Clinical Trials Register

Summary
EudraCT Number:	2013-005486-39
Sponsor's Protocol Code Number:	GO29293
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-06-25
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

2013-005486-39

A.3

Full title of the trial

A PHASE II, MULTICENTER, SINGLE-ARM STUDY OF MPDL3280A IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC UROTHELIAL
BLADDER CANCER

ESTUDIO FASE II, MULTICÉNTRICO, DE UN UNICO BRAZO DE TRATAMIENTO, CON MPDL3280A EN PACIENTES CON CARCINOMA UROTELIAL DE VEJIGA LOCALMENTE AVANZADO O METASTÁSICO

A.3.1

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

A study of MDPL3280A in patients with advanced bladder cancer.

Estudio de MDPL3280A en pacientes con cancer de vejiga avanzado

A.4.1

Sponsor's protocol code number

GO29293

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	Roche Farma, S.A. en nombre de F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann La Roche Ltd
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	F. Hoffmann La Roche Ltd
B.5.2	Functional name of contact point	Trial Infor. Line-TISL (Marta M.)
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+34 913257300
B.5.6	E-mail	global.rochegenentechtrials@roche.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	MPDL3280A-RO5541267-F-03
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	-
D.3.9.1	CAS number	-
D.3.9.2	Current sponsor code	MPDL3280A
D.3.9.3	Other descriptive name	RO5541267
D.3.9.4	EV Substance Code	SUB126162
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	60
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

Bladder cancer

Cancer de Vejiga

E.1.1.1

Medical condition in easily understood language

Bladder cancer

Cancer de Vejiga

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluated the efficacy of MPDL3280A in patients with locally advanced or metastatic urothelial bladder cancer as measured by independent review facility assessed ORR using RECIST v1.1 and investigator assess ORR according to modified RECIST

Evaluar la eficacia de MPDL3280A en pacientes con CUV localmente avanzado o metastásico, que se determinará por un centro de revisión independiente basándose en Índice de respuesta objetiva (IRO) según RECIST v1.1 y el IRO evaluado por el investigador de acuerdo con los criterios RECIST modificados

E.2.2

Secondary objectives of the trial

To evaluate PFS, DOR by RECIST v1.1 as assessed by independent review; to evaluate PFS and DOR according to modified RECIST as assessed by investigators; to evaluate ORR, DOR, and PFS according to RECIST v1.1 as assessed by the investigator; to evaluate OS and 1-year OS; to characterize the safety and tolerability of MPDL3280A; to characterize the pharmacokinetics of MPDL3280A; and to evaluate the incidence and tiers of anti-therapeutic antibodies against MPDL3280A

Evaluar la SLP y la duración de la respuesta (DR), determinadas por el CRI de acuerdo con los criterios RECIST v1.1
Evaluar la SLP y la DR, determinadas por el investigador de acuerdo con los criterios RECIST modificados
Evaluar el IRO, la DR y la SLP, determinados por el investigador de acuerdo con los criterios RECIST v1.1
Evaluar la SG y la SG a 1 año
Evaluar la seguridad y la tolerancia de MPDL3280A
Definir la farmacocinética de MPDL3280A
Evaluar la incidencia y los títulos de ATA contra MPDL3280A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

?Ability to comply with protocol
?Age > 18 years
?Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, urethra)
?Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to have sufficient viable tumor content prior to study enrollment; tumor specimens will be evaluated for PD-L1 expression; patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with Medical Monitor.
?Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Patients with ECOG 2 are allowed in Cohort 1.
?Life expectancy > 12 weeks
?Measurable disease, as defined by RECIST v1.1
Previously irradiated lesions should not be counted as target lesions.
?Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
?For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 6 months after the last dose of MPDL3280A.

Cohort 1-Specific Inclusion Criteria
?No prior chemotherapy for inoperable locally advanced or metastatic or recurrent UBC
?Ineligible (?unfit?) for cisplatin-based chemotherapy as defined by any one of the following criteria:
Impaired renal function (glomerular filtration rate [GFR] > 30 but < 60 mL/min). GFR should be assessed by direct measurement (i.e., creatinine clearance or ethyldediaminetetra-acetate) or, if not available, by calculation from serum/plasma creatinine (Cockcroft-Gault formula) A hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies Grade 2 or greater peripheral neuropathy (i.e., sensory alteration or parasthesis including tingling)
ECOG performance score of 2
Cohort 2-Specific Inclusion Criteria
?Disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin [GC], methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC], CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence

-Capacidad para cumplir con los requisitos del protocolo
-Edad >= 18 años
-Carcinoma de células transicionales del urotelio (incluyendo pelvis renal, uréter, vejiga urinaria, uretra) localmente avanzado o metastásico documentado histológica o citológicamente
-Disponibilidad de muestras de tumor representativas fijadas en formalina e incluidas en parafina (FFPE), preparadas en bloques de parafina (opción preferida), o un mínimo de 15 secciones no teñidas, junto con el correspondiente informe de histopatología, para el análisis en el laboratorio central, y que se determine tener suficiente tejido tumoral viable antes de la inclusión en el estudio; las muestras tumorales serán evaluadas para la expresión de PD-L1; los pacientes en los que se disponga de menos de 15 (pero no menos de 10) secciones no teñidas en el período basal pueden ser elegibles, tras considerarlo con el monitor médico.
-Estado funcional ECOG 0 o 1. Está permitida la inclusión de pacientes con estado funcional ECOG 2 en la cohorte 1.
-Esperanza de vida>=12 semanas
-Enfermedad medible, definida de acuerdo con los criterios RECIST v1.1. Las lesiones irradiadas previamente no se considerarán lesiones diana
-Función hematológica y de órganos diana adecuada, definida por los resultados de laboratorio siguientes obtenidos en los 14 días previos a la administración de la primera dosis del tratamiento del estudio
-Las mujeres potencialmente fértiles y los varones con pareja potencialmente fértil deben comprometerse a utilizar (por su parte y/o la de su pareja) uno o varios métodos anticonceptivos altamente eficaces (es decir, aquellos que tienen una tasa de fallos baja [< 1% al año] cuando se utilizan de manera constante y correcta) y a continuar usándolos hasta 6 meses después de recibir la última dosis de MPDL3280A
Criterios de inclusión específicos para la cohorte 1:
-Pacientes no tratados previamente con quimioterapia para CUV localmente avanzado o metastásico inoperable o recurrente
-Pacientes no elegibles (es decir, ?no aptos?) para recibir quimioterapia basada en cisplatino, que se definen como aquellos que cumplen cualquiera de los criterios siguientes: Función renal alterada (GFR >30, pero < 60 ml/min). La GFR se debe medir con un método directo (es decir, aclaramiento de creatinina o etilendiaminotetraacetato) o, si no fuese posible, mediante el cálculo de creatinina sérica/plasmática (fórmula de Cockcroft- Gault) Pérdida auditiva (medida en audiometría) de 25 dB en dos frecuencias contiguas. Neuropatía periférica de grado ? 2 (es decir, alteración sensorial o parestesia incluyendo hormigueo). Estado funcional ECOG 2
Criterios de inclusión específicos para la cohorte 2:
-Progresión de la enfermedad durante o después de un tratamiento con al menos un régimen basado en platino (p. ej. GC, MVAC, CarboGem, etc.) para carcinoma urotelial localmente avanzado o metastásico inoperable o para la recurrencia de la enfermedad

E.4

Principal exclusion criteria

Cancer Specific Exclusion Criteria
?Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment; the following exceptions are allowed:
?Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
?Active or untreated central nervous system (CNS) metastases as determined by CT or MRI evaluation during screening and prior radiographic assessments
?Leptomeningeal disease
?Uncontrolled tumor-related pain
?Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
?Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
?Malignancies other than UBC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
General Medical Exclusion Criteria
?Pregnant and lactating women
?History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
?Known hypersensitivity to Chinese hamster ovary cell products or any component of the MPDL3280A formulation
?History of autoimmune disease
?History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
?Serum albumin <2.5 g/dL
?Positive test for HIV
Medication-Related Exclusion Criteria:
?Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
?Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
?Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial

Criterios de exclusión específicos del cáncer
-Administración de cualquier tratamiento anticanceroso aprobado, incluyendo quimioterapia u hormonoterapia, en las 3 semanas previas al inicio del tratamiento del estudio.
-Tratamiento con cualquier otro agente en investigación o participación en otro ensayo clínico con intención terapéutica en los 28 días previos a la inclusión en el estudio.
-Metástasis del sistema nervioso central (SNC) activas o no tratadas, evidenciadas en la evaluación con TAC o RM realizada durante el período de selección y en estudios radiográficos previos.
-Enfermedad leptomeníngea.
-Dolor relacionado con el tumor, no controlado.
-Derrame pleural, pericárdico o ascitis no controlados que requieran drenaje repetido (una vez al mes o con más frecuencia.
-Hipercalcemia no controlada o hipercalcemia sintomática que requiera la administración continuada de bisfosfonatos o denosumab.
-Neoplasias malignas distintas de CUV en los 5 años previos al día 1 del ciclo 1, exceptuando aquellas que tengan un riesgo insignificante de metástasis o muerte, que sean tratadas con intención curativa
Criterios de exclusión médicos generales:
- Mujeres embarazadas y en período de lactancia
-Antecedentes de reacciones alérgicas severas, anafilácticas u otras reacciones de hipersensibilidad a anticuerpos quiméricos o humanizados o a proteínas de fusión
-Hipersensibilidad documentada a productos elaborados con células de ovario de hámster chino o a cualquier excipiente de la formulación de MPDL3280A
-Antecedentes de enfermedades autoinmunes
- Antecedentes de fibrosis pulmonar idiopática, neumonía organizada (p. ej. bronquiolitis obliterante), neumonitis inducida por fármacos, neumonitis idiopática o evidencia de neumonitis activa en el TAC de tórax realizado en el período de selección
-Albúmina sérica< 2,5 g/dl
- Resultado positivo en la prueba del VIH
Criterios de exclusión relacionados con las medicaciones
? Tratamiento previo con agonistas de CD137 o inhibidores de puntos de control inmunitarios.
? Tratamiento sistémico con agentes inmunoestimuladores en las 6 semanas previas al día 1 del ciclo 1 o durante cinco semividas del fármaco, dependiendo de lo que sea más corto
-Pacientes que estén recibiendo tratamiento sistémico con corticosteroides u otros inmunosupresores en las 2 semanas previas al día 1 del ciclo 1 o que previsiblemente requerirán tratamiento sistémico con inmunosupresores durante el estudio

E.5 End points

E.5.1

Primary end point(s)

IRF-assessed ORR according to RECIST v1.1 and investigator-assessed ORR according to modified RECIST criteria

Respuesta objetiva (RO) evaluada por el CRI de acuerdo con los criterios RECIST v1.1
RO evaluada por el investigador de acuerdo con los criterios RECIST modificados

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluated radiographically every 9 weeks following C1D1 for 1 year, then every 12 weeks. Analysis will be performed approximately 6 months after the last patient is enrolled into the study.

Evaluación radiografica cada 9 semanas desde C1D1 durante el primer año, y cada 12 semanas a partir del primer año. Se realizarán análisis a los 6 meses de la inclusión del último paciente del estudio.

E.5.2

Secondary end point(s)

DOR and PFS assessed by the IRF and investigator assessed per RECIST v1.1, OS, and 1-year OS; DOR and PFS per modified RECIST

Evaluar la SLP y la duración de la respuesta (DR), determinadas por el CRI e investigador de acuerdo con los criterios RECIST v1.1; DR y SLP de acuerdo a criterios RECIST modificados.

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluated radiographically every 9 weeks following C1D1 for 1 year, then every 12 weeks. Analysis will be performed approximately 6 months after the last patient is enrolled into the study.

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

Yes

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

immune- and bladder specific biomarkers predictive for response; PD-L1 IHC.

Biomarcadores predictivos de respuesta relacionados con la inmunidad y vejiga; Inmunohistoquimica PD-L1.

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.8.2.4

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

Canada

France

Germany

Italy

Netherlands

Spain

United Kingdom

United States

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

The end of study is defined as the date of the last follow-up visit of the last patient
enrolled and is expected to occur approximately 12 months after the last patient enrolls in the study.

El final del estudio se define como la fecha del último seguimiento del último paciente incluido y se espera que ocurra aproximadamente 12 meses despues del último paciente incluido en el 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

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:

265

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

106

F.4.2.2

In the whole clinical trial

330

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)

Patients with stable disease or better at the end of the initial treatment period will discontinue treatment with MPDL3280A but will continue follow-up for up to 2 years and may re-initiate single-agent MPDL3280A therapy if they experience disease progression, with approval from the Medical Monitor.

Pacientes con enfermedad estable o mejoria al final del periodo de tratamiento inicial discontinuarán tratamiento con MPDL3280A pero continuarán con seguimiento hasta 2 años y pueden reiniciar terapia con MPDL3280A como agente único, con la aprobación del monitor médico si experimentan progresión de la enfermedad.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-07-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-07

P. End of Trial
P.	End of Trial Status	Completed

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