Clinical Trials Register

Summary
EudraCT Number:	2017-000538-78
Sponsor's Protocol Code Number:	INCB39110-301
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-11-06
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

Italy - Italian Medicines Agency

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

Studio randomizzato, in doppio cieco, controllato con placebo, di fase 3 per la valutazione di itacitinib o placebo in combinazione con corticosteroidi per il trattamento di prima linea della malattia del trapianto contro l’ospite in fase acuta

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

Uno studio di valutazione della sicurezza ed efficacia di itacitinib o placebo in combinazione con corticosteroidi per il trattamento di prima linea della malattia del trapianto contro l’ospite in fase acuta

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.5.4	Telephone number	13024986960
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Soggetti di sesso maschile e femminile di età superiore o uguale a 18 anni, che hanno ricevuto un trapianto allogenico di cellule staminali emopoietiche (allo-HSCT) e che hanno sviluppato un’aGVHD di grado II-IV.

E.1.1.1

Medical condition in easily understood language

Acute graft versus host disease after allogeneic stem cell transplantation

Sviluppo di aGVHD (malattia del trapianto contro l'ospite) a seguito del trapianto allogenico di cellule staminali emopoietiche

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	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.1.2 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.1.3

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).

Confrontare l’efficacia di itacitinib in combinazione con corticosteroidi rispetto a placebo in combinazione con corticosteroidi in termini di tasso di risposta globale (ORR) al Giorno 28 in soggetti con malattia del trapianto contro l’ospite in fase acuta (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.

-Confrontare l’efficacia tra le coorti di trattamento in un’ulteriore caratteristica clinica chiave (obiettivo chiave secondario).
- Confrontare gli altri esiti di risposta e di efficacia a lungo termine tra le coorti di trattamento.
- Determinare l’incidenza e la gravità degli eventi avversi (EA) e degli eventi avversi seri.
-Valutare i parametri farmacocinetici di itacitinib quando somministrato in combinazione con corticosteroidi.
-Valutare l’incidenza del rigetto del secondo trapianto.
-Valutare l’uso e la sospensione di corticosteroidi.
-Valutare l’uso e la sospensione di farmaci immunosoppressori.
-Valutare l’incidenza delle esacerbazioni (flare) di aGVHD.
-Valutare l’incidenza di 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 days if ablative therapy was previously used). Use of growth factor supplementation is allowed.

-Maschi o femmine di almeno 18 anni di età.
-Aver ricevuto 1 allo-HSCT da donatore qualsiasi (parente o estraneo con qualunque grado di compatibilità HLA) e da fonte qualsiasi (midollo osseo, cellule staminali periferiche o da sangue del cordone ombelicale) per neoplasia o disturbo ematologico. I destinatari di regimi di condizionamento mieloablativi e a intensità ridotta sono idonei.
-Sospetto clinico di aGVHD di grado II-IV secondo i criteri MAGIC, che insorge secondariamente ad allo-HSCT e a qualunque regime profilattico della GVHD. La biopsia dovrebbe essere eseguita per confermare patologicamente l’aGVHD; nei casi in cui il campione è negativo, non può essere prelevato oppure la procedura è clinicamente controindicata, il sospetto clinico di aGVHD da parte del medico curante è sufficiente, purché si escludano adeguatamente diagnosi alternative di effetti correlati al farmaco o di infezione.
-Evidenza di attecchimento mieloide (es. conta assoluta dei neutrofili >=0,5 × 109/l per 3 giorni consecutivi se, in precedenza, è stata usata la terapia mieloablativa). È consentito il ricorso all’integrazione con fattori di crescita.

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.

-Aver ricevuto più di 1 allo-HSCT.
-Aver ricevuto corticosteroidi sistemici per aGVHD per più di 2 giorni.
-Presenza di sindrome che si sovrappone con la GVHD.
-Presenza di infezione non controllata attiva.

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).

ORR al Giorno 28, definito come proporzione di soggetti che mostrano una risposta completa (CR), un’ottima risposta parziale (VGPR) o una risposta parziale (PR).

E.5.1.1

Timepoint(s) of evaluation of this end point

28 days

28 giorni

E.5.2

Secondary end point(s)

- Nonrelapse mortality (NRM) at Month 6, defined as the proportion of subjects who died due to causes other than malignancy relapse at Month 6.
- NRM at Months 9, 12, and 24.
- ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR at Days 14, 56, and 100.
- 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 discontinued will be censored at the death date or the previous assessment.
- Time to response, defined as the interval from treatment initiation to first response.
- Relapse rate of malignant and nonmalignant hematologic diseases, defined as the proportion of subjects whose underlying hematologic disease 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.

- Mortalità senza recidiva (NRM) a 6 mesi, definita come proporzione di soggetti deceduti per cause diverse dalla recidiva del tumore a 6 mesi. (Endpoint chiave secondario)
- ORR, definito come proporzione di soggetti che mostrano CR, VGPR o PR ai Giorni 14, 56 e 100
- NRM a 9, 12 e 24 mesi
- Sarà calcolata la DOR (Duration of response [durata della risposta]) per i rispondenti. La DOR è definita come il tempo intercorso dall'inizio della risposta fino alla perdita di risposta. I soggetti che sono deceduti o si sono ritirati saranno depennati dalla data del decesso o dalla precedente valutazione.
- Tempo alla risposta, definito come tempo intercorso dall'inizio del trattamento e la prima risposta.
- Tasso di recidiva delle malattie ematologiche maligne e non maligne, definito come proporzione di soggetti in cui si ripresenta la malattia ematologica.
- Tasso di mortalità correlata alla recidiva del tumore, definito come proporzione di soggetti la cui neoplasia si ripresenta e ha un esito fatale.
- Sopravvivenza libera da insuccesso, definita come proporzione di soggetti che sono ancora in vita, non hanno avuto recidive, non hanno richiesto ulteriore terapia per aGVHD e non hanno evidenziato segni o sintomi di malattia del trapianto contro l’ospite cronica (cGVHD) a 6 mesi.
- Sopravvivenza complessiva (OS), definita come l’intervallo fra l’arruolamento nello studio e il decesso per qualsiasi causa.
- I dati clinici di sicurezza (es. EA, infezioni) saranno riportati in tabelle ed elencati.
- Cmax, Cmin, tmax, AUC e CL/F.
- Tasso di incidenza del rigetto del secondo trapianto, definito come >95% delle cellule del destinatario dopo attecchimento senza segni di recidiva, OPPURE ritrapianto per neutropenia (<0,5 × 109/l) e/o trombocitopenia secondarie (<20 × 109/l) entro 2 mesi dopo il trapianto.
- Dose media e totale di corticosteroidi ai Giorni 28, 56, 100 e 180; proporzione di soggetti che sospendono i corticosteroidi ai Giorni 56 e 100.
- Proporzione di soggetti che sospendono gli immunosoppressori ai Giorni 56 e 100.
-Tasso di incidenza delle esacerbazioni di aGVHD fino al Giorno 100.
- Tasso di incidenza di cGVHD ai Giorni 180 e 365.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

14, 28, 56, 100 giorni
6, 9, 12, 24 mesi

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

Information not present in EudraCT

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.

Lo studio si concluderà quando il 75% dei soggetti avrà raggiunto la mortalità trapianto-correlata a 2 anni, sarà deceduto o risulterà perso al follow-up. La fine dello studio non può essere determinata poiché ogni soggetto arruolato nello studio può continuare a ricevere il trattamento finché non viene osservato il beneficio e/o non sono soddisfatti i criteri di interruzione del trattamento.

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

Nessuno

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

2017-08-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-12

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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