Clinical Trials Register

Summary
EudraCT Number:	2021-001010-10
Sponsor's Protocol Code Number:	na
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-09-06
Trial 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

2021-001010-10

A.3

Full title of the trial

A Phase 2 Open-Label, Multicenter Clinical Study of the Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Profiles of CGT9486 as a Single Agent in Patients With Advanced Systemic Mastocytosis

Studio clinico di fase 2, multicentrico, in aperto, sui profili di sicurezza, efficacia, farmacocinetica e farmacodinamica di CGT9486 quale agente singolo in pazienti con mastocitosi sistemica avanzata

A.3.1

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

A Study of CGT9486 in Patients with Advanced Systemic Mastocytosis

Studio di CTG9486 in pazienti con mastocitosi sistemica avanzata

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04996875

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	Cogent Biosciences, 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	COGENT BIOSCIENCES, 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	Cogent Biosciences, Inc
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	200 Cambridge Park Drive, Suite 2500
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02140
B.5.3.4	Country	United States
B.5.4	Telephone number	+16178303008
B.5.5	Fax number	000000
B.5.6	E-mail	casey.judge@cogentbio.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.3.1	Product name	CGT9486
D.3.2	Product code	[na]
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.3.9.1	CAS number	1616385-51-3
D.3.9.2	Current sponsor code	CGT9486
D.3.9.3	Other descriptive name	PLX9486
D.3.9.4	EV Substance Code	SUB197172
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	50
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Advanced Systemic Mastocytosis (AdvSM)

Mastocitosi Sistemica Avanzata (AdvSM)

E.1.1.1

Medical condition in easily understood language

Mastocytosis

Mastocitosi

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	10056453
E.1.2	Term	Aggressive systemic mastocytosis
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

Part 1: Dose Optimization
- To determine the optimal dose of oral CGT9486 in patients with AdvSM
Part 2: Expansion
- To determine the efficacy of CGT9486 at the selected optimal dose in patients with AdvSM

Parte 1: Ottimizzazione della Dose
Determinare la dose ottimale di CGT9486 per via orale in pazienti con AdvSM
Parte 2: Espansione
Determinare l’efficacia di CGT9486 alla dose ottimale selezionata nei pazienti con AdvSM

E.2.2

Secondary objectives of the trial

Part 1 (Dose Optimization) and Part 2 (Expansion):
- To characterize the safety and tolerability of CGT9486 in patients with AdvSM
- To evaluate additional efficacy parameters with CGT9486 in patients with AdvSM
- To determine the effects of CGT9486 on serum tryptase
- To determine the effects of CGT9486 on KIT D816V mutation allele
burden
- To evaluate histopathologic response in the blood and bone marrow
- To assess the PK of CGT9486 in patients with AdvSM
- To assess patient-reported outcomes in patients with AdvSM

Parte 1 (Ottimizzazione della Dose) e Parte 2 (Espansione):
- Caratterizzare la sicurezza e la tollerabilità di CGT9486 nei pazienti con AdvSM
- Valutare ulteriori parametri di efficacia con CGT9486 nei pazienti con AdvSM
- Determinare gli effetti di CGT9486 sulla triptasi sierica
- Determinare gli effetti di CGT9486 sul carico allelico della mutazione D816V di KIT
- Valutare la risposta istopatologica nel sangue e nel midollo osseo
- Valutare la PK di CGT9486 nei pazienti con AdvSM
- Valutare gli esiti riferiti dai pazienti nei pazienti con AdvSM

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Diagnosed with 1 of the following advanced mastocytosis diagnoses by
Eligibility Committee:
a. Aggressive Systemic Mastocytosis (ASM)
b. Systemic Mastocytosis with an Associated Hematologic Neoplasm (SMAHN)
c. Mast Cell Leukemia (MCL)
2. Measurable disease according to modified IWG-MRT-ECNM criteria
3. ECOG (0 to 3)
4. Have clinically acceptable local laboratory screening results (clinicalchemistry, hematology) within certain limits

1. Diagnosi di mastocitosi avanzata con 1 delle seguenti diagnosi dal Comitato di ammissibilità:
a. Mastocitosi sistemica aggressiva (ASM)
b. Mastocitosi sistemica con neoplasia ematologica associata (SMAHN)
c. Leucemia dei mastociti (MCL)
2. Malattia misurabile secondo i criteri IWG-MRT-ECNM modificati
3. ECOG (da 0 a 3)
4. Avere risultati di screening di laboratorio locale clinicamente accettabili (clinico-chimico, ematologico) entro certi limiti

E.4

Principal exclusion criteria

1. Persistent toxicity from previous therapy for Advanced Systemic Mastocytosis that has not resolved to = Grade 1
2. Associated hematologic neoplasm requiring immediate antineoplastic therapy
3. Clinically significant cardiac disease
4. Known positivity for the FIP1L1 PDGFRA fusion (Patients with eosinophilia without detectable KIT D816V mutation must also lack the PDGFRA fusion mutation prior to enrollment)
5. Seropositive for human immunodeficiency virus (HIV) 1 or 2, positive for hepatitis B surface antigen, or positive for hepatitis C virus (HCV) antibody
6. History of clinically significant bleeding event within 30 days before the first dose of study drug or need for therapeutic anticoagulation on study
7. Diagnosed with or treated for malignancy other than the disease under study within the prior 3 years before enrollment
8. Received any cytoreductive therapy or any investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon, and any antibody therapy less than 28 days, before screening bone marrow biopsy
9. Received hematopoietic growth factor support within 14 days before the first dose of study drug
10. Received strong CYP3A4 inhibitors or inducers before the first dose of study drug
11. Need for treatment with steroids

1. Tossicità persistente da una precedente terapia per la mastocitosi sistemica avanzata che non si è risolta a = grado 1
2. Neoplasia ematologica associata che richiede una terapia antineoplastica immediata
3. Malattia cardiaca clinicamente significativa
4. Positività nota per la fusione FIP1L1 PDGFRA (i pazienti con eosinofilia senza mutazione rilevabile KIT D816V devono anche non avere la mutazione di fusione PDGFRA prima dell'arruolamento)
5. Sieropositivo per il virus dell'immunodeficienza umana (HIV) 1 o 2, positivo per l'antigene di superficie dell'epatite B o positivo per l'anticorpo del virus dell'epatite C (HCV)
6. Storia di un evento emorragico clinicamente significativo entro 30 giorni prima della prima dose del farmaco in studio o necessità di anticoagulazione terapeutica in studio
7. Diagnosi o trattamento per una neoplasia diversa dalla malattia in studio nei 3 anni precedenti l'arruolamento
8. Ricezione di qualsiasi terapia citoriduttiva o di qualsiasi agente sperimentale nei 14 giorni, e per cladribina, interferone alfa, interferone pegilato, e qualsiasi terapia con anticorpi nei 28 giorni, prima della biopsia del midollo osseo di screening
9. Ha ricevuto il supporto del fattore di crescita ematopoietico entro 14 giorni prima della prima dose del farmaco in studio
10. Ha ricevuto forti inibitori o induttori del CYP3A4 prima della prima dose del farmaco in studio
11. Necessità di trattamento con steroidi

E.5 End points

E.5.1

Primary end point(s)

Part 1: Dose Optimization
-Safety assessments and dose modifications; PK and PD assessments;
ORR
Part 2: Expansion
-ORR

Parte 1: Ottimizzazione della dose
-Valutazioni di sicurezza e modifiche della dose; valutazioni PK e PD;
ORR
Parte 2: Espansione
-ORR

E.5.1.1

Timepoint(s) of evaluation of this end point

Defined in the endpoint or according to the time points listed in the Schedule of Assessments and Procedures (Table 1 of the Protocol) and Schedule of Pharmacokinetics, Pharmacodynamics, and Biomarker Assessments (Table 2 of the Protocol)

Definito nell'endpoint o in base alle tempistiche elencate nel Programma di valutazioni e procedure (Tabella 1 del Protocollo) e nel Programma di valutazioni di farmacocinetica, farmacodinamica e biomarcatori (Tabella 2 del Protocollo)

E.5.2

Secondary end point(s)

Part 1 (Dose Optimization) and Part 2 (Expansion):
-Incidence of AEs, SAEs, and AEs leading to dose modifications, and
changes from baseline in laboratory results
-DOR
-TTR
-PFS
-OS
-PPR
-Changes in spleen and liver size
-Changes in serum tryptase levels
-Changes in levels of KIT D816V mutation allele burden
-Change in pathologic findings in the blood and bone marrow
-Plasma concentration of CGT9486
-PGIC and change in the following patient-reported outcome measures: PGIS, MC-QoL, and MAS

Parte 1 (ottimizzazione della dose) e Parte 2 (espansione):
-Incidenza di AEs, SAEs, e AEs che portano a modifiche della dose, e
cambiamenti dal basale nei risultati di laboratorio
-DOR
-TTR
-PFS
-OS
-PPR
-Cambiamenti nelle dimensioni della milza e del fegato
-Cambiamenti nei livelli di triptasi sferica
-Cambiamenti nei livelli di carico allelico della mutazione KIT D816V
-Cambiamenti nei risultati patologici nel sangue e nel midollo osseo
-Concentrazione plasmatica di CGT9486
-PGIC e cambiamento nelle seguenti misure di risultato riferite dal paziente: PGIS, MC-QoL e MAS

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

Tolerability of CGT9486 in patients with AdvSM

Tollerabilità di CGT9486 in pazienti con AdvSM

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

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

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

United States

Austria

France

Poland

Netherlands

Spain

Switzerland

Germany

Italy

Belgium

Norway

United Kingdom

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 continue until all subjects have completed at least 2 years of follow up for overall survival, withdrawn from study participation, been lost to follow-up, or died, whichever occurs first

Lo studio continuerà fino a quando tutti i soggetti non avranno completato almeno 2 anni di follow-up per la sopravvivenza globale, ritirati dallo studio partecipazione, perso al follow-up o deceduto, a seconda di quale evento si verifica per primo

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

140

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

2022-09-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-09-27

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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