Clinical Trials Register

Summary
EudraCT Number:	2017-000538-78
Sponsor's Protocol Code Number:	INCB39110-301
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-07-28
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

Portugal - INFARMED

A.2

EudraCT number

2017-000538-78

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Itacitinib or Placebo in Combination With Corticosteroids for the Treatment of First-Line Acute Graft Versus-Host Disease

A.3.1

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

A study evaluating safety and efficacy of Itacitinib or Placebo in combination with corticosteroids for the treatment of first-line acute graft versus-host disease

A.3.2

Name or abbreviated title of the trial where available

GRAVITAS-301

A.4.1

Sponsor's protocol code number

INCB39110-301

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	Incyte Corporation
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	Incyte Corporation
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	Incyte Corporation
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	1801 Augustine Cut-Off
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	DE 19803
B.5.3.4	Country	United States
B.5.5	Fax number	13024252734
B.5.6	E-mail	RA@incyte.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 / 3117 / 1964
D.3 Description of the IMP
D.3.1	Product name	Itacitinib
D.3.2	Product code	INCB039110
D.3.4	Pharmaceutical form	Modified-release 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	ITACITINIB ADIPATE
D.3.9.1	CAS number	1334302-63-4
D.3.9.2	Current sponsor code	INCB039110 ADIPATE
D.3.9.3	Other descriptive name	ITACITINIB ADIPATE
D.3.9.4	EV Substance Code	SUB184194
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.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	Tablet
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

Male or female, 18 years of age or older who have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) and have developed Grade II to IV acute GVHD

E.1.1.1

Medical condition in easily understood language

Acute graft versus host disease after allogeneic stem cell transplantation

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066260
E.1.2	Term	Acute graft versus host disease
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066262
E.1.2	Term	Acute graft versus host disease in skin
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066264
E.1.2	Term	Acute graft versus host disease in intestine
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10066263
E.1.2	Term	Acute graft versus host disease in liver
E.1.2	System Organ Class	10021428 - Immune system disorders

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

Compare the efficacy of itacitinib in combination with corticosteroids versus placebo in combination with corticosteroids in terms of overall response rate (ORR) at Day 28 in subjects with acute graft-versus-host disease (aGVHD).

E.2.2

Secondary objectives of the trial

- Compare the efficacy between treatment cohorts at a subsequent key clinical landmark (key secondary objective).
- Compare additional response and longer-term efficacy outcomes between treatment cohorts.
- Assess the incidence and severity of adverse events (AEs) and serious adverse events.
- Evaluate the pharmacokinetics of itacitinib when administered in combination with corticosteroids.
- Evaluate the incidence of secondary graft failure.
- Evaluate the use and discontinuation of corticosteroids.
- Evaluate the use and discontinuation of immunosuppressive medications.
- Evaluate the incidence of aGVHD flares.
- Evaluate the incidence of cGVHD.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male or female, 18 years of age or older.
• Has undergone 1 allo-HSCT from any donor (related or unrelated with
any degree of HLA matching) and any donor source (bone marrow, peripheral blood stem cells, or cord blood) for a hematologic malignancy or disorder. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible.
• Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any GVHD prophylaxis regimen. Biopsies should be obtained to pathologically confirm aGVHD; in cases where a biopsy is negative, is unable to be obtained, or is clinically contraindicated, clinical suspicion of aGVHD by the treating physician is sufficient, provided that alternative diagnoses of drug effects or infection are adequately ruled out.
• Evidence of myeloid engraftment (eg, absolute neutrophil count ≥ 0.5 × 109/L for 3 consecutive assessments if ablative therapy was previously used). Use of growth factor supplementation is allowed.

E.4

Principal exclusion criteria

• Has received more than 1 allo-HSCT.
• Has received more than 2 days of systemic corticosteroids for acute-GVHD.
• Presence of GVHD overlap syndrome.
• Presence of an active uncontrolled infection.

E.5 End points

E.5.1

Primary end point(s)

ORR at Day 28, defined as the proportion of subjects demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 28

E.5.2

Secondary end point(s)

- NRM at Month 6, defined as the proportion of subjects who died due to causes other than malignancy relapse at Month 6 (key secondary endpoint).
- ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR at Days 14, 56, and 100.
- NRM at Months 9, 12, and 24.
- DOR for responders will be calculated. The DoR is defined from the time of the onset of response to loss of response. Subjects who died or discontinue will be censored at the death date or the previous assessment
- Duration of response, defined as the interval from first response until graft-versus-host disease (GVHD) progression or death.
- Time to response, defined as the interval from treatment initiation to first response.
- Relapse rate of malignant and non malignant hematologic diseases, defined as the proportion of subjects whose underlying hematologic disease relapses.
- Malignancy relapse rate, defined as the proportion of subjects whose underlying malignancy relapses.
- Malignancy relapse-related mortality rate, defined as the proportion of subjects whose malignancy relapses and has a fatal outcome.
- Failure-free survival, defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD), at Month 6.
- Overall survival (OS), defined as the interval from study enrollment to death due to any cause.
- Clinical safety data (eg, AEs, infections) will be tabulated and listed.
- Cmax, Cmin, tmax, AUC, and CL/F.
- Incidence rate of secondary graft failure, defined as > 95% recipient cells any time after engraftment with no signs of relapse, OR retransplantation because of secondary neutropenia (< 0.5 × 109/L) and/or thrombocytopenia (< 20 × 109/L) within 2 months of transplant.
- Average and cumulative corticosteroid dose at Days 28, 56, 100, and 180; proportion of subjects who discontinue corticosteroids at Days 56 and 100.
- Proportion of subjects who discontinue immunosuppressive medications at Days 56 and 100.
- Incidence rate of aGVHD flares through Day 100.
- Incidence rate of cGVHD at Days 180 and 365.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 14, 28, 56, 100
Months 6, 9, 12 and 24

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

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

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

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

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

Australia

Canada

Israel

Korea, Republic of

New Zealand

Singapore

Switzerland

Taiwan

Turkey

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

The study will end once 75% of subjects have achieved 2-year transplant-related mortality, have died, or have been lost to follow-up.

An end of the trial can not be determined as each subject enrolled in the study may continue to receive study treatment as long as benefit is being observed and/or treatment withdrawal criteria are not met.

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:

393

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

200

F.4.2.2

In the whole clinical trial

436

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)

None

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

2017-07-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-07-13

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