Clinical Trials Register

Summary
EudraCT Number:	2012-004018-33
Sponsor's Protocol Code Number:	PH-F16IL2TAXO-03/12
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-02-04
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

Spain - AEMPS

A.2

EudraCT number

2012-004018-33

A.3

Full title of the trial

A Phase II study of the tumour-targeting human F16IL2 monoclonal antibody-cytokine fusion protein in combination with paclitaxel versus paclitaxel alone in patients with Merkel cell carcinoma.

Estudio de Fase II del anticuerpo monoclonal fusionado a citoquina, F16IL2, específico de tumor en combinación con paclitaxel comparado con paclitaxel solo, en pacientes con carcinoma celular de Merkel

A.3.1

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

A Phase II study of the tumour-targeting human F16IL2 monoclonal antibody-cytokine fusion protein in combination with paclitaxel versus paclitaxel alone in patients with Merkel cell carcinoma.

A.3.2

Name or abbreviated title of the trial where available

F16IL2 plus paclitaxel in metastatic Merkel cell carcinoma

A.4.1

Sponsor's protocol code number

PH-F16IL2TAXO-03/12

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	Philogen S.p.A.
B.1.3.4	Country	Italy
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	Immomec FP7 call HEALTH 2011.2.4.1.-1
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Philogen S.p.A.
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Località Bellaria n. 35
B.5.3.2	Town/ city	Sovicille
B.5.3.3	Post code	53018
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039057717816
B.5.5	Fax number	003905771781690
B.5.6	E-mail	regulatory@philogen.com

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	Paclitaxel
D.2.1.1.2	Name of the Marketing Authorisation holder	Hospira UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Paclitaxel
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.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	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	Interleukin-2 fused to the F16 single chain Fv antibody
D.3.2	Product code	F16IL2
D.3.4	Pharmaceutical form	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	teleukin
D.3.9.2	Current sponsor code	F16IL2
D.3.9.3	Other descriptive name	F16IL2
D.3.9.4	EV Substance Code	SUB29009
D.3.10	Strength
D.3.10.1	Concentration unit	million IU million international units
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	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Merkel cell carcinoma

Carcinoma celular de Merkel

E.1.1.1

Medical condition in easily understood language

Merkel cell carcinoma (primary small cell carcinoma of the skin)

Carcinoma celular de Merkel

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	10064025
E.1.2	Term	Merkel cell carcinoma
E.1.2	System Organ Class	100000004864

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 compare the efficacy of F16IL2 in combination with paclitaxel vs. paclitaxel monotherapy, in terms of overall survival rate at 12 months after beginning of study treatments, in patients with metastatic Merkel cell carcinoma, who are not amenable to surgery.

Therapieansprechen von F16IL2 in Kombination mit Paclitaxel im Vergleich mit Alleingabe von Paclitaxel, in Hinsicht auf Gesamtüberlebenszeitrate 12 Monate nache Beginn der Studienbehandlungen bei Patienten mit nicht operierbarem Merkelzellkarzinom.

E.2.2

Secondary objectives of the trial

To investigate safety and tolerability of the combination treatment of F16IL2 and paclitaxel. To investigate the treatment efficacy in terms of response to treatment measured as ORR and DCR.

Bestimmung von Sicherheit und Verträglichkeit von F16IL2 in Kombination mit Paclitaxel. Bestimmung der Objektiven Ansprechrate (ORR) und Krankheits Kontrollrate (DCR).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

?Patients with advanced or metastatic Merkel cell carcinoma (MCC) not amenable to surgery and who have not received previous systemic therapy with taxanes; diagnosis of MCC must be histologically confirmed (evaluation of primary lesions or advanced disease) and endorsed by the IMMOMEC central dermatopathology center (central review of diagnosis at the Department of General Dermatology, Medical University of Graz). Patients must be amenable for paclitaxel treatment according to the discretion of the principal investigator;
? Patients aged >/= 18 ? 75 years;
? ECOG performance status ? 1;
? Patients must have measurable disease including cutaneous and subcutaneous metastases as defined by RECIST v.1.1 criteria or immune related response Criteria (irRC) as assessed by CT or MRI and/or ultrasound within 4 weeks before the first study drug administration.
? All acute side effects from any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ? 1;.
? Adequate hematologic, liver and renal function:
o Absolute neutrophil count (ANC) ? 1.5 x 10^9/L, platelets ? 100 x 10^9/L, haemoglobin (Hb) ? 9.0 g/dl
o Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate aminotransferase ? 3 x upper limit of reference range (ULN), and total bilirubin ? 2.0 mg/gL unless liver involvement by the tumor, in which case the transaminase levels could be ? 5 x ULN
o Creatinine ? 1.5 ULN or 24 h creatinine clearance ? 50 mL/min
? Negative serum pregnancy test for females of childbearing potential within 14 days of starting treatment;
? If of childbearing potential, agreement to use adequate contraceptive methods (e.g., oral contraceptives, condoms, or other adequate barrier controls, intrauterine contraceptive devices, or sterilization) beginning at the screening visit and continuing until 3 months following last treatment with study drug;
? Evidence of a personally signed and dated EC-approved Informed Consent form indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the study;
? Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

1) Pacientes con carcinoma avanzado o metastásico de células de Merkel (MCC), no susceptible de cirugía y que no han recibido terapia sistémica previa con taxanos, el diagnóstico de MCC debe ser confirmado histológicamente (evaluación de las lesiones primarias o enfermedad avanzada) y aprobado por el centro dermatopatología centrol IMMOMEC (revisión central de diagnóstico en el Departamento de Dermatología de la Universidad, Medicina de Graz). Los pacientes deben ser susceptibles de tratamiento con paclitaxel de acuerdo a la discreción ción del investigador principal. 2) Los pacientes de edad ? 18 ? 75 años. 3) Estado general de ECOG ? 1. 4) Los pacientes deben tener enfermedad medible incluyendo metástasis cutánea y subcutánea según la definición de criterios RECIST v.1.1 o los criterios de respuesta inmune relacionados (RICR) según la evaluación de CT o MRI y / o ecografía dentro de las 4 semanas antes de la primera droga en estudio administración. 5) Todos los efectos secundarios agudos de cualquier tratamiento previo debe haber sido resuelto con Criterios de Terminología Común para Eventos Adversos (CT CAE) del National Cancer Institute (NCI) (v4.03) Grado ? 1. 6) Adecuada funcion hematológica, del hígado y renal. 7) Recuento asbosluto de neutrofilos (ANC) ) ? 1.5 x 109/L, plaquetas ? 100 x 109/L, hemoglobina (Hb) ? 9.0 g/dl. 8) La fosfatasa alcalina (AP), alanina aminotransferasa (ALT) y / o aspartato aminotransferasa ? 3 veces el límite superior del rango de referencia (LSN) y bilirrubina total ? 2,0 mg / gL a menos que la afectación hepática por el tumor, en cuyo caso los niveles de transaminasas podría ser ? 5 x LSN. 9) La creatinina ? 1,5 LSN o aclaramiento en 24 h de creatinina ? 50 ml / min. 10) Resultado negativo en la prueba serica de embarazo en las mujeres en edad fértil dentro de los 14 días de iniciar el tratamiento. 11) Si potencialmente fértil, acuendo en utilizar métodos anticonceptivos adecuados (por ejemplo, anticonceptivos orales, preservativos, u otros controles de barrera adecuados, dispositivos anticonceptivos intrauterinos o esterilización) a partir de la visita de selección y continuando hasta 3 meses después del último tratamiento con el medicamento del estudio. 11)La evidencia de un formulario, aprobado por el CE, de consentimiento firmado y fechado personalmente que indica que el paciente (o representante legalmente aceptable) ha sido informado de todos los aspectos pertinentes del estudio. 12) Disposición y capacidad para cumplir con las visitas programadas, plan de tratamiento, pruebas de laboratorio y otros procedimientos de estudio.

E.4

Principal exclusion criteria

? Life expectancy of less than 3 months;
? Any previous taxanes therapy;
? Previous or concurrent CLL patients;
? Any other malignancy from which the patient has been disease-free for less than 2 years prior to study entry, with the exception of adequately treated and cured cervical carcinoma in situ, basal or squamous cell carcinoma, superficial bladder cancer, or in situ melanoma;
? Presence of uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study;
? Presence of known brain metastases;
? Chronic-active hepatitis B, C, or HIV;
? Severe cardiovascular disease:
o History of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris;
o Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria);
o Irreversible cardiac arrhythmias requiring permanent medication;
o LVEF </= 50% and/or abnormalities observed during baseline 2D-ECHO or 12-lead ECG investigations;
o Uncontrolled hypertension;
o Ischemic peripheral vascular disease (Grade IIb-IV);
? Severe rheumatoid arthritis; or other uncontrolled autoimmune disease;
? Severe diabetic retinopathy;
? History of allograft or stem cell transplantation;
? Major trauma including major surgery (e.g. visceral surgery) within 4 weeks of administration of study treatment;
? Known history of allergy to IL-2, taxanes, cremophor or other intravenously administered human proteins/peptides/antibodies;
? Pregnancy or breast-feeding. Female patient must agree to use effective contraception, or be surgically sterile or postmenopausal. The definition of effective contraception will be based on the European guideline ICH M3 rev 2.
? Treatment with an investigational study drug within four weeks before beginning of treatment with F16IL2;
? Previous treatment with monoclonal antibodies for biological therapy in the four weeks before administration of study treatment;
? Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.

1) La esperanza de vida es menorde 3 meses. 2) Cualquier terapia anterior con taxanos. 3) Pacientes con CLL anterior o simultáoas. 4) Cualquier otro cáncer del que el paciente ha estado libre de enfermedad por menos de 2 años antes de la entrada en el estudio, con la excepción de carcinoma cervical en el carcinoma de células in situ, basales o escamosas, cáncer de vejiga superficial, o melanoma in situ adecuadamente tratado y curado. 5) Presencia de infecciones no controladas u otra enfermedad grave concomitante, que, en la opinión del investigador, ponen al paciente en riesgo indebido o puedeb interferir con el estudio. 6) La presencia de metástasis cerebrales conocidas. 7) Hepatitis B, C o VIH crónico o activo. 8) Enfermedad cardiovascular grave. 9) Historia de síndromes coronarios agudos o subagudos, incluyendo infarto de miocardio, inestable angina de pecho estable o severa. 10) Insuficiencia cardiaca (> Grado II, New York Heart Association (NYHA)). 11) Arritmias cardíacas irreversibles que requieren medicación permanente. 12) FEVI <50% y / o anomalías observadas durante la línea base eco-2D ó 12 derivaciones de ECG investigaciones. 13) Hipertensión no controlada. 14) Enfermedad vascular periférica isquémica (Grado IIb-IV). 15) Artritis reumatoide severa, u otra enfermedad autoinmune fuera de control. 16) Retinopatía diabética severa. 17) Historia del trasplante de células madre o aloinjerto. 18) Trauma más importantes, incluyendo una cirugía mayor (cirugía visceral, por ejemplo) dentro de las 4 semanas de la administración del tratamiento del estudio. 19) Historia conocida de alergia a IL-2, taxanos, cremophor u otros administrados por vía intravenosa proteínas humanas / péptidos / anticuerpos. 20) Embarazo o lactancia. Paciente de sexo femenino deben ponerse de acuerdo para utilizar un método anticonceptivo eficaz, o por e quirúrgicamente estéril o postmenopáusicas. La definición de la anticoncepción eficaz se basa en la directriz ICH Europea M3 rev 2. 21) El tratamiento con un fármaco de estudio de investigación dentro de cuatro semanas antes de iniciar el tratamiento con F16IL2. 22) El tratamiento previo con anticuerpos monoclonales para terapia biológica en las cuatro semanas antes de la administración del tratamiento del estudio. 23) Todas las condiciones que, en opinión del investigador podría dificultar el cumplimiento del protocolo de estudio.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is overall survival rate at 12 months.

El punto primario del estudio es la tasa de supervivencia global a 12 meses.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months.

12 meses

E.5.2

Secondary end point(s)

The secondary endpoints of this study are (1) safety and tolerability assessment of the combination treatment of F16IL2 and paclitaxel in terms of adverse events, clinical laboratory evaluations, vital signs and physical examinations(2) treatment efficacy evaluation in terms of response to treatment measured as ORR and DCR.

Los puntos secundarios del estudio son: 1) comprobacion de la seguridad y tolerabilidad del tratamiento de combinacion de F16IL2 y paclitaxel en terminos de eventos adversos, evaluaciones clinicas de laboratorio, signos vitales y examenes fisicos, 2) evualuacion de la eficacia del tratamiento en terminos de respuesta al tratamiento medidoc como ORR y DCR.

E.5.2.1

Timepoint(s) of evaluation of this end point

(1) 24 weeks
(2) 12 months

(1) 24 semanas
(2) 12 meses

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

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

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

LPLV

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.1.1.1

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

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

Information not present in EudraCT

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

F.4.2.2

In the whole clinical trial

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Immomec FP7 call HEALTH 2011.2.4.1-1
G.4.3.4	Network Country	Austria

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-07-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-25

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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