Clinical Trials Register

Summary
EudraCT Number:	2020-003657-30
Sponsor's Protocol Code Number:	DAY101001
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-06-22
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

Denmark - DHMA

A.2

EudraCT number

2020-003657-30

A.3

Full title of the trial

FIREFLY-1: A Phase 2, Open-Label, Multicenter Study to Evaluate the
Safety and Efficacy of the Oral Pan-RAF Inhibitor DAY101 in Pediatric
Patients with RAF-Altered, Recurrent or Progressive Low-Grade Glioma and
Advanced Solid Tumors

A.3.1

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

A Phase 2 Study to Test Effects of Using DAY101 in Children with Brain Cancer

A.3.2

Name or abbreviated title of the trial where available

FIREFLY-1

A.4.1

Sponsor's protocol code number

DAY101001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04775485

A.5.4

Other Identifiers

Name:

IND

Number:

108340

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/442/2023

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Day One Biopharmaceuticals, Inc. (Day One)
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	Day One Biopharmaceuticals, Inc. (Day One)
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	Parexel International (IRL) Limited
B.5.2	Functional name of contact point	Melissa Kenny
B.5.3	Address:
B.5.3.1	Street Address	70 Sir John Rogerson's Quay
B.5.3.2	Town/ city	Dublin
B.5.3.3	Post code	2
B.5.3.4	Country	Ireland
B.5.4	Telephone number	-
B.5.6	E-mail	clinicaltrial.enquiries@parexel.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/3/21/2434
D.3 Description of the IMP
D.3.1	Product name	Tovorafenib
D.3.2	Product code	DAY101
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.3.8	INN - Proposed INN	Tovorafenib
D.3.9.1	CAS number	1096708-71-2
D.3.9.2	Current sponsor code	DAY101
D.3.9.3	Other descriptive name	MLN2480, TAK-580, BSK1369, BIIB024, QHA01, C200601001-FP
D.3.9.4	EV Substance Code	SUB89679
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/21/2434
D.3 Description of the IMP
D.3.1	Product name	Tovorafenib
D.3.2	Product code	DAY101
D.3.4	Pharmaceutical form	Powder for oral suspension
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tovorafenib
D.3.9.1	CAS number	1096708-71-2
D.3.9.2	Current sponsor code	DAY101
D.3.9.3	Other descriptive name	MLN2480, TAK-580, BSK1369, BIIB024, QHA01, C200601001-FP
D.3.9.4	EV Substance Code	SUB89679
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	300
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

RAF-Altered, Recurrent or Progressive Low-Grade Glioma and Advanced
Solid Tumors in pediatric patients.

E.1.1.1

Medical condition in easily understood language

Brain tumor in children and young adults

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10065443
E.1.2	Term	Malignant glioma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

Arm 1 (Low-Grade Glioma)
To evaluate the efficacy of tovorafenib as measured by the overall response rate as determined by an independent radiology review committee following treatment with tovorafenib in pediatric patients aged 6 months to 25 years, inclusive, with a relapsed or progressive low-grade glioma harboring a known activating BRAF alteration.

Arm 2 (Low-Grade Glioma Extension)
To assess the safety and tolerability of tovorafenib in pediatric patients aged 6 months to 25 years, inclusive, with a relapsed or progressive low-grade glioma harboring a known or expected to be activating RAF alteration.

Arm 3 (Advanced Solid Tumor)
To evaluate the preliminary efficacy of tovorafenib as measured by the overall response rate as determined by the treating investigator following treatment with tovorafenib in pediatric patients aged 6 months to 25 years, inclusive, with a relapsed or progressive advanced solid tumor harboring a known or expected to be activating RAF fusion.

E.2.2

Secondary objectives of the trial

Arm 1 (Low-Grade Glioma):
- To assess safety and tolerability of tovorafenib
- To determine the relationship between pharmacokinetics (PK) and drug effects, including efficacy and safety

Arm 2 (Low-Grade Glioma Extension):
- To determine the ORR based on RANO-HGG criteria as determined by the treating investigator

Arm 3 (Advanced Solid Tumor):
-To assess the safety and tolerability of tovorafenib in pediatric patients with advanced solid tumors

For the complete list of secondary objectives please refer to the protocol
Section 2 "Study Objectives".

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients must be age 6 months to 25 years, inclusive, with:
a) Arm 1 (Low-Grade Glioma): A relapsed or progressive low-grade
glioma (LGG) with a documented known activating BRAF alteration.
b) Arm 2 (Low-Grade Glioma Extension): A relapsed or progressive low-
grade glioma with a
documented known or expected to be activating BRAF mutation or RAF
fusion.
c) Arm 3 (Advanced Solid Tumor): Locally advanced or metastatic solid
tumor with a documented
known or expected to be activating RAF fusion.

- Patients must have histopathologic verification of malignancy at either
original diagnosis or relapse.

- Must have received at least one line of prior systemic therapy and have
documented evidence of radiographic progression

- Patients must have evaluable and/or measurable disease as specified
below:
a) Arm 1 (Low-Grade Glioma):Must have at least one measurable lesion.
b) Arm 2 (Low-Grade Glioma Extension): Must have evaluable and/or
measurable disease
c) Arm 3 (Advanced Solid Tumor): Must have at least one measurable
lesion

- Patients must have Karnofsky (those 16 years and older) or Lansky
(those younger than 16 years) performance score of at least 50.

For the complete list of the inclusion criteria, please refer to the
protocol.

E.4

Principal exclusion criteria

- Patient has symptoms of clinical progression without radiographically recurrent or radiographically progressive disease.
- Patient has history of any major disease, other than the primary malignancy under study, that might interfere with safe protocol participation
- Patient has major surgery within 14 days (2 weeks) prior to C1D1
- Patient has clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to C1D1
- Patient is currently enrolled in any other investigational treatment study. Participation in a concurrent observational or bio-sampling study is allowed.

For the complete list of the exclusion criteria, please refer to the protocol.

E.5 End points

E.5.1

Primary end point(s)

Arm 1 (Low-Grade Glioma):
ORR by RANO-HGG criteria

Arm 2 (Low-Grade Glioma Extension)
Type, frequency, and severity of adverse events (AEs) and laboratory
abnormalities

Arm 3 (Advanced Solid Tumor)
Measured by the proportion of patients with best overall confirmed
response of complete response
(CR) or partial response (PR) by RECIST v1.1 criteria

E.5.1.1

Timepoint(s) of evaluation of this end point

Please see Appendix A of the protocol.

E.5.2

Secondary end point(s)

Arm 1 (Low-Grade Glioma):
-Type, frequency, and severity of AEs and laboratory abnormalities
- Pharmacokinetic profile of DAY101 (e.g., area under the concentration-time curve [AUC], Cmin, etc.)
- time following initiation of DAY101 to progression or death in patients treated with DAY101
- length of response in patients with best overall confirmed response of CR or PR
- time to first response following initiation of DAY101 in patients with best overall confirmed response of CR or PR

Arm 2 (Low-Grade Glioma Extension):
- Measured by the proportion of patients with best overall confirmed response of CR or PR as
determined by the RANO criteria
-Measured by the proportion of patients with best overall confirmed response of CR or PR by
RAPNO–low-grade glioma criteria

Arm 3 (Advanced Solid Tumor):
-Type, frequency, and severity of AEs and laboratory abnormalities
-Pharmacokinetic profile of DAY101 (e.g., AUC, Cmin, etc.)

For the complete list of secondary endpoints please refer to the protocol

E.5.2.1

Timepoint(s) of evaluation of this end point

Please see Appendix A of the protocol for further details.

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

Yes

E.6.13.1

Other scope of the trial description

Tolerability

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.8.3

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

Singapore

Switzerland

Australia

Canada

Israel

Korea, Republic of

United Kingdom

United States

Denmark

Germany

Netherlands

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

LSLV

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

Yes

F.1.1

Number of subjects for this age range:

140

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Young children not of age to provide consent. Parents/guardians may give consent on behalf of their children.

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Pacific Pediatric Neuro-Oncology Consortium (PNOC)
G.4.3.4	Network Country	United States

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-08-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-29

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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