Clinical Trials Register

Summary
EudraCT Number:	2016-002689-30
Sponsor's Protocol Code Number:	MedOPP107
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-01-04
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

Spain - AEMPS

A.2

EudraCT number

2016-002689-30

A.3

Full title of the trial

Multicenter open-label, phase II trial, to evaluate the efficacy and safety of nal-IRI for progressing brain metastases in patients with HER2-negative breast cancer

Ensayo fase II, abierto y multicéntrico para evaluar la eficacia y
seguridad de nal-IRI en pacientes con cáncer de mama HER2
negativo con metástasis cerebrales en progresión

A.3.1

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

Trial, to evaluate the efficacy and safety of nal-IRI for progressing brain metastases in patients with HER2-negative breast cancer

Ensayo para evaluar la eficacia y seguridad de nal-IRI en pacientes con cáncer de mama HER2 negativo con metástasis cerebrales en progresión

A.3.2

Name or abbreviated title of the trial where available

PHENOMENAL

A.4.1

Sponsor's protocol code number

MedOPP107

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	Medica Scientia Innovation Research (MedSIR ARO)
B.1.3.4	Country	Spain
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	Baxalta GmbH
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	Medica Scientia Innovation Research (MedSIR ARO)
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Rambla de Cataluña, 2
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08007
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034932214135000
B.5.5	Fax number	0034932992382000
B.5.6	E-mail	cristina.masferrer@medsir.org

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	ONIVYDE
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxalta Innovations GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Concentrate 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	irinotecan hydrochloride trihydrate (salt in a pegylated liposomal formulation)
D.3.9.3	Other descriptive name	IRINOTECAN HYDROCHLORIDE TRIHYDRATE
D.3.9.4	EV Substance Code	SUB45873
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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

Progressing brain metastases in patients with HER2-negative breast cancer.

Pacientes con cáncer de mama HER2 negativo con metástasis cerebrales medibles y en progresión.

E.1.1.1

Medical condition in easily understood language

Progressing brain metastases in patients with breast cancer

Pacientes con cáncer de mama con metástasis cerebrales medibles y en progresión.

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
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 assess the efficacy of nal-IRI in patients with HER2-
negative metastatic breast cancer who have documented CNS progression following WBRT, SRS and/or surgery, as determined by the RANO-BM criteria

Evaluar la eficacia de nal-IRI en pacientes con cáncer de mama HER2 negativo metastásico
que presenten progresión en el SNC tras RTH, RCE o cirugía, basándose en los criterios
RANO-BM.

E.2.2

Secondary objectives of the trial

-To determine the rate of CNS disease stabilization on week
12.
-To determine the objective response rate, according to a
volumetric parameter and to RECIST 1.1 criteria.
-Clinical benefit rate (total number of objective responses
plus stable disease lasting at least 12 weeks).
-Safety and tolerability (by CTCAE v4 criteria).
-Median progression-free survival (PFS).
-Median overall survival (OS).

-Determinar la tasa de estabilización de la enfermedad del SNC en la semana 12
según los criterios RECIST v1.1.
-Determinar la tasa de respuesta objetiva según un parámetro volumétrico y los criterios RECIST 1.1.
-Tasa de beneficio clínico (número total de respuestas objetivas más enfermedad estable que dure al menos 24 semanas).
-Seguridad y tolerabilidad (según los criterios CTCAE v4).
-Mediana de la supervivencia libre de progresión (SLP).
-Mediana de la supervivencia global (SG).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Female or male patients > 18 years
2. Patients must have a diagnosis of metastatic breast cancer.
3. Patients should have been pretreated with taxanes at any
time prior to the study enrolment if not formally
contraindicated.
4. At least one prior chemotherapy regimen for advanced
disease.
5. Evidence of new and/or progressive brain metastases
following previous WBRT and/or SRS and/or surgery.
6. At least one brain lesion needed to be measurable (≥10 mm
on T1-weighted, gadolinium-enhanced magnetic resonance
imaging).
7. HER2 negative breast cancer defined as 0 - 1+ by
immunohistochemistry or FISH negative result.
8. ECOG performance status <2.
9. Life expectancy >12 weeks.
10. Patients must have sufficient organ and marrow function as
defined below:
a. Hematopoietic parameters:
i. Absolute neutrophil count ≥ 1,5 x 109/L
ii. Platelets ≥ 100 x 109/L
iii. Haemoglobin ≥ 9 mg/dL
b. Hepatic parameters:i. Total bilirubin ≤ 1.5 mg/dL
ii. AST (SGOT)/ALT (SGPT) ≤ 2.5 X
institutional upper limit of normal
c. Renal parameters:
i. Creatinine ≤ 1.5 X institutional upper limits of
normal, OR
ii. Creatinine clearance ≥ 60 mL/min/1.73 m2 for
pts w/ creatinine levels > institutional normal.
11. Participants of childbearing potential must agree to use
adequate contraception prior to study entry and for the
duration of study participation as well as a negative serum
pregnancy test within 7 days of study enrolment.
12. Ability to understand and the willingness to sign a written
informed consent.

1. Pacientes de ambos sexos > 18 años de edad.
2. Pacientes con un diagnóstico de cáncer de mama metastásico.
3. Pacientes que hayan recibido tratamiento previo con taxanos en algún momento antes de la inclusión en el estudio, si no están formalmente contraindicados.
4. Al menos una pauta previa de quimioterapia para enfermedad avanzada
5. Evidencia de metástasis cerebrales nuevas o progresivas tras RTH, RCE o cirugía.
6. Al menos una lesión cerebral debe ser medible (≥10 mm en resonancia magnética potenciada en T1 con gadolinio).
7. Cáncer de mama HER2 negativo definido como 0 - 1+ mediante inmunohistoquímica o resultado negativo en FISH.
8. Estado funcional ECOG < 2.
9. Esperanza de vida > 12 semanas.
10. Pacientes con una función orgánica y medular suficiente tal como se define a continuación:
a. Parámetros hematopoyéticos:
• Recuento absoluto de neutrófilos ≥ 1.5 x 109/l
• Plaquetas ≥ 100 x 109/l
• Hemoglobina ≥ 9 mg/dl
b. Parámetros hepáticos:
• Bilirrubina total ≤ 1,5 mg/dl
• AST (SGOT)/ALT (SGPT) ≤ 2,5 x límite superior de normalidad
del centro
c. Parámetros renales:
• Creatinina ≤ 1,5 x límite superior de normalidad del centro O
• Aclaramiento de creatinina ≥ 60 ml/min/1,73 m2 para pacientes con niveles de creatinina > valor normal del centro
11. Los participantes en edad fértil deben aceptar utilizar un método anticonceptivo adecuado antes de entrar en el estudio y durante su participación en el mismo, así como presentar un resultado negativo en la prueba de embarazo en suero durante
los 7 días anteriores a su inclusión en el estudio.
12. Pacientes que sean capaces de comprender y deseen firmar un consentimiento informado escrito.

E.4

Principal exclusion criteria

1. Patients must not have previously received nal-IRI or
any other form of irinotecan, conventional or liposomal.
2. Patients who have received prior anti-cancer treatment
with chemotherapy, endocrine therapy, immunotherapy
or radiotherapy within 3 weeks (6 weeks for nitrosoureas
or mitomycin-C) prior to starting study treatment.
3. Radiation therapy encompassing more than 30% of
bone marrow.
4. Significant chronic gastrointestinal disorder with diarrhea
as a major symptom (i.e Crohn’s disease, ulcerative
colitis, malabsorption, or grade ≥ 2 diarrhea of any
etiology at baseline)
5. Have a serious concomitant systemic disorder (e.g.
active infection including HIV, or cardiac disease)
incompatible with the study (at the discretion of
investigator), previous history of bleeding diathesis, or
treatment with Sintrom.
6. Patients who have symptomatic lymphangitis, dyspnoea
at rest or meningeal carcinomatosis. (Patients with
asymptomatic involvement may be enrolled in the study.)
7. Patients must be recovered from any clinically relevant
toxic effects of any prior surgery, radiotherapy or other
therapy intended for the treatment of breast cancer. For
peripheral neuropathy, up to CTCAE (v4.0) Grade 2 is
acceptable for patients with pre-existing condition.
8. Patients may not be receiving any other investigational
or anticancer agents while on the study.
9. History of other malignancies, which could affect
compliance with the protocol or interpretation of the
results. Patients with malignancies diagnosed more than
5 years prior to study day 1, adequately treated
carcinoma in situ of the cervix or basal or squamous cell
skin are generally eligible.
10. Pregnant or lactating women.
11. NYHA Class III or IV congestive heart failure, ventricular
arrhythmias or uncontrolled blood pressure. Or known
abnormal ECG with clinically significant abnormal
findings.
12. Active infection or an unexplained fever >38.5°C
(excluding tumoral fever), which in the physician’s
opinion might compromise the patient’s health.
13. Patients with other significant disease or disorders that,
in the Investigator's opinion, would exclude the patient
from the study.
14. Current use or any use in the last two weeks of strong
CYP3A-enzyme inducers/inhibitors and/or strong
UGT1A inhibitors
15. Known hypersensitivity to any of the components of
nanoliposomal irinotecan (nal-IRI) other liposomal
irinotecan formulations or irinotecan.

1. Pacientes que no hayan recibido previamente nal-IRI u otra forma de irinotecán, convencional o liposomal.
2. Pacientes que hayan recibido tratamiento previo contra el cáncer con quimioterapia, terapia endocrina, inmunoterapia o radioterapia durante las 3 semanas anteriores (6 semanas de nitrosoureas o mitomicina C) antes del inicio del tratamiento del estudio.
3. Radioterapia en más del 30% de la médula ósea.
4. Trastorno gastrointestinal crónico significativo con diarrea como síntoma principal (es decir, enfermedad de Crohn, colitis ulcerosa, mala absorción o diarrea de cualquier etiología de grado ≥ 2 en la basal).
5. Trastorno sistémico concomitante grave (p. ej., infección activa, incluido VIH, o enfermedad cardíaca) incompatible con el estudio (según el criterio del investigador), antecedentes de diátesis hemorrágica o tratamiento con Sintrom.
6. Pacientes con linfangitis sintomática, disnea de reposo o carcinomatosis meníngea. (En el estudio pueden incluirse pacientes con afectación asintomática).
7. Los pacientes deben haberse recuperado de cualquier efecto tóxico clínicamente relevante de cualquier cirugía previa, radioterapia u otra terapia para el tratamiento del cáncer de mama. En el caso de neuropatía periférica, se acepta hasta un grado
2 de los CTCAE (v4.0) en los pacientes con enfermedad previa.
8. Los pacientes no pueden recibir ningún otro fármaco anticancerígeno o en investigación mientras participen en el estudio.
9. Antecedentes de otros tumores malignos que podrían afectar al cumplimiento del protocolo o a la interpretación de los resultados. Los pacientes con tumores malignos diagnosticados más de 5 años antes del día 1 del estudio, carcinoma de cérvix estadio 0, carcinoma basal o carcinoma de células escamosas de la piel
adecuadamente tratados, suelen ser elegibles.
10. Mujeres embarazadas o en periodo de lactancia.
11. Insuficiencia cardíaca congestiva de clase III o IV de la NYHA, arritmias ventriculares o presión arterial no controlada. O ECG conocido con resultados anómalos clínicamente significativos.
12. Infección activa o fiebre de origen desconocido > 38,5 ºC (excepto fiebre tumoral) que pueda comprometer la salud del paciente según el criterio del médico.
13. Pacientes con otra enfermedad o trastorno significativos según el criterio del investigador podría excluir al paciente del estudio.
14. Uso actual o cualquier uso de inductores/inhibidores potentes de la enzima CYP3A o inhibidores potentes de UGT1A durante las dos últimas semanas.

E.5 End points

E.5.1

Primary end point(s)

Central Nervous System Overall Response Rate (ORR) per the RANO-BM criteria.

Tasa de respuesta global del sistema nervioso central (TRG del SNC) según los criterios
RANO-BM.

E.5.1.1

Timepoint(s) of evaluation of this end point

Complete response (CR) will be defined as the disappearance of all CNS target lesions sustained for at least 4 weeks; no new lesions, no corticosteroids; stable or improved clinically.
We will describe number and proportion of patients with CNS overall response in first stage and total sample. We will estimate the proportion of responders with the 95% Pearson-Clopper confidence intervals. We will estimate the uniformly minimum
variance unbiased estimator (UMVUE), p-value and 95% confidence interval

La respuesta completa se definirá como la desaparición de todas las lesiones del SNC mantenidas durante al menos 4 semanas; sin lesiones nuevas, sin corticosteroides; estable o mejorado clínicamente.
Describiremos el número y la proporción de pacientes con respuesta global del SNC en la primera
Etapa y en la muestra total. Vamos a estimar la proporción de respondedores con intervalos de confianza de Pearson-Clopper al 95%. Vamos a estimar el Estimador Insesgado de Varianza Uniformemente Mínima (UMVUE), el p valor e intervalo de confianza al 95%

E.5.2

Secondary end point(s)

CNS CBR at 12w
ORR
Clinical Benefit Rate (CBR)
Safety
Median progression-free survival (PFS)
Median overall survival (OS)

TBC del SNC en la semana 12
TRG
TBC
Seguridad
Mediana de la SLP
Mediana de la SG

E.5.2.1

Timepoint(s) of evaluation of this end point

Within 12 weeks.

A las 12 semanas

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

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

EoS is defined as the Last Patient Last Visit (LPLV) at the end of the follow-up period.
This will be the last data collection point, which can be a clinic visit or a laboratory sample. EoS will occur at 12 months after the last patient has been included into the study, unless premature termination of the study.

El fin del estudio se define como la última visita del último paciente (LPLV) al final del período de seguimiento.
Este será el último punto de recogida de datos, que puede ser una visita clínica o una muestra de laboratorio. El fin del estudio ocurrirá 12 meses después de que el último paciente haya sido incluido en el estudio, a menos que se de una terminación prematura del estudio.

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

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

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.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

Ninguno

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

2017-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-10

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

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