 109/L, and hemoglobin ³ 9 g/dL. · Bilirubin level either normal or < 1.5 x ULN. · AST (SGOT) and ALT (SGPT) £ 2.5 x ULN (£ 5 x ULN if liver metastasis are present). · Serum creatinine < 1.5 x ULN. · Signed written informed consent

· Diagnosi di NSCLC confermata citologicamente o istologicamente. · Istotipo non squamoso. · Stadio di malattia IV (M1a o M1b) o IIIB (purché con metastasi ai linfonodi sovraclaveari) secondo il sistema di stadi azione TNM VII edizione. · Pazienti di entrambi i sessi. · Età ³70 anni. · Performance status 0-1 secondo ECOG. · Pazienti alla prima diagnosi o con recidiva dopo chirurgia primaria. · Almeno una lesione target o non target secondo i criteri RECIST versione 1.1. · Aspettativa di vita di almeno 3 mesi. · Neutrofili ³ 1.500/mm³, piastrine ³ 100.000/mm³, emoglobina ³9 g/dl. · Creatininemia < 1.5 volte il valore massimo normale. · AST e/o ALT £ 2.5 volte il valore massimo normale o £ 5 volte il valore massimo normale in presenza di metastasi epatiche. · Bilirubinemia £1.5 volte il valore massimo normale. · Consenso informato scritto.

E.4

Principal exclusion criteria

· Prior chemotherapy or therapy with systemic anti-neoplastic therapy for advanced disease. Prior surgery and/or localised irradiation is permitted. Prior adjuvant chemotherapy is permitted if it did not contain gemcitabine and pemetrexed and if at least 6 months elapsed from the end of adjuvant chemotherapy. · Any unstable systemic disease (including active infections, significant cardiovascular disease or myocardial infarction within the previous year, any significant hepatic, renal or metabolic disease), metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of study medications or render the patient at high risk from treatment complications. · Any other malignancies within 5 years (except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer or surgically resected prostate cancer with normal PSA). · Patients with symptomatic brain metastasis or spinal cord compression that has not yet been treated with surgery and/or radiation; patients with CNS metastases or spinal cord compression previously treated with surgery and/or radiation are eligible if they are asymptomatic and do not require steroids (anti-seizure medications are allowed). · Known or suspected hypersensitivity to any of the study drugs.

· Precedente terapia medica antineoplastica per la malattia metastatica. La precedente chirurgia e/o trattamento radiante sono consentiti. NB.: la precedente terapia medica adiuvante è permessa, purché non contenente gemcitabina o pemetrexed e terminata da almeno 6 mesi. · Precedente o concomitante neoplasia maligna (escluso il carcinoma cutaneo baso o spinocellulare, il carcinoma in situ della cervice uterina, purché adeguatamente trattati e il carcinoma della prostata resecato con PSA nella norma) diagnosticata nei 5 anni precedenti alla data di registrazione. · Pazienti con compressione midollare o metastasi cerebrali sintomatiche. (NB.: sono eleggibili i pazienti portatori di metastasi cerebrali o di compressione midollare purché asintomatiche, anche dopo trattamento chirurgico o radiante. La terapia medica con antiedemigeni o antiepilettici, successiva a trattamenti chirurgici o radianti, non costituisce motivo di esclusione). · Presenza di patologie sistemiche non adeguatamente trattate (incluse infezioni attive, patologie significative cardiovascolari o infarto del miocardio nei 12 mesi precedenti, epatiche, renali o metaboliche) che a giudizio del medico rendano non praticabile il trattamento chemioterapico. · Ipersensibilità nota o sospetta ad uno dei farmaci in studio.

E.5 End points

E.5.1

Primary end point(s)

overall survival

sopravvivenza globale

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 3 weeks in the treatment; every 12 weeks last treatment

ogni 3 settimane durante il trattamento; ogni 12 settimane alla fine del trattamento

E.5.2

Secondary end point(s)

toxicity; progression-free survival; response rate; quality of life.

tossicità; sopravvivenza libera da progressione; risposta obiettiva; qualità di vita.

E.5.2.1

Timepoint(s) of evaluation of this end point

Every 3 weeks in the treatment; every 12 weeks last treatment

ogni 3 settimane durante il trattamento; ogni 12 settimane alla fine del trattamento

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

Yes

E.8.2.2

Placebo

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

Number of subjects for this age range:

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

550

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

550

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

2012-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-22

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

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