Clinical Trials Register

Summary
EudraCT Number:	2013-005134-38
Sponsor's Protocol Code Number:	ABRAMYO
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:	2013-12-18
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

2013-005134-38

A.3

Full title of the trial

Phase I-II study of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) in combination with liposomal encapsulated doxorubicin (LDox) in patients with HER2 negative metastatic breast cancer
(ABRAMYO STUDY)

STUDIO DI FASE I-II DI TRATTAMENTO SETTIMANALE DI NAB-PACLITAXEL (nanoparticle albumin-bound-PACLITAXEL) IN COMBINAZIONE CON DOXORUBICINA LIPOSOMIALE (LDox) IN PAZIENTI CON TUMORE DELLA MAMMELLA IN FASE AVANZATA HER2 NEGATIVO
(STUDIO ABRAMYO)

A.3.1

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

PHASE I-II STUDY OF THE ASSOCIATION OF TAXOLO BOUND TO ALBUMNI AND LIPOSOMIAL ANTHRACYCLINE FOR THE TREATMENT OF ADVANCED BREAST CANCER

STUDIO DI FASE I-II CON L'ASSOCIAZIONE DI TAXOLO LEGATO AD ALBUMINA E ANTRACICLINA LIPOSOMIALE PER IL TRATTAMENTO DEL TUMORE DELLA MAMMELLA IN FASE AVANZATA

A.4.1

Sponsor's protocol code number

ABRAMYO

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	ISTITUTI FISIOTERAPICI OSPITALIERI - IRE
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	CELGENE
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	TEVA ITALIA
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	ISTITUTI FISIOTERAPICI OSPITALIERI - IRE
B.5.2	Functional name of contact point	ALESSANDRA FABI
B.5.3	Address:
B.5.3.1	Street Address	VIA ELIO CHIANESI 53
B.5.3.2	Town/ city	ROME
B.5.3.3	Post code	00144
B.5.3.4	Country	Italy
B.5.6	E-mail	fabi@ifo.it

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	MYOCET
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA PHARMA B.V.
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.3.1	Product name	MYOCET
D.3.4	Pharmaceutical form	Powder, dispersion and solvent for concentrate for dispersion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	ABRAXANE
D.2.1.1.2	Name of the Marketing Authorisation holder	CELGENE
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.3.1	Product name	ABRAXANE
D.3.4	Pharmaceutical form	Powder and suspension for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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)	Yes
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

Her2 negative metastatic breast cancer first line

Tumore della mammella metastatico her2 negativo in prima linea

E.1.1.1

Medical condition in easily understood language

Advanced breast cancer

Tumore della mammella 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	16.1
E.1.2	Level	PT
E.1.2	Classification code	10006198
E.1.2	Term	Breast cancer recurrent
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

Phase I: selection of the appropriate dose level for the nab-paclitaxel/LDox combination
Phase II: Treatment efficacy

Fase I: selezione del livello di dose appropriata della combinazione di nab-paclitaxel/LDox.
Fase II: Efficacia del trattamento

E.2.2

Secondary objectives of the trial

Objective tumor response rates [complete response (CR) and partial response (PR)] according to RECIST criteria.
• Duration of Response.
• Failure free survival (FFS) measured from the start of therapy to the date of disease progression, relapse, or disease- or treatment-related death.
• Overall survival (OS) measured from the start of therapy to the death of patient
• Clinical Benefit [CR+PR+stable disease (SD> 6 months)]
• Safety and tolerability
SPARC microenvironment signature (SMS) analysis whenever possible

• tasso di risposta [risposta completa (CR) e risposta parziale (PR)] secondo i criteri RECIST. • durata della risposta. •sopravvivenza libera da fallimento (FFS) misurata dalla inizio della terapia alla data di morte da progressione o legata al trattamento • sopravvivenza globale (OS) misurata dall'inizio della terapia alla morte• beneficio clinico [malattia stabile (SD > 6 mesi) di CR PR] •Tollerabilità
SPARC analisi (quando possible)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically or cytologically confirmed HER-2 negative, newly diagnosed breast cancer
• Metastatic breast cancer with measurable disease (by RECIST criteria)
• Age >18
• PS: 0-2
• No prior chemotherapy for metastatic disease
• ≥12 months since adjuvant paclitaxel and/or anthracyclines therapy
• Patients not candidates for endocrine therapy
• No peripheral neuropathy grade > 1
• No brain metastases or clinically serious concurrent illnesses
• Previous anthracycline (adjuvant setting) maximum dose of doxorubicin 360 mg/mq and epirubicin 480 mg/mq
• Adequate organ function (obtained within 14 days prior to treatment study) as evidenced by:
o Absolute neutrophil count (ANC) 1.5 X 109/L without myeloid growth factor support for 7 days preceding the lab assessment;
o Haemoglobin (Hgb) 9 g/dL (90 g/L); < 9 g/dL (< 90 g/L) is acceptable if hemoglobin is corrected to 9 g/dL (90 g/L) as assessed by the central laboratory by growth factor or transfusion prior to randomization;
o Platelet count 75 X 109/L without blood transfusions for 7 days preceding the lab assessment;
o Bilirubin 1.5 X upper limit of normal (ULN), except for patients with a documented history of Gilbert’’s disease; Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 2.5 X ULN (for patients with liver metastases 5 X ULN);
o Alkaline phosphatase 3 X ULN (for patients with liver metastases, 5 X ULN);
o Serum creatinine 1.5 mg/dL (133 μmol/L) or calculated creatinine clearance 50 mL/min (using Cockcroft-Gault formula);
o Women of childbearing potential (WCBP): negative serum pregnancy test (this test is required of all women unless post-menopausal, defined as 12 consecutive months since last regular menses, or surgically sterile). Women of childbearing potential must agree to use a highly effective methods of birth control (defined as those, alone or in combination, that result in a low failure rate [ie, less than 1% per year] when used consistently and correctly, such as surgical sterilization, an intrauterine device, or two barrier methods [eg, condom or cervical barrier, such as the diaphragm]). In certain countries (if permitted by law), WCBP may agree to complete heterosexual abstinence during the time of participation in this trial. Protections against pregnancy must be continued for at least 8 months after the last dose of study drug
o Bisphosphonate use is allowed.
o Life expectancy > 12 weeks
o Written informed consent

• HER-2 negativo istologicamente o citologicamente confermato,
• nuova diagnosi cancro mammario
• •carcinoma mammario metastatico con malattia misurabile (criteri RECIST )
• • età >18
• • PS: da 0 a 2
• • non precedentemente sottoposti a chemioterapia per la malattia metastatica
• Ptogressione ≥12 mesi dal trattamento adiuvante con paclitaxel e/o terapia con antracicline
• Patients non candidatia terapia antiormonale
• Assenza di neuropatia periferica di grade > 1
•Non metastasi cerebrale o clinicamente gravi malattie concomitanti •precedente con antracicline (adiuvante) massima dose di doxorubicina 360 mg/mq e epirubicina 480 mg/mq •adeguata funzione degli organi (ottenuta entro 14 giorni prima del trattamento studio) come evidenziato da: oAbsolute conta dei neutrofili (ANC) 1,5 X 109/L) senza mieloidi supporto del fattore di crescita per 7 giorni precedenti il laboratorio valutazione; oHaemoglobin (Hgb) 9 g/dL (90 g/L); < 9 g/dL (< 90 g/L) è accettabile se l'emoglobina è corretto a 9 g/dL (90 g/L) come risulta dalla valutazione del laboratorio centrale di fattore di crescita o di trasfusione prima di randomizzazione; Oplatelet contare 75 X 109/L senza trasfusioni di sangue per 7 giorni precedenti il laboratorio valutazione; oBilirubin 1,5 volte il limite superiore della norma (LSN), fatta eccezione per i pazienti con una storia documentata di Gilbert"s malattia; alanina aminotransferasi (ALT). E l'aspartato aminotransferasi (AST) 2,5 X LSN. (per i pazienti con metastasi epatiche 5 X ULN); o Alkaline fosfatasi 3 X ULN (per pazienti con creatinine 1.5 mg/dL (133 μmol/L) o calculated clearance creatinina 50 mL/min ( Cockcroft-Gault formula);
• donne in età fertile: test sierologico negativo (test di gravidanza; questa prova è richiesta a tutte le donne a meno che in fase di post-menopausa, definito come 12 mesi consecutivi dopo l'ultima mestruazione regolare o chirurgicamente sterile). Le donne in età fertile devono accordarsi sull'uso di metodi altamente efficace per il controllo delle nascite.. Protezioni contro la gravidanza deve essere continuato per almeno 8 mesi dopo l'ultima dose del farmaco in studio
• Bisphosphonate.
• Aspettativa di vita > 12 settimane
• Consenso informato scritto

E.4

Principal exclusion criteria

• No previous therapy with nab-paclitaxel and liposomal doxorubicin
• Concomitant use of biologic agents for the treatment of cancer including antibodies (eg, bevacizumab,) or any investigational agent(s).
• Significant known cardiovascular impairment (NYHA CHF > grade 2, unstable angina, myocardial infarction within the previous 6 months prior to randomization, or existing serious cardiac arrhythmia).
• VECF (Ventricular Ejecion Cardiac Fraction)≤ 50%
• Female patients who are pregnant or lactating, who plan to get pregnant, or who have a positive serum pregnancy test prior to randomization.
• Prior malignancy (other than breast cancer) except for non-melanoma skin cancer and carcinoma in situ (of the cervix or bladder), unless diagnosed and definitively treated more than 5 years prior to randomization.
• Severe/uncontrolled intercurrent illness within the previous 28 days prior to randomization.
• Any other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation.
• Patients with psychiatric illness, social situation or geographical situation that would preclude informed consent or limit compliance with study requirements, as determined by the Investigator.

• Nessuna terapia precedente con nab-paclitaxel e doxorubicina liposomiale
• Uso concomitante di agenti biologici per il trattamento del cancro, compresi gli anticorpi (per esempio, il bevacizumab,) o di qualsiasi sperimentazione agent(s).
• Significativa insufficienza cardiovascolare nota (NYHA CHF > grado 2, angina instabile, infarto miocardico nei 6 mesi precedenti prima della randomizzazione, esistenti o grave aritmia cardiaca).
• FEV (Frazione ventricolare cardiaca Ejecion) ≤ 50
• Le pazienti in gravidanza o che allattano, che intendono avere una gravidanza, o che hanno un test di gravidanza + prima della randomizzazione.
• Precedenti neoplasie maligne (diversi dal cancro al seno), ad eccezione di tumore cutaneo non-melanoma e carcinoma in situ (della cervice o vescica), a meno che non diagnosticata e trattata definitivamente più di 5 anni prima della randomizzazione.
• Gravi e incontrollate malattie intercorrenti nei precedenti 28 giorni prima della randomizzazione.
• Altri importanti condizioni morbose che, a giudizio dello sperimentatore, non indicano l’entrata alo studio

E.5 End points

E.5.1

Primary end point(s)

Phase I: grade 3 grade 4 toxicity
Phase II: Progression Free Survival

Fase I: tossicità di grado 3 o di grado 4
Fase II: Sopravvivenza libera da progressione

E.5.1.1

Timepoint(s) of evaluation of this end point

Six months

Sei mesi

E.5.2

Secondary end point(s)

Overall response rate
Overall Survival
Disease control rate

Tasso di risposte compelte e parziali
Sopravvivenza
Tasso di ocntrollo di malattia

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months

12 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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Combination drugs

Combinazione di farmaci

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

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

Ultima visita ultimo 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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

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.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

Nessuna

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

2014-03-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-17

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

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