Clinical Trials Register

Summary
EudraCT Number:	2014-000349-59
Sponsor's Protocol Code Number:	0244190615-02
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:	2014-03-19
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

2014-000349-59

A.3

Full title of the trial

METAL (METformin in Advanced Lung cancer) study: PHASE II STUDY OF METFORMIN PLUS ERLOTINIB IN SECOND LINE THERAPY OF STAGE IV NON SMALL CELL LUNG CANCER (NSCLC) PATIENTS

Studio METAL (metformina nel tumore del polmone in fase avanzata): studio di fase II di metformina più erlotinib in seconda lionea di trattamento in pazienti con non small cell lung cancer metastatico.

A.3.1

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

METAL trial: metformin plus erlotinib in patients with metastatic lung cancer in second line therapy

Metal trial: combinazione di metformina più erltoinib in seconda linea di trattamento in pazienti con tumore del polmone avanzato

A.4.1

Sponsor's protocol code number

0244190615-02

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	department of experimental and clinical medicine "F. Magrassi"
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	department of experimental and clinical medicine "F. Magrassi"
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	department of experimental and clinical medicine "F. Magrassi"
B.5.2	Functional name of contact point	fortunato ciardiello
B.5.3	Address:
B.5.3.1	Street Address	via pansini 5
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	00390815666745
B.5.5	Fax number	00390815666732

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	tarceva
D.2.1.1.2	Name of the Marketing Authorisation holder	roche registration limited 6 flacon way shire park welwyn garden city AL7 1tw regno unito
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	erlotinib
D.3.2	Product code	L01XE03
D.3.4	Pharmaceutical form	Capsule
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	ERLOTINIB
D.3.9.1	CAS number	183321-74-6
D.3.9.4	EV Substance Code	SUB16423MIG
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	150
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	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

Patients with metastatic non small cell lung cancer in second line therapy

pazienti con NSCLC in fase metastatica in seconda line adi trattamento

E.1.1.1

Medical condition in easily understood language

Patinets with advanced lung cancer

pazienti con tumore del polmone in stadio avanzato

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The study is a two-part trial, where a safety Run-in part of metformin combined with erlotinib will be followed by a Phase II part of metformin plus erlotinib. Primary objective of the safety run in part is to determine the MTD and the recommended Phase II dose of metformin combined with erlotinib as second-line treatmentin subjects with NSCLC harboringwild-type EGFR gene.
Primaryobjective of the phase II part are:
• To assess the percentage of patientswithoutdiseaseprogressionat 10 weeks.
• To assess the median progression free survival of the second-line combination metformin and erlotinib in subjects with NSCLCharboring wild-type EGFR gene.

Lo studio è diviso in due parti: UNA SAFETY RUN IN PART E UNA PHASE II PART.
l'obiettivo primario della safety run in part è quello di definire la dose massima tollerata (MTD) e la dose di metformina+erlotinib da testare nello studio di fase II in pazienti con NSCLC in II linea di trattamento, che non presentano mutazioni nel gene EGFR.
Gli obiettivi primari della phase II part sono:
- Definire la percentuale di pazienti liberi da progressione a 10 settimane
- Definire la sopravvivenza mediana libera da progressione in II linea in pazienti con NSCLC che non presentano mutazione del gene EGFR

E.2.2

Secondary objectives of the trial

Secondary objectives of the safety run in part are:
• To assess the pharmacokinetics (PK) of metformin and erlotinib when combined in subjects with NSCLCharboring wild-type EGFR gene.
• To determine safety and tolerability of metformin and erlotinib when combined in subjects with NSCLCharboring wild-type EGFR gene.
• To explore antitumor activity of metformin and erlotinib when combined in subjects with NSCLCharboring wild-type EGFR gene.
• To explore candidate markers or tumor characteristics predictive of antitumor activity
Secondary objectives of the phase II part are:
• To assess the anti-tumor activity, in terms of response rate, overall survival, QoL, of metformin and erlotinib when combined in subjects with NSCLCharboring wild-type EGFR gene.
• To determine safety and tolerability of metformin and erlotinib when combined in subjects with NSCLCharboring wild-type EGFR gene.
• To explore candidate markers or tumor characteristics predictive of antitumor activity

gli obiettivi secondari della safety run in part sono:
- Valutare la farmacocinetica dell’associazione metformina ed erlotinib
- Determinare la sicurezza e la tollerabilità dell’associazione metformina ed erlotinib Valutare l’attività antitumorale della combinazione metformina ed erlotinib
- Valutare marcatori o caratteristiche tumorali predittive dell’attività antitumorale;
- Esplorare marcatori circolanti presenti nel siero.
Gli obiettivi secondari della Phase II part sono:
- Definire l’attività antitumorale in termini di percentuale di risposta, sopravvivenza globale e qualità di vita dell’associazione metformina ed erlotinib
- Determinare la sicurezza e la tollerabilità dell’associazione metformina ed erlotinib
- Valutare marcatori o caratteristiche tumorali predittive dell’attività antitumorale;

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Signed written informed consents
• Patients be age >18 years
• Patients must have histologically or cytologically confirmed non small cell carcinoma of the lung and are previously treated
• Patient must have measurable stage IV disease (includes M1a, M1b stages or recurrent disease) (according to the 7th edition of the TNM classification system).
• Patients must have a Life Expectancy of greater than 12 weeks.
• Patients must have an ECOG performance status 0 or 1 (Karnofsky> 70%).
• Patients must have normal organ and marrow function as defined below, within one week prior to randomization:
- Neutrophils> 1.5 x 109/L, platelets > 100 x 109/L, and hemoglobin >9 g/dL
- Bilirubin level either normalor <1.5 x ULN
- ASAT and ALAT <2.5 x ULN (< 5 x ULN if liver metastasis are present)
- Serum creatinine < 1.5 x ULN
- Alkaline phosphatase < 4 x ULN

• O2 saturation >93%.
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Patients must have the ability to understand and the willingness to sign a written informed consent document.

1. Modulo di consenso informato approvato dal Comitato Etico firmato e datato
2. Età maggiore o uguale a18
3. Diagnosi istologica o citologica di carcinoma polmonare non a piccole cellule (NSCLC) precedentemente trattato
4. Malattia misurabile in IV stadio (compresi gli stadi M1a, M1b o malattia ricorrente, secondo la 7° edizione della classificazione TNM)
5. Aspettativa di vita superiore alle 12 settimane
6. Performance status 0-1, secondo la scala ECOG (Karnofsky> 70).
7. Buona funzionalità d’organo e del midollo entro una settimana prima della randomizzazione definita come di seguito:
-Conta assoluta dei neutrofili (ANC) > 1,500 cellule/mm3, piastrine >100x109/L ed emoglobina >9 g/dL
- Bilirubina < 1.5 x ULN (Limite Superiore di Normalità)
- ASAT (SGOT), ALAT (SGPT) < 2.5 x ULN (in caso di metastasi epatiche sono accettati valori < 5 ULN)
- Creatinina serica < 1.5 x ULN
- Fosfatasi alcalina < 4 x ULN
- Saturazione dell’ossigeno >93%
8. Accettazione da parte di donne in età fertile e degli uomini con potenziale riproduttivo all’utilizzo di metodi contraccettivi adeguati ed efficaci (metodo ormonale o barriera di controllo delle nascite; astinenza) prima dell’entrata in studio, dalla firma del consenso informato e per tutta la durata dello studio. In caso di gravidanza odi sospetto di gravidanza durante la partecipazione a questo studio, la paziente deve informare immediatamente il Suo medico curante.
9. I pazienti devono avere la capacità di comprendere la volontà di firmare un documento di consenso informato scritto.

E.4

Principal exclusion criteria

• Patients with EGFR/ALK mutated histologically proven NSCLC
• Type 1 or 2 Diabetes
• Patients with uncontrolled undercurrents illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements.
• Patients receiving immunotherapy, hormonal-therapy and or radiotherapy within 2 weeks prior to entering the study. Note: Those who have not recovered from adverse events due to these agents administered will be considered ineligible.
• Patients with uncontrolled brain metastasis. Note: Patients with brain metastases must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks, and must be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or other agents used in the study are excluded.
• Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol
• Any investigational agent(s) within 4 weeks prior to entry
• Previous exposure to EGF, monoclonal antibodies, signal transduction inhibitors or EGFR targeting therapy
• Legal incapacity or limited legal capacity
• Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent
• Women who are pregnant or breastfeeding
• Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Patients with a previous malignancy but without evidence of disease for  5 years will be allowed to enter the trial)

La presenza di una qualsiasi delle caratteristiche sotto elencate non consentirà al paziente di prendere parte allo studio:
1. Pazienti affetti da NSCLC con mutazione del gene EGFR o riarrangiamento di ALK
2. Diabete mellito di tipo I o II
3. Pazienti con infezioni, insufficienza cardiaca congestizia, angina instabile (sintomatologia di angina a riposo), nuova manifestazione di angina (con inizio negli ultimi 3 mesi), infarto miocardico nei 6 mesi precedenti l’inizio del trattamento, aritmia cardiaca, malattia psichiatrica o sociali che potrebbero interferire con la partecipazione del paziente allo studio o con la valutazione dei risultati dello studio.
4. Pazienti trattati con immunoterapia, terapia ormonale e/o radioterapia entro 2 settimane prima di entrare nello studio. Nota: Coloro che non hanno recuperato da eventi avversi dovuti a questi farmaci somministrati saranno considerati non ammissibili.
5. Pazienti con metastasi cerebrali non controllate. Nota: I pazienti con metastasi cerebrali devono avere lo stato neurologico stabile dopo terapia locale (chirurgia o radioterapia) per almeno 2 settimane, in assenza di disfunzione neurologica
6. Ipersensibilità conosciuta al farmaco in studio, alla classe di farmaci cui appartiene il farmaco in studio o agli eccipienti presenti nella formulazione.
7. Concomitante terapia sistemica immunitaria cronica, chemioterapia o terapia ormonale non indicate nel protocollo di studio.
8. Qualsiasi farmaco sperimentale entro 4 settimane prima dell'arruolamento nello studio.
9. Precedente esposizione a EGF, anticorpi monoclonali, inibitori della trasduzione del segnale o terapia con farmaci anti- EGFR.
10. Incapacità giuridica o capacità legale limitata
11. Condizione medica o psicologica che, a parere dello sperimentatore non permetterebbe al paziente di completare lo studio o firmare il consenso informato significativo.
12. Donne in gravidanza o in allattamento. Donne potenzialmente fertili devono fare un test di gravidanza entro i 7 giorni precedenti l’inizio del trattamento, e comunque prima dell’inizio del trattamento deve essere documentato il risultato di un test di gravidanza negativo.
13. Precedente o concomitante tumore maligno, che si distingue per sito primario d’insorgenza o istologia dal carcinoma del polmone non a piccole cellule nei 5 anni precedenti l’inclusione, ad eccezione del carcinoma della pelle purchè non-melanoma edel carcinoma in situ della cervice uterina.

E.5 End points

E.5.1

Primary end point(s)

o studio è diviso in due parti: UNA SAFETY RUN IN PART E UNA PHASE II PART.
l'obiettivo primario della safety run in part è quello di definire la dose massima tollerata (MTD) e la dose di metformina+erlotinib da testare nello studio di fase II in pazienti con NSCLC in II linea di trattamento, che non presentano mutazioni nel gene EGFR.
Gli obiettivi primari della phase II part sono:
- Definire la percentuale di pazienti liberi da progressione a 10 settimane
- Definire la sopravvivenza mediana libera da progressione in II linea in pazienti con NSCLC che non presentano mutazione del gene EGFR

E.5.1.1

Timepoint(s) of evaluation of this end point

18 mounths

18 mesi

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

18 mounths

18 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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

E.8.1.1

Randomised

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)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Until PFS or wishes of the patient or investigator decision

Fino a progressione di malattia o ritiro del consenos o volontà del paziente

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 months

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:

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

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)

none

nessuno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	department of experimental and clinical medicine F magrassi
G.4.3.4	Network Country	Italy

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-05-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-16

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

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