Clinical Trials Register

Summary
EudraCT Number:	2020-002818-41
Sponsor's Protocol Code Number:	MO42319
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-04-28
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

France - ANSM

A.2

EudraCT number

2020-002818-41

A.3

Full title of the trial

A RANDOMIZED, MULTICENTER, DOUBLEBLIND, PLACEBO-CONTROLLED PHASE III STUDY OF THE EFFICACY AND SAFETY OF TRASTUZUMAB EMTANSINE IN COMBINATION WITH ATEZOLIZUMAB OR PLACEBO IN PATIENTS WITH HER2-POSITIVE AND PD-L1-POSITIVE LOCALLY ADVANCED OR METASTATIC BREAST CANCER WHO HAVE RECEIVED PRIOR TRASTUZUMAB- (+/- PERTUZUMAB) AND TAXANE-BASED THERAPY (KATE3).

A.3.1

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

A Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination with Atezolizumab or Placebo in Patients with HER2-Positive and PD-L1-Positive Locally Advanced or Metastatic Breast Cancer who Have Received Prior Trastuzumab- (+/- Pertuzumab) and Taxane-Based Therapy (KATE3).

A.3.2

Name or abbreviated title of the trial where available

KATE3

A.4.1

Sponsor's protocol code number

MO42319

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	F. Hoffmann-La Roche Ltd
B.1.3.4	Country	Switzerland
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	F. Hoffmann-La Roche Ltd
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Genentech Inc. c/o F. Hoffmann-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.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	KADCYLA®
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.3.4	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 emtansine
D.3.9.1	CAS number	1018448-65-1
D.3.9.2	Current sponsor code	RO5304020
D.3.9.3	Other descriptive name	T-DM1, Trastuzumab-MCC-DM1
D.3.9.4	EV Substance Code	SUB35467
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	160
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 comprised of a humanized monoclonal antibody (trastuzumab) and emtansine (DM1).
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	Tecentriq
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.3.4	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	ATEZOLIZUMAB
D.3.9.1	CAS number	1380723-44-3
D.3.9.2	Current sponsor code	RO5541267
D.3.9.3	Other descriptive name	MPDL3280A, Anti-PDL1, Anti-PD-L1, aPDL1, PRO#303280
D.3.9.4	EV Substance Code	SUB178312
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	60
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	Antineoplastic agent, humanized immunoglobulin G1 (IgG1) monoclonal antibody.

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locally advanced / metastatic breast cancer

E.1.1.1

Medical condition in easily understood language

Breast cancer where the tumor has spread to nearby tissues or lymph nodes (locally advanced breast cancer, LABC) or has spread to other parts of the body (metastatic breast cancer, MBC)

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10072740
E.1.2	Term	Locally advanced 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 demonstrate superiority of the experimental over the control treatment with respect to progression-free survival (PFS) and overall survival (OS).

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo beyond PFS and OS;
• To evaluate the safety of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo;
• To characterize the pharmacokinetics (PK) of trastuzumab emtansine and atezolizumab when given in combination;
• To evaluate the immune response to atezolizumab and trastuzumab emtansine when given in combination.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age >= 18 years
• Histologically determined HER2+/PD-L1+ LABC or MBC that is unresectable and who have received prior trastuzumab- (+/- pertuzumab) and taxane-based therapy
• Measurable disease per RESIST version 1.1
• Histologically centrally determined HER2+ and PD-L1+ of representative tumor tissue specimen(s) prior to randomization
• For patients with bilateral breast cancer, HER2 positivity must be centrally determined preferably in a metastatic biopsy or if not available in primary tumor from both left and right breast; at least one biopsy must be centrally determined as PD-L1 positive
• A formalin-fixed paraffin-embedded tumor specimen in a paraffin block or at least 17 slides containing unstained, freshly cut, serial sections must be submitted prior to study enrollment
• Willing to provide blood samples before treatment start, while on-study, and at progression, for standard of care follow-up and exploratory research on biomarkers
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Life expectancy >= 6 months
• Adequate hematologic and end-organ function
• Negative HIV test at screening
• For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs during the treatment period and for 7 months after the final dose of study treatment
• For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm during the treatment period and for 7 months after the final dose of study treatment.

E.4

Principal exclusion criteria

• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to Cycle 1, Day 1
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Receipt of any anti-cancer drug/biologic or investigational treatment 21 days prior to Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1; recovery of treatment-related toxicity consistent with other eligibility criteria
• Prior treatment with trastuzumab emtansine in metastatic setting
• History of exposure to protocol defined cumulative doses of anthracyclines
• Symptomatic or actively progressing central nervous system metastases; asymptomatic CNS lesions ≤ 2cm without clinical requirement for local intervention or asymptomatic patients with treated CNS lesions are eligible after fulfillment more detailed requirements of the protocol
• History of leptomeningeal disease
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Current Grade >= 3 peripheral neuropathy (according to the NCI CTCAE v5.0)
• Active hepatitis B and hepatitis C
• Current treatment with anti-viral therapy for HBV
• Active or history of autoimmune disease or immune deficiency
• Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Active tuberculosis
• Cardiopulmonary dysfunction
• Major surgical procedure, other than for diagnosis, or significant traumatic injury within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• History of malignancy within 5 years prior to initiation of study treatment, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death
• Current severe, uncontrolled systemic disease
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of study treatment
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, excipients of any drugs formulated in polysorbate 80 or 20 or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Known allergy or hypersensitivity to any component of the trastuzumab emtansine formulation
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of study treatment.

E.5 End points

E.5.1

Primary end point(s)

1. Progression-free survival (investigator assessed)
2. Overall survival

E.5.1.1

Timepoint(s) of evaluation of this end point

1-2. Up to 78.1 months.

E.5.2

Secondary end point(s)

1. Objective response rate
2. Duration of response
3. Progression-free survival by a blinded independent central review committee
4. Progression-free survival in patients with baseline brain metastases
5. Overall survival in patients with baseline brain metastases
6. Central nervous system progression-free survival
7. Mean absolute and mean change-from-baseline scores in function (Physical, Role) and global health status/quality of life (QoL) as measured by the scales of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30
8. The proportion of patients with clinically meaningful deterioration in GHS/QoL physical, and role function as measured by scales of the EORTC QLQ-C30
9. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
10. Change from baseline in targeted clinical laboratory test results
11. Presence, frequency of occurrence, severity, and/or degree of interference with daily function of selected symptomatic treatment toxicities, as measured by the National Cancer Institute Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument
12. Change from baseline in symptomatic treatment toxicities, as measured by the PRO-CTCAE at pre-specified time points and an additional item regarding the overall burden experienced due to side effects of treatment from the EORTC item library
13. Serum concentration of atezolizumab, trastuzumab emtansine, total trastuzumab, and plasma DM1, versus time
14. To characterize the prevalence and incidence of anti-drug antibody (ADA) to atezolizumab in the presence of trastuzumab emtansine at pre-specified timepoints
15. To characterize the prevalence and incidence of ADA to trastuzumab emtansine in the presence and absence of atezolizumab at pre-specified timepoints

E.5.2.1

Timepoint(s) of evaluation of this end point

1-6. Up to 78.1 months
7-8. Day 1 of Cycle 1-3, 5, 7, 9, 11, 13, every second cycle thereafter, at study discontinuation (SD)/early discontinuation (ED) visit, 3 months after SD/ED visit
9. Up to 78.1 months
10. Up to 78.1 months
11. Up to 78.1 months
12. Up to 78.1 months
13. For atezolizumab: Day 1 of Cycle 1-4, 8, every 8 cycles thereafter, at SD/ED; for trastuzumab emtansine and total trastuzumab: Day 1 of Cycle 1, 2 and 4, SD/ED; for DM1: Day 1 of Cycle 1 and 4
14. Day 1 of Cycle 1-4, 8, every 8 cycles thereafter, SD/ED
15. Day 1 of Cycle 1 and 4, SD/ED

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

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity, biomarker, health status (patient-reported outcomes)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

105

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

Brazil

Canada

China

Colombia

Egypt

Korea, Republic of

Mexico

Philippines

Russian Federation

Turkey

United States

Croatia

Finland

France

Germany

Greece

Hungary

Italy

Norway

Poland

Portugal

Slovenia

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of study is planned to occur after approximately 184 OS events are obtained (approximately 40 months after the primary efficacy analysis of PFS [and concurrent first interim analysis of OS]). The end of this study is defined as the date when the last patient, last visit occurs, or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later.

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:

300

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

210

F.4.2.2

In the whole clinical trial

350

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)

The Sponsor will offer continued access to Roche IMPs (trastuzumab emtansine and atezolizumab) free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product, available at the following website: http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
Patients may be eligible to receive trastuzumab emtansine or trastuzumab emtansine in combination with atezolizumab as part of an extension study.

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

2021-05-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-06-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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