Clinical Trials Register

Summary
EudraCT Number:	2012-002669-37
Sponsor's Protocol Code Number:	EMR200066-007
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:	2012-11-06
Trial results	View 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

2012-002669-37

A.3

Full title of the trial

A multicentre, open label, randomized Phase II trial of the MEK inhibitor pimasertib or dacarbazine in previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma.

Studio di fase II, multicentrico, in aperto, randomizzato, con il MEK inibitore pimasertib o con dacarbazina in pazienti affetti da melanoma cutaneo maligno metastatico o localmente avanzato con N-Ras mutato non trattati in precedenza.

A.3.1

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

Clinical trial comparing the safety and efficacy of pimasertib and dacarbazine in previously untreated patients with locally advanced or metastatic malignant cutaneous melanoma showing the so-called N-Ras mutation.

studio clinico per valutare la sicurezza e la efficacia di pimasertib e dacarbazina in pazienti, non trattati in precedenza, affetti da melanoma cutaneo maligno metastatico o localmente avanzato con N-Ras mutato

A.4.1

Sponsor's protocol code number

EMR200066-007

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	MERCK SERONO SA
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Merck Serono S.A.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Merck KGaA
B.5.2	Functional name of contact point	Communication Center Merck KGaA
B.5.3	Address:
B.5.3.1	Street Address	Frankfurter Strasse 250
B.5.3.2	Town/ city	Darmstadt
B.5.3.3	Post code	64293
B.5.3.4	Country	Germany
B.5.4	Telephone number	+ 49 6151 72 5200
B.5.5	Fax number	+ 49 6151 72 2000
B.5.6	E-mail	service@merck.de

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	No
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	pimasertib
D.3.2	Product code	MSC1936369B
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.3.8	INN - Proposed INN	pimasertib
D.3.9.1	CAS number	1236361-78-6
D.3.9.3	Other descriptive name	MSC1936369B
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	15
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	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.2.1.1.1	Trade name	Dacarbazina Medac 1000 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac GmbH
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.3.4	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	DACARBAZINE
D.3.9.1	CAS number	4342-03-4
D.3.9.4	EV Substance Code	SUB06882MIG
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	1000
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	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	No
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	pimasertib
D.3.2	Product code	MSC1936369B
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.3.8	INN - Proposed INN	pimasertib
D.3.9.1	CAS number	1236361-78-6
D.3.9.3	Other descriptive name	MSC1936369B
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	30
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

N-RAS mutated locally advanced or metastatic malignant cutaneous melanoma

Melanoma cutaneo maligno metastatico o localmente avanzato con N-Ras mutato

E.1.1.1

Medical condition in easily understood language

Cancer

Tumore

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	LLT
E.1.2	Classification code	10025655
E.1.2	Term	Malignant melanoma of skin
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

To compare the progression-free survival (PFS) of previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma treated with either pimasertib or dacarbazine.

Confrontare la sopravvivenza libera da progressione (PFS) dei soggetti trattati con pimasertib o dacarbazina in soggetti non trattati in precedenza, affetti da melanoma cutaneo maligno metastatico o localmente avanzato con N-Ras mutato.

E.2.2

Secondary objectives of the trial

Efficacy - Compare the objective response of subjects treated with either pimasertib or dacarbazine. - Compare the disease control of subjects treated with either pimasertib or dacarbazine. - Evaluate the overall survival of subjects treated with either pimasertib or dacarbazine. - Compare the Quality of Life of subjects treated with either pimasertib or dacarbazine. Safety - Compare the safety profile of subjects treated with pimasertib or dacarbazine. Pharmacokinetics - Assess the pharmacokinetics of pimasertib in melanoma subjects and to evaluate relationships between exposure and response as well as exposure and AEs. Pharmacogenetics and Biomarkers - Describe the relationship between basal tumor characteristics and circulating markers and pimasertib anti-tumor activity. Explore genes that are important in the drug metabolizing enzymes and transporters of pimase...

Obiettivi secondari
Efficacia
• Confrontare la risposta oggettiva dei soggetti trattati con pimasertib o dacarbazina.
• Confrontare il controllo della malattia dei soggetti trattati con pimasertib o dacarbazina.
• Valutare la sopravvivenza globale (OS) dei soggetti trattati con pimasertib o dacarbazina.
• Confrontare la qualità della vita (tramite FACT-Melanoma) dei soggetti trattati con pimasertib o dacarbazina.
Sicurezza
• Confrontare il profilo di sicurezza dei soggetti trattati con pimasertib o dacarbazina.
Farmacocinetica
• Valutare la farmacocinetica (PK) di pimasertib nei soggetti con melanoma e valutare i rapporti tra esposizione e risposta e tra esposizione ed eventi avversi (AE).
Farmacogenetica e biomarcatori
• Descrivere il rapporto tra le caratteristiche basali del tumore (es. genotipo, prodotti genici) e i marcatori in circolazione e l’attività anti-......

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects with measurable, histologically or cytologically confirmed, unresectable locally advanced or metastatic cutaneous melanoma (stage III c or M1a-c) N-Ras mutated. If N-Ras mutational status is unknown at screening, it must be prospectively defined before inclusion. If N-Ras mutational status is already known before screening, it must be retrospectively confirmed after inclusion by the sponsor. 2. Tumor lesions amenable to biopsy or available tumor tissue as archival samples. 3. Age ≥ 18 years. 4. Has read and understood the informed consent form and is willing and able to give informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments. 5. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential are defined as: ''All female subjects after puberty unless they are post-menopausal for at least two years, or are surgically sterile''. 6. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose of trial medication. Effective contraception is defined as the method of contraception with a failure rate of less than 1% per year. Adequate contraception is defined as follows: two barrier methods or one barrier method with a spermicidal or intrauterine device or oral contraception for female partners of male subjects.

Per l’ammissione allo studio devono essere soddisfatti tutti i criteri di inclusione seguenti:
1. Soggetti con melanoma cutaneo misurabile, confermato istologicamente o citologicamente, non resecabile, localmente avanzato o metastatico (stadio III c o M1a-c), con N-Ras mutato . Se lo stato di mutazione N-Ras non è noto allo screening, deve essere definito in prospettiva prima dell’inclusione. Se lo stato di mutazione N-Ras è già noto prima dello screening, deve essere confermato in retrospettiva dopo l’inclusione a opera dello sponsor.
2. Lesioni tumorali assoggettabili a biopsia o tessuto tumorale disponibile come campioni archiviati.
3. Età ≥ 18 anni.
4. Il soggetto ha letto e compreso il modulo di consenso informato e intende ed è in grado di fornire il consenso informato. Il soggetto comprende pienamente i requisiti dello studio e intende conformarsi a tutte le visite e le valutazioni previste.
5. Le donne potenzialmente fertili devono presentare un test di gravidanza sul sangue negativo alla visita di screening. Per gli scopi di questo studio, le donne potenzialmente fertili sono definite come: “Tutti i soggetti di sesso femminile dopo la pubertà, a meno che non siano in post-menopausa da almeno due anni oppure sterili in seguito a chirurgia”.
6. I soggetti di sesso femminile potenzialmente fertili e i soggetti di sesso maschile con partner donne potenzialmente fertili devono acconsentire a evitare una gravidanza mediante l’uso di un contraccettivo nelle 2 settimane precedenti, durante e per quattro settimane dopo l’ultima dose di farmaco sperimentale. La contraccezione efficace viene definita come il metodo contraccettivo con un tasso di insuccesso inferiore a 1% all’anno. La contraccezione adeguata viene definita come segue: due metodi a barriera o un metodo a barriera con spermicida o dispositivo intrauterino o contraccettivo orale per partner di sesso femminile di soggetti di sesso maschile.

E.4

Principal exclusion criteria

1. Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma (excluding adjuvant treatment). 2. Has non-measurable lesions, disease not evaluable by RECIST v. 1.1 3. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1. 4. Has bone marrow impairment as evidenced by Hemoglobin < 10.0 g/dL, Neutrophil count <1.5 x 10^9/L, platelets < 100 x 10^9/L. 5. Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min (according to the Cockcroft-Gault formula). 6. Has liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT >2.5 x ULN, for subjects with liver involvement AST/ALT >5 x ULN. 7. Has significant cardiac conduction abnormalities, including QTc prolongation of >480 ms and/or pacemaker or clinically relevant impaired cardiovascular function (NYHA Class III/IV). 8. Has hypertension uncontrolled by medication 9. Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension). 10. Has known active CNS metastases unless previously radiotherapy treated, stable by CT scan for at least 3 months without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants. 11. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease, or conditions that may hamper compliance and/or absorption of the tested product. 12. Known HIV positivity, active hepatitis C, or active hepatitis B. 13. Has undergone surgical intervention within 28 days from Day 1 of trial drug treatment. 14. Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from Day 1 of trial drug treatment. 15. Has history of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has a psychiatric condition that might impair the subject well-being or preclude full participation in the trial. 16. Has known hypersensitivity to dacarbazine. 17. Is a pregnant or nursing female. 18. Participated in another clinical trial within the past 28 days.

Un soggetto non è idoneo a questo studio se soddisfa uno qualsiasi dei seguenti criteri di esclusione:
1. È stato sottoposto a precedente trattamento sistemico per melanoma cutaneo metastatico o localmente avanzato (fatta eccezione per trattamento adiuvante).
2. Presenta lesioni non misurabili, patologia non valutabile tramite RECIST v. 1.1.
3. Presenta uno stato di performance Eastern Cooperative Oncology Group (ECOG PS) >1.
4. Ha un problema al midollo osseo, come dimostrato da emoglobina < 10,0 g/dl, conta dei neutrofili <1,5 x 109/l, piastrine < 100 x 109/l.
5. Ha una disfunzione renale, come dimostrato da clearance della creatinina calcolata <60 ml/min (secondo la formula di Cockroft e Gault).
6. Presenta un’anomalia della funzionalità epatica, definita da bilirubina totale > 1,5 x ULN o AST/ALT >2,5 x ULN, per soggetti con interessamento epatico AST/ALT >5 x ULN.
7. Soffre di anomalie significative della conduzione cardiaca, tra cui prolungamento del QTc >480 ms e/o pacemaker o funzione cardiovascolare compromessa e rilevante a livello clinico (Classe NYHA III/IV).
8. Soffre di ipertensione non controllata da farmaci.
9. Presenta una patologia degenerativa della retina (degenerazione della retina ereditaria o degenerazione maculare legata all’età), storia di uveite o storia di occlusione della vena della retina (RVO) o patologia oculare considerata fattore di rischio per RVO (es. glaucoma non controllato o ipertensione oculare).
10. Presenta metastasi CNS attive note, tranne se precedentemente trattate con radioterapia, la cui stabilità da almeno 3 mesi viene confermata da TAC, senza traccia di edema cerebrale e con assenza di requisiti per corticosteroidi o anticonvulsivi.
11. Storia di difficoltà nella deglutizione, malassorbimento o altra patologia gastrointestinale cronica o condizione in grado di ostacolare la conformità e/o l’assorbimento del prodotto testato.
12. Positività nota a HIV, epatite C attiva o epatite B attiva.
13. È stato sottoposto a intervento chirurgico entro 28 giorni dal Giorno 1 del trattamento con farmaco sperimentale.
14. Ha ricevuto una precedente radioterapia estesa a oltre il 30% delle riserve di midollo osseo o è stato sottoposto a precedente trapianto di midollo osseo/cellule staminali entro 5 anni dal Giorno 1 del trattamento sperimentale.
15. Ha una storia di una qualsiasi altra patologia medica significativa, come intervento chirurgico allo stomaco o all’intestino tenue di notevole entità, recente drenaggio di volumi significativi di asciti o versamento pleurico oppure soffre di una condizione psichica che potrebbe pregiudicare il benessere del soggetto o precludere la completa partecipazione allo studio.
16. Soffre di ipersensibilità nota a dacarbazina.
17. È un soggetto di sesso femminile in gravidanza o in allattamento.
18. Ha partecipato a un altro studio clinico nei 28 giorni precedenti l’inizio di questa sperimentazione.

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival, defined as the time from randomization to the first documentation of objective disease progression (according to RECIST v. 1.1) as determined by the investigator or death, whichever comes first. Death will be considered as an event only if it is reported within 12 weeks after the last tumor assessment without progression.

PFS definita come il tempo intercorso tra la randomizzazione e la prima progressione oggettiva documentata della malattia (in base a RECIST v. 1.1) come stabilito dallo sperimentatore oppure il decesso, a seconda dell’evento che si verificherà per primo. Il decesso sarà considerato un evento solo se riferito entro 12 settimane dall'ultima valutazione del tumore senza progressione.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT.

Baseline; al Giorno 1 dei cicli 3, 5, 7, 9, 11, 13 e quindi ogni 4 cicli; al termine dello studio.

E.5.2

Secondary end point(s)

*Efficacy All efficacy endpoints involving RECIST v. 1.1 criteria will be based upon investigator assessment. Independent central review of scans will be performed retrospectively for the purpose of sensitivity analyses. - Objective response defined as complete or partial tumor response according to RECIST v. 1.1 criteria. - Disease control defined as the proportion of subjects with complete response, partial response, or stable disease for > 3 months, according to RECIST v. 1.1 criteria. - Progression-free survival rate at six months from the time of randomization based upon objective disease progression (according to RECIST v. 1.1 as defined for PFS above. - Overall survival defined as the time from randomization to death from any cause. - Overall survival rate at 12 months from the time of randomization. - Change in patient-reported QoL (assessed by FACT-Melanoma) from baseline assessment to last assessment prior to objective disease progression (according to RECIST v. 1.1). *Safety - Treatment-emergent adverse events (TEAEs), SAEs, deaths. - Clinically significant changes in safety-related laboratory parameters according to NCI-CTC v 4.0 and abnormal vital signs. *Pharmacokinetics - Plasma PK parameters estimates of pimasertib * Pharmacogenetics and Biomarkers - Gene products and genetic alterations in tumor biopsies. - Predictive markers in plasma - Potential genetic variations in gDNA obtained from PBMC, associated with differences in PK (i.e., DMET genes) and profile of pimasertib.

Efficacia
Tutti gli endpoint di efficacia che coinvolgono i criteri RECIST v. 1.1 saranno basati sulla valutazione dello sperimentatore.
• La risposta oggettiva è definita come risposta del tumore parziale o completa in base ai criteri RECIST v. 1.1.
• Il controllo della malattia è definito come risposta completa, risposta parziale o malattia stabile per >3 mesi in base ai criteri RECIST v. 1.1.
• Tasso di PFS a 6 mesi dal momento della randomizzazione sulla base della progressione oggettiva della patologia (in base a RECIST v. 1.1), come definita per PFS sopra.
• OS, definita come il tempo intercorso tra la randomizzazione e il decesso per una qualsiasi causa
• Tasso di OS a 12 mesi dal momento della randomizzazione.
• Cambiamento nella QoL riportata dal soggetto (valutazione mediante FACT-Melanoma) dalla valutazione della baseline all'ultima valutazione prima della progressione oggettiva della malattia (in base a RECIST v. 1.1).
Sicurezza
• Eventi avversi originati dal trattamento (TEAE), eventi avversi seri (SAE), decessi.
• Cambiamenti clinicamente significativi nei parametri di laboratorio correlati alla sicurezza in base a NCI-CTC v 4.0 e anomalie nei segni vitali.
Farmacocinetica
• Stime del parametro di farmacocinetica nel plasma di pimasertib.
Farmacogenetica e biomarcatori
• Prodotti genici e alterazioni genetiche nelle biopsie tumorali
• Marcatori predittivi nel plasma
• Potenziali variazioni genetiche nel gDNA ottenuto da PBMC, associate a differenze nel profilo farmacocinetico (cioè geni DMET) di pimasertib.

E.5.2.1

Timepoint(s) of evaluation of this end point

- OR & Disease control: Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT - PFS rate: 6 months from time of randomization - OS: time of death from any cause. - OS rate: 12 months from time of randomization. - Change in patient-reported QoL: at last assessment prior to objective disease progression - TEAEs, SAEs, deaths.: Screening up to Post treatment assessment (30+/- 3 days after last drug intake). - Vital signs: Baseline; Pre-dose on day 1, 8 of cycle 1, 2; Day 1 of every cycles thereafter; EoT; PTP - PK: Day 8, 15 of cycle 1; Day 1 of cycle 2 - Gene products and genetic alterations: Baseline - Predictive markers in plasma: Day 1 of cycle 1 - Potential genetic variations: Cycle 1 day 1 for pimasertib arm only.

- Risposta oggettiva: Baseline; al Giorno 1 dei cicli 3, 5, 7, 9, 11, 13 e quindi ogni 4 cicli; al termine dello studio.
- Tasso di PFS: a 6 mesi dalla randomizzazione.
- OS: tempo della morte per qualsiasi causa.
- Tasso OS: a 12 mesi dalla randomizzazione.
- Cambiamento della QoL: all'ultima valutazione prima della progressione oggettiva della malattia.
- TEAEs, SAEs, morte: dallo screening all'ultima visita post trattamento (30+/-3 giorni dall'ultima somministrazione).
Segni vitali: Baseline; prima del trattamento al giorno 1 e 8 del ciclo 1 e 2; Giorno 1 di ogni ciclo; EoT; PTP.
-Farmacocinetica: Giorno 8 e 15 del ciclo 1; Giorno 1 del ciclo 2.
- Prodotti genici e alterazioni genetiche: Baseline.
- Marcatori predittivi nel plasma: Giorno 1 del ciclo 1.
- .....

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

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Israel

New Zealand

South Africa

Switzerland

United States

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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)

Yes

F.1.2.1

Number of subjects for this age range:

157

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

131

F.4.2.2

In the whole clinical trial

184

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)

After leaving the trial, e.g., due to progressive disease or withdrawal of
consent, the subjects will have full and unrestricted access to
appropriate diagnostic or therapeutic care at the discretion of the
investigator or another treating physician.

Dopo aver abbandonato lo studio, per esempio progressione della malattia o ritiro del consenso, il paziente avrà qaccesso, senza alcuna restrizione, alle più apprpriate terapie e tecniche diagnostiche a discrezione dello sperimentatore o di un altro medico.

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

2012-11-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-30

P. End of Trial
P.	End of Trial Status	Completed

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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