Clinical Trials Register

Summary
EudraCT Number:	2011-001988-52
Sponsor's Protocol Code Number:	EORTC90101
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-01-15
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

2011-001988-52

A.3

Full title of the trial

Phase II clinical trial exploring the activity of crizotinib in patients with advanced solid tumors induced by causal alterations of specific receptors (ALK and MET/HGF receptor tyrosine kinases) expressed by cancer sells.

Sperimentazione clinica di fase 2 su vari tumori per la valutazione di crizotinib (PF-02341066) in pazienti con tumori in stadio avanzato, indotti da alterazioni causali di ALK e/o MET ("CREATE")

A.3.1

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

Sperimentazione clinica di fase 2 su vari tumori per la valutazione di crizotinib (PF-02341066) in pazienti con tumori in stadio avanzato, indotti da alterazioni causali di ALK e/o MET ("CREATE")

A.4.1

Sponsor's protocol code number

EORTC90101

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01524926

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	E.O.R.T.C. - EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT OF CANCER
B.1.3.4	Country	Belgium
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	Pfizer
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	EORTC
B.5.2	Functional name of contact point	Project Mgt & Regulatory Unit
B.5.3	Address:
B.5.3.1	Street Address	Avenue E. Mounier 83/11
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+32 (2) 774 1653
B.5.5	Fax number	+32 (2) 774 1030
B.5.6	E-mail	regulatory@eortc.be

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	XALKORI
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Capsule, hard
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.3.9.1	CAS number	877399-52-5
D.3.9.2	Current sponsor code	PF-02341066
D.3.9.4	EV Substance Code	SUB32267
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	200
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.2.1.1.1	Trade name	Xalkori
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Capsule, hard
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.3.9.1	CAS number	877399-52-5
D.3.9.2	Current sponsor code	Crizotinib
D.3.9.3	Other descriptive name	CRIZOTINIB
D.3.9.4	EV Substance Code	SUB32267
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	250
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

Locally advanced and/or metastatic malignant tumor (anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, papillary renal cell carcinoma type 1, alveolar soft part sarcoma, clear cell sarcoma or alveolar rhabdomyosarcoma) deemed incurable by conventional surgery, radiotherapy, systemic therapy or any other means

Localmente avanzato e / o metastatico tumore maligno (linfoma anaplastico a grandi cellule, tumore infiammatorio miofibroblastico, papillare renale carcinoma a cellule di tipo 1, sarcoma alveolare mollica, sarcoma a cellule chiare o rabdomiosarcoma alveolare) ritenuto incurabile dalla chirurgia tradizionale, radioterapia, terapia sistemica o di qualsiasi altro mezzi

E.1.1.1

Medical condition in easily understood language

Local diagnosis of locally advanced and/or metastatic sub types of lymphoma, RCC and soft tissue sarcoma deemed incurable by surgery, radiotherapy, systemic therapy or any other means.

Diagnosi locale di sottotipi localmente avanzato e / o metastatico di linfoma, sarcoma dei tessuti molli RCC e ritenuto incurabile dalla chirurgia, radioterapia, terapia sistemica o qualsia

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	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10065867
E.1.2	Term	Alveolar rhabdomyosarcoma
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	15.1
E.1.2	Level	PT
E.1.2	Classification code	10002227
E.1.2	Term	Anaplastic large cell lymphoma T- and null-cell types
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	15.1
E.1.2	Level	PT
E.1.2	Classification code	10001882
E.1.2	Term	Alveolar soft part sarcoma
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	15.1
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The study zill primarily assess the efficacy of crizotinib in a variety of tumors zith alterations in ALK and/or MET pathways. The targeted patient population zill include patients zith tumors harboing specific alterations leading to ALK and/or MET activation,where tyrosine kinase inhibitors against these targets have not yet been adequately explored.

Lo studio Zill principalmente valutare l'efficacia di crizotinib in una varietà di tumori alterazioni zith in ALK e / o TEM percorsi. Il mirata Zill popolazione di pazienti sono i tumori dei pazienti zith harboing specifiche alterazioni che portano alla ALK e / o attivazione MET, in cui gli inibitori della tirosin-chinasi nei confronti di questi obiettivi non sono ancora adeguatamente esplorato.

E.2.2

Secondary objectives of the trial

To study the specificity of the kinase inhibitor for tumors in all cohorts by explorative comparison of treatment results in patients with the same disease type with and without genetic alterations in ALK and/or MET. To investigate sensitive and reliable methodologies for patient screening for such defects, to be potentially cross-validated and further developed by an accredited laboratory in later steps, based on prospectively collected biological material from this trial. To explore whether molecularly driven, high quality multi-tumor screening Phase II trials are feasible in a multiinstitutional, multidisciplinary setting, when screening and tratment are perfor;ed by EORTC (+:-additional selected sites). To study soluble serum factors leading to MET pathway activation as predictive biomarkers for response to tratment.

Per studiare la specificità della chinasi per tumori in tutti coorti rispetto esplorativa dei risultati del trattamento in pazienti con la stessa malattia tipo con e senza alterazioni genetiche in ALK e / o TEM. Per studiare metodologie sensibili ed affidabili per lo screening dei pazienti per tali difetti, per essere potenzialmente cross-validati e ulteriormente sviluppato da un laboratorio accreditato nei passaggi successivi, sulla base di materiale biologico raccolti prospetticamente da questa prova. Per esplorare zhether molecolarmente orientata, di alta qualità multi-tumorali di screening studi di Fase II sono fattibili in un multi-istituzionale, l'impostazione multidisciplinare, quando lo screening e il tratamento sono prestazioni, ed da EORTC.Studiare i fattori solubili del siero che portano alla via di attivazione MET come biomarcatori predittivi di risposta al tratamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Step 1 registration: *Local diagnosis of locally advanced and/or metastatic malignant tumor (defined befor) deemed incurable by conventional surgery, radiotherapy, systemic therapy or any other means.* Mandatory shipment of tumor-containing tissue blocks. Step 2 registration: *Measurable disease according to RECIST 1.1 with target lesion of at least 20mm (or 10mm on spiral CT scans). *Minimum age 15 years, no upper age limit. *Eastern Cooperative OncologyGroup (ECOG) performance status 0-2. *Adequate hematological function:ANC≥1x109/L, platelets≥30x109/L and hemoglobin≥8g/dl. *Adequate renal function:serum creatinine ≤2xULN.*Adequeta liver function:Bilirubin ≤1.5xULN. AST and ALT≤2.5xULN in the qbsence of liver metastases and ≤5xULN if liver function abnormalities are due to the underlying malignancy. *Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;those conditions should be discussed with the patient before registration in te trial. *Negative pregnancy test. *All patients (male and female) of childbearing/reproduxtive potential must use adequate birth control measures during the study treatment period and for at least three months after the last study tratment. *Written consent before registration. *Additional inclusion criteria linked to specific tumor type are described in the protocol in section 3.2

Passaggio 1 registrazione: diagnosi * locale di localmente avanzato e / o metastatico tumore maligno (definito befor) ritenuto incurabile dalla chirurgia tradizionale, radioterapia, terapia sistemica o qualsiasi altro mezzo spedizione * obbligatorio di tumore contenenti blocchi di tessuto.. Fase 2 di registrazione: * malattia misurabile secondo i criteri RECIST 1.1 con lesione bersaglio di almeno 20 mm (o 10 mm in TC spirale). * Età minima 15 anni, senza limiti di età superiore. * Eastern Cooperative OncologyGroup (ECOG) performance status 0-2. * Funzione adeguata ematologiche: ANC ≥ 1x109 / L, piastrine ≥ 30x109 / L e di emoglobina ≥ 8g/dl. * Funzione renale adeguata:. Creatinina sierica ≤ 2xULN * funzionalità epatica Adequeta: Bilirubina ≤ 1.5xULN. AST e ALT ≤ 2.5xULN nel qbsence di metastasi epatiche e 5xULN ≤ se alterazioni della funzionalità epatica sono dovuti al tumore di base. * Assenza di qualsiasi psicologica, familiare, condizione sociologica o geografica potenzialmente ostacolano il rispetto del protocollo di studio e follow-up calendario; tali condizioni deve essere discussa con il paziente prima della registrazione nella prova te. * Test di gravidanza negativo. * Tutti i pazienti (uomini e donne) in età fertile / reproduxtive devono utilizzare adeguate misure contraccettive durante il periodo di trattamento dello studio e per almeno tre mesi dopo al trattamento ultimo studio. * Consenso scritto prima della registrazione. Criteri di inclusione * supplementari legate al tipo specifico di tumore sono descritti nel protocollo nella sezione 3.2

E.4

Principal exclusion criteria

Step 2 registration: *Carcinomatous meningitis or leptomeningeal disease. *Treatment zith any other investigational drug within the past 4 weeks or within less than 4 half-life times of the investigational drug before tratment with crizotinib (whatever is the longest period). *Prior therapy directly targeting ALK and/or MET, previous tratment with crizotinib.*Previous and active malignancy for the last three years with the exception of non-melanoma skin cancer, localized cervical cancer, localized and presumably cured prostate cancer or adequately treatedbasal or squamous cell skin carcinoma. *Acute or chronic severe gastrointestinal conditions such as diarrhea or ulcer. *Current congestive heart failure. *Ongoing cardiac dysrhythmias of NCI CTCAE Grade >2. *Uncontrolled atrial fibrillation of any grade. *Pregnant women.

Passaggio 2 di registrazione: * meningite carcinomatosa o malattia leptomeningea. * Il trattamento zith qualsiasi altro farmaco sperimentale nelle ultime 4 settimane o in meno di 4 volte l'emivita del farmaco in fase di sperimentazione prima di tratamento con crizotinib (qualunque sia il periodo più lungo). * La terapia preventiva di mira direttamente ALK e / o MET, tratamento precedente con crizotinib. * Malignità precedente e attiva per gli ultimi tre anni, con l'eccezione di non-melanoma, cancro della pelle, localizzato il cancro cervicale, localizzato e presumibilmente curato il cancro alla prostata o adeguatamente treatedbasal o carcinoma a cellule squamose della pelle. * Gravi condizioni acute o croniche gastrointestinali come diarrea o ulcera. * Corrente insufficienza cardiaca congestizia. * In corso di aritmie cardiache di grado NCI CTCAE> 2. * Fibrillazione atriale non controllata di qualsiasi grado. * Le donne in gravidanza.

E.5 End points

E.5.1

Primary end point(s)

Response rate documented by RECIST 1.1 (with response confirmation).

Tasso di risposta documentato secondo i criteri RECIST 1.1 (con conferma di risposta)

E.5.1.1

Timepoint(s) of evaluation of this end point

At the end of trial (per cohort)

Alla fine della prova (per coorte)

E.5.2

Secondary end point(s)

Safety (CTAE v4.0) Progression free survival Clinical benefit, as assessed by the rate of CR+PR+Stable Disease (SD) Overall survival Duration of clinical benefit

•Sicurezza (CTAE v 4.0) •Sopravvivenza libera da progressione •Tasso di controllo della malattia •Sopravvivenza globale •Durata della risposta •Endpoint di ricerche correlate Sicurezza:Eventi avversi, farmaci concomitanti ed esami di laboratorio.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the end of the trial (per cohort)

Alla fine del processo (per coorte)

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

Translational research

Ricerca traslazionale

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