Clinical Trials Register

Summary
EudraCT Number:	2014-003924-34
Sponsor's Protocol Code Number:	GETNE-1407
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:	2014-12-22
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

2014-003924-34

A.3

Full title of the trial

A phase II trial to assess the activity and safety of Palbociclib in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET).

Estudio fase II para evaluar la actividad y seguridad de palbociclib en pacientes con tumores neuroendocrinos pancreáticos bien o moderadamente diferenciados (pNET) con enfermedad avanzada

A.3.1

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

A phase II trial to assess the activity and safety of Palbociclib in patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET).

Estudio fase II para evaluar la actividad y seguridad de palbociclib en pacientes con tumores neuroendocrinos pancreáticos bien o moderadamente diferenciados (pNET) con enfermedad avanzada

A.4.1

Sponsor's protocol code number

GETNE-1407

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	Grupo Español de Tumores Neuroendocrinos (GETNE)
B.1.3.4	Country	Spain
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	Pfizer, S.L.U.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TFS
B.5.2	Functional name of contact point	Yolanda Martín
B.5.3	Address:
B.5.3.1	Street Address	Avda. Europa, 20B
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	20108
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3491490 9690
B.5.5	Fax number	+3491490 9721
B.5.6	E-mail	yolanda.martin@tfscro.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	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	Palbociclib
D.3.2	Product code	PD0332991
D.3.4	Pharmaceutical form	Capsule
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	NA
D.3.9.1	CAS number	571190-30-2
D.3.9.2	Current sponsor code	PD-0332991
D.3.9.3	Other descriptive name	PALBOCICLIB
D.3.9.4	EV Substance Code	SUB130860
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	125
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

Patients with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors

Pacientes con un tumor neuroendocrino pancreático metastásico bien o moderadamente diferenciado

E.1.1.1

Medical condition in easily understood language

pancreatic neuroendocrine tumors

Tumores Neuroendocrinos de origen pancreático

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10068916
E.1.2	Term	Pancreatic neuroendocrine tumor metastatic
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	17.1
E.1.2	Level	PT
E.1.2	Classification code	10068909
E.1.2	Term	Pancreatic neuroendocrine tumour metastatic
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

?Objective Response rate (ORR)

Tasa de respuesta objetiva

E.2.2

Secondary objectives of the trial

?Progression Free Survival (PFS)
?Time to Tumor Progression (TTP)
?Duration of response (DR)
Overall survival (OS)
?Safety
?Biomarkers

-Supervivencia libre de progresión
-Tiempo hasta la progresión del tumor
-Duración de la respuesta
-Supervivencia global
-Seguridad del tratamiento con palbociclib
-Valor pronóstico/predictivo de biomarcadores inmunohistoquímicos de ciclo celular

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically or cytologically proven diagnosis of pancreatic neuroendocrine tumors (pNET) with Ki67 assessment of < or = 20% (well and moderately differentiated) with evidence of unresectable disease or metastatic disease. Locally advanced disease must not be amendable to resection or radiation therapy with curative intent.
2. Overexpression of Cdk4 and/or phospho-Rb1 and/or cyclin D1 in tumor tissue sample from tumor biopsy or prior primary tumor resection (Molecular study will be conducted at CNIO and logistic is described later). Therefore availability of paraffin-embedding tumor tissue sample is needed.
3. Documented progression of the disease by CT scan, MRI, or Octreoscan within 12 months prior to baseline.
4. Previous treatments with chemotherapy, antiangiogenics, or interferon are permitted providing that toxicity has resolved to < grade 1 at study entry and that last treatment was at least 4 weeks prior to baseline assessment. Patients may be treated with somatostatin analogues during the trial. Concomitant interferon treatment is not permitted.
5. Measurable disease as per RECIST. Measurable lesions that have been previously radiated will not be considered target lesions unless increase in size has been observed following completion of radiation therapy.
6. Able to swallow oral compound
7. Male or female, 18 years of age or older.
8. ECOG performance status less than 2.
9. Life expectancy greater than 12 weeks.
10. The definitions of minimum adequacy for organ function required prior to study entry are as follows. In addition, safety precautions provided in the product labeling for the anticipated control arm chemotherapy must be observed.
? Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ?2.5 x upper limit of normal (ULN), or AST and ALT ?5 x ULN if liver function abnormalities are due to underlying malignancy
? Total serum bilirubin ?1.5 x ULN
? Serum albumin ?3.0 g/dL
? Absolute neutrophil count (ANC) ?1500/?L
? Platelets ?100,000/?L
? Hemoglobin ?9.0 g/dL
? Creatinin clearance < 40 mL/min
11. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

1. Edad ? 18 años capaces de otorgar su consentimiento informado.
2. Estado funcional ECOG (Eastern Cooperative Oncology Group) ? 2
3. Tumores neuroendocrinos pancreáticos (pNET) diagnosticado histológicamente o histológicamente con un Ki67 ? 20% (tumores bien o moderadamente diferenciados).
4. Evidencia de enfermedad irresecable o metastásica. Si se trata de una enfermedad localmente avanzada, no será susceptible de resección quirúrgica o tratamiento radioterápico con intento curativo.
5. Progresión tumoral documentada por TC, RM u Octreoscán en los 12 meses previos a la visita basal.
6. El tratamiento previo con quimioterapia, antiangiogénicos o interferón será permitido en caso de que la toxicidad se haya resuelto hasta un grado ? 1 en el momento de la inclusión en el estudio y deberán haber transcurrido al menos 4 semanas desde su última administración.
7. Los pacientes podrán recibir tratamiento concomitante con análogos de somatostatina si el investigador lo considera apropiado. No se permitirá el tratamiento concomitante con interferón.
8. Enfermedad medible por criterios RECIST 1.1. Las lesiones medibles que hayan sido previamente radiadas no serán consideradas como lesiones diana a no ser que el incremento de tamaño se haya observado tras la finalización de dicho tratamiento.
9. El paciente deberá ser capaz de ingerir la medicación vía oral.
10. Esperanza de vida superior a 12 semanas.
11. Se requieren los siguientes valores analíticos de una adecuada función orgánica y de la médula ósea.
? Aspartato aminotransferasa (AST) y Alanina aminotransferasa (ALT) ?2.5 veces por el límite superior de la normalidad (LSN), o AST y ALT ?5 x LSN si la alteración en la función hepática es secundaria a una enfermedad tumoral subyacente.
? Bilirrubina sérica total ?1.5 x LSN
? Albúmina sérica ?3.0 g/dL
? Recuento absoluto de neutrófilos ?1500/µL.
? Plaquetas ? 100 000/µL
? Hemoglobina ? 5,6 mmol/L (9 g/dL)
? Aclaramiento de creatinina > 40 mL/min (Fórmula Cockroft and Gault)
12. Consentimiento informado con fecha y firma indicando que el paciente (o el representante aceptado legalmente) ha sido informado sobre todos los aspectos pertenecientes al estudio previamente a su inclusión.
13. El paciente deberá ser capaz de cumplir con las visitas requeridas por el estudio, el tratamiento, los análisis de laboratorio y otros procedimientos del estudio.

E.4

Principal exclusion criteria

1. Prior chemotherapy regimen or biological treatment for locally advanced or metastatic transitional cell carcinoma of the urinary tract.
2. Prior treatment on Cdk4 inhibitor under clinical trial.
3. Creatinine clearance < 40 ml/min using Cockroft and Gault formula.
4. Major surgery, radiation therapy, or systemic therapy within 3 weeks of study randomization except palliative radiotherapy to non-target metastatic lesions.
5. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
6. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term oral glucocorticoids taken concurrently or within last 3 months prior to randomization
7. Prior radiation therapy to >25% of the bone marrow.
8. Current treatment on another clinical trial.
9. Uncontrolled brain metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. Patients should have completed surgery or radiation therapy for existing brain metastases, should not have documented increase in size over the previous 3 months prior to first dose of treatment on study and should be asymptomatic.
10. Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
11. Any of the following within the 12 months prior to starting study treatment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, cerebrovascular accident including transient ischemic attack, or pulmonary embolus.
12. Ongoing cardiac dysrhythmias of NCI CTCAE grade ?2, atrial fibrillation of any grade, or QTc interval >450 msec for males or >470 msec for females.
13. Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy)
14. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO daily for deep vein thrombosis prophylaxis is allowed).
15. Known human immunodeficiency virus infection.
16. Pregnancy or breastfeeding. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to randomization.
17. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

1. Tratamiento previo con un inhibidor de Cdk4 bajo ensayo clínico.
2. Cirugía mayor, radioterapia o tratamiento sistémico en las 3 semanas previas a la inclusión en el estudio, excepto en el caso del tratamiento radioterápico paliativo sobre lesiones metastásicas no diana.
3. Tratamiento previo con quimioterapia a altas dosis que haya requerido soporte hematopoyético de rescate.
4. Tratamiento inmunosupresor como ciclosporina, tacrolimus, azatioprina o tratamiento prolongado con corticoides administrados de forma concomitante o en los 3 meses previos a la inclusión en el estudio.
5. Tratamiento, dentro de los 7 días previos a la inclusión en el estudio de fármacos inhibidores o inductores potentes conocidos de CYP3A4 o que prolongan el intervalo QT.
6. Tratamiento radioterápico previo sobre >25% de la médula ósea.
7. Tratamiento dentro de otro ensayo clínico concomitante.
8. Presencia de enfermedad metastásica cerebral no controlada, compresión medular, carcinomatosis meníngea o enfermedad leptomeníngea. Los pacientes deberán haber completado la cirugía o radioterapia para las lesiones cerebrales preexistentes, sin documentarse un incremento en el tamaño de las mismas en los tres meses previos a la primera dosis del tratamiento del estudio y deben ser asintomáticas.
9. Diagnóstico de una segunda neoplasia en los últimos 3 años, excepto tumores cutáneos escamosos o basaliomas adecuadamente tratados o carcinomas in situ de cérvix o de vejiga.
10. Enfermedad cardio/cerebrovascular clínicamente significativa en los 12 meses previos al inicio del tratamiento, que incluye:
? Infarto de miocardio
? Angina severa/inestable
? Implantación de bypass en arteria periférica o coronaria
? Insuficiencia cardiaca congestiva clase III o IV de la New York Heart Association (NYHA) o pacientes con historia de insuficiencia cardiaca congestiva clase III o IV de la NYHA, a no ser que un ecocardiograma o MUGA en los 3 meses previos a la selección muestre una fracción de eyección del ventrículo izquierdo ?45 %.
? Accidente cerebrovascular que incluya accidente isquémico transitorio.
? Tromboembolismo pulmonar.
11. Arritmias cardíacas (NCI CTCAE versión 4.0 grado ?2), fibrilación auricular de cualquier grado o intervalo QTc >450 mseg para varones o >470 mseg para mujeres.
12. Hipertensión mal controlada a pesar del tratamiento óptimo (>150/100 mmHg)
13. Tratamiento actual con acenicumarol a dosis terapéuticas (se permitirá la administración de bajas dosis de acenocumarol hasta 2mg/24h para profilaxis de trombosis venosa profunda).
14. Infección conocida del virus de la inmunodeficiencia humana (VIH).
15. Embarazo o lactancia. Todas aquellas mujeres en edad fértil deberán presentar un test de embarazo negativo (sangre u orina) de forma previa a la inclusión en el estudio.
16. Cualquier enfermedad (médica o psiquiátrica) o motivo que, en opinión del investigador, interfiera con la capacidad del paciente para participar en el ensayo clínico, colocando al paciente en una situación de riesgo excesivo o complicando la interpretación de los datos de seguridad y siendo inapropiado para la inclusión en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Objective Response rate (ORR)

Tasa de respuesta objetiva

E.5.1.1

Timepoint(s) of evaluation of this end point

Progression disease

Progresión de la enfermedad

E.5.2

Secondary end point(s)

?Progression Free Survival (PFS)
?Time to Tumor Progression (TTP)
?Duration of response (DR)
Overall survival (OS)
?Safety
?Biomarkers

E.5.2.1

Timepoint(s) of evaluation of this end point

Progression disease

Progresión de la enfermedad

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

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

Yes

E.6.13.1

Other scope of the trial description

Biomarkers

Biomarcadores

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

Treatment on study will continue until disease progression is documented according to the RECIST or it is in the best interest of the patient to discontinue as judged by the investigator (decisions may be based on achievement of maximum benefit or tolerability issues).

El tratamiento con palbociclib se continuará hasta la progresión de la enfermedad, toxicidad inaceptable, incumplimiento del protocolo, retirada del consentimiento informado por parte del paciente o por decisión del investigador.

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

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. Clinical practice.

Ninguna. Práctica clínica habitual

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

2015-02-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-12

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

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IMP with orphan designation in the indication
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