Clinical Trials Register

Summary
EudraCT Number:	2016-004339-19
Sponsor's Protocol Code Number:	UTX-TGR-204
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:	2017-03-10
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

2016-004339-19

A.3

Full title of the trial

A Multi-Center, Open-Label, Extension Study of Ublituximab (TG-1101) in Combination with TGR-1202 for Patients Previously Enrolled in Protocol UTX-TGR-304

Estudio de extensión multicéntrico y abierto de ublituximab (TG-1101) en combinación con
TGR-1202 para pacientes inscritos anteriormente en el protocolo UTX-TGR-304

A.3.1

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

Extension Study for Patients Previously Enrolled in Protocol UTX-TGR-304

Estudio de extensión para pacientes previamente inscritos en el protocolo UTX-TGR-304

A.4.1

Sponsor's protocol code number

UTX-TGR-204

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	TG Therapeutics
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	TG Therapeutics
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	Cambridge Regulatory Services Ltd
B.5.2	Functional name of contact point	Pallav Shah
B.5.3	Address:
B.5.3.1	Street Address	2 Cabot House, Compass Point Business Park, Stocks Bridge Way,
B.5.3.2	Town/ city	St Ives, Cambridgeshire
B.5.3.3	Post code	PE27 5JL
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441480465755
B.5.5	Fax number	+441480463984
B.5.6	E-mail	pallavshah@cambreg.co.uk

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	Ublituximab
D.3.2	Product code	TG-1101
D.3.4	Pharmaceutical form	Solution for injection
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	UBLITUXIMAB
D.3.9.2	Current sponsor code	TGR-1101
D.3.9.3	Other descriptive name	IgG1 immunoglobulins
D.3.9.4	EV Substance Code	SUB182428
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: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TGR-1202
D.3.2	Product code	TGR-1202
D.3.4	Pharmaceutical form	Tablet
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	TGR-1202
D.3.9.2	Current sponsor code	TGR-1202
D.3.9.3	Other descriptive name	(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1- yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4 methylbenzenesulfonate
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic Lymphocytic Leukemia

Leucemia Linfocítica Crónica

E.1.1.1

Medical condition in easily understood language

CLL is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer cells start in the bone marrow but then go into the blood.

La LLC es un tipo de cáncer originado en médula ósea de células que se convierten en un tipo de células de la sangre(linfocitos).Empieza en médula ósea y después las células cancerosas van a la sangre

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	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10008976
E.1.2	Term	Chronic lymphocytic leukemia
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

For patients previously on Arms B, C, & D of Study UTX-TGR-304:
Primary Objective
• To determine the overall response rate (ORR) defined as the sum of complete responses (CR) and partial responses (PR)

For patients previously on Arm A of Study UTX-TGR-304:
Primary Objective
• To evaluate the progression-free survival (PFS) and duration of response (DOR)

Para pacientes que participaron en los grupos B, C y D del estudio UTX-TGR-304:
Objetivos principales
- Determinar la tasa de respuesta global (TRG) definida como la suma de respuestas completas (RC) y respuestas parciales (RP)

Para pacientes que participaron en el grupo A del estudio UTX-TGR-304:
Objetivos principales
- Evaluar la supervivencia sin progresión (SSP) y la duración de la respuesta (DR)

E.2.2

Secondary objectives of the trial

For patients previously on Arms B, C, & D of Study UTX-TGR-304:
Secondary Objective
• To evaluate the progression-free survival (PFS) and duration of response (DOR)
• To evaluate the % of patients that achieve MRD negativity
• To evaluate the safety of ublituximab in combination with TGR-1202

For patients previously on Arm A of Study UTX-TGR-304:
Secondary Objective
• To evaluate the safety of ublituximab in combination with TGR-1202

Para pacientes que participaron en los grupos B, C y D del estudio UTX-TGR-304:
Objetivos secundarios
- Evaluar la supervivencia sin progresión (SSP) y la duración de la respuesta (DR)
- Evaluar el % de pacientes que alcanzan negatividad de EMR (enfermedad mínima residual)
- Evaluar la seguridad de ublituximab en combinación con TGR-1202

Para pacientes que participaron en el grupo A del estudio UTX-TGR-304:
Objetivos secundarios
- Evaluar la seguridad de ublituximab en combinación con TGR-1202

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Prior treatment in clinical trial UTX-TGR-304: a. Confirmed progression by IRC from either Arms B, C, or D. and b. Non-progressing patients from Arm A may be eligible for enrollment when protocol UTX-TGR-304 is completed.
2. Adequate organ system function, defined as follows: a. absolute neutrophil count (ANC) > 750 / platelet count > 40,000; b. Total bilirubin < or = 1.5 times the upper limit of normal (ULN); c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < or =2.5 x ULN if no liver involvement or < or =5 x the ULN if known liver involvement; d. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault formula)
3. ECOG performance status < or = 2
4. Ability to swallow and retain oral medication
5. Willingness and ability to comply with trial and follow-up procedures, give written informed consent

1. Tratamiento anterior en el ensayo clínico UTX-TGR-304
a. Progresión confirmada por el CRI en los grupos B, C o D
b. Los pacientes sin progresión del grupo A podrán ser aptos para su inclusión cuando finalice el protocolo UTX-TGR-304
2. Función adecuada del sistema orgánico, definida como:
a. Recuento absoluto de neutrófilos (RAN) >750/recuento de plaquetas >40 000
b. Bilirrubina total < o =1,5 veces el límite superior de la normalidad (LSN)
c. Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) < o =2,5 x LSN si no hay afectación hepática o < o =5 x el LSN si hay una afectación hepática.
d. Aclaramiento de creatinina calculado >30 ml/min. (según la fórmula de Cockcroft-Gault)
3. Estado funcional según ECOG < o =2
4. Capacidad para tragar y retener la medicación oral
5. Voluntad y capacidad de cumplir con los procedimientos del ensayo y de seguimiento, y para dar el consentimiento informado por escrito

E.4

Principal exclusion criteria

1. Prior treatment with obinutuzumab + chlorambucil (Arm B patients) or ublituximab (Arm C patients) within 7 days of Cycle 1/Day 1.
2. Patients refractory to (progressing on) UTX-TGR-304 Treatment Arm A (ublituximab + TGR-1202).
3. Known histological transformation from CLL to an aggressive lymphoma (i.e. Richter’s transformation).
4. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails. NOTE: Patients may be receiving prophylactic
antiviral or antibacterial therapies at investigator discretion. Use of anti-pneumocystis prophylaxis is encouraged.
5. Woman who are pregnant or lactating.

1. Tratamiento anterior con obinutuzumab + clorambucilo (pacientes del grupo A) o ublituximab (pacientes del grupo C) en los 7 días anteriores al ciclo 1/día 1.
2. Pacientes resistentes (en progresión) en el grupo de tratamiento A (ublituximab + TGR-1202) del estudio UTX-TGR-304.
3. Transformación histológica conocida de la CLL a un linfoma agresivo (esto es, síndrome de Richter).
4. Indicios de infección vírica, micótica o bacteriana sistémica continuada, excepto infecciones micóticas localizadas de la piel o las uñas. NOTA: los pacientes pueden estar recibiendo tratamientos profilácticos antivíricos o antibióticos, a discreción del investigador. Se recomienda el uso de profilaxis frente a la neumocistosis.
5. Mujer embarazada o en periodo de lactancia.

E.5 End points

E.5.1

Primary end point(s)

1) Overall response rate (ORR). ORR is defined as sum of CR and PR rates.
2) Complete Response (CR) Rate. CR rate is defined as the proportion of patients who achieve a CR.
3) Progression-free survival (PFS). PFS is defined as the interval from enrollment to the earlier of the first documentation of definitive disease progression or death from any cause.Definitive disease progression based on standard criteria (Hallek et al. 2008) and occurring for any reason (i.e., increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than lymphocytosis.
4) Minimal Residual Disease (MRD) Negativity Rate. MRD negativity rate is defined as the proportion of patients who are MRD negative.
5) Duration of response (DOR). DOR is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause.

1) Tasa de respueta global (TGR) . La TRG se define como la suma de las tasas de RC y RP.
2) Tasa de respuesta completa (RC). La tasa de RC se define como la proporción de pacientes que logran una RC.
3) Supervivencia sin progresión (SSP). La SSP se define como el intervalo desde la inclusión hasta lo que suceda antes: la primera documentación de la progresión de la enfermedad definitiva o la muerte por cualquier causa.
Progresión de la enfermedad definitiva en base a los criterios de referencia (Hallek et al. 2008) y que se dé por cualquier motivo (es decir, linfadenopatía creciente, organomegalia o afectación de la médula ósea; descensos en el recuento de plaquetas, hemoglobina o recuento de
neutrófilos; o empeoramiento de los síntomas relacionados con la enfermedad) distintos a la linfocitosis.
4) Tasa de negatividad de enfermedad mínima residual (EMR). La tasa de negatividad de EMR se define como la proporción de pacientes
que tienen una EMR negativa.
5) Duración de la respuesta (DR). La DR se define como el intervalo desde la primera documentación de la RC o la RP hasta lo que suceda antes: primera documentación de la progresión de la enfermedad definitiva o la muerte por cualquier causa.

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluations are to be obtained following the completions of cycles 3, 6, 9 12, 15, 18 and every 3 cycles. A cycle being 28 days. Patients who discontinue from study treatment (either for toxicity or physician choice) and have not progressed will continue to be followed for progression.as per the institutional standard of care or until a new anti-cancer treatment is initiated.

E.5.2

Secondary end point(s)

1) Minimal Residual Disease (MRD) Negativity Rate. MRD negativity rate is defined as the proportion of patients who are MRD negative.
2) Progression-free survival (PFS). PFS is defined as the interval from enrollment to the earlier of the first documentation of definitive disease progression or death from any cause.
3) Duration of response (DOR). DOR is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause.
4) Safety evaluation

1) Tasa de negatividad de enfermedad mínima residual (EMR). La tasa de negatividad de EMR se define como la proporción de pacientes que tienen una EMR negativa.
2) Supervivencia sin progresión (SSP). La SSP se define como el intervalo desde la inclusión hasta lo que suceda antes: la primera documentación de la progresión de la enfermedad definitiva o la muerte por cualquier causa.
3) Duración de la respuesta (DR). La DR se define como el intervalo desde la primera documentación de la RC o la RP hasta lo que suceda antes: primera documentación de la progresión de la enfermedad definitiva o la muerte por cualquier causa.
4) evaluaciones de seguridad

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluations are to be obtained following the completions of cycles 3, 6, 9 12, 15, 18 and every 3 cycles. A cycle being 28 days. Patients who discontinue from study treatment (either for toxicity or physician choice) and have not progressed will continue to be followed for progression as per the institutional standard of care or until a new anti-cancer treatment is initiated.
Safety - All AEs will be reported and evaluated using National Cancer Institute’s Common Terminology Criteria (CTCAE) v4.0

Las evaluación se harán tras finalizar los ciclos 3, 6, 9, 12, 15, 18 y cada 3 cliclos. Los ciclos son de 28 días. Los pacientes que interrumpan el tratamiento (bien por toxicidad o a criterio del médico) y que no hayan progresado serán seguidos hasta progresión, según el tratamiento estándar en el centro o hasta que empiece una nueva linea de tratamiento
Seguridad - se notificarán todos los acontecimientos adversos y se evaluarán usando el National Cancer Institute’s Common Terminology Criteria (CTCAE) v4.0

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

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

E.8.1.1

Randomised

Information not present in EudraCT

E.8.1.2

Open

Yes

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Poland

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

Patients who discontinue from study treatment (either for toxicity or physician choice) and have not progressed will continue to be followed for progression as per the institutional standard of care or until a new anti-cancer treatment is initiated

Los pacientes que interrumpan el tratamiento (bien por toxicidad o a criterio del médico) y que no hayan progresado serán seguidos hasta progresión, según el tratamiento estándar en el centro o hasta que empiece una nueva linea de tratamiento

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

200

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)

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

2017-04-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-31

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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