Clinical Trials Register

Summary
EudraCT Number:	2015-002731-17
Sponsor's Protocol Code Number:	GS-US-339-1562
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-26
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2015-002731-17

A.3

Full title of the trial

A Phase 1b-2, Open-Label, Dose Escalation and Expansion Study Evaluating
the Safety and Efficacy of Entospletinib (ENTO [GS-9973]) combined with Vincristine (VCR) in Adult Subjects with Relapsed or Refractory B-cell Non- Hodgkin Lymphoma (NHL)

1b-2. fázisú, nyílt, dózisnövelő és -kiterjesztő vizsgálat a vinkrisztinnel (VCR) együtt adott entospletinib (ENTO [GS-9973]) biztonságosságának és hatásosságának értékelésére kiújult vagy refrakter B-sejtes non-Hodgkin limfómában (NHL) szenvedő betegeknél

A.3.1

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

A Clinical Study to investigate the Safety and Efficacy of Entospletinib (ENTO) in combination with standard of care in adult subjects with Non-Hodgkin Lymphoma (NHL).

A.4.1

Sponsor's protocol code number

GS-US-339-1562

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02568683

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	Gilead Sciences, 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	Gilead Sciences, 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	Gilead Sciences International Ltd
B.5.2	Functional name of contact point	Clinical Trials Mailbox
B.5.3	Address:
B.5.3.1	Street Address	Flowers Building, Granta Park
B.5.3.2	Town/ city	Abington, Cambridge
B.5.3.3	Post code	CB21 6GT
B.5.3.4	Country	United Kingdom
B.5.5	Fax number	+ 441223897 284
B.5.6	E-mail	clinical.trials@gilead.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	GS-9973
D.3.4	Pharmaceutical form	Film-coated 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	Entospletinib
D.3.9.3	Other descriptive name	ENTOSPLETINIB
D.3.9.4	EV Substance Code	SUB178740
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	100
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	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	GS-9973
D.3.4	Pharmaceutical form	Film-coated 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	Entospletinib
D.3.9.3	Other descriptive name	ENTOSPLETINIB
D.3.9.4	EV Substance Code	SUB178740
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Vincristine Sulphate
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	Vincristine
D.3.4	Pharmaceutical form	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	Vincristine Sulphate
D.3.9.1	CAS number	57-22-77
D.3.9.3	Other descriptive name	VINCRISTINE SULFATE
D.3.9.4	EV Substance Code	SUB05101MIG
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	1
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 or refractory B-cell Non-Hodgkin Lymphoma and relapsed or refractory Diffuse Large B-cell Lymphoma.

E.1.1.1

Medical condition in easily understood language

Non-Hodgkin Lymphoma and Diffuse Large B-cell Lymphoma

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

To evaluate the safety of Entospletinib (ENTO) with vincristine (VCR) in subjects with relapsed or refractory NHL

E.2.2

Secondary objectives of the trial

•The safety and efficacy of ENTO with vincristine (VCR) in the dose escalation stage in adult subjects with relapsed or refractory B-cell NHL.
•Attain the minimally effective or the recommended phase 2 expansion dose of ENTO in combination with VCR in adult subjects with relapsed or refractory B-cell NHL.
•To evaluate the safety and therapeutic response to ENTO when administered in combination with VCR in the dose expansion stage in adult subjects with relapsed or refractory DLBCL.
• To evaluate the safety of ENTO when administered in combination with VCR in the dose expansion stage in adult subjects with relapsed or refractory B-cell NHL (histologies other than DLBCL)
• To evaluate therapeutic response to ENTO when administered in combination with VCR in the dose expansion stage in adult subjects with relapsed or refractory B-cell NHL (histologies other than DLBCL)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subjects ≥ 18 years of age
2) Measurable disease by computed tomograph (CT)/ and/or positron- emission tomography CT (PET-CT)
3) A) Dose Escalation Stage: Confirmed Diagnosis of relapsed or refractory Non-Hodgkin Lymphoma (NHL) treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy
regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician

B) Dose Expansion Cohorts:
i) Expansion Cohort A: Diagnosis of relapsed or refractory DLBCL
treated with prior
treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician.
ii) Expansion Cohort B: Diagnosis of relapsed or refractory B-cell NHL (other than DLBCL) treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen
containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician
4) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky performance status ≥ 70
5) Adequate organ function defined by the screening laboratory inclusion listed below and Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO or MUGA

E.4

Principal exclusion criteria

1) Diagnosis of Primary Mediastinal Large B-cell Lymphoma
2) A life threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety or interfere with the absorption or metabolism of ENTO
3) Active or symptomatic CNS disease or epidural involvement
4) Uncontrolled intercurrent illness including, but not limited to, unstable angina pectoris or psychiatric illness/social situations that would limit compliance with study requirements
5) Current/ongoing neuropathy (sensory or motor) Grade > 1 or any history of Grade ≥ 3 neuropathy with prior VCR or chemotherapy exposure (documentation by history is adequate to exclude)
6) Contraindication to receive VCR or any planned protocol-specified chemotherapy
7) Eligible for autologous stem cell transplant
8) History of myelodysplastic syndrome, allogeneic stem cell or solid organ transplantation
9) History of any other non-lymphoid malignancy other than the registrational
histology or any other non-lymphoid malignancy except for the
following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to the start of study drug, or any other cancer that has been in complete remission without treatment for ≥ 5 years prior to enrollment

E.5 End points

E.5.1

Primary end point(s)

Occurrence of adverse events and laboratory abnormalities defined as DLTs for ENTO in combination with VCR in subjects in the dose escalation stage with relapsed or refractory NHL

E.5.1.1

Timepoint(s) of evaluation of this end point

1. For dose escalation stage, incidence of adverse events defined as dose
limiting toxicities (DLTs) for ENTO in combination with VCR in
participants with relapsed or refractory NHL
[Time Frame: Up to 28 days]

2. For dose escalation stage, incidence of laboratory abnormalities
defined as dose-limiting toxicities (DLTs) for ENTO in combination with
VCR in participants with relapsed or refractory NHL
[Time Frame: Up to 28 days]

E.5.2

Secondary end point(s)

Safety:

1 .Occurrence of adverse events and laboratory abnormalities not defined as DLTs for ENTO with VCR in subjects in the dose escalation stage with relapsed or refractory B-cell NHL

2. Occurrence of adverse events and laboratory abnormalities for ENTO with VCR in subjects in dose expansion stage with relapsed or refractory DLBCL

3. Occurrence of adverse events and laboratory abnormalities for ENTO with VCR in subjects in the dose expansion stage with relapsed or refractory B-cell NHL (non-DLBCL)

Efficacy:

4.Objective response rate (ORR) will be determined from the subjects' best response during therapy of ENTO with VCR and will include complete response (CR) or partial response (PR)

5. Progression free survival (PFS) will be defined as the interval from the first dose of ENTO to the earlier of the first documentation of definitive disease progression or death from any cause

6. Overall survival (OS) will be defined as the interval from the start of study treatment to death from any cause.

7. Duration of response (DOR) will be defined as time from the first response (CR or PR) is achieved until the earlier of the first documentation of definitive disease progression or death from any cause

8. Time to response (TTR) will be defined as time from the first dose of
ENTO to the first time the response (CR or PR) is achieved

Exposure:
9. Drug administration and duration of exposure of study treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

1.[Time Frame: Up to 6 months plus 30 days]
2. [Time Frame: Up to 6 months plus 30 days]
3.[Time Frame: Up to 6 months plus 30 days]
4. [Time Frame: Up to 6 months plus 5 years]
5. [Time Frame: Up to 6 months plus 5 years]
6. [Time Frame: Up to 6 months plus 5 years]
7. [Time Frame: Up to 6 months plus 5 years]
8. [Time Frame: Up to 6 months plus 5 years]
9. [Time Frame: Up to 6 months]
10. [Time Frame: Up to 6 months]

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Dose Esclation and Dose Expansion study

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

Hungary

Italy

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

End of study will be defined when the last patient reaches the last scheduled follow-up timepoint, is lost to follow-up, withdraws from the study, dies, or the time at which the Sponsor closes the study.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

F.4.2.2

In the whole clinical trial

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)

After a patient has completed/terminated their study participation, long term care for the participant will remain the responsibility of their primary treating physicians.

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

2016-02-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-06-22

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