Clinical Trials Register

Summary
EudraCT Number:	2020-005048-46
Sponsor's Protocol Code Number:	D9673C00007
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-02-08
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 - PEI

A.2

EudraCT number

2020-005048-46

A.3

Full title of the trial

An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously-Treated Advanced/Metastatic
HER2-Positive Breast Cancer (DESTINY-Breast12)

A.3.1

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

A study to investigate the efficacy and safety of trastuzumab deruxtecan in patients With or Without Brain Metastasis Who Have Previously-Treated Advanced or Metastatic HER2 Positive Breast Cancer

A.3.2

Name or abbreviated title of the trial where available

DESTINY-Breast12

A.4.1

Sponsor's protocol code number

D9673C00007

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04739761

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	NA
B.5.3.2	Town/ city	NA
B.5.3.3	Post code	NA
B.5.3.4	Country	United States
B.5.4	Telephone number	NA
B.5.5	Fax number	NA
B.5.6	E-mail	information.center@astrazeneca.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	Trastuzumab Deruxtecan
D.3.2	Product code	DS-8201a
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Trastuzumab Deruxtecan
D.3.9.1	CAS number	1599440-13-7
D.3.9.2	Current sponsor code	DS-8201a
D.3.9.3	Other descriptive name	T-DXd
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)	Yes
	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Antibody drug conjugate

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

Treatment of patients with HER2-positive breast cancer with or without brain metastasis

E.1.1.1

Medical condition in easily understood language

Advanced or metastatic HER2-positive breast 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	23.0
E.1.2	Level	PT
E.1.2	Classification code	10065430
E.1.2	Term	HER2 positive breast cancer
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 describe the overall treatment effect of T DXd in HER2-positive MBC
patients with or without baseline BM

E.2.2

Secondary objectives of the trial

1. To describe the treatment effect on the development and progression of BM in patients with or without baseline BM using additional efficacy measurements

2. To describe efficacy in patients with stable or untreated BM

3. To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2-positive MBC patients with or without baseline BM

4. To describe the safety profile of T-DXd

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key inclusion Criteria:
1. Pathologically documented breast cancer that:
(a) Is unresectable/advanced or metastatic, and
(b) Has confirmed HER2-positive status as determined according to ASCO/CAP guidelines (Wolff et al, 2018) evaluated at a local laboratory
2. Participant must have either:
(a) No evidence of BM, or
(b) Untreated BM on screening contrast brain MRI / CT scan
(i)not needing immediate local therapy, or
(ii)For participants with untreated CNS lesions:
- if lesion ≤ 2 cm, no discussion with study physician is required prior to enrollment
- if lesion is > 2.0 cm, discussion with and approval from the study physician is required prior to enrollment, or
(c) Previously treated stable or progressing BM
(i) Previously treated BM with local therapy may either be radiographically stable for ≥ 4 weeks since completion of treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy
(ii) Patients treated with CNS local therapy for newly identified
lesions found on contrast brain MRI/CT scan performed during
screening for this study who also have other sites of disease assessable by RECIST 1.1
3. Participants with BMs brain metastases must be neurologically stable and:
(a) Be receiving the equivalent of dexamethasone ≤ 3 mg/day if treatment is required
(b) If receiving an anticonvulsant regimen, the regimen must have been stable for ≥ 14 days before first day of dosing
(c) Relevant records of any CNS treatment must be available to allow for classification of TLs and NTLs
4. Previous breast cancer treatment:
(a) Radiologic or objective evidence of disease progression on or after HER2 targeted therapies.
Note: Disease progression within 6 months after adjuvant treatment with HER2 targeted therapies is also acceptable.
(b) No more than 2 lines/regimens of therapy in the metastatic setting.
Note: A line/regimen of treatment should be counted based on a
progression event.

E.4

Principal exclusion criteria

1. Known or suspected LMD
2. Prior exposure to tucatinib treatment
3. Based on screening brain MRI, participants must not have any of the following:
(a) Any untreated brain lesions > 2.0 cm in size
(b) Ongoing use of systemic corticosteroids for control of symptoms of BMs at a total daily dose of > 3 mg of dexamethasone (or equivalent).
(c) Any brain lesion thought to require immediate local therapy,
(d) Have poorly controlled (> 1/week) generalized or complex partial seizures, or
manifest neurologic progression due to BMs notwithstanding CNS-directed therapy
4. Has spinal cord compression

E.5 End points

E.5.1

Primary end point(s)

Participants without BM at baseline (Cohort 1):
ORR by RECIST 1.1 per ICR
Participants with BM at baseline (Cohort 2):
PFS by RECIST 1.1 per ICR

E.5.1.1

Timepoint(s) of evaluation of this end point

- assessed until progression or death

E.5.2

Secondary end point(s)

1. Participants in both cohorts:
 - OS
 - DoR by RECIST per ICR
 - Time to progression by RECIST per ICR
 - DoT on subsequent lines of therapy
 - PFS2
Participants without BM at baseline (Cohort 1):
 - Incidence of new symptomatic CNS metastasis during treatment

In patients who develop isolated CNS progression, receive local therapy, and continue on protocol therapy:
 - Time to next progression (CNS or extracranial) or death
 - Site (CNS vs extracranial vs both) of next progression

2. Participants with BM at baseline (Cohort 2):
 - ORR by RECIST 1.1 per ICR
 - CNS PFS by CNS RECIST 1.1 per ICR
 - Time to new CNS lesions
 - CNS ORR by CNS RECIST 1.1 per ICR
 - CNS DoR by CNS RECIST 1.1 per ICR

3. Changes in symptoms, functioning, and HRQoL as measured by
 - All patients: EORTC QLQ-C30, NANO scale, Cognitive Tests
 - BM patients: MDASI brain tumor-specific items
 - ILD/pneumonitis patients: SGRQ-I

4. - Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory results, and ECGs.
Assessments related to AEs will also include:
 - Rate of investigator-assessed ILD/pneumonitis
 - Rate of AEs among patients with baseline BM who are treated with concurrent high-dose
steroid (total daily dose > 2 mg dexamethasone or equivalent)

E.5.2.1

Timepoint(s) of evaluation of this end point

The timepoints for key secondary endpoints are: please see section secondary endpoints for corresponding timepoints below
- assessed until progression or death
- AEs and SAEs throughout the treatment period and including the safety follow-up (40+ up to 7 days after discontinuation of all study interventions)

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

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

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)

Yes

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

Yes

E.8.1.7.1

Other trial design description

2 cohorts

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

Switzerland

Australia

Canada

Japan

Russian Federation

United Kingdom

United States

Belgium

Denmark

Finland

Germany

Ireland

Italy

Netherlands

Norway

Poland

Portugal

Spain

Sweden

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

Completing the last expected visit/contact of the last patient undergoing the study.
He/she has completed all phases of the study as per SoAs (including follow-up for OS).

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:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

333

F.4.2.2

In the whole clinical trial

500

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)

After final DCO for this study, AZ will continue to supply T-DXd to participants who received T-DXd until meeting any discontinuation criteria as defined in Protocol. Where possible, if commercial T-DXd is available in local market then this route should be used. In the event that a roll-over or safety extension study is available at time of final DCO and DB closure, participants currently receiving T-DXd treatment may be transitioned to such a study and would be asked to sign a new ICF.

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

2021-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-06-02

P. End of Trial
P.	End of Trial Status	Ongoing

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