Clinical Trials Register

Summary
EudraCT Number:	2016-001256-22
Sponsor's Protocol Code Number:	GL0817-01
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:	2016-08-30
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

2016-001256-22

A.3

Full title of the trial

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Determine the Safety and Efficacy of GL-0817 (with Cyclophosphamide) for the Prevention of Recurrence in HLA-A2+ Patients with High-Risk Squamous Cell Carcinoma of the Oral Cavity

Ensayo clínico en fase II, aleatorizado, doble ciego, controlado con placebo, para determinar la seguridad y la eficacia de GL-0817 (con ciclofosfamida) para la prevención de recidiva en pacientes con HLA-A2+ con carcinoma de células escamosas de alto riesgo de la cavidad oral

A.3.1

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

A clinical study to test the safety and efficacy of study drug GL-0817 in patients with High-Risk Squamous Cell Carcinoma of the Oral Cavity

Un estudio clínico para comprobar la seguridad y la eficacia del fármaco en estudio GL-0817 en pacientes con carcinoma de células escamosas de alto riesgo de la cavidad oral

A.4.1

Sponsor's protocol code number

GL0817-01

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	Gliknik Inc
B.1.3.4	Country	United States
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	Gliknik Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gliknik Inc
B.5.2	Functional name of contact point	Clinical Development
B.5.3	Address:
B.5.3.1	Street Address	801 W. Baltimore St. Suite 501A
B.5.3.2	Town/ city	Baltimore, Maryland
B.5.3.3	Post code	21201
B.5.3.4	Country	United States
B.5.4	Telephone number	+34656577065
B.5.6	E-mail	jherpst@gliknik.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.3.2	Product code	GL-0817
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not assigned yet
D.3.9.2	Current sponsor code	GL-0817
D.3.9.3	Other descriptive name	GL-0817
D.3.9.4	EV Substance Code	SUB183949
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	1.5
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.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	Leukine
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Sargramostim
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SARGRAMOSTIM
D.3.9.1	CAS number	123774-72-1
D.3.9.2	Current sponsor code	Leukine
D.3.9.3	Other descriptive name	Recombinant human granulocyte macrophage colony stimulating factor(yeast) rhGM-CSF
D.3.9.4	EV Substance Code	SUB10450MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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	Yes
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: 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	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	Hiltonol
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular 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	59789-29-6
D.3.9.2	Current sponsor code	Poly ICLC
D.3.9.3	Other descriptive name	POLYINOSINIC POLYCYTIDYLIC ACID, POLY-L-LYSINE,CARBOXYMETHYLCELLULOSE
D.3.9.4	EV Substance Code	SUB179613
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	2
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: 4
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	Endoxan
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Romania
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	cyclophosphamide
D.3.4	Pharmaceutical form	Powder for solution for injection/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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50-18-0
D.3.9.4	EV Substance Code	SUB06859MIG
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	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	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Intramuscular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention of Recurrence in HLA-A2+ Patients with High-Risk Squamous Cell Carcinoma of the Oral Cavity

Prevención de recidiva en pacientes con HLA-A2 + con alto riesgo de carcinoma de células escamosas de la cavidad oral

E.1.1.1

Medical condition in easily understood language

Prevention of reappearance of cancer in patients with High-Risk Squamous Cell Carcinoma of the Oral Cavity

Prevención de reaparición de cáncer en pacientes con alto riesgo de carcinoma de células escamosas de la cavidad oral

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	HLT
E.1.2	Classification code	10026660
E.1.2	Term	Malignant oral cavity neoplasms
E.1.2	System Organ Class	100000004856

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 compare the disease-free interval of all randomized subjects in the primary analysis population by treatment arm in an intent-to-treat analysis at 2 years following randomization.

Comparar el intervalo sin enfermedad de todos los sujetos aleatorizados en la población de análisis principal por grupo de tratamiento en un análisis por intención de tratar a los 2 años de la aleatorización.

E.2.2

Secondary objectives of the trial

- Compare disease-free survival (DFS), overall survival (OS)
- Compare disease-free interval in a per protocol analysis
- Safety assessment

- Comparar la supervivencia sin enfermedad (SSE), la supervivencia global (SG)
- Comparar el intervalo sin enfermedad en un análisis por protocolo
- Análisis de la seguridad

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age >= 18 years
2. Histologic diagnosis of squamous cell carcinoma of the oral cavity
3. Patients must have undergone primary gross total resection (no re-resected patients are allowed) with fulfillment of at least 1 of the following histologic criteria for high-risk disease:
• Histologic involvement of 2 or more regional lymph nodes
• Any lymph node with histologic extracapsular extension (ECS)
• Close (<3mm) or positive surgical margins on microscopic evaluation with no gross residual tumor
4. No evidence of locoregional disease or distant metastases at screening. Subjects must have negative scans (CT, CT-PET or MRI) for locoregional recurrence, brain or lung metastases. A negative biopsy will be mandated in patients with a positive scan. Other evaluations should be performed as clinically indicated.
5. No history of distant metastases.
6. Tumor tissue from surgery or biopsy must be available to determine MAGE-A3 expression for correlative studies.
7. Following surgery, the patient must have received external beam radiotherapy (58-66 Gy in 2 Gy fractions, 5 days per week) with concomitant cisplatin starting within 8 weeks of surgery. The cumulative dose of cisplatin the subject received must be >= 150 mg/m2. Protocol therapy must be initiated within a period of 4-8 weeks (28-56 days) following the end of RT.
8. The patient is, in the investigator’s opinion, adequately recovered from the effects of surgery and chemoradiotherapy to participate in this study.
9. Blood HLA-A2 phenotype
10. ECOG Performance Status =< 1
11. Laboratory values obtained =< 14 days prior to randomization:
• Absolute neutrophil count (ANC) >= 1500/μL (without intervention, e.g., G-CSF)
• Platelets >= 75,000/μL (without intervention, e.g., transfusion)
• Hemoglobin >= 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb >=8.0 g/dl is acceptable).
• Alkaline phosphatase =< 2.5 x upper limit of normal (ULN)
• AST and ALT =< 2 x ULN
• Creatinine < 2 x ULN
• Bilirubin < 1.5x ULN (except for patients with Gilbert’s disease, for whom the upper acceptable limit of serum bilirubin is 3mg/dL)
12. A female subject is eligible to enter the study if she is:
• not pregnant or nursing; Female participants must not breastfeed during the study and for a period of 30 days following the last dose.
• of non-childbearing potential (i.e., women who had a hysterectomy, are postmenopausal which is defined as 1 year without menses, have both ovaries surgically removed or have current documented tubal ligation); or
• of childbearing potential (i.e., women with functional ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhea [even severe], women who are perimenopausal or have just begun to menstruate. These women must have a negative serum pregnancy test at screening, and agree to one of the following:
− complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent and 6 months after the last dose of study agent; or
− consistent and correct use of 1 of the following highly effective methods of birth control for one month prior to the start of the study agent and 6 months after the last dose:
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
• progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
• intrauterine device (IUD)
• intrauterine hormone-releasing system ( IUS)
• bilateral tubal occlusion
• vasectomized partner (if vasectomized is the sole sexual partner and has received medical confirmation of surgical success)
13. A male subject who is sexually active with a woman of childbearing potential is eligible to enter the study if he agrees to use effective contraception throughout the study and for 6 months after the last dose of study agent.
14. The subject must be capable of understanding the investigational nature, potential risks and benefits of the study and capable of providing valid informed consent. The subject must provide study specific informed consent prior to any protocol procedures that are not a part of standard care, including consent for assessment of HLA-A2 status, mandatory tissue submission for MAGE-A3 analysis and correlative studies.
15. The subject must be willing to return to the study center for vaccinations and study-related follow up procedures including blood and tumor collections and completion of imaging studies as required by the protocol.

1. Edad >= 18 años
2. Diagnóstico histológico de carcinoma de células escamosas de la cavidad oral
3. Los pacientes deberán haberse sometido a resección total primaria (no están permitidos pacientes resecados de nuevo) con cumplimiento de al menos 1 de los siguientes criterios histológicos de enfermedad de alto riesgo:
- Afectación histológica de 2 o más ganglios linfáticos regionales
- Cualquier ganglio linfático con extensión histológica extracapsular (ECS)
- Márgenes quirúrgicos próximos (< 3 mm) o positivos a la evaluación microscópica sin tumor residual macroscópico
4. Sin signos de enfermedad locorregional o metástasis a distancia en la selección. Los sujetos deberán tener resultados negativos en las imágenes (TAC, PET-TAC o IRM) para recidiva locorregional, metástasis cerebral o pulmonar. Será obligatoria una biopsia negativa para los pacientes con una exploración positiva. Se realizarán otras evaluaciones según esté médicamente indicado.
5. Sin antecedentes de metástasis a distancia.
6. El tejido tumoral procedente de la cirugía o biopsia deberá estar disponible para determinar la expresión de MAGE-A3 para estudios correlativos.
7. Después de la cirugía, el paciente deberá haber recibido radioterapia de rayos externos (58-66 Gy en 2 Gy fracciones, 5 días a la semana) con cisplatino concomitante comenzando en las 8 semanas siguientes a la cirugía. La dosis acumulativa de cisplatino que recibió el sujeto deberá ser >= 150 mg/m2. El tratamiento del protocolo deberá iniciarse dentro de un período de 4-8 semanas (28-56 días) después de finalizar la RT.
8. El paciente, a criterio del investigador, se ha recuperado adecuadamente de los efectos de la cirugía y la quimioterapia para participar en este estudio.
9. Fenotipo HLA-A2 en sangre
10. Estado funcional ECOG =< 1
11. Valores de laboratorio obtenidos =< 14 días antes de la aleatorización:
- Recuento absoluto de neutrófilos (RAN) >= 1500/μL (sin intervención, por ej., de G-CSF)
- Plaquetas >= 75.000/μL (sin intervención, por ej., de transfusión)
- Hemoglobina >= 8,0 g/dl (Nota: El uso de transfusión u otra intervención para lograr Hgb >=8,0 g/dl es aceptable).
- Fosfatasa alcalina =< 2,5 x límite superior de la normalidad (LSN)
- AST y /ALT =< 2 x LSN
- Creatinina < 2 x LSN
- Bilirrubina < 1,5x LSN (excepto para los pacientes con la enfermedad de Gilbert, para los que el límite superior aceptable de la bilirrubina en suero es 3 mg/dL)
12. Una mujer es elegible para entrar en el estudio si:
• no está embarazada o en período de lactancia. Las mujeres participantes no deberán amamantar a sus hijos durante el estudio ni durante un período de 30 días después de la última dosis.
• no tiene capacidad reproductiva; o
• con capacidad reproductiva. Esta categoría incluye a las mujeres con oligomenorrea [incluso grave], mujeres perimenopáusicas o que acaben de empezar a menstruar. Estas mujeres deberán tener un resultado negativo en el test de embarazo en suero en la selección y aceptar cumplir uno de los siguientes puntos:
− abstinencia completa del coito desde 2 semanas antes de la administración de la 1.ª dosis de fármaco del estudio y 6 meses después de la última dosis de fármaco del estudio; o
− uso correcto y sistemático de uno de los siguientes métodos anticonceptivos altamente eficaces durante un mes antes del inicio del fármaco del estudio y 6 meses después de la última dosis:
• anticoncepción hormonal combinada (estrógenos y progestágenos) asociada con inhibición de la ovulación (oral, intravaginal, transdérmica)
• anticoncepción hormonal a base de progestágenos asociada con inhibición de la ovulación (oral, inyectable, implantable)
• dispositivo intrauterino (DIU)
• sistema intrauterino de liberación hormonal (SIU)
• oclusión tubárica bilateral
• pareja vasectomizada (si la pareja vasectomizada es el único compañero sexual y ha recibido confirmación médica del éxito quirúrgico)
13. Un sujeto varón sexualmente activo con una mujer con capacidad reproductiva es elegible para entrar en el estudio si acepta el uso de métodos anticonceptivos eficaces durante todo el estudio y durante 6 meses después de la última dosis de fármaco del estudio.
14. El sujeto deberá ser capaz de entender la naturaleza investigacional, los posibles riesgos y beneficios del estudio y ser capaz de facilitar un consentimiento informado válido. El sujeto deberá facilitar un consentimiento informado específico del estudio antes de cualquier procedimiento del protocolo que no forme parte de la atención habitual, incluido el consentimiento para la evaluación del estado de HLA-A2, la aportación obligatoria de tejido para análisis de MAGE-A3 y estudios correlativos.
15. El sujeto deberá regresar voluntariamente al centro de investigación para someterse a vacunaciones y procedimientos de seguimiento relacionados con el estudio, incluidas las obtenciones de sangre y tumores y la compleción de estudios de imagen según lo requiera el protocolo.

E.4

Principal exclusion criteria

1. Known HIV or hepatitis B/C infection (testing not required). Subjects who are hepatitis C antibody positive may be enrolled if they are confirmed to have a negative viral load at screening.
2. Subjects with active autoimmune disease or a history of autoimmune disease requiring systemic steroids or other immunosuppressive treatment.
3. Subjects who have used systemic corticosteroids or other immunosuppressants for any condition within 14 days of randomization. Inhaled or topical steroids are permitted.
4. Any medical condition which would, in the investigator’s opinion, compromise the patient’s ability to mount an immune response, renders the patient a poor candidate for this trial or could confound the results of the study
5. Major surgery or traumatic injury within 28 days of randomization
6. Prior splenectomy or organ allograft
7. Any other prior, concurrent or planned chemotherapy, immunotherapy, radiotherapy, device, or investigational therapy for this cancer other than those specified in this study.
8. History of other malignancy (i.e., excluding disease under study) within 3 years of randomization. Exceptions include: adequately-treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix or breast, or adequately treated non-metastatic prostate cancer.
9. Known hypersensitivity to GM-CSF, yeast-derived products or any component of the GM-CSF drug product (e.g., mannitol) or poly-ICLC (e.g., carboxymethylcellulose).

1. Infección conocida por VIH o hepatitis B o C (no es necesario análisis). Los sujetos que son positivos a los anticuerpos a la hepatitis C pueden ser incluidos si se confirma que poseen una carga viral negativa en la selección.
2. Los sujetos con enfermedad autoinmune activa o antecedentes de enfermedad autoinmune que requiera esteroides sistémicos u otro tratamiento inmunosupresor.
3. Sujetos que hayan utilizado corticosteroides sistémicos u otros inmunosupresores para cualquier enfermedad en los 14 días previos a la aleatorización. Están permitidos los esteroides tópicos o inhalados.
4. Cualquier enfermedad que, a criterio del investigador, comprometa la capacidad del paciente para soportar una respuesta inmunitaria, implica que el paciente es un mal candidato para este ensayo o podría confundir los resultados del estudio
5. Cirugía mayor o lesión traumática en los 28 días previos a la aleatorización
6. Esplenectomía previa o aloinjerto de órgano
7. Cualquier otra quimioterapia, inmunoterapia, radioterapia, dispositivo o tratamiento en investigación previo, concurrente o programado para este cáncer distinto de los especificados en este estudio.
8. Antecedentes de otra neoplasia (es decir, salvo la enfermedad en estudio) en los 3 años siguientes a la aleatorización. Las excepciones comprenden: cáncer de células escamosas o de células basales adecuadamente tratado, carcinoma in situ de cervix o de mama, o cáncer de próstata no metastásico adecuadamente tratado.
9. Hipersensibilidad conocida a GM-CSF, productos derivados de las levaduras o a cualquier componente del medicamento GM-CSF (por ej. manitol) o poly-ICLC (por ej. carboxilmetilcelulosa).

E.5 End points

E.5.1

Primary end point(s)

2-year disease-free interval from randomization.

intervalo libre de enfermedad de 2 años desde la aleatorización

E.5.1.1

Timepoint(s) of evaluation of this end point

2 years

2 años

E.5.2

Secondary end point(s)

• Median DFI/DFS
• Disease-free interval and disease-free survival at 3 and 5 years
• Overall survival at 2, 3, and 5 years
• Safety and tolerability
• Humoral or cellular immune responses by the following measures:
− Induction of antigen-specific T cell response
− Induction of pro-inflammatory cytokines
− ELISA detection of peptide-specific antibodies
Key secondary endpoint: 2-years disease-free survival from randomization.

• La mediana de DFI / DFS
• intervalo libre de enfermedad y supervivencia libre de enfermedad a los 3 y 5 años
• La supervivencia global a los 2, 3 y 5 años
• La seguridad y tolerabilidad
• La respuesta inmune humoral o celular según las siguientes medidas:
- La inducción de la respuesta de las células T específicas de antígeno
- La inducción de citoquinas pro-inflamatorias
- Prueba ELISA de detección de anticuerpos específicos del péptido
Criterio principal de valoración secundario: 2 años de supervivencia libre de la enfermedad desde la aleatorización.

E.5.2.1

Timepoint(s) of evaluation of this end point

2,3 and 5 years

2,3 y 5 años

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Czech Republic

Germany

Hungary

Poland

Serbia

Spain

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

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

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:

130

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

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

120

F.4.2.2

In the whole clinical trial

228

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)

Standard care

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

2016-11-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-07

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

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