Clinical Trials Register

Summary
EudraCT Number:	2014-000148-14
Sponsor's Protocol Code Number:	PLX108-10
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-03-23
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

Denmark - DHMA

A.2

EudraCT number

2014-000148-14

A.3

Full title of the trial

A Double-blind, Randomized, Placebo-controlled Phase 3 Study of Orally Administered PLX3397 in Subjects with Pigmented Villonodular Synovitis or Giant Cell Tumor of the Tendon Sheath ENLIVEN

A.3.1

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

A clinical trial comparing the effectiveness of PLX3397 against placebo in the treatment of Pigmented Villonodular Synovitis or Giant Cell Tumor of the Tendon Sheath

A.4.1

Sponsor's protocol code number

PLX108-10

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02371369

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	Daiichi Sankyo , 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	Daiichi Sankyo Development Limited
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Daiichi Sankyo Pharma Development
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Daiichi Sankyo Company, Limited
B.4.2	Country	Japan
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Daiichi Sankyo , Inc
B.5.2	Functional name of contact point	Clinical Trial Information Contact
B.5.3	Address:
B.5.3.1	Street Address	211 Mt. Airy Road
B.5.3.2	Town/ city	Basking Ridge, NJ
B.5.3.3	Post code	NJ 07920-2311
B.5.3.4	Country	United States
B.5.4	Telephone number	+19089927009
B.5.5	Fax number	+17329065690
B.5.6	E-mail	eu_cta@dsi.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	EMA/OD/279/14
D.3 Description of the IMP
D.3.1	Product name	Pexidartinib
D.3.2	Product code	PLX3397
D.3.4	Pharmaceutical form	Capsule
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	pexidartinib
D.3.9.1	CAS number	1029044-16-3
D.3.9.2	Current sponsor code	PLX3397
D.3.9.3	Other descriptive name	PLX3397 HCL
D.3.9.4	EV Substance Code	SUB33175
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pigmented villonodular synovitis (PVNS) / giant cell tumour of tendon sheath (GCT-TS)

E.1.1.1

Medical condition in easily understood language

tumour of the tendon sheath

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10062856
E.1.2	Term	Giant cell tumour of tendon sheath benign
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

The primary objective of this study is to compare the response rate of PLX3397 with that of placebo per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) at Week 25 in subjects with symptomatic, locally advanced PVNS or GCT-TS.

E.2.2

Secondary objectives of the trial

The secondary efficacy objectives are to evaluate: (i) patient-reported outcomes (PROs), including the Brief Pain Inventory (BPI) Worst Pain Numeric Rating Scale (NRS) item, Patient-reported Outcomes Measurement Information System (PROMIS) Physical Function Scale, and Worst Stiffness NRS item, at Week 25; (ii) response based on TVS at Week 25; (iii) range of motion at Week 25; and (iv) duration of response.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years.
2. A diagnosis of PVNS or GCT-TS (i) that has been histologically confirmed either by a pathologist at the treating institution or a central pathologist, and (ii) where surgical resection would be associated with potentially worsening functional limitation or severe morbidity (locally advanced disease), with morbidity determined consensually by qualified personnel (eg, two surgeons or a multi-disciplinary tumor board).
3. Measurable disease as defined by RECIST 1.1 (except that a minimal size of 2cm is required) , assessed from MRI scans by a central radiologist.
4. Symptomatic disease because of active PVNS or GCT-TS, defined as one or more of the following:
a. a worst pain of at least 4 at any time during the week preceding the screening visit (based on scale of 0 to 10, with 10 representing “pain as bad as you can imagine”).
b. a worst stiffness of at least 4 at any time during the week preceding the screening visit (based on a scale of 0 to 10, with 10 representing “stiffness as bad as you can imagine”).
5. Stable prescription of analgesic regimen during the 2 weeks prior to randomization.
6. During the 2 weeks prior to randomization, at least 4 of 7 consecutive days of BPI Worst Pain NRS items and Worst Stiffness NRS items completed correctly.
7. Women of childbearing potential must have a negative serum pregnancy test within the 14-day period prior to randomization. (Where demanded by local regulations, this test may be required within 72 hours of randomization.)
8. Males and females of childbearing potential are permitted in the study so long as they consent to avoid getting their partner pregnant or becoming pregnant, respectively, by using a highly effective contraception method, as described below, throughout the study and for up to 90 days after completion. Highly effective methods of contraception include: intra-uterine device (nonhormonal or hormonal), bilateral tubal occlusion, vasectomy, sexual abstinence, or barrier methods (e.g., condom, diaphragm) used in combination with hormonal methods associated with inhibition of ovulation, intra-uterine device; surgical sterilization (including partner’s vasectomy) or sexual abstinence. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year. Women who have documentation of at least 12 months of spontaneous amenorrhea and have an FSH level > 40 mIU/mL will be considered postmenopausal.
9. Adequate hematologic, hepatic, and renal function, defined by:
• Absolute neutrophil count ≥ 1.5 × 109/L • AST/ALT ≤ 1.5 × ULN
• Hemoglobin > 10 g/dL • Total bilirubin ≤ 1.5 × ULN
• Platelet count ≥ 100 × 109/L • Serum creatinine ≤ 1.5 × ULN
10. Willingness and ability to complete the BPI Worst Pain NRS item, Worst Stiffness NRS item, PROMIS Physical Function Scale, and other self-assessment instruments throughout the study.
11. Willingness and ability to use an electronic diary.
12. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements.

E.4

Principal exclusion criteria

1. Investigational drug use within 28 days of randomization.
2. Previous use of pexidartinib or any biologic treatment targeting CSF-1 or the CSF1R; previous use of oral tyrosine kinase inhibitors, eg, imatinib or nilotinib, are allowed.
3. Active cancer (either concurrent or within the last year of starting study treatment) that requires therapy (eg, surgical chemotherapy or radiation therapy), with the exception of adequately treated basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma insitu of the cervix or breast or prostrate carcinoma with a prostrate
specific antigen value <0.2 ng/mL.
4. Known metastatic PVNS/GCT-TS.
5. Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus or known active or chronic infection with human immunodeficiency virus.
6. Known active tuberculosis.
7. Significant concomitant arthropathy in the affected joint, serious illness, uncontrolled infection, or a medical or psychiatric history that, in the investigator’s opinion, would likely interfere with the person’s study participation or the interpretation of his or her results.
8. Women who are breastfeeding.
9. A screening Fridericia corrected QT interval (QTcF) ≥ 450 ms (men) or ≥ 470 ms (women).
10. MRI contraindications.
11. History of hypersensitivity to any excipients in the investigational product
12. Inability to swallow capsules.

E.5 End points

E.5.1

Primary end point(s)

The proportion of subjects who achieve a complete or partial response at the Week 25 visit based on centrally read MRI scans and RECIST 1.1.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 25

E.5.2

Secondary end point(s)

The following evaluations comprise the secondary efficacy endpoints:
1. Mean change from baseline in range of motion of the affected joint,
relative to a reference standard for the same joint, at the Week 25 visit
2. Proportion of responders based on centrally evaluated MRI scans and
TVS at the Week 25 visit
3. Mean change from baseline score in the PROMIS Physical Function
Scale at the Week 25 visit
4. Mean change from baseline score in the Worst Stiffness NRS item at
the Week 25 visit
5. Proportion of responders based on the BPI Worst Pain NRS item and
analgesic use by BPI-30 definition
6. Duration of response (CR or PR) based on MRI and RECIST 1.1
7. Duration of response (CR or PR) based on MRI and TVS

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 25

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

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the 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

Australia

Canada

Denmark

France

Germany

Hungary

Italy

Netherlands

Poland

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

100

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

126

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)

Subjects who complete Part 2 will be eligible to continue for longer efficacy and safety follow-up or to enter a separate protocol to continue receiving PLX3397 until disease progression, unacceptable toxicity, or the ocurrence of other termination criteria.

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

2015-03-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-30

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