Clinical Trials Register

Summary
EudraCT Number:	2018-003727-10
Sponsor's Protocol Code Number:	MO40598
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:	2020-01-17
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

2018-003727-10

A.3

Full title of the trial

A PHASE III, OPEN-LABEL, MULTICENTER, RANDOMIZED STUDY EVALUATING THE SAFETY AND EFFICACY OF POLATUZUMAB VEDOTIN IN COMBINATION WITH RITUXIMAB PLUS GEMCITABINE PLUS OXALIPLATIN (R-GEMOX) VERSUS R-GEMOX ALONE IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA

ESTUDIO DE FASE III, ABIERTO, MULTICÉNTRICO Y ALEATORIZADO PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE POLATUZUMAB VEDOTINA EN COMBINACIÓN CON RITUXIMAB MÁS GEMCITABINA MÁS OXALIPLATINO
(R-GEMOX) FRENTE A R-GEMOX EN PACIENTES CON LINFOMA DIFUSO DE CÉLULAS B GRANDES EN RECAÍDA/RESISTENTE

A.3.1

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

A Study Evaluating the Safety and Efficacy of Polatuzumab Vedotin in Combination with Rituximab Plus Gemcitabine Plus Oxaliplatin (R-GemOx) Versus R-GemOx Alone in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Estudio que evalúa la seguridad y eficacia de Polatuzumab Vedotin en combinación con Rituximab Plus Gemcitabine Plus Oxaliplatin (R-GemOx) versus R-GemOx en pacientes con linfoma difuso / refractario difuso linfocitos grandes

A.4.1

Sponsor's protocol code number

MO40598

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. U. que realiza el ensayo en España y que actúa como representante 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 Information Support Line-TISL
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	34913257300
B.5.5	Fax number	34913248195
B.5.6	E-mail	spain.start_up_unit@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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2013
D.3 Description of the IMP
D.3.1	Product name	polatuzumab vedotin
D.3.2	Product code	RO5541077
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	POLATUZUMAB VEDOTIN
D.3.9.2	Current sponsor code	RO5541077
D.3.9.4	EV Substance Code	SUB177827
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	20
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: 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	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	SUB12570MIG
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	10
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	Yes
D.2.1.1.1	Trade name	Gitrabin
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC
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.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.4	EV Substance Code	SUB07892MIG
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	38
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	Oxaliplatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXALIPLATIN
D.3.9.1	CAS number	61825-94-3
D.3.9.4	EV Substance Code	SUB09490MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
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	Oxaliplatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	OXALIPLATIN
D.3.9.1	CAS number	61825-94-3
D.3.9.4	EV Substance Code	SUB09490MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed/refractory diffuse large B-cell lymphoma (DLBL)

Linfoma difuso de células B grandes en recaída/resistente (DLCBG)

E.1.1.1

Medical condition in easily understood language

DLBL is a cancer of B cells, a type of white blood cell responsible for producing antibodies, it is the most common type of non-Hodgkin lymphoma

LDCBG es un cáncer de células B, un tipo de glóbulo blanco responsable de producir anticuerpos, es el tipo más común de linfoma no Hodgkin

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10012857
E.1.2	Term	Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) refractory
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10012856
E.1.2	Term	Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation) recurrent
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10012855
E.1.2	Term	Diffuse large cell lymphoma (Diffuse large B-cell lymphoma) (Working Formulation)
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Stage 1
• To evaluate the safety and tolerability of Polatuzumab vedotin (Pola) -
R-GemOx as a combination therapy on basis of incidence, nature and
severity of physical findings and adverse events (AEs)), with a specific
focus on peripheral neuropathy, according to the National Cancer
Institute Common Terminology Criteria for Adverse Events, Version 5
(NCI CTCAE v5.0)
Stage 2
• To evaluate the efficacy of Pola-R-GemOx compared with R-GemOx
alone on basis of overall survival (OS)

-Etapa 1
Evaluar la seguridad y la tolerabilidad de Polatuzumab vedotin (Pola) -
R-GemOx como terapia combinada en función de la incidencia, la naturaleza y gravedad de los hallazgos físicos y eventos adversos (EA), con un centrarse en la neuropatía periférica, según el National Cancer
Instituto de Criterios de Terminología Común para Eventos Adversos, Versión 5 (NCI CTCAE v5.0)
Etapa 2
• Evaluar la eficacia de Pola-R-GemOx en comparación con R-GemOx
solo sobre la base de la supervivencia general (OS)

E.2.2

Secondary objectives of the trial

To Evaluate:
• Safety, tolerability of Pola-R-GemOx as a combination therapy, Pola-RGemOx compared to R-GemOx, basis of incidence, assessment of
peripheral neuropathy, tolerability, prevalence of anti-drug antibodies
(ADA), incidence/nature/severity of AEs (Stage 1, 2)
• Efficacy of Pola-R-GemOx, Pola-R-GemOx compared to R-GemOx alone on basis of complete response (CR), objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), OS (Pola-R-GemOx)-Stage 1, event-free survival (EFS), duration of OR (DOR) (Stage 1, 2)
• Pharmacokinetic (PK) of pola, basis of PK profile of pola in
combination R-GemOx (Stage 1, 2)
• Immunogenicity of pola, basis of prevalence of ADAs (Stage 1, 2)
• Impact of treatment, disease on aspects of health-related quality of
life (Stage 2)

Para evaluar:
• Seguridad, tolerabilidad de Pola-R-GemOx como terapia combinada, Pola-R GemOx en comparación con R-GemOx, base de incidencia, evaluación de neuropatía periférica, tolerabilidad, prevalencia de anticuerpos antidrogas (ADA), incidencia / naturaleza / gravedad de los AA (Etapa 1, 2)
• Eficacia de Pola-R-GemOx, Pola-R-GemOx en comparación con R-GemOx solo sobre la base de la respuesta completa (RC), tasa de respuesta objetiva (ORR), mejor respuesta general (BOR), supervivencia libre de progresión (PFS), OS (Pola-R GemOx) -Etapa 1, supervivencia libre de eventos (EFS), duración de OR (DOR) (Etapa
1, 2)
• Farmacocinética (PK) de pola, base del perfil PK de pola en combinación R-GemOx (Etapa 1, 2)
• Inmunogenicidad de pola, base de prevalencia de ADA (Etapa 1, 2)
• Impacto del tratamiento, la enfermedad en aspectos de la calidad relacionada con la salud de vida (Etapa 2)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >= 18 years
- Ability to comply with the study protocol, in the investigator's
judgment
- Histologically-confirmed DLBCL, not otherwise specified or history of
transformation of indolent disease to DLBCL
- Relapsed or refractory disease
- At least one (>= 1) line of prior systemic therapy
- At least one bi-dimensionally measurable lesion
- Eastern Cooperative Oncology Group performance status of 0, 1 or 2
- Adequate hematological function
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for 12 months after the final dose of pola or rituximab
- For men: agreement to remain abstinent or use contraceptive
measures, and agreement to refrain from donating sperm, with a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of oxand/or gem

--Edad ≥ 18 años en el momento de firmar el documento de consentimiento informado.
-Capacidad para cumplir el protocolo del estudio, a criterio del investigador.
-Linfoma difuso de células B grandes confirmado histológicamente, no especificado de otra manera (NOS) O historial de transformación de enfermedad indolente a LDCBG.
- Enfermedad resistente o en recaída
-Al menos una línea (≥ 1) de terapia sistémica previa
-Al menos una lesión medible en dos dimensiones
-Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0, 1 o 2.
-Función hematológica adecuada
-Mujeres con capacidad de procrear: compromiso de practicar la abstinencia o utilizar métodos anticonceptivos y no donar óvulos. Las mujeres deberán practicar la abstinencia sexual o utilizar métodos anticonceptivos con un índice de fallos < 1% anual durante el período de tratamiento y durante 12 meses después de la última dosis de polatuzumab vedotina o rituximab.
-Varones: compromiso de practicar la abstinencia o utilizar métodos anticonceptivos y de no donar semen con una pareja femenina con capacidad de procrear que no esté embarazada, los varones que no estén esterilizados quirúrgicamente deberán mantener la abstinencia o utilizar un preservativo más un método anticonceptivo adicional que juntos tengan un índice de fallos < 1% anual durante el período de tratamiento y durante 6 meses después de la última dosis de oxaliplatino y/o gemcitabina

E.4

Principal exclusion criteria

- History of severe allergic or anaphylactic reactions to humanized or
murine monoclonal antibodies (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
- Contraindication to R, gem or ox
- Peripheral neuropathy assessed to be > Grade 1 according to NCI
CTCAE v5.0 at enrollment
- Prior use of pola or a gem + platinum-based agent combination
- Enrollment in any previous or ongoing pola trial
- Treatment with radiotherapy, chemotherapy, immunotherapy,
immunosuppressive therapy, or any investigational agent for the
purposes of treating cancer within 2 weeks prior to Cycle 1 Day 1
- Planned autologous or allogeneic stem cell transplantation at time of recruitment
- Primary or secondary central nervous system lymphoma at the time
of recruitment
- Richter's transformation or prior chronic lymphocytic leukemia
- Any of the following abnormal laboratory values, unless abnormal
laboratory values are due to underlying lymphoma per the investigator:
o Creatinine > 1.5 x upper limit of normal (ULN) or a measured
creatinine clearance < 30 mL/min
o Aspartate aminotransferase or alanine aminotransferase > 2.5 x ULN
o Total bilirubin >= 1.5 x ULN. Patients with documented Gilbert disease may be enrolled if total bilirubin is <= 3 x ULN
o International normalized ratio or prothrombin time > 1.5 x ULN in the absence of therapeutic anticoagulation
o Partial thromboplastin time or activated partial thromboplastin time >
1.5 x ULN in the absence of a lupus anticoagulant
- History of other malignancy that could affect compliance with the
protocol or interpretation of results
- Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or significant pulmonary disease
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or
other infection at study enrollment or any major episode of infection
within 4 weeks prior to Cycle 1 Day 1
- Patients with suspected or latent tuberculosis
- Positive test results for chronic hepatitis B virus infection and
hepatitis C virus antibody
- Known history of human immunodeficiency virus seropositive status
- Vaccination with a live vaccine within 4 weeks prior to treatment
- Recent major surgery (within 6 weeks before the start of Cycle 1 Day
1) other than for diagnosis
- Any other diseases, metabolic dysfunction, physical examination
finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of an investigational
drug or that may affect the interpretation of the results or render the
patient at high risk from treatment complications
- Pregnant or breastfeeding, or intending to become pregnant during
the study or within 12 months after the last dose of study drug

-Antecedentes de reacciones alérgicas o anafilácticas graves a los anticuerpos monoclonales humanizados o murinos (o las proteínas de fusión relacionadas con anticuerpos recombinantes) o sensibilidad o alergia a los productos de origen murino.
- Contraindicación de rituximab, gemcitabina u oxaliplatino.
- Neuropatía periférica evaluada como grado > 1 según los CTCAE del NCI v5.0 en el momento de la inclusión.
- Uso previo de polatuzumab vedotina o una combinación de gemcitabina + platino.
- Inclusión en cualquier ensayo previo o en curso de polatuzumab vedotina.
- Radioterapia, quimioterapia, inmunoterapia, tratamiento inmunodepresor o cualquier fármaco en investigación para tratar el cáncer en las 2 semanas previas al día 1 del ciclo 1.
- Trasplante autólogo o alogénico de células madre planeado en el momento del reclutamiento
-Linfoma primario o secundario del sistema nervioso central (SNC) en el momento del reclutamiento.
-Transformación de Richter o LLC previa.
- Cualquiera de los siguientes valores analíticos anómalos, a menos que se deban al linfoma subyacente según el investigador:
-Creatinina > 1,5 veces el límite superior de la normalidad (LSN) o aclaramiento de creatinina medido < 30 ml/min.
- Aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) > 2,5 veces el LSN.
- Bilirrubina total ≥ 1,5 veces el LSN. Los pacientes con enfermedad de Gilbert documentada podrán participar si la bilirrubina total es ≤ 3 veces el LSN.
-Índice normalizado internacional (INR) o tiempo de protrombina (TP) > 1,5 veces el LSN en ausencia de anticoagulación terapéutica.
- Tiempo de tromboplastina parcial (TTP) o tiempo de tromboplastina parcial activada (TTPa) > 1,5 veces el LSN en ausencia de anticoagulante lúpico.
-Antecedentes de otros procesos malignos que puedan afectar al cumplimiento del protocolo o a la interpretación de los resultados.
-Indicios de enfermedades concomitantes no controladas e importantes que puedan afectar al cumplimiento del protocolo o a la interpretación de los resultados, tales como enfermedad cardiovascular importante o enfermedad pulmonar importante
-Infección activa conocida por bacterias, virus, hongos, micobacterias, parásitos u otros microorganismos en el momento de la inclusión en el estudio o cualquier episodio importante de infección en las 4 semanas previas al día 1 del ciclo 1.
-Pacientes con sospecha de tuberculosis o con tuberculosis latente
-Resultados positivos de las pruebas de infección crónica por el virus de la hepatitis B y Resultados positivos de anticuerpos contra el virus de la hepatitis
-Antecedentes conocidos de seropositividad para el virus de la inmunodeficiencia humana (VIH).
-Vacunación con una vacuna de microorganismos vivos en las 4 semanas previas a la aleatorización.
-Intervención de cirugía mayor reciente (en las 6 semanas anteriores al día 1 del ciclo 1), excepto con fines diagnósticos.
-Cualquier otra enfermedad, disfunción metabólica, hallazgo en la exploración física o resultado analítico que haga sospechar de forma razonable una enfermedad o proceso que contraindique el uso de un medicamento experimental o que pueda afectar a la interpretación de los resultados o que suponga un alto riesgo de sufrir complicaciones del tratamiento para el paciente.
-Embarazo o lactancia, o intención de quedarse embarazada durante el estudio o en los 12 meses siguientes a la última dosis del fármaco del estudio.

E.5 End points

E.5.1

Primary end point(s)

Stage 1
1. Incidence, nature and severity of physical findings and adverse events (AEs), with a specific focus on peripheral neuropathy, according to the NCI CTCAE v5.0
Stage 2
2. OS

Nivel 1
1. Incidencia, naturaleza y gravedad de los hallazgos físicos y los eventos adversos. (EA), con un enfoque específico en la neuropatía periférica, de acuerdo con el NCI CTCAE v5.0
Etapa 2
2. OS

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to 90 days or the initiation of non-protocol-specified antilymphoma treatment after the last dose of study drug
2. Up to 25 months

1. Hasta 90 días o el inicio del tratamiento de antilinfoma no especificado en el protocolo después de la última dosis del fármaco del estudio.
2. Hasta 25 meses.

E.5.2

Secondary end point(s)

1. Incidence and assessment of peripheral neuropathy, as measured bythe Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity 12-Item Scale (FACT-GOG/Ntx12) (Stage 1 and 2)
2. Incidence, nature and severity of AEs (including peripheral
neuropathy) according to NCI CTCAE v5.0 and physical findings (Stage
2)
3. Tolerability, as measured by dose interruptions, dose reductions and
dose intensity (Stage 1 and 2)
4. Prevalence of ADAs to pola at baseline and incidence of ADAs during
the study (Stage 1 and 2)
5. CR as determined by an independent review committee (IRC) (Stage
2)
6. CR as determined by investigator (Stage 1 and 2)
7. ORR as determined by an IRC (Stage 2)
8. ORR as determined by investigator (Stage 1 and 2)
9. BOR as determined by investigator (Stage 1 and 2)
10. PFS as determined by investigator (Stage 1 and 2)
11. OS (Stage 1)
12. EFSeff (Stage 1 and 2)
13. DOR as determined by investigator (Stage 2)
14. Maximum concentrations (Cmax) of pola with R-GemOx (Stage 1 and
2)
15. Through concentration (Ctrough) of pola with R-GemOx (Stage 1 and
2)
16. Time to deterioration in physical functioning and fatigue as
measured by the European Organisation for the Research and Treatment
of Cancer Quality-of-Life Questionnaire, Core 30 (Stage 2)
17. Time to progression in lymphoma symptoms as measured by the
Functional Assessment of Cancer Therapy-Lymphoma subscale (Stage 2)
18. Change from baseline in peripheral neuropathy as measured by the
FACT/GOG-NTX-12 subscale score (Stage 2)

1. Incidencia y evaluación de la neuropatía periférica, medida por
La Evaluación Funcional de la Terapia del Cáncer / Oncología Ginecológica
Escala de 12 elementos de neurotoxicidad grupal (FACT-GOG / Ntx12) (Etapa 1 y 2)
2. Incidencia, naturaleza y gravedad de los AA (incluidos los periféricos
neuropatía) según NCI CTCAE v5.0 y hallazgos físicos (Etapa
2)
3. Tolerabilidad, medida por interrupciones de dosis, reducciones de dosis y
intensidad de dosis (Etapa 1 y 2)
4. Prevalencia de ADA a pola al inicio e incidencia de ADA durante
el estudio (Etapa 1 y 2)
5. CR según lo determinado por un comité de revisión independiente (IRC) (Etapa
2)
6. RC según lo determinado por el investigador (Etapa 1 y 2)
7. ORR según lo determinado por un IRC (Etapa 2)
8. ORR según lo determinado por el investigador (Etapa 1 y 2)
9. BOR según lo determine el investigador (Etapa 1 y 2)
10. SLP según lo determine el investigador (Etapas 1 y 2)
11. OS (Etapa 1)
12. EFSeff (Etapa 1 y 2)
13. DOR según lo determinado por el investigador (Etapa 2)
14. Concentraciones máximas (Cmax) de pola con R-GemOx (Etapa 1 y
2)
15. A través de la concentración (Ctrough) de pola con R-GemOx (Etapa 1 y
2)
16. Tiempo de deterioro del funcionamiento físico y fatiga a medida que
medido por la Organización Europea para la Investigación y el Tratamiento
del cuestionario de calidad de vida del cáncer, núcleo 30 (estadio 2)
17. Tiempo de progresión en los síntomas del linfoma medido por el
Evaluación funcional de la subescala de terapia de cáncer-linfoma (Etapa 2)
18. Cambio desde el inicio en la neuropatía periférica medido por el
FACT / GOG-NTX-12 puntaje de subescala (Etapa 2)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 1 of Cycle 1-8 and at end of treatment/discontinuation and long
term follow-up
2. Up to 90 days or the initiation of non-protocol-specified antilymphoma treatment after the last dose of study drug
3. Up to 25 months
4. At baseline (Day -28 to -1), Day 1 of Cycle 1, 2, 4; treatment
completion/early termination, post-treatment follow-up
5-13. Up to 25 Months
14-15. Day 1 of Cycle 1, 2, 4; treatment completion/early termination,
post-treatment follow-up
16-17. Day 1 of Cycle 1-8, end of treatment/discontinuation and longterm follow-up
18. Baseline, Day 1 of Cycle 1-8, end of treatment/discontinuation and
long-term follow-up

1. Día 1 del Ciclo 1-8 y al final del tratamiento / interrupción y larga
seguimiento a plazo
2. Hasta 90 días o el inicio del tratamiento de antilinoma no especificado en el protocolo después de la última dosis del fármaco del estudio.
3. Hasta 25 meses.
4. Al inicio (día -28 a -1), día 1 del ciclo 1, 2, 4; tratamiento
finalización / terminación temprana, seguimiento posterior al tratamiento
5-13. Hasta 25 meses
14-15. Día 1 del ciclo 1, 2, 4; finalización del tratamiento / terminación temprana,seguimiento postratamiento
16-17. Día 1 del ciclo 1-8, finalización del tratamiento / interrupción y seguimiento a largo plazo
18. Línea de base, Día 1 del Ciclo 1-8, fin del tratamiento / interrupción y seguimiento a largo plazo

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

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

immunogenicity

inmunogenicidad

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Pola-RGemOx vs RGemOx alone

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

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

This is an event-driven trial. The clinical cut-off date for the final OS analysis will be confirmed when the targeted number of mortality events (121 deaths) have occurred

Este es un estudio basado en acontecimientos. La fecha de corte de los datos clínicos para el análisis final de la SG se confirmará cuando se haya producido el número previsto de episodios de mortalidad (121 muertes)

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

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:

108

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

108

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

113

F.4.2.2

In the whole clinical trial

216

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)

Currently, the Sponsor does not have any plans to provide Sponsor study drugs (polatuzumab vedotin, rituximab, oxaliplatin and gemcitabine) or any other study treatments or interventions to patients who have completed the study. The Sponsor may evaluate whether to continue providing polatuzumab vedotin or rituximab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.

Actualmente, el Sponsor no tiene ningún plan para proporcionar medicamentos del estudio del Sponsor (polatuzumab vedotin, rituximab, oxaliplatino y gemcitabina) ni ningún otro tratamiento o intervención del estudio a pacientes que lo hayan completado. El Patrocinador puede evaluar si continuará suministrando polatuzumab vedotina o rituximab de acuerdo con la Política global de Roche sobre acceso continuo a medicamentos en investigación.

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

2019-12-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-12-03

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

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