Clinical Trials Register

Summary
EudraCT Number:	2010-023602-12
Sponsor's Protocol Code Number:	CRO-2010-48
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:	2011-12-16
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

2010-023602-12

A.3

Full title of the trial

A FEASIBILITY STUDY EVALUATING THE EFFICACY AND SAFETY OF SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR (HCC) CARCINOMA AND HIV INFECTION TREATED WITH HAART REGIMENS

Studio di fattibilita' che valuta l'efficacia e la tolleranza del Sorafenib (NEXAVAR) associato alla terapia antiretrovirale altamente efficace (HAART) nei pazienti con infezione da HIV ed epatocarcinoma avanzato.

A.3.2

Name or abbreviated title of the trial where available

sorafenib-HAART

A.4.1

Sponsor's protocol code number

CRO-2010-48

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	CENTRO DI RIFERIMENTO ONCOLOGICO DI AVIANO
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	NEXAVAR*112CPR RIV 200MG
D.2.1.1.2	Name of the Marketing Authorisation holder	BAYER 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	Film-coated tablet
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.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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	Yes
D.3.11.13.1	Other medicinal product type	terapia a bersaglio molecolare
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	TELZIR*1FL 60CPR RIV 700MG
D.2.1.1.2	Name of the Marketing Authorisation holder	VIIV HEALTHCARE Srl
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	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	Fosamprenavir
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	700
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	Yes
D.3.11.13.1	Other medicinal product type	Terapia antivirale
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	Yes
D.2.1.1.1	Trade name	NORVIR*FL 84CPS MOLLI 100MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ABBOTT Srl
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	Capsule, soft
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	Ritonavir
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	100
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	Yes
D.3.11.13.1	Other medicinal product type	antivirale

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

HIV-positive patients with advanced HCC

Pazienti HIV positivi con epatocarcinoma avanzato

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	10036706
E.1.2	Term	Primary liver cancer non-resectable
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	LLT
E.1.2	Classification code	10008919
E.1.2	Term	Chronic HIV infection
E.1.2	System Organ Class	10021881 - Infections and infestations

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

To assess the efficacy and safety of sorafenib in HCC patients with HIV receiving PI-based HAART regimens.

Lo studio valuta la fattibilita' e l'efficacia della combinazione del sorafenib con un'HAART a base di IP, nei pazienti con infezione da HIV ed HCC in stadio avanzato di malattia.

E.2.2

Secondary objectives of the trial

To assess:
STEP A and STEP B:
• Overall Survival
• OS rate at 6 months
• Evaluation of Response Rate (RR)
• Evaluation of impact on HIV infection (HIV-RNA viral load, CD4-CD8 counts)
• Evaluation of Quality of life (FACT-Hep)
• Evaluation of the role of innate immunity (receptors of NK and TNK cells) and adaptive immunity (interferon-class I and immuno-complexes) in relationship to clinical response and HCV viral load in HCV co-infected patients.
• Evaluation of serum proteomic profile and 2D-DIGE approaches in relationship to drug toxicity and clinical response

Individuare:
• Sopravvivenza globale
• Tasso di Sopravvivenza a 6 mesi
• Impatto sull’infezione da HIV
• Qualita' di vita con il questionario FACT-Hep
• Ruolo dell'immunita' innata ( recettori NK e cellule Natural Killer,NK) e adattiva (Interferon e immunocomplessi) in pazienti con coinfezione HIV-HCV e correlazione con la viremia di HCV.
• Valutazione proteomica su siero e tessuto (2D-DIGE) in relazione alla risposta clinica e alla tossicita'.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. HIV infection serologically proven
2. HCC cytologically/histologically proven or diagnosed according to AASLD guidelines for whom invasive treatment modalities (resection, loco-regional therapies) are not indicated (57).
3. Child–Pugh score A and B7
4. Age ≥ 18 years
5. ECOG Performance Status ≤ 2
6. Life expectancy of at least 12 weeks
7. Presence at least of one measurable lesion according to mRECIST criteria (95). Lesions must be measured by CT-scan or MRI.
8. CD4 counts > 100 cells/µL and HIV viral load < 50 copies/mL
9. Adequate bone marrow, liver and renal function as assessed by the following laboratory measurements, to be conducted within 7 days prior to screening:

1. Diagnosi sierologica di infezione da HIV
2. Diagnosi citologica/istologica di HCC o diagnosi non invasiva in accordo alle linee guida AASLD
3. Child–Pugh score A and B7
4. Eta' ≥ 18 anni
5. ECOG Performance Status ≤ 2
6. Spettanza di vita di almeno 3 mesi
7. Presenza di almeno una lesione misurabile sec. i criteri RECIST modificati. Le lesioni devono essere misurate con la TAC o l'RNM
8. Conta dei CD4> 100/µL e viremia HIV< 50 cp/mL
9. Adeguata riserva funzionale d'organo, valutata entro 7 giorni dall'arruolamento:

E.4

Principal exclusion criteria

1. History of cardiac disease: congestive heart failure >NYHA class 2; active CAD (MI more than 6 months prior to study entry is allowed); cardiac arrythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension
2. Active clinically serious infections (> grade 2 NCI-CTC version 4.0)
3. Active AIDS-defining infections within the last 6 months or other active AIDS-defining diseases (according to CDC Classification system for HIV infection) including patients with Kaposi sarcoma
4. Patients with CD4 counts < 100 cells/ µL and/or HIV infection that has full drug resistance to any class
5. NNRTI-based HAART or Atazanavir or Tipranavir PI-based HAART
6. Hepatic encephalopathy ≥ CTC G2
7. Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry)
8. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
9. History of organ allograft or autologous transplant
10. Patients with evidence or history of bleeding diathesis
11. Patients with clinically significant GI bleeding within 30 days prior to study entry
12. Renal failure requiring dialysis
13. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry.

1. Presenza di una cardiomiopatia: scompenso cardiaco >NYHA classe 2; cardiopatia ischemica attiva (IMA entro 6 mesi); aritmie che richiedono terapia( ad esclusione dei beta-bloccanti e digossina) o ipertensione non controllata dalla terapia.
2. Infezioni in fase attiva (> grado 2della scala NCI-CTC versione 4.0
3. Infezioni opportunistiche diagnostiche per AIDS nei 6 mesi precedenti o assenza di altre patologie diagnostiche per AIDS, incluso il KS,
4. Conta dei CD4 < 100 cells/ µL e/o refrattarieta' all'HAART
5. Regimi HAART contenenti NNRTIs o atazanavir o tipranavir
6. Encefalopatia epatica di grado > 2
7. Metastasi cerebrali e/o infiltrazione meningea non controllate dalla terapia.
8. Presenza di sindrome vertiginosa che richiede una terapia con antiepilettici o steroidi.
9. Pregresso trapianto
10. Diatesi allergica
11. Emorragie gastriche entro 30 giorni dall'arruolamento
12. Insufficienza renale trattata con dialisi
13. Tumori sincroni o metacroni, ad eccezione del Tis cervice, carcinomi basocelluare della cute, carcinomi vescicali non invasivi o qualsiasi neoplasia trattata >3 anni prima dell'arruolamento.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is Time to Progression (TTP). TTP will be evaluated according to mRECIST criteria(95) in all patients treated in Step A and Step B.

L'efficacia verra' valutata con il parametro del Tempo di Progressione( "Time To Progression",TTP) calcolato in base ai criteri RECIST modificati. L'analisi comprendera' sia i pazienti della fase A che quelli della fase B.

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)

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

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.8.2.4

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	38
F.4.2	For a multinational trial
F.4.2.1	In the EEA	38
F.4.2.2	In the whole clinical trial	38

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

2011-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-02-24

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

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