Clinical Trials Register

Summary
EudraCT Number:	2021-000603-21
Sponsor's Protocol Code Number:	D967RC00001
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-12-08
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2021-000603-21

A.3

Full title of the trial

A Phase 3 Open-label Trial of Neoadjuvant Trastuzumab Deruxtecan (T-DXd) Monotherapy or T-DXd followed by THP Compared to ddAC-THP in Participants with High-risk
HER2-positive Early-stage Breast Cancer (DESTINY-Breast11)

Otwarte badanie III fazy dotyczące leczenia neoadjuwantowego trastuzumabem derukstekanem (T-Dxd) w monoterapii lub T-Dxd w sekwencji ze schematem THP (paklitaksel + trastuzumab + pertuzumab) w porównaniu do schematu ddAC-THP (doksorubicyna + cyklofosfamid, a następnie THP) u chorych na raka piersi o wysokim ryzyku z nadmierną ekspresją HER2 we wczesnym stadium (DESTINY-Breast11)

A.3.1

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

DESTINY-Breast11 will compare trastuzumab deruxtecan (T-DXd) alone or in sequence with other medications, known as THP, with standard of care treatment (ddAC-THP) and determine its safety and efficacy in patients with HER2-positive early breast cancer.

DESTINY-Breast11 badanie porównujące leczenie trastuzumabem derukstekanem (T DXd) lub leczenia T-DXd, a następnie innymi lekami określonymi jako THP w porównaniu z terapią standardową (ddAC-THP) i określające jego bezpieczeństwo i skuteczność u chorych na raka piersi o wysokim ryzyku z nadmierną ekspresją HER2 we wczesnym stadium

A.3.2

Name or abbreviated title of the trial where available

DESTINY-Breast11

A.4.1

Sponsor's protocol code number

D967RC00001

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	Karlebyhus Astraallen
B.5.3.2	Town/ city	Södertälje
B.5.3.3	Post code	SE 51 85
B.5.3.4	Country	Sweden
B.5.6	E-mail	ClinicalTrialTransparency@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	DS8201a
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	No
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.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	Bentadax
D.2.1.1.2	Name of the Marketing Authorisation holder	Bendalis GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Paclitaxel
D.3.4	Pharmaceutical form	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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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	perjeta
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Pharma (Schweiz) AG, Basel
D.2.1.2	Country which granted the Marketing Authorisation	Switzerland
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	Pertuzumab
D.3.4	Pharmaceutical form	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	Pertuzumab
D.3.9.1	CAS number	380610-27-5
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	No
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	No
D.IMP: 4
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	Herzuma
D.2.1.1.2	Name of the Marketing Authorisation holder	Celltrion Healthcare Hungary Kft.
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	Trastuzumab
D.3.4	Pharmaceutical form	Powder 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
D.3.9.1	CAS number	180288-69-1
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
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	Doxorubicin Teva 2mg/ml Concentration for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Doxorubicin
D.3.4	Pharmaceutical form	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	Doxorubicin
D.3.9.1	CAS number	23214-92-8
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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: 6
D.1.2 and D.1.3	IMP Role	Comparator
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	Endoxan
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter Oncology
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Cyclophosphamide
D.3.4	Pharmaceutical form	Powder for solution for injection
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	Cyclophosphamide
D.3.9.1	CAS number	50-18-0
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	500
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: 7
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	perjeta
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	Pertuzumab
D.3.4	Pharmaceutical form	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	Pertuzumab
D.3.9.1	CAS number	380610-27-5
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	No
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	No
D.IMP: 8
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	Bentadax
D.2.1.1.2	Name of the Marketing Authorisation holder	Bendalis GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Paclitaxel
D.3.4	Pharmaceutical form	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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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: 9
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	Paclitaxel 6 mg/ml Concentrate for Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Paclitaxel
D.3.4	Pharmaceutical form	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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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: 10
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	Paclitaxel Hospira 6mg/ml Concentrate for Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA PRODUCTOS FARMACÉUTICOS Y HOSPITALARIOS S.L
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Paclitaxel
D.3.4	Pharmaceutical form	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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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: 11
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	Paclitaxel Amneal 6mg/ml Concentrate for Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Amneal Pharma Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Paclitaxel
D.3.4	Pharmaceutical form	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	Paclitaxel
D.3.9.1	CAS number	33069-62-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
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: 12
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	Ontruzant
D.2.1.1.2	Name of the Marketing Authorisation holder	Samsung Bioepis NL B.V.
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	Trastuzumab
D.3.4	Pharmaceutical form	Powder 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
D.3.9.1	CAS number	180288-69-1
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	No
D.IMP: 13
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	Trazimera
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Europe MA EEIG
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	Trastuzumab
D.3.4	Pharmaceutical form	Powder 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
D.3.9.1	CAS number	180288-69-1
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	No
D.IMP: 14
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	Kanjinti
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V
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	Trastuzumab
D.3.4	Pharmaceutical form	Powder 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
D.3.9.1	CAS number	180288-69-1
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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	No
D.IMP: 15
D.1.2 and D.1.3	IMP Role	Comparator
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	Doxorubicin Hydrochloride Bendalis 2mg/ml Solution for Injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Bendalis GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Doxorubicin
D.3.4	Pharmaceutical form	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	Doxorubicin
D.3.9.1	CAS number	23214-92-8
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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: 16
D.1.2 and D.1.3	IMP Role	Comparator
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	Doxorubicin Hydrochloride (Adrimedac) 2mg/ml Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Doxorubicin
D.3.4	Pharmaceutical form	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	Doxorubicin
D.3.9.1	CAS number	23214-92-8
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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: 17
D.1.2 and D.1.3	IMP Role	Comparator
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	Ribodoxo® 2 mg/ml Solution for Injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Hikma Farmacêutica (Portugal)
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Doxorubicin
D.3.4	Pharmaceutical form	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	Doxorubicin
D.3.9.1	CAS number	23214-92-8
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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

Early stage HER2-positive breast cancer (T stage >= T3, lymph node positive, or inflammatory)

HER2-pozytywny rak piersi we wczesnym stadium (stadium T: ≥ T3, z zajętymi węzłami chłonnymi lub zapalny)

E.1.1.1

Medical condition in easily understood language

Early breast cancer

Rak piesi we wczesnym stadium

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10025541
E.1.2	Term	Malignant breast neoplasm
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This is a Phase 3, open-label, three-arm study to determine the safety and efficacy of T-DXd monotherapy or T-DXd followed by THP as neoadjuvant treatment compared to standard of care (ddAC-THP) in participants with locally advanced or inflammatory HER2-positive early breast cancer.

The target population of interest in this study is participants with high-risk HER2-positive early breast cancer. Participants will be randomized in a 1:1:1 ratio to one of the following intervention groups: T DXd monotherapy (Arm A), T-DXd followed by THP (Arm B), or ddAC-THP (Arm C).

The primary objective is to demonstrate the superiority of neoadjuvant T-DXd alone or in sequence with THP relative to ddAC-THP by assessment of pCR (pathological complete response, ypT0/Tis ypN0) using central evaluation in participants with HER2-positive early breast cancer.

Jest to badanie fazy III, prowadzone metodą otwartej próby w 3 grupach leczenia, oceniające bezpieczeństwa i skuteczności neoadiuwantowej monoterapii trastuzumabem derukstekanem (T-DXd) lub leczenia T-DXd, a następnie paklitaksel + trastuzumab + pertuzumab (THP), w porównaniu z leczeniem doksorubicyna + cyklofosfamid, następnie paklitaksel + trastuzumab + pertuzumab (ddAC-THP) u uczestników z miejscowo zaawansowanym lub zapalnym HER2-pozytywnym rakiem piersi we wczesnym stadium.
Populacja badana to uczestnicy z HER2-ppozytywnym rakiem piersi wysokiego ryzyka we wczesnym stadium. Uczestnicy będą randomizowani w stosunku 1:1:1 do jednej z grup: monoterapia T DXd (grupa A), T-DXd, a następnie THP (grupa B) lub ddAC-THP (grupa C).
Głównym celem badania jest wykazanie przewagi neoadiuwantowego leczenia T-DXd w monoterapii lub po kolei z THP względem ddAC-THP drogą oceny pCR (ypT0/Tis ypN0) w oparciu o centralne badanie uczestników z HER2-pozytywnym rakiem piersi we wczesnym stadium

E.2.2

Secondary objectives of the trial

To assess the effectiveness of neoadjuvant T-DXd alone or in sequence with THP relative to ddAC-THP by assessment of a (i) secondary definition of pCR (ypT0/Tis ypN0) using central evaluation, (ii) 3-year EFS (event-free survival), (iii) 3-year IDFS (invasive-disease free survival), and (iv) OS (overall survival). Data will also be collected to demonstrate the tolerability, safety, immunogenicity and PK of the investigational product.

Ocenić skuteczność neoadiuwantowego leczenia produktem T-DXd w monoterapii lub po kolei z THP względem ddAC-THP drogą oceny (i) drugorzędowej definicji pCR (ypT0 ypN0) w oparciu o centralne badanie, (ii) wskaźnika czasu przeżycia bez zdarzeń (EFS) po upływie 3 lat, (iii) wskaźnika czasu przeżycia bez choroby inwazyjnej (IDFS) po upływie 3 lat i (iv) całkowitego czasu przeżycia (OS). Zbierane będą także dane dotyczące tolerancji, bezpieczeństwa, immunogenności i farmakokinetyki badanego produktu.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key Inclusion Criteria:
- Patients must be at least 18 years of age.
- Histologically documented HER2-positive EBC participants with:
(a) Locally assessed HER2-positive (IHC 3+ or ISH+) according to ASCO-CAP guidelines and prospectively centrally confirmed as HER2 positive based on a tumour sample

(b) Unifocal and multifocal tumours (> 1 tumour confined to the same quadrant as the primary tumour) must have 1 focus sampled and centrally confirmed as HER2 positive

(c) Multi-centric tumours (multiple tumours involving > 1 quadrant of the breast) must have 1 lesion from each involved quadrant sampled and centrally confirmed as HER2 positive. All quadrants tested must be centrally confirmed as HER2 positive

(d) Tumours documented as HR-positive (either ER and/or PgR positive [ER or PgR ≥ 1%]) or HR-negative (ER and PgR negative) by local assessment per ASCO-CAP guidelines (Allison et al 2020)

(e) Clinical stage at presentation (based on mammogram or breast MRI assessment): T0-4 (inclusive of inflammatory breast cancer), N1-3, M0 or ≥ T3, N0, M0 as determined by the AJCC staging system, 8th edition (Hortobagyi et al 2017)

(f) Pathologic confirmation of nodal involvement with malignancy as determined by fine-needle aspiration or core-needle biopsy, when applicable.

- FFPE tissue block (2 cores) or 20 freshly-cut, serial tumor slides for HER2 assessment by central lab. If blocks are incomplete or fewer than 20 slides are available, participants may be eligible following discussion with the AstraZeneca Study Physician
- ECOG performance status of 0 or 1 at randomization
- Adequate organ and bone marrow function
- LVEF ≥ 50% within 28 days before randomization

1. Kobiety lub mężczyźni w wieku ≥ 18 lat
2. Uczestnicy z histologicznie udokumentowanym HER2-pozytywnym EBC oraz:
a. Ocenionym miejscowo rakiem HER2-pozytywnym (IHC 3+ lub ISH+) wg wytycznych ASCO-CAP (patrz załącznik N) i prospektywnie potwierdzonym w centralnym badaniu jako HER2 pozytywny w oparciu o próbkę guza
b. Guzem jednoogniskowym lub w przypadku guzów wieloogniskowych (> 1 guz ograniczony do tego samego kwadrantu co guz pierwotny) należy pobrać próbkę z 1 ogniska, która musi w centralnym badaniu zostać potwierdzona jako HER2 pozytywna
c. W przypadku guzów wieloośrodkowych (liczne guzy obejmujące > 1 kwadrant piersi) należy pobrać próbkę 1 zmiany z każdego zajętego kwadrantu, która musi w centralnym badaniu zostać potwierdzona jako HER2 pozytywna. Wszystkie badane kwadranty muszą w centralnym badaniu zostać potwierdzone jako HER2 pozytywne
d. Guzy udokumentowane jako HR-pozytywne (ER i/lub PgR-pozytywne [ER lub PgR ≥ 1%]) lub HR-negatywne (ER i PgR-negatywne) ocenione miejscowo zgodnie z wytycznymi ASCO-CAP (Allison i wsp., 2020)
e. Stadium kliniczne w chwili wykrycia (w oparciu o mammografię lub RM piersi): T0 4 (włącznie z zapalnym rakiem piersi), N1-3, M0 lub ≥ T3, N0, M0 wg systemu klasyfikacji stopnia zaawansowania AJCC, wydanie VIII (Kueng i Gershenwald 2020)
f. Histopatologiczne potwierdzenie zajęcia węzłów chłonnych z nowotworem złośliwym stwierdzonym w oparciu o biopsję aspiracyjną cienkoigłową lub gruboigłową, jeśli dotyczy
3. Odpowiednia próbka guza w postaci bloków tkanek FFPE (co najmniej 2 biopsje gruboigłowe) lub 20 świeżo wyciętych, seryjnych preparatów guza do oceny pod kątem HER2 w laboratorium centralnym. Jeśli bloki tkankowe są niekompletne lub dostępnych jest mniej niż 20 „slajdów”, uczestnicy mogą kwalifikować się po dyskusji z Monitorem Medycznym badania, który jest członkiem AstraZeneca
4. Stan sprawności w momencie randomizacji wynoszący 0 lub 1 wg ECOG
5. Wydolna czynność narządów i szpiku kostnego
6. LVEF ≥ 50% w okresie 28 dni przed randomizacją

E.4

Principal exclusion criteria

Key Exclusion Criteria:
- Prior history of invasive breast cancer
- Any primary malignancy within 3 years, except adequately resected non-melanoma skin cancer, or curatively treated in situ disease
Note: This includes a second current breast primary malignancy (ie, bilateral breast cancer)
- History of DCIS, except for participants treated with mastectomy only > 5 years prior to current diagnosis
- Prior sentinel lymph node biopsy or axillary lymph node dissection before initiation of neoadjuvant treatment
- Prior systemic therapy for the treatment of breast cancer
- Previous treatment with anthracyclines, cyclophosphamide or taxanes for any malignancy; cyclophosphamide allowed for non-cancer treatment if last dose > 6 months
- Ineligible for any medication in the control Arm C
- Any concurrent anticancer treatment
- History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any pulmonary disorder
- Investigator judgement of 1 or more of the following:
(a) Mean resting corrected QTcF interval of >470 ms (females) or >450 ms (males)

(b) History of QT prolongation associated with other medications that required discontinuation of that medication or any medication known to prolong QT interval and cause TdP.

(c) Congenital long QT syndrome, family history of long QT syndrome or unexplained death under 40 years in first degree relatives

- History of arrhythmia, symptomatic or uncontrolled atrial fibrillation or asymptomatic sustained ventricular tachycardia

1. Inwazyjny rak piersi w wywiadzie
2. Dowolny pierwotny nowotwór złośliwy w okresie 3 lat, z wyjątkiem odpowiednio usuniętego nieczerniakowego raka skóry lub choroba poddana radykalnemu leczeniu in situ
Uwaga: Obejmuje to drugi obecny pierwotny nowotwór złośliwy piersi (tj. obustronny rak piersi)
3. DCIS w wywiadzie, z wyjątkiem uczestników poddanych tylko mastektomii > 5 lat przez obecnym rozpoznaniem
4. Biopsja węzła wartowniczego lub usunięcie pachowego węzła chłonnego przed rozpoczęciem terapii neoadiuwantowej
5. Wcześniejsze leczenie ogólnoustrojowe w leczeniu raka piersi
6. Wcześniejsze leczenie dowolnego nowotworu złośliwego antracyklinami, cyklofosfamidem lub taksanami; leczenie cyklofosfamidem jest dozwolone, jeśli ostatnia dawka została podana > 6 miesięcy (przed obecnym rozpoznaniem)
7. Uczestnik nie kwalifikuje się do przyjmowania jakichkolwiek leków w grupie kontrolnej A
8. Jakiekolwiek równocześnie stosowane leczenie przeciwnowotworowe
9. ILD (niezakaźna)/zapalenie płuc w wywiadzie, które wymagały podania steroidów, aktualnie ILD/zapalenie płuc lub brak możliwości wykluczenia podejrzenia ILD/zapalenia płuc w badaniu obrazowym podczas oceny przesiewowej
10. Współistniejące istotne klinicznie choroby dotyczące płuc, w tym między innymi jakakolwiek podstawowa choroba płuc
11. W ocenie badacza 1 lub więcej z poniższych:
a. Średni skorygowany odstęp QTcF w spoczynku > 470 ms (kobiety)
lub > 450 ms (mężczyźni)
b. Stwierdzone w wywiadzie wydłużenie odstępu QT związane z innymi lekami, które wymagało odstawienia tych leków, lub jakiekolwiek równolegle przyjmowane leki, o których wiadomo, że prowadzą do wydłużenia odstępu QT i do TdP
c. Wrodzony zespół długiego odstępu QT, zespół długiego odstępu QT lub niewyjaśnione nagłe zgony przed ukończeniem 40 lat w wywiadzie rodzinnym u krewnych pierwszego stopnia
12. Zaburzenia rytmu serca w wywiadzie, objawowe lub niewyrównane migotanie przedsionków, bądź bezobjawowy utrwalony częstoskurcz komorowy

E.5 End points

E.5.1

Primary end point(s)

pCR (ypT0/Tis ypN0): Rate of pCR is defined as the proportion of participants who have no evidence by H&E staining of residual invasive disease in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0) by central evaluation following completion of neoadjuvant therapy.

pCR (ypT0/Tis ypN0): definiowany jako odsetek uczestników, u których barwienie H+E nie wykazało obecności resztkowej choroby inwazyjnej w całości poddanej resekcji próbki tkanki piersiowej ani w żadnych próbkach z regionalnych węzłów chłonnych (ypT0/Tis ypN0) w oparciu o centralne badanie, po zakończeniu terapii neoadiuwantowej.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients should undergo surgery no earlier than 3 weeks and no later than 6 weeks following administration of the last cycle of the randomized treatment. Surgical specimens will be sent for central assessment of pCR.

Pacjenci powinni przejść zabieg chirurgiczny nie wcześniej niż 3 tygodnie i nie później niż 6 tygodni po podaniu ostatniego cyklu randomizowanego leczenia. Próbka pobrana podczas zabiegu będzie wysłana w celu dokonania centralnej oceny pCR.

E.5.2

Secondary end point(s)

1) pCR (ypT0 ypN0): Rate of pCR is defined as the proportion of participants who have no evidence by H&E staining of residual invasive disease and in situ cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0 ypN0) following completion of neoadjuvant therapy..

2) EFS

3) IDFS

4) OS

5) HRQoL: Symptomatic AEs assessed by the PRO CTCAE and items from the EORTC Item Library. Overall side-effect bother measured by PGI-TT at each time point in each treatment arm. Physical function assessed by the EORTC QLQ-C30 Physical Function Scale. The measure of interest will be the proportion of participants who have maintained or improved physical functioning while on neoadjuvant treatment, as measured by EORTC QLQ-C30 at each time point in each treatment arm.

6) Safety and Tolerability: Safety and tolerability will be evaluated in terms of occurrence of AEs, SAEs and changes from baseline in vital signs, clinical laboratory results, ECGs, and ECHO/MUGA.

Heart failure: NYHA Class III and IV heart failure during the neoadjuvant treatment period (pre- and post‑surgery) and at end of study

Decreases in LVEF will be evaluated by determining the percentage of participants with decreases in LVEF of at least 10 points from baseline and to below 50% during neoadjuvant treatment period (pre- and post‑surgery).

7) PK of T-DXd: Serum concentration of T-DXd, anti-HER2 antibody, and DXd.

8) Immunogenicity for T-DXd: Number and percentage of participants who develop ADAs for T-DXd.

1. pCR (ypT0 ypN0): definiowany jako odsetek uczestników, u których barwienie H+E nie wykazało obecności resztkowej choroby inwazyjnej w całości poddanej resekcji próbki tkanki piersiowej ani w żadnych próbkach z regionalnych węzłów chłonnych (ypT0 ypN0) po zakończeniu terapii neoadiuwantowej.
2. EFS
3. IDFS
4. OS
5. HRQoL: Objawowe AE ocenione przy użyciu kwestionariuszy PRO CTCAE oraz punktów wybranych z biblioteki punktów EORCT. Ogólne obciążenie zdarzeniami niepożądanymi zmierzone przy użyciu kwestionariuszy PGI-TT w każdym punkcie czasowym w każdej grupie leczenia. Funkcjonowanie fizyczne ocenione w oparciu o EORTC Skala funkcjonowania fizycznego QLQ-C30. Analizowanym parametrem będzie odsetek uczestników, których zakres funkcjonowania fizycznego utrzymał się lub uległ poprawie w okresie leczenia neoadiuwantowego, w oparciu o pomiar EORTC QLQ-C30 w każdym punkcie czasowym w każdej grupie leczenia
6. Bezpieczeństwo i tolerancja: Bezpieczeństwo i tolerancja będą oceniane na podstawie występowania AE, SAE oraz zmian od oceny wyjściowej w zakresie podstawowych parametrów życiowych, wyników badań laboratoryjnych, EKG oraz ECHO/MUGA.
Niewydolność serca zostanie oceniona drogą ustalenia odsetka uczestników z niewydolnością serca klasy III i IV wg NYHA w okresie leczenia neoadiuwantowego (przed i po zabiegu chirurgicznym) i na koniec badania.
Zmniejszenie LVEF zostanie ocenione drogą ustalenia odsetka pacjentów ze zmniejszeniem LVEF o co najmniej 10 punktów od oceny wyjściowej i do poniżej 50% w trakcie leczenia neoadiuwantowego (przed i po zabiegu chirurgicznym).
7. Farmakokinetyka T-DXd: Stężenie T-DXd, miano przeciwciał anty-HER2 oraz DXd w surowicy.
8. Immunoenność T-DXd: Liczba i odsetek uczestników, u których wystąpiły ADA w związku z T-DXd.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Patients should undergo surgery no earlier than 3 weeks and no later than 6 weeks following administration of the last cycle of the randomized treatment. Surgical specimens will be sent for central assessment of pCR..

2) Time from date of randomization until disease progression precluding initial surgery, invasive disease recurrence (local, regional, distant, or contralateral), or death from any cause

3) Time from surgery until invasive disease recurrence

4) Time from randomization to death from any cause

5) Time from administration during neoadjuvant treatment until long-term follow-up

6) Until end of study

7) While on study treatment until end of study

8) Up to follow-up period

1. Pacjenci powinni przejść zabieg chirurgiczny nie wcześniej niż 3 tygodnie i nie później niż 6 tygodni po podaniu ostatniego cyklu randomizowanego leczenia. Próbka pobrana podczas zabiegu będzie wysłana w celu dokonania centralnej oceny pCR.
2. Czas od randomizacji do progresji choroby wykluczającej wstępny zabieg chirurgiczny, nawrotu choroby inwazyjnej (miejscowego, regionalnego, odległego lub kontralateralneo) lub śmierci z jakiejkolwiek przyczyny.
3. Czas od zabiegu chirurgicznego do nawrotu choroby inwazyjnej
4. Czas od randomizacji do śmierci z jakiejkolwiek przyczyny
5. Czas od podania dawki w trakcie leczenia neoadjuwantowego do długoterminowej obserwacji
6. Do zakończenia badania
7. W trakcie badanego leczenia do zakończenia badania
8. Do okresu obserwacji

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

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

ddAC-THP (doxorubicin and cyclophosphamide followed by paclitaxel + trastuzumab + pertuzumab)

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

Peru

Philippines

Taiwan

Brazil

Canada

China

India

Japan

Korea, Republic of

Russian Federation

Saudi Arabia

Thailand

United States

Bulgaria

Germany

Italy

Poland

Spain

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 (LSLV)

Zakończenie ostatniej przewidzianej wizyty/kontaktu ostatniego pacjenta biorącego udział w badania (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

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:

765

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

135

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

A legally accepted representative can provide consent if the subject is
not able

W przypadku niezdolności pacjenta do samodzielnego wyrażenia zgody, taką zgodę może wyrazić jego prawny przedstawiciel

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

270

F.4.2.2

In the whole clinical trial

900

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)

Long-term/Survival F/U visits will be performed until death, withdrawal of consent, or study closure, whichever occurs first.

No intervention is planned after the end of the study.

Wizyty z zakresu długoterminowej obserwacji/oceniające przeżycie będą przeprowadzane do zgonu, wycofania zgody lub zamknięcia badania, którekolwiek nastąpi wcześniej.
Po zakończeniu badania nie planuje się leczenia.

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

2021-12-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-22

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

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