Clinical Trials Register

Summary
EudraCT Number:	2018-000635-27
Sponsor's Protocol Code Number:	2002
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-08-14
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

Germany - BfArM

A.2

EudraCT number

2018-000635-27

A.3

Full title of the trial

Brigatinib in Patients With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non–Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib

A.3.1

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

Brigatinib in Patients With Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non–Small-Cell Lung Cancer (NSCLC) Progressed on Alectinib or Ceritinib

A.4.1

Sponsor's protocol code number

2002

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	ARIAD Pharmaceuticals, Inc.(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd.)
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	ARIAD Pharmaceuticals, Inc.(a wholly-owned subsidiary of Takeda Pharmaceutical Ltd.)
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	Takeda Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Diana Aronin
B.5.3	Address:
B.5.3.1	Street Address	40 Landsdowne Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02139
B.5.3.4	Country	United States
B.5.4	Telephone number	+1617444 4423
B.5.5	Fax number	+1617551 3742
B.5.6	E-mail	diana.aronin@takeda.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	Yes
D.2.1.1.1	Trade name	Alunbrig
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Brigatinib
D.3.2	Product code	AP26113
D.3.4	Pharmaceutical form	Film-coated 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	Brigatinib
D.3.9.1	CAS number	1197953-54-0
D.3.9.2	Current sponsor code	AP26113
D.3.9.3	Other descriptive name	AP26113
D.3.9.4	EV Substance Code	SUB32682
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	90
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	Yes
D.2.1.1.1	Trade name	Alunbrig
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Brigatinib
D.3.2	Product code	AP26113
D.3.4	Pharmaceutical form	Film-coated 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	Brigatinib
D.3.9.1	CAS number	1197953-54-0
D.3.9.2	Current sponsor code	AP26113
D.3.9.3	Other descriptive name	AP26113
D.3.9.4	EV Substance Code	SUB32682
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	180
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: 3
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	Yes
D.2.1.1.1	Trade name	Alunbrig
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Brigatinib
D.3.2	Product code	AP26113
D.3.4	Pharmaceutical form	Film-coated 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	Brigatinib
D.3.9.1	CAS number	1197953-54-0
D.3.9.2	Current sponsor code	AP26113
D.3.9.3	Other descriptive name	AP26113
D.3.9.4	EV Substance Code	SUB32682
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	30
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

Anaplastic Lymphoma Kinase-Positive (ALK+), Advanced Non–Small-Cell Lung Cancer (NSCLC)

E.1.1.1

Medical condition in easily understood language

Metastatic or locally advanced non-small cell lung cancer

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	10059515
E.1.2	Term	Non-small cell lung cancer metastatic
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

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the efficacy of brigatinib, as evidenced by confirmed objective response rate (ORR), in patients with ALK+ locally advanced or metastatic NSCLC whose disease has progressed on therapy with alectinib or ceritinib.

E.2.2

Secondary objectives of the trial

1. To characterize the durability of efficacy with brigatinib.
2. To assess intracranial efficacy of brigatinib.
3. To assess the overall survival (OS).
4. To assess the safety and tolerability of brigatinib.
5. To collect plasma concentration-time data for brigatinib to contribute to population pharmacokinetic analyses.
6. To assess patient-reported symptoms and health-related quality of life (HRQOL).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent and not a participant for curative therapy) or stage IV non–small-cell lung cancer (NSCLC).
2. Must meet both of the following 2 criteria:
a. Have documentation of anaplastic lymphoma kinase (ALK) rearrangement by a positive result from any laboratory test® approved by the food and drug administration (FDA) or Have documented ALK rearrangement by a different test (non–FDA-approved local lab tests) and have provided tumor sample to the central laboratory. (Note: Central laboratory ALK rearrangement testing results are not required to be obtained before randomization.)
b. Had been on any one of the ALK tyrosine kinase inhibitor (TKIs) (alectinib, ceritinib, crizotinib) for at least 12 weeks before progression.
3. Had progressive disease (PD) while on alectinib or ceritinib
4. Had alectinib or ceritinib as the most recent ALK inhibitor therapy.
5. Have at least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 as assessed by the investigator.
6. Had recovered from toxicities related to prior anticancer therapy to national cancer institute common terminology criteria for adverse events (NCI CTCAE), version 4.03, Grade =1. (Note: Treatment-related alopecia or peripheral neuropathy that are Grade >1 are allowed if deemed irreversible.) and have adequate major organ functions.
7. Have a life expectancy of ≥3 months.

E.4

Principal exclusion criteria

1. Had received any prior ALK-targeted TKI other than crizotinib, alectinib, or ceritinib.
2. Had received both alectinib and ceritinib.
3. Had previously received more than 3 regimens of systemic anticancer therapy for locally advanced or metastatic disease.
4. Had symptomatic brain metastasis (parenchymal or leptomeningeal). Participants with asymptomatic brain metastasis or who have stable symptoms that did not require an increased dose of corticosteroids to control symptoms in the past 7 days before the first dose of brigatinib may be enrolled.
5. Had current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Participants with leptomeningeal disease and without cord compression are allowed.
6. Had a cerebrovascular accident or transient ischemic attack within 6 months before first dose of brigatinib.
7. Had an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics.
8. Had malabsorption syndrome or other gastrointestinal (GI) illness that could affect oral absorption of brigatinib.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is confirmed ORR, as assessed by the IRC, per Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 in the full analysis set population.

E.5.1.1

Timepoint(s) of evaluation of this end point

Overall timeframe will be pending on final sample size.

E.5.2

Secondary end point(s)

1. Confirmed ORR, as assessed by the investigator, per RECIST version 1.1.
2. DOR as assessed by the investigator and IRC.
3. PFS as assessed by the investigator and IRC.
4. Disease control rate (DCR), defined as best overall response of complete response (CR), partial response (PR) or
stable disease (SD) ≥6 weeks by RECIST version 1.1, as assessed by the investigator and IRC.
5. Time to response as assessed by the investigator and IRC.
6. Confirmed iORR in patients with brain metastases at baseline, as assessed by the IRC.
7. Duration of intracranial response in patients with brain metastases at baseline, as assessed by the IRC.
8. Intracranial progression-free survival (iPFS) in patients with brain metastases at baseline, as assessed by the IRC.
9. OS.
10. Safety/tolerability (CTCAE version 4.03).
11. HRQOL assessed with the global health status/quality of life (QOL) and other function and symptom from
EORTC QLQ-C30 (version 3.0), and EORTC QLQ-LC13.

E.5.2.1

Timepoint(s) of evaluation of this end point

Overall timeframe will be pending on final sample size.

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

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

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

To evaluate exploratory biomarkers

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.8.2.4

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

Austria

Canada

China

France

Germany

Hong Kong

Israel

Italy

Korea, Republic of

Netherlands

Spain

Sweden

Taiwan

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 when either all patients die or 3 years have passed since the last patient started
study treatment, whichever comes first.

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

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

103

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)

Patients will continue to be treated with brigatinib until they experience objective disease progression per RECIST version 1.1, as assessed by the investigator, or intolerable toxicity. With medical monitor approval, treatment may be continued at 180 mg QD or may be escalated to 240 mg QD after initial progression if there is still potential for clinical benefit.

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

2018-10-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-23

P. End of Trial
P.	End of Trial Status	Completed

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