A Study of Trastuzumab Emtansine in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer Who Have Received Prior Anti-HER2 And Chemotherapy-based Treatment

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01702571
• Collaborator: (none)
• Enrollment: 2,185
• Locations: 300
• Arms: 2
• Actual Duration (Months): 92.1
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This two-cohort, open-label, multicenter study will assess the safety, efficacy and tolerability of trastuzumab emtansine in participants with HER2-positive locally advanced breast cancer (LABC) or metastatic breast cancer (mBC) who have received prior anti-HER2 and chemotherapy-based treatment. Participants in Cohort 1 will be drawn from the general participant population; Cohort 2 will include only Asian participants.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Trastuzumab Emtansine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2185 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Two-Cohort, Open-Label, Multicenter Study of Trastuzumab Emtansine (T-DM1) in HER2-Positive Locally Advanced or Metastatic Breast Cancer Patients Who Have Received Prior Anti-HER2 and Chemotherapy-Based Treatment
• Actual Study Start Date: Nov 27, 2012
• Actual Primary Completion Date: Jul 31, 2020
• Actual Study Completion Date: Jul 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trastuzumab Emtansine (All Participants) This cohort will enroll all participants with HER2-positive, unresectable, LABC or mBC who have received prior anti-HER2 and chemotherapy treatment and have progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants will receive trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	Drug: Trastuzumab Emtansine; Participants will receive trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenously on Day 1 of a 3-week cycle every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.; Other Names: RO5304020, T-DM1, Kadcyla
Experimental: Trastuzumab Emtansine (Asian Participants) This cohort will enroll Asian race participants with HER2-positive, unresectable, LABC or mBC who have received prior anti-HER2 and chemotherapy treatment and have progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants will receive trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	Drug: Trastuzumab Emtansine; Participants will receive trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenously on Day 1 of a 3-week cycle every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.; Other Names: RO5304020, T-DM1, Kadcyla

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events of Primary Interest (AEPIs) [Baseline up to approximately 7 years]

   The AEPIs in this study were defined as the following: adverse events (AEs) Grade >/= 3, specifically, hepatic events, allergic reactions, thrombocytopenia and hemorrhage events, all Grade >/= 3 AEs related to trastuzumab emtansine and pneumonitis events of all grades.

Secondary Outcome Measures

1. Percentage of Participants With Specific AEPIs [Baseline up to approximately 7 years]

   The AEPIs in this study were defined as the following: adverse events (AEs) Grade >/= 3, specifically, hepatic events, allergic reactions, thrombocytopenia and hemorrhage events, all Grade >/= 3 AEs related to trastuzumab emtansine and pneumonitis events of all grades.

2. Percentage of Participants With Adverse Events of Special Interest (AESIs) [Baseline up to approximately 7 years]

   AESIs included: 1) Potential drug-induced liver injury, which included any potential case of drug-induced liver injury as, assessed by laboratory criteria for Hy's law (AST and/or ALT elevations that were >3 × ULN, Concurrent elevation of total bilirubin >2 × ULN (or clinical jaundice if total bilirubin measures were not available), except in participants with documented Gilbert's syndrome. Those with Gilbert's syndrome, elevation of direct bilirubin >2 × ULN was used instead. 2) Suspected transmission of an infectious agent by study drug was defined as any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic. A transmission of an infectious agent suspected from clinical symptoms or laboratory findings indicating an infection in a participant exposed to a medicinal product.

3. Progression-Free Survival According to Response Evaluation for Solid Tumors (RECIST) Version (v) 1.1 As Per Investigator Assessment [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)]

   Progression free survival is defined as the time (in months) between the date of first dose and the date of disease progression or death from any cause. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).

4. Overall Survival [Baseline until death (up to approximately 7 years)]

   Overall survival is defined as time to death, which is the time from the date of dosing until the date of death, regardless of the cause of death.

5. Percentage of Participants With Best Overall Response (Complete Response [CR] or Partial Response [PR]) According to RECIST v 1.1 As Per Investigator Assessment [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)]

   Best Overall Response reported here is the Best confirmed Overall Response. To be assigned a status of PR or CR, i.e., to be a responder, changes in tumor measurements had to be confirmed by repeat assessments that had to be performed no less than 4 weeks after the criteria for response were first met, i.e., participants needed to have two consecutive assessments of PR or CR. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

6. Percentage of Participants With Clinical Benefit (CR or PR or Stable Disease [SD]) According to RECIST v 1.1 [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)]

   Clinical Benefit was defined as CR plus PR plus SD. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD: neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.

7. Duration of Response (DOR) According to RECIST v 1.1 [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)]

   DOR is defined as the period from the date of initial confirmed PR or CR (whichever occurs first) until the date of PD or death from any cause. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).

8. Time to Response According to RECIST v 1.1 [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)]

   Time to Response is defined as the time from first dose to first documentation of confirmed PR or CR (whichever occurs first). CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

9. Number of Hospital Visits [Baseline up to approximately 7 years]

   The number of hospital visits were recorded to evaluate the resoruce expenditures while participants were on study treatment.

10. Type of Hospital Visits [Baseline up to approximately 7 years]

    The type of hospital visits (intensive care unit (ICU) versus other) were recorded to evaluate the resoruce expenditures while participants were on study treatment. The number of participants with at least one ICU visit are based on the number of participants with at least one hospital visit, in each group.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• HER2-positive disease determined locally

• Histologically or cytologically confirmed invasive breast cancer

• Prior treatment for breast cancer in the adjuvant, unresectable, locally advanced or metastatic setting must include both chemotherapy, alone or in combination with another agent, and an anti-HER2 agent, alone or in combination with another agent

• Documented progression of incurable, unresectable, LABC, or mBC, defined by the investigator: progression must occur during or after most recent treatment for LABC/mBC or within 6 months of completing adjuvant therapy

• Measurable and/or non-measurable disease

• Left ventricular ejection fraction (LVEF) >/=50% by either echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2

• Adequate organ function

• Use of highly effective contraception as defined by the protocol

Exclusion Criteria:

• History of treatment with trastuzumab emtansine

• Prior enrollment into a clinical study containing trastuzumab emtansine regardless of having received trastuzumab emtansine or not

• Peripheral neuropathy of Grade >/= 3 per National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) v 4.0

• History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer

• History of receiving any anti-cancer drug/biologic or investigational treatment within 21 days prior to first study treatment except hormone therapy, which can be given up to 7 days prior to first study treatment; recovery of treatment-related toxicity consistent with other eligibility criteria

• History of exposure to cumulative doses of anthracyclines

• History of radiation therapy within 14 days of first study treatment. The participant must have recovered from any resulting acute toxicity (to Grade </=1) prior to first study treatment.

• Metastatic central nervous system (CNS) disease only

• Brain metastases which are symptomatic

• History of a decrease in LVEF to less than (<) 40% or symptomatic congestive heart failure (CHF) with previous trastuzumab treatment

• History of symptomatic CHF (New York Heart Association [NYHA] Classes II-IV) or serious cardiac arrhythmia requiring treatment

• History of myocardial infarction or unstable angina within 6 months of first study treatment

• Current dyspnea at rest due to complications of advanced malignancy or requirement for continuous oxygen therapy

• Current severe, uncontrolled systemic disease (clinically significant cardiovascular, pulmonary, or metabolic disease)

• Pregnancy or lactation

• Currently known active infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus

• History of intolerance (such as Grade 3-4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins or any component of the product

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CEMIC	Buenos Aires		Argentina	C1431FWO
2	Centro Oncologico Riojano Integral (CORI)	La Rioja		Argentina	F5300COE
3	Hospital Privado De Comunidad; General Practice	Mar Del Plata		Argentina	7600
4	Mater Hospital; Patricia Ritchie Centre for Cancer Care and Research	North Sydney	New South Wales	Australia	2059
5	Calvary Mater Newcastle; Medical Oncology	Waratah	New South Wales	Australia	2298
6	Westmead Hospital; Medical Oncology and Pallative Care	Westmead	New South Wales	Australia	2145
7	Haematology & Oncology Clinics of Australia Research Centre	South Brisbane	Queensland	Australia	4101
8	Ashford Cancer Center Research	Kurralta Park	South Australia	Australia	5037
9	Peter MacCallum Cancer Centre; Medical Oncology	Melbourne	Victoria	Australia	3000
10	Sunshine Hospital; Oncology Research	St Albans	Victoria	Australia
11	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6150
12	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg		Austria	5020
13	Medizinische Universität Wien; Univ.Klinik für Frauenheilkunde - Klinik für Gynäkologie	Wien		Austria	1090
14	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Abt. für Onkologie	Wien		Austria	1090
15	Institut Jules Bordet	Anderlecht		Belgium	1070
16	UZ Brussel	Brussel		Belgium	1090
17	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
18	GHdC Site Notre Dame	Charleroi		Belgium	6000
19	UZ Antwerpen	Edegem		Belgium	2650
20	UZ Gent	Gent		Belgium	9000
21	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
22	CHU Sart-Tilman	Liège		Belgium	4000
23	Clinique Ste-Elisabeth	Namur		Belgium	5000
24	Sint Augustinus Wilrijk, Apotheek	Wilrijk		Belgium	2610
25	*X*Instituto Nacional do Cancer - INCA	Rio de Janeiro	RJ	Brazil	20560-120
26	Hospital Sao Lucas - PUCRS	Porto Alegre	RS	Brazil	90610-000
27	Centro de Pesquisas Oncologicas - CEPON	Florianopolis	SC	Brazil	88034-000
28	Hospital Sirio Libanes; Centro de Oncologia	Sao Paulo	SP	Brazil	01308-050
29	Hospital Sao Jose	Sao Paulo	SP	Brazil	01321-001
30	MHAT Serdika; Department of medical oncology	Sofia		Bulgaria	1303
31	SHATO - Sofia	Sofia		Bulgaria	1756
32	SHATOD - Sofia	Sofia		Bulgaria	1784
33	District Oncology Dispensary Wit Stationary	Varna		Bulgaria	9010
34	BC Cancer - Surrey	Surrey	British Columbia	Canada	V3V 1Z2
35	British Columbia Cancer Agency (Bcca) - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
36	Dr. H. Bliss Murphy Cancer Centre; Oncology	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
37	Royal Victoria Regional Health Centre; c/o Oncology Clinical Trials	Barrie	Ontario	Canada	L4M 6M2
38	London Regional Cancer Centre	London	Ontario	Canada	N6A 4L6
39	Southlake Regional Health Center; Community Care Clinic / Oncology	Newmarket	Ontario	Canada	L3Y 2P9
40	St. Michael'S Hospital	Toronto	Ontario	Canada	M5B 1W8
41	Hopital Maisonneuve- Rosemont; Oncology	Montreal	Quebec	Canada	H1T 2M4
42	Mcgill University - Royal Victoria Hospital; Oncology	Montreal	Quebec	Canada	H3A 1A1
43	Cancer Hospital Chinese Academy of Medical Sciences.	Beijing		China	100021
44	Beijing Cancer Hospital	Beijing		China	100142
45	Chinese PLA General Hospital	Beijing		China	100853
46	Sun Yat-sen Memorial Hospital	Guangzhou		China	510000
47	Sun Yet-sen University Cancer Center	Guangzhou		China	510060
48	Harbin Medical University Cancer Hospital	Harbin		China	150081
49	Jiangsu Cancer Hospital	Nanjing City		China	211100
50	Fudan University Shanghai Cancer Center	Shanghai City		China	200120
51	Tianjin Cancer Hospital	Tianjin		China	300060
52	Zhejiang Cancer Hospital	Zhejiang		China	310022
53	Clinical Hospital Centre Zagreb	Zagreb		Croatia	10000
54	Aalborg Universitetshospital, Klinik Kirurgi-Kræft, Onkologisk afd.	Aalborg		Denmark	9000
55	Herlev Hospital; Afdeling for Kræftbehandling	Herlev		Denmark	2730
56	Nordsjællands Hospital, Hillerød, Onkologisk Afdeling	Hillerod		Denmark	3400
57	Rigshospitalet; Onkologisk Klinik	København Ø		Denmark	2100
58	Odense Universitetshospital, Onkologisk Afdeling R	Odense C		Denmark	5000
59	Sygehus Syd Roskilde; Onkologisk/haematologisk ambulatorium	Roskilde		Denmark	4000
60	Vejle Sygehus; Onkologisk Afdeling	Vejle		Denmark	7100
61	Hospital Metropolitano de Santiago	Santiago		Dominican Republic	51000
62	Clinica Alcivar, torre 1;Private office	Guayaquil		Ecuador	EC090114
63	Hospital Solca Portoviejo; Oncologia	Portoviejo		Ecuador	EC130104
64	North Estonia Medical Centre Foundation; Oncology Center	Tallinn		Estonia	13419
65	Helsingin yliopistollinen keskussairaala	Helsinki		Finland	00290
66	KYS Sadesairaala; Syopatautien poliklinikka	Kuopio		Finland	70210
67	Tampere University Hospital; Dept of Oncology	Tampere		Finland	33520
68	Turku Uni Central Hospital; Oncology Clinics	Turku		Finland	20520
69	Clinique De L Europe; Radiotherapie Chimiotherapie	Amiens		France	80090
70	ICO Paul Papin; Oncologie Medicale.	Angers		France	49055
71	Institut Sainte Catherine	Avignon		France	84082
72	Hopital Jean Minjoz - CHU de Besançon	Besançon		France	25030
73	Clinique Tivoli; Chimiotherapie Radiotherapie	Bordeaux		France	33030
74	Institut Bergonie; Oncologie	Bordeaux		France	33076
75	Polyclinique Bordeaux Nord Aquitaine; Chimiotherapie Radiotherapie	Bordeaux		France	33077
76	Cli De La Porte De Saint Cloud; Hop De Jour De Chimiotherapie	Boulogne-billancourt		France	92100
77	Hopital Morvan; Oncologie - Radiotherapie	Brest		France	29609
78	Centre Francois Baclesse; Radiotherapie	Caen		France	14076
79	Centre Jean Perrin; Oncologie	Clermont Ferrand		France	63011
80	Centre Georges Francois Leclerc; Oncologie 3	Dijon		France	21079
81	Chu Grenoble - Hopital Albert Michallon; Departement de Cancero-Hematologie	Grenoble		France	38043
82	Centre Hartmann	Levallois Perret		France	92300
83	Centre Oscar Lambret; Senologie	Lille		France	59020
84	Clinique Chenieux; Oncology	Limoges		France	87039
85	Ch Bretagne Sud Site Scorff; Oncologie Medicale	Lorient		France	56100
86	Centre Leon Berard	Lyon		France	69008
87	Institut Paoli Calmettes; Oncologie Medicale	Marseille		France	13273
88	Hopital Layne; Medecine Ambulatoire	Mont-de-marsan		France	40024
89	Centre Val Aurelle Paul Lamarque; Recherche Clinique	Montpellier		France	34298
90	Centre Antoine Lacassagne; Hopital De Jour A2	Nice		France	06189
91	Institut Curie; Oncologie Medicale	Paris		France	75231
92	HOPITAL TENON; Cancerologie Medicale	Paris		France	75970
93	Polyclinique Francheville; Med Chimiotherapie Radiotherapie	Perigueux		France	24000
94	Centre Catalan D' Oncologie	Perpignan		France	66000
95	Clinique Armoricaine Radiologie; Hopital de Jour	Plerin		France	22190
96	Pole Regional De Cancerologie	Poitiers		France	86021
97	Institut Jean Godinot; Oncologie Medicale	Reims CEDEX		France	51056
98	Polyclinique De Courlancy; Centre Radiotherapie Oncologie	Reims		France	51057
99	Centre Eugene Marquis; Unite Huguenin	Rennes		France	35042
100	Centre Henri Becquerel; Oncologie Medicale	Rouen		France	76038
101	Ico Rene Gauducheau; Oncologie	Saint Herblain		France	44805
102	Centre Rene Huguenin; CONSULT SPECIALISEES	St Cloud		France	92210
103	Centre Paul Strauss; Oncologie Medicale	Strasbourg		France	67065
104	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse		France	31059
105	Clinique Pasteur; Oncologie Medicale	Toulouse		France	31076
106	Centre Henry S Kaplan - CHU Bretonneau ; service oncologie	Tours		France	37044
107	Centre Alexis Vautrin; Oncologie Medicale	Vandoeuvre-les-nancy		France	54519
108	Institut Gustave Roussy; Pathologie Mammaire	Villejuif		France	94805
109	Hämatologisch-onkologische Praxis Dr. med. - Heinrich, - Bangerter	Augsburg		Germany	86150
110	Praxis Dres. Schilling & Till	Berlin		Germany	10317
111	Schwerpunktpraxis Onkologie/Hämatologie Dr. Dirk Pott, Dr. Christian Tirier und Carla Verena u.w.	Bottrop		Germany	46236
112	Onkozentrum Dres. Göhler	Dresden		Germany	01127
113	Dres. Joerg Weniger, Annette Bittrich und Berit Schuetze	Erfurt		Germany	99085
114	Universitätsklinikum Erlangen; Frauenklinik	Erlangen		Germany	91054
115	OncoResearch Lerchenfeld GmbH	Hamburg		Germany	22081
116	HOPA MVZ GmbH	Hamburg		Germany	22767
117	Medizinische Hochschule Zentrum Frauenheilkunde Abt.Gynäkologische Onkologie	Hannover		Germany	30625
118	Institut für Versorgungsforschung in der Onkologie GbR Koblenz	Koblenz		Germany	56068
119	Klinikum Leverkusen; Med. Klinik III / Onkologie	Leverkusen		Germany	51375
120	Klinikum der Universität München; Campus Großhadern; Klinik und Poliklinik für Frauenheilkunde	Muenchen		Germany	81377
121	Universitätsklinikum Münster; Klinik für Frauenheilkunde und Geburtshilfe	Münster		Germany	48149
122	Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe	Offenbach		Germany	63069
123	Praxis für Hämatologie und Onkologie	Porta Westfalica		Germany	32457
124	Universitaetsfrauenklinik; Und Poliklinik Am Klinikum	Rostock		Germany	18059
125	Universitätsklinik Tübingen; Frauenklinik	Tübingen		Germany	72076
126	HELIOS Dr. Horst Schmidt Kliniken Wiesbaden; Klinik für Gynäkologie und gynäkologische Onkologie	Wiesbaden		Germany	65199
127	Hämatologisch-Onkologische Schwerpunktpraxis Dres. Schlag & Schöttker	Würzburg		Germany	97080
128	University General Hospital of Heraklion	Crete		Greece	711 10
129	Uni Hospital of Ioannina; Oncology Dept.	Ioannina		Greece	455 00
130	University Hospital of Patras Medical Oncology	Patras		Greece	265 04
131	Papageorgiou General Hospital; Medical Oncology	Thessaloniki		Greece	564 29
132	Centro Oncológico Sixtino / Centro Oncológico SA	Guatemala		Guatemala	01010
133	Princess Margaret Hospital; Oncology	Hong Kong		Hong Kong
134	Prince of Wales Hosp; Dept. Of Clinical Onc	Shatin		Hong Kong
135	Ogyi, Orszagos Gyogyszereszeti Intezet	Budapest		Hungary	1051
136	Szent Imre Hospital; Dept. of Oncology	Budapest		Hungary	1115
137	Orszagos Onkologiai Intezet; B Belgyogyaszati Osztaly	Budapest		Hungary	1122
138	Magyar Honvedseg Egeszsegugyi Kozpont; Fázis I-es Klinikai Farmakológiai Vizsgálóhely	Budapest		Hungary	H-1077
139	Kaposi Mor County Hospital; Dept. of Oncology	Kaposvar		Hungary	7400
140	Landspitali University Hospital, Department of Medical Oncology	Reykjavik		Iceland	101
141	Cipto Mangunkusumo General Hospital; Hematology & Oncology	Jakarta		Indonesia	10430
142	Dharmais National Cancer Center	Jakarta		Indonesia	11420
143	MRCCC Siloam Semanggi Hospital	Jakarta		Indonesia	12930
144	Cork Uni Hospital; Oncology Dept	Cork		Ireland
145	St Vincent'S Uni Hospital; Medical Oncology	Dublin		Ireland	4
146	Mater Misericordiae Uni Hospital; Oncology	Dublin		Ireland	7
147	University Hospital Limerick - Oncology	Limerick		Ireland
148	Azienda Ospedaliera San Giuseppe Moscati	Avellino	Campania	Italy	83100
149	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli	Campania	Italy	80131
150	Università degli Studi Federico II; Clinica di Oncologia Medica	Napoli	Campania	Italy	80131
151	Ospedale Bellaria; U.O. Oncologia Medica	Bologna	Emilia-Romagna	Italy	40133
152	A.O.U. Policlinico di Modena	Modena	Emilia-Romagna	Italy	40124
153	Az. Osp. Ospedale Civile; U.O. Di Oncologia Medica Ed Ematologia	Piacenza	Emilia-Romagna	Italy	29100
154	RCCS - Centro di Riferimento; Oncologia Medica B	Aviano (PN)	Friuli-Venezia Giulia	Italy	33081
155	Divisione Onc Med dell'Azienda	Udine	Friuli-Venezia Giulia	Italy	33100
156	Policlinico Umberto i di Roma; dip. Scienze Radiologiche, Oncologiche, Anatomopatologiche	Roma	Lazio	Italy	00161
157	Ospedale S.S. Trinità Nuovo; Divisione Oncologia	Sora	Lazio	Italy	03039
158	IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A	Genova	Liguria	Italy	16132
159	ASST DI CREMONA; Unità di Patologia Mammaria Senologia e Breast Unit	Cremona	Lombardia	Italy	26100
160	ASST DI LECCO; Oncologia Medica	Lecco	Lombardia	Italy	23900
161	Ospedale San Raffaele; Medical Oncology	Milano	Lombardia	Italy	20132
162	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1	Milano	Lombardia	Italy	20133
163	Istituto Europeo Di Oncologia	Milano	Lombardia	Italy	20141
164	Fondazione Salvatore Maugeri; Divisione Di Oncologia Medica	Pavia	Lombardia	Italy	27100
165	Casa di Cura Multimedica S.p.A.; Dipartimento Oncologico	Sesto San Giovanni (MI)	Lombardia	Italy	20099
166	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte	Italy	10060
167	Ospedale Maggiore Della Carita; Oncologia Medica	Novara	Piemonte	Italy	28100
168	A.O. Città della Salute e della Scienza - Presidio Molinette; divisione oncologia medica	Torino	Piemonte	Italy	10126
169	Ospedale Antonio Perrino; Oncologia Medica	Brindisi	Puglia	Italy	72100
170	Ospedale Vito Fazzi; Div. Oncoematologia	Lecce	Puglia	Italy	73100
171	Az Ospedaliera Nuovo Garibaldi Quartiere Nesima; Oncologia Medica	Catania	Sicilia	Italy	95122
172	A.O.U Careggi	Florence	Toscana	Italy	50124
173	Azienda usl 5 Di Pisa-Ospedale Di Pontedera;U.O. Oncologia	Pontedera	Toscana	Italy	56025
174	Ospedale Misericordia E Dolce; Oncologia Medica	Prato	Toscana	Italy	59100
175	Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica	Perugia	Umbria	Italy	06156
176	Ospedale Civile; Oncologia Medica	Camposampiero	Veneto	Italy	35012
177	Ospedale Busonera; Oncologia Medica	Padova	Veneto	Italy	35128
178	A.O.U.I. VERONA-OSPEDALE BORGO TRENTO; ONCOLODIA MEDICA-d.O.	Verona	Veneto	Italy	37126
179	Kyungpook National University Medical Center	Daegu		Korea, Republic of	41404
180	Gachon Medical School Gil Medical Center; Medical Oncology	Incheon		Korea, Republic of	405-760
181	Seoul National Uni Hospital; Dept. of Internal Medicine/Hematology/Oncology	Seoul		Korea, Republic of	03080
182	Yonsei University Severance Hospital; Medical Oncology	Seoul		Korea, Republic of	120-752
183	Korea University Anam Hospital; Oncology Haemotology	Seoul		Korea, Republic of	136-705
184	CHL Hopital Municipal; Oncology	Luxembourg		Luxembourg	1210
185	Hospital General de México	Mexico City	Mexico CITY (federal District)	Mexico	06726
186	Medica Sur Centro Oncologico Integral	D.f.		Mexico	14050
187	Hospital Hmg Coyoacan	DF		Mexico	04110
188	CENTRO MÉDICO NACIONAL SIGLO XXI; Hospital de Especialidades Oncología	Mexico City		Mexico	06725
189	Inst. Nacional de Cancerologia; Investigacion Clinica	Mexico City		Mexico	14000
190	Instituto Nacional de Ciencias Médicas Y de La Nutricion Zubirán	Mexico City		Mexico	Tlalpan 14000
191	Antoni Van Leeuwenhoek Ziekenhuis; Inwendige Geneeskunde	Amsterdam		Netherlands	1066 CX
192	Amphia Ziekenhuis	Breda		Netherlands	4819 EV
193	MC Haaglanden; Oncologie	Den Haag		Netherlands	2512 VA
194	Deventer Ziekenhuis; Interne Geneeskunde	Deventer		Netherlands	7416 SE
195	Ziekenhuisgroep Twente, Hengelo	Hengelo		Netherlands	7555 DL
196	Spaarne Ziekenhuis; Inwendige Geneeskunde	Hoofddorp		Netherlands	2134 TM
197	Medisch Centrum Leeuwarden; Interne	Leeuwarden		Netherlands	8934 AD
198	Orbis Medisch Centrum; Inwendige Geneeskunde	Sittard-Geleen		Netherlands	6162 BG
199	Twee Steden Ziekenhuis - Locatie Tilburg; Interne Geneesekunde	Tilburg		Netherlands	5042 AD
200	Oslo Universitetssykehus HF; Ullevål sykehus	Oslo		Norway	0450
201	Centro Hemato Oncologico Panama	Panama		Panama	0832
202	Centro Oncologico America	Panama		Panama	0834-02723
203	Instituto;Oncologico Miraflores	Lima		Peru	18
204	Clinica de Especialidades Medicas	Lima		Peru	Lima 41
205	Bialostockie Centrum Onkologii; Oddzial Onkologii Klinicznej	Bialystok		Poland	15-027
206	Szpital Specjalistyczny POO im. ks. B.Markiewicza; Dzienny Oddz Chemioter i Hematologii Onkol	Brzozów		Poland	36-200
207	Świętokrzyskie Centrum Onkologii; Dział Chemioterapii	Kielce		Poland	25-734
208	Szpital Uniwersytecki w Krakowie, Oddział Kliniczny Kliniki Onkologii	Kraków		Poland	30-688
209	Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina, Klinika Onkologii	Otwock		Poland	05-400
210	Wojewódzki Szpital Specjalistyczny Nr 3	Rybnik		Poland	44-200
211	IPO de Lisboa; Servico de Oncologia Medica	Lisboa		Portugal	1099-023
212	Hospital da Luz; Departamento de Oncologia Medica	Lisboa		Portugal	1500-650
213	IPO do Porto; Servico de Oncologia Medica	Porto		Portugal	4200-072
214	Narodny Onkologicky Ustav; Oddelenie klinickej onkologie A	Bratislava		Slovakia	833 10
215	Fakultna nemocnica Trencín; Onkologicke odd.	Trencin		Slovakia	911 71
216	Institute of Oncology Ljubljana	Ljubljana		Slovenia	1000
217	Hospital General Universitario de Elche; Servicio de Oncologia	Elche	Alicante	Spain	03203
218	Hospital General de Elda; Servicio de Oncologia	Elda	Alicante	Spain	03600
219	Hospital Univ. Central de Asturias; Servicio de Oncologia	Oviedo	Asturias	Spain	33011
220	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Badalona	Barcelona	Spain	08916
221	Corporacio Sanitaria Parc Tauli; Servicio de Oncologia	Sabadell	Barcelona	Spain	8208
222	Hospital de Jerez de la Frontera; Servicio de Oncologia	Jerez de La Frontera	Cadiz	Spain	11407
223	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba	Spain	14004
224	Hospital de Donostia; Servicio de Oncologia Medica	San Sebastian	Guipuzcoa	Spain	20080
225	Hospital Universitario Son Espases	Palma De Mallorca	Islas Baleares	Spain	07014
226	Hospital Universitario Materno Infantil de Gran Canaria; Servicio de Oncologia	Las Palmas de Gran Canaria	LAS Palmas	Spain	35016
227	Hospital de Gran Canaria Dr. Negrin; Servicio de Oncologia	Las Palmas de Gran Canaria	LAS Palmas	Spain	35020
228	Hospital Severo Ochoa; Servicio de Oncologia	Leganes	Madrid	Spain	28911
229	Hospital Quiron de Madrid; Servicio de Oncologia	Pozuelo de Alarcon	Madrid	Spain	28223
230	Hospital Xeral Cíes; Servicio de Oncologia	Vigo	Pontevedra	Spain	36312
231	Hospital Universitari Sant Joan de Reus; Servicio de Oncologia	Reus	Tarragona	Spain	43204
232	Hospital de Cruces; Servicio de Oncologia	Bilbao	Vizcaya	Spain	48903
233	Hospital General Univ. de Alicante; Servicio de Oncologia	Alicante		Spain	3010
234	Hospital del Mar; Servicio de Oncologia	Barcelona		Spain	08003
235	Hospital Quiron Barcelona; Servicio de Oncologia	Barcelona		Spain	08024
236	Hospital San Pedro De Alcantara; Servicio de Oncologia	Caceres		Spain	10003
237	Hospital Universitari de Girona Dr. Josep Trueta; Servicio de Oncologia	Girona		Spain	17007
238	Hospital Universitario San Cecilio; Servicio de Oncologia	Granada		Spain	18003
239	Complejo Hospitalario de Jaen-Hospital Universitario Medico Quirurgico; Servicio de Oncologia	Jaen		Spain	23007
240	Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología	La Coruña		Spain	15006
241	Hospital Universitari Arnau de Vilanova de Lleida; Servicio de Oncologia	Lerida		Spain	25198
242	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid		Spain	28034
243	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio de Oncologia	Madrid		Spain	28050
244	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga		Spain	29010
245	Complejo Hospitalario de Pontevedra; Servicio de Oncologia	Pontevedra		Spain	36002
246	Instituto Valenciano Oncologia; Oncologia Medica	Valencia		Spain	46009
247	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia		Spain	46010
248	Hospital General Universitario de Valencia; Servicio de oncologia	Valencia		Spain	46014
249	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza		Spain	50009
250	Karolinska Hospital; Oncology - Radiumhemmet	Stockholm		Sweden	171 76
251	Norrlands universitetssjukhus; Onkologkliniken	Umeå		Sweden
252	National Cheng Kung Uni Hospital; Surgery	Tainan		Taiwan	704
253	Chi-Mei Medical Centre; Hematology & Oncology	Tainan		Taiwan	710
254	VETERANS GENERAL HOSPITAL; Department of General Surgery	Taipei		Taiwan	00112
255	Department of Surgery, King Chulalongkorn Memorial Hospital	Bangkok		Thailand	10330
256	Pramongkutklao Hospital; Medicine - Medical Oncology Unit	Bangkok		Thailand	10400
257	Maharaj Nakorn Chiang Mai Hospital; Department of Surgery/Head Neck and Breast Unit; Clinical Trial	Chiang Mai		Thailand	50200
258	Gazi Uni Medical Faculty Hospital; Oncology Dept	Ankara		Turkey	06500
259	Gaziantep University Medical Faculty, Medical Oncology Department	Gaziantep		Turkey	27310
260	Bezmialem Vakif Univ Medical; Bezmialem Vakif Univ T	Istanbul		Turkey	34093
261	Istanbul Uni Cerrahpasa Medical Faculty Hospital; Medical Oncology	Istanbul		Turkey	34300
262	Istanbul Uni of Medicine Faculty; Oncology Dept	Istanbul		Turkey	34390
263	Kartal Dr Lutfi Kirdar Sehir Hastanesi; Medical Oncology Department	Istanbul		Turkey	34865
264	Marmara Uni Faculty of Medicine; Medical Oncology	Istanbul		Turkey	34890
265	Ege Uni Medical Faculty Hospital; Oncology Dept	Izmir		Turkey	35100
266	Dokuz Eylul Uni ; Medical Oncology	Izmir		Turkey	35340
267	Kocaeli University Faculty of Medicine; Medical oncology	Izmit		Turkey	31380
268	Tawam Hospital	Al Ain		United Arab Emirates	15258
269	Aberdeen Royal Infirmary	Aberdeen		United Kingdom	AB25 2ZN
270	University Hospital Birmingham Queen Elizabeth Hospital	Birmingham		United Kingdom	B17 0NH
271	Kent & Canterbury Hospital	Canterbury		United Kingdom	CT1 3NG
272	University Hospital coventry; Oncology Department	Coventry		United Kingdom	CV2 2DX
273	Eastborne District General Hospital	Eastbourne		United Kingdom	BN21 2UD
274	Western General Hospital; Clinical Oncology	Edinburgh		United Kingdom	EH4 2XU
275	St Margaret'S Hospital; Breast Unit	Epping		United Kingdom	CM16 6TN
276	Royal Devon & Exeter Hospital; Oncology Centre	Exeter		United Kingdom	EX2 5DW
277	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
278	Diana Princess of Wales Hosp.	Grimsby		United Kingdom	DN33 2BA
279	Huddersfield Royal Infirmary	Huddersfield		United Kingdom	HD3 3EA
280	Castle Hill Hospital; The Queen's Centre for Oncology & Haematology	Hull		United Kingdom	HU16 5JQ
281	Ipswich Hospital; Oncology Pharmacy	Ipswich		United Kingdom	IP4 5PD
282	Royal Lancaster Infirmary, Morecambe Bay Hospitals Nhs Trust	Lancaster		United Kingdom	LA1 4RP
283	Royal Free Hospital; Dept of Oncology	London		United Kingdom	NW3 2QG
284	Guys & St Thomas Hospital; Department of Oncology	London		United Kingdom	SE1 9RT
285	St George'S Hospital; Oncology Research Office /Oncology Opd	London		United Kingdom	SW17 ORE
286	Sarah Cannon Research Institute	London		United Kingdom	W1G 6AD
287	Maidstone & Tonbridge Wells Hospital; Kent Oncology Center	Maidstone		United Kingdom	ME16 9QQ
288	Christie Hospital; Breast Cancer Research Office	Manchester		United Kingdom	M20 4QL
289	Mount Vernon Hospital	Middlesex		United Kingdom	HA6 2RN
290	Plymouth Oncology Centre; Clinical Trials Unit	Plymouth		United Kingdom	PL6 8DH
291	Queen Alexandra Hospital, Portsmouth	Portsmouth		United Kingdom	PO6 3LY
292	Queen's Hospital; Oncology	Romford		United Kingdom	RM7 0AG
293	Weston Park Hospital; Cancer Clinical Trials Centre	Sheffield		United Kingdom	S10 2SJ
294	Royal Shrewsbury Hospital	Shrewsbury		United Kingdom	SY3 8XQ
295	Singleton Hospital; Pharmacy	Swansea		United Kingdom	SA2 8QA
296	Yeovil District Hospital; Macmillan Cancer Unit	Yeovil		United Kingdom	BA21 4AT
297	York District Hospital	York		United Kingdom	YO31 8HE
298	Unidad de Mastologia y Atencion a la Mujer	Barcelona		Venezuela	6001
299	Instituto Oncológico Luis Razetti	Caracas		Venezuela	1010
300	Instituto de Oncologia y Hematologia UCV	Caracas		Venezuela	1020

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Jul 18, 2019
• Statistical Analysis Plan - Feb 2, 2020

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01702571
• Other Study ID Numbers: MO28231; 2012-001628-37
• First Posted: Oct 8, 2012
• Last Update Posted: Apr 4, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Breast Neoplasms; Trastuzumab; Ado-Trastuzumab Emtansine; Maytansine

Study Results

Participant Flow

Recruitment Details	Cohort 1 has 2003 participants and Cohort 2 has 182 participants representing the total enrollment study number. Cohort 1 was conducted in 281 centers in 40 countries worldwide whereas Cohort 2 was conducted in an Asian population in 14 centers in China, Thailand and Indonesia.
Pre-assignment Detail	Two participants (one in Corhort 1 and Corhot 2) were not included in the safety population as one didn't receive study treatment and one did not qualify under the inclusion criteria.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Period Title: Overall Study
STARTED	2003	182
COMPLETED	494	65
NOT COMPLETED	1509	117

Baseline Characteristics

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)	Total
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	Total of all reporting groups
Overall Participants	2003	182	2185
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.5 (11.4)	49.1 (10.1)	54.1 (11.4)
Sex: Female, Male (Count of Participants)
Female	1989 99.3%	182 100%	2171 99.4%
Male	14 0.7%	0 0%	14 0.6%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	1397 69.7%	0 0%	1397 63.9%
Black	21 1%	0 0%	21 1%
Asian	72 3.6%	182 100%	254 11.6%
Native American	41 2%	0 0%	41 1.9%
N/A as per local regulation	466 23.3%	0 0%	466 21.3%
Unknown	3 0.1%	0 0%	3 0.1%
Other	2 0.1%	0 0%	2 0.1%
Missing	1 0%	0 0%	1 0%
Race/Ethnicity, Customized (Number) [Number]
Hispanic/Latino	300 15%	0 0%	300 13.7%
Chinese	29 1.4%	147 80.8%	176 8.1%
N/A as per local regulation	997 49.8%	16 8.8%	1013 46.4%
Other	417 20.8%	19 10.4%	436 20%
Mixed	9 0.4%	0 0%	9 0.4%
Indian (Indian subcontinent)	4 0.2%	0 0%	4 0.2%
Unknown	247 12.3%	0 0%	247 11.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events of Primary Interest (AEPIs)
Description	The AEPIs in this study were defined as the following: adverse events (AEs) Grade >/= 3, specifically, hepatic events, allergic reactions, thrombocytopenia and hemorrhage events, all Grade >/= 3 AEs related to trastuzumab emtansine and pneumonitis events of all grades.
Time Frame	Baseline up to approximately 7 years

Outcome Measure Data

Analysis Population Description

The safety population included all participants who had received at least 1 dose of study medication.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2002	181
Number (95% Confidence Interval) [Percentage of Participants]	23.1 1.2%	51.4 28.2%

2. Secondary Outcome

Title	Percentage of Participants With Specific AEPIs
Description	The AEPIs in this study were defined as the following: adverse events (AEs) Grade >/= 3, specifically, hepatic events, allergic reactions, thrombocytopenia and hemorrhage events, all Grade >/= 3 AEs related to trastuzumab emtansine and pneumonitis events of all grades.
Time Frame	Baseline up to approximately 7 years

Outcome Measure Data

Analysis Population Description

The safety population included all participants who had received at least 1 dose of study medication.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2002	181
AEs Grade >/= 3 for hepatic events	6.9 0.3%	12.2 6.7%
AEs Grade >/= 3 for allergic reactions	2.3 0.1%	1.1 0.6%
AEs Grade >/= 3 for thrombocytopenia	3.7 0.2%	36.5 20.1%
AEs Grade >/= 3 for hemorrhage events	2.3 0.1%	1.7 0.9%
AEs Grade >/= 3 related to trastuzumab emtansine	18.4 0.9%	48.6 26.7%
Pneumonitis of all grades	1.0 0%	2.2 1.2%

3. Secondary Outcome

Title	Percentage of Participants With Adverse Events of Special Interest (AESIs)
Description	AESIs included: 1) Potential drug-induced liver injury, which included any potential case of drug-induced liver injury as, assessed by laboratory criteria for Hy's law (AST and/or ALT elevations that were >3 × ULN, Concurrent elevation of total bilirubin >2 × ULN (or clinical jaundice if total bilirubin measures were not available), except in participants with documented Gilbert's syndrome. Those with Gilbert's syndrome, elevation of direct bilirubin >2 × ULN was used instead. 2) Suspected transmission of an infectious agent by study drug was defined as any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic. A transmission of an infectious agent suspected from clinical symptoms or laboratory findings indicating an infection in a participant exposed to a medicinal product.
Time Frame	Baseline up to approximately 7 years

Outcome Measure Data

Analysis Population Description

The safety population included all participants who had received at least 1 dose of study medication.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2002	181
Potential drug-induced liver injury	1.2 0.1%	1.1 0.6%
Suspected transmission of an infectious agent	0.2 0%	0.0 0%

4. Secondary Outcome

Title	Progression-Free Survival According to Response Evaluation for Solid Tumors (RECIST) Version (v) 1.1 As Per Investigator Assessment
Description	Progression free survival is defined as the time (in months) between the date of first dose and the date of disease progression or death from any cause. Progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population included all participants enrolled in the study.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2003	182
Median (95% Confidence Interval) [months]	6.8	5.7

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as time to death, which is the time from the date of dosing until the date of death, regardless of the cause of death.
Time Frame	Baseline until death (up to approximately 7 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants enrolled in the study.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2003	182
Median (95% Confidence Interval) [months]	27.2	29.5

6. Secondary Outcome

Title	Percentage of Participants With Best Overall Response (Complete Response [CR] or Partial Response [PR]) According to RECIST v 1.1 As Per Investigator Assessment
Description	Best Overall Response reported here is the Best confirmed Overall Response. To be assigned a status of PR or CR, i.e., to be a responder, changes in tumor measurements had to be confirmed by repeat assessments that had to be performed no less than 4 weeks after the criteria for response were first met, i.e., participants needed to have two consecutive assessments of PR or CR. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants enrolled in the study. Only participants with measurable disease were included in the analysis.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	1613	169
Number (95% Confidence Interval) [Percentage of Participants]	29.3 1.5%	29.6 16.3%

7. Secondary Outcome

Title	Percentage of Participants With Clinical Benefit (CR or PR or Stable Disease [SD]) According to RECIST v 1.1
Description	Clinical Benefit was defined as CR plus PR plus SD. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD: neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants enrolled in the study. Only participants with measurable disease were included in the analysis.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	1613	169
Number (95% Confidence Interval) [Percentage of Participants]	47.1 2.4%	39.6 21.8%

8. Secondary Outcome

Title	Duration of Response (DOR) According to RECIST v 1.1
Description	DOR is defined as the period from the date of initial confirmed PR or CR (whichever occurs first) until the date of PD or death from any cause. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 millimeters (mm).
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants enrolled in the study. Only participants with measurable disease were included in the analysis.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	1613	169
Median (95% Confidence Interval) [months]	13.8	14.2

9. Secondary Outcome

Title	Time to Response According to RECIST v 1.1
Description	Time to Response is defined as the time from first dose to first documentation of confirmed PR or CR (whichever occurs first). CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.
Time Frame	Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 12 weeks during treatment period thereafter 28-42 days after the last dose or every 3-6 months up to approximately 7 years)

Outcome Measure Data

Analysis Population Description

ITT Population included all participants enrolled in the study. Only responders were included in the analysis.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	473	50
Median (95% Confidence Interval) [months]	22.3	8.3

10. Secondary Outcome

Title	Number of Hospital Visits
Description	The number of hospital visits were recorded to evaluate the resoruce expenditures while participants were on study treatment.
Time Frame	Baseline up to approximately 7 years

Outcome Measure Data

Analysis Population Description

The safety population included all participants who had received at least 1 dose of study medication.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2002	181
Mean (Standard Deviation) [Number of Hospital Visits]	2.7 (2.78)	2.1 (1.70)

11. Secondary Outcome

Title	Type of Hospital Visits
Description	The type of hospital visits (intensive care unit (ICU) versus other) were recorded to evaluate the resoruce expenditures while participants were on study treatment. The number of participants with at least one ICU visit are based on the number of participants with at least one hospital visit, in each group.
Time Frame	Baseline up to approximately 7 years

Outcome Measure Data

Analysis Population Description

The safety population included all participants who had received at least 1 dose of study medication.

Arm/Group Title	Trastuzumab Emtansine (All Participants)	Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.	This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
Measure Participants	2002	181
Other Hospital Visit	558 27.9%	33 18.1%
ICU Visit	39 1.9%	0 0%

Adverse Events

Time Frame	Baseline up to approximately 7 years
Adverse Event Reporting Description	The analysis of AEs focused on treatment-emergent AEs (TEAEs) which were AEs that occurred on the day of or after first administration of study drug.
Arm/Group Title	Trastuzumab Emtansine (All Participants)		Trastuzumab Emtansine (Asian Participants)
Arm/Group Description	This cohort (Cohort 1) enrolled all participants with HER2 positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.		This cohort (Cohort 2) enrolled Asian race participants with HER2-positive, unresectable, LABC or mBC who had received prior anti-HER2 and chemotherapy treatment and had progressed on or after the most recent treatment for LABC or mBC, or within 6 months of completing adjuvant therapy. Participants received trastuzumab emtansine every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression.
All Cause Mortality
	Trastuzumab Emtansine (All Participants)		Trastuzumab Emtansine (Asian Participants)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1072/2002 (53.5%)		77/181 (42.5%)
Serious Adverse Events
	Trastuzumab Emtansine (All Participants)		Trastuzumab Emtansine (Asian Participants)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	427/2002 (21.3%)		36/181 (19.9%)
Blood and lymphatic system disorders
ANAEMIA	13/2002 (0.6%)	14	0/181 (0%)	0
BONE MARROW FAILURE	1/2002 (0%)	1	0/181 (0%)	0
DISSEMINATED INTRAVASCULAR COAGULATION	1/2002 (0%)	1	0/181 (0%)	0
FEBRILE NEUTROPENIA	1/2002 (0%)	1	0/181 (0%)	0
THROMBOCYTOPENIA	11/2002 (0.5%)	11	10/181 (5.5%)	11
Cardiac disorders
ACUTE CORONARY SYNDROME	3/2002 (0.1%)	3	1/181 (0.6%)	1
ANGINA PECTORIS	1/2002 (0%)	1	0/181 (0%)	0
CARDIAC ARREST	1/2002 (0%)	1	0/181 (0%)	0
CARDIAC FAILURE	1/2002 (0%)	1	0/181 (0%)	0
CARDIAC TAMPONADE	1/2002 (0%)	1	0/181 (0%)	0
CARDIO-RESPIRATORY ARREST	1/2002 (0%)	1	0/181 (0%)	0
PALPITATIONS	1/2002 (0%)	1	1/181 (0.6%)	1
PERICARDIAL EFFUSION	2/2002 (0.1%)	2	0/181 (0%)	0
SUPRAVENTRICULAR TACHYCARDIA	2/2002 (0.1%)	2	0/181 (0%)	0
Ear and labyrinth disorders
VERTIGO	3/2002 (0.1%)	3	0/181 (0%)	0
Endocrine disorders
ADRENAL INSUFFICIENCY	1/2002 (0%)	1	0/181 (0%)	0
HYPERTHYROIDISM	1/2002 (0%)	1	0/181 (0%)	0
Eye disorders
BLINDNESS	1/2002 (0%)	2	0/181 (0%)	0
CATARACT	0/2002 (0%)	0	1/181 (0.6%)	1
RETINAL VEIN THROMBOSIS	1/2002 (0%)	1	0/181 (0%)	0
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/2002 (0%)	1	0/181 (0%)	0
ABDOMINAL PAIN	4/2002 (0.2%)	12	1/181 (0.6%)	1
ABDOMINAL PAIN UPPER	2/2002 (0.1%)	2	0/181 (0%)	0
ANAL FISSURE	1/2002 (0%)	1	0/181 (0%)	0
ANAL HAEMORRHAGE	2/2002 (0.1%)	4	0/181 (0%)	0
ASCITES	2/2002 (0.1%)	6	0/181 (0%)	0
COLITIS	3/2002 (0.1%)	3	0/181 (0%)	0
CONSTIPATION	3/2002 (0.1%)	3	0/181 (0%)	0
DIARRHOEA	4/2002 (0.2%)	4	0/181 (0%)	0
DUODENAL ULCER	2/2002 (0.1%)	2	0/181 (0%)	0
DUODENAL ULCER HAEMORRHAGE	1/2002 (0%)	2	0/181 (0%)	0
DYSPHAGIA	2/2002 (0.1%)	3	0/181 (0%)	0
GASTRIC ANTRAL VASCULAR ECTASIA	1/2002 (0%)	1	0/181 (0%)	0
GASTRIC HAEMORRHAGE	1/2002 (0%)	10	0/181 (0%)	0
GASTRIC ULCER	1/2002 (0%)	1	0/181 (0%)	0
GASTRITIS	3/2002 (0.1%)	3	0/181 (0%)	0
GASTRITIS EROSIVE	1/2002 (0%)	1	0/181 (0%)	0
GASTRODUODENAL ULCER	1/2002 (0%)	1	0/181 (0%)	0
GASTROINTESTINAL HAEMORRHAGE	3/2002 (0.1%)	10	0/181 (0%)	0
GINGIVAL BLEEDING	1/2002 (0%)	1	0/181 (0%)	0
GLOSSITIS	1/2002 (0%)	1	0/181 (0%)	0
INTESTINAL OBSTRUCTION	2/2002 (0.1%)	3	0/181 (0%)	0
LOWER GASTROINTESTINAL HAEMORRHAGE	1/2002 (0%)	2	1/181 (0.6%)	2
MELAENA	2/2002 (0.1%)	8	0/181 (0%)	0
NAUSEA	5/2002 (0.2%)	6	1/181 (0.6%)	1
OESOPHAGEAL FISTULA	1/2002 (0%)	1	0/181 (0%)	0
OESOPHAGEAL VARICES HAEMORRHAGE	1/2002 (0%)	4	0/181 (0%)	0
PANCREATITIS ACUTE	1/2002 (0%)	3	0/181 (0%)	0
PERIODONTAL DISEASE	1/2002 (0%)	1	0/181 (0%)	0
PROCTALGIA	1/2002 (0%)	1	0/181 (0%)	0
RECTAL HAEMORRHAGE	1/2002 (0%)	2	0/181 (0%)	0
SMALL INTESTINAL HAEMORRHAGE	1/2002 (0%)	2	0/181 (0%)	0
SMALL INTESTINAL OBSTRUCTION	1/2002 (0%)	1	0/181 (0%)	0
STOMATITIS	1/2002 (0%)	1	0/181 (0%)	0
SUBILEUS	2/2002 (0.1%)	4	0/181 (0%)	0
TOOTH LOSS	1/2002 (0%)	1	0/181 (0%)	0
UPPER GASTROINTESTINAL HAEMORRHAGE	3/2002 (0.1%)	6	2/181 (1.1%)	6
VOMITING	17/2002 (0.8%)	19	1/181 (0.6%)	1
General disorders
ASTHENIA	3/2002 (0.1%)	3	0/181 (0%)	0
CATHETER SITE ERYTHEMA	1/2002 (0%)	1	0/181 (0%)	0
CHILLS	2/2002 (0.1%)	6	0/181 (0%)	0
DEATH	5/2002 (0.2%)	5	0/181 (0%)	0
FATIGUE	1/2002 (0%)	1	0/181 (0%)	0
GENERAL PHYSICAL HEALTH DETERIORATION	4/2002 (0.2%)	4	0/181 (0%)	0
HYPERTHERMIA	2/2002 (0.1%)	2	0/181 (0%)	0
IMPLANT SITE DEHISCENCE	1/2002 (0%)	1	0/181 (0%)	0
INFLAMMATION	1/2002 (0%)	1	0/181 (0%)	0
INFLUENZA LIKE ILLNESS	1/2002 (0%)	1	0/181 (0%)	0
MALAISE	1/2002 (0%)	1	0/181 (0%)	0
MULTIPLE ORGAN DYSFUNCTION SYNDROME	3/2002 (0.1%)	3	1/181 (0.6%)	1
PYREXIA	13/2002 (0.6%)	42	0/181 (0%)	0
SUDDEN DEATH	0/2002 (0%)	0	1/181 (0.6%)	1
Hepatobiliary disorders
CHOLECYSTITIS	3/2002 (0.1%)	3	0/181 (0%)	0
CHOLESTASIS	2/2002 (0.1%)	2	0/181 (0%)	0
DRUG-INDUCED LIVER INJURY	1/2002 (0%)	3	1/181 (0.6%)	3
HEPATIC FAILURE	5/2002 (0.2%)	10	0/181 (0%)	0
HEPATIC FUNCTION ABNORMAL	1/2002 (0%)	1	0/181 (0%)	0
HEPATIC PAIN	1/2002 (0%)	1	0/181 (0%)	0
HEPATOTOXICITY	7/2002 (0.3%)	14	0/181 (0%)	0
JAUNDICE	1/2002 (0%)	1	0/181 (0%)	0
NODULAR REGENERATIVE HYPERPLASIA	3/2002 (0.1%)	6	0/181 (0%)	0
NON-CIRRHOTIC PORTAL HYPERTENSION	1/2002 (0%)	2	0/181 (0%)	0
PORTAL HYPERTENSION	2/2002 (0.1%)	4	0/181 (0%)	0
Immune system disorders
ALLERGIC OEDEMA	1/2002 (0%)	3	0/181 (0%)	0
HYPERSENSITIVITY	2/2002 (0.1%)	6	0/181 (0%)	0
Infections and infestations
ABSCESS	1/2002 (0%)	1	0/181 (0%)	0
ACINETOBACTER INFECTION	1/2002 (0%)	1	0/181 (0%)	0
ARTHRITIS INFECTIVE	1/2002 (0%)	1	0/181 (0%)	0
BACTERAEMIA	1/2002 (0%)	1	0/181 (0%)	0
BACTERIAL INFECTION	1/2002 (0%)	1	0/181 (0%)	0
BACTERIAL SEPSIS	1/2002 (0%)	1	0/181 (0%)	0
BRAIN ABSCESS	1/2002 (0%)	1	0/181 (0%)	0
BREAST CELLULITIS	2/2002 (0.1%)	2	0/181 (0%)	0
BRONCHITIS	3/2002 (0.1%)	4	0/181 (0%)	0
CATHETER SITE INFECTION	1/2002 (0%)	1	0/181 (0%)	0
CELLULITIS	8/2002 (0.4%)	10	0/181 (0%)	0
CLOSTRIDIUM DIFFICILE COLITIS	1/2002 (0%)	1	0/181 (0%)	0
CYSTITIS	1/2002 (0%)	1	0/181 (0%)	0
DENGUE HAEMORRHAGIC FEVER	0/2002 (0%)	0	1/181 (0.6%)	1
DEVICE RELATED INFECTION	6/2002 (0.3%)	6	0/181 (0%)	0
ENCEPHALITIS	1/2002 (0%)	1	0/181 (0%)	0
ENDOCARDITIS	2/2002 (0.1%)	2	0/181 (0%)	0
ERYSIPELAS	4/2002 (0.2%)	5	0/181 (0%)	0
GASTROENTERITIS	2/2002 (0.1%)	2	0/181 (0%)	0
GASTROENTERITIS NOROVIRUS	1/2002 (0%)	1	0/181 (0%)	0
GASTROENTERITIS VIRAL	1/2002 (0%)	1	0/181 (0%)	0
GASTROINTESTINAL VIRAL INFECTION	1/2002 (0%)	1	0/181 (0%)	0
HERPES ZOSTER	2/2002 (0.1%)	2	0/181 (0%)	0
INFECTION	3/2002 (0.1%)	3	0/181 (0%)	0
INFECTIOUS PLEURAL EFFUSION	1/2002 (0%)	1	0/181 (0%)	0
INFECTIVE EXACERBATION OF BRONCHIECTASIS	1/2002 (0%)	1	0/181 (0%)	0
INTERVERTEBRAL DISCITIS	1/2002 (0%)	1	0/181 (0%)	0
KLEBSIELLA BACTERAEMIA	1/2002 (0%)	1	0/181 (0%)	0
LISTERIOSIS	1/2002 (0%)	1	0/181 (0%)	0
LIVER ABSCESS	1/2002 (0%)	1	0/181 (0%)	0
LOWER RESPIRATORY TRACT INFECTION	9/2002 (0.4%)	10	0/181 (0%)	0
MASTITIS	2/2002 (0.1%)	2	0/181 (0%)	0
MENINGITIS	1/2002 (0%)	1	0/181 (0%)	0
OTITIS MEDIA	3/2002 (0.1%)	3	0/181 (0%)	0
PERITONITIS	2/2002 (0.1%)	2	0/181 (0%)	0
PHARYNGITIS	1/2002 (0%)	1	1/181 (0.6%)	1
PNEUMOCOCCAL INFECTION	1/2002 (0%)	1	0/181 (0%)	0
PNEUMONIA	22/2002 (1.1%)	23	8/181 (4.4%)	8
PNEUMONIA STREPTOCOCCAL	1/2002 (0%)	1	0/181 (0%)	0
PNEUMONIA VIRAL	1/2002 (0%)	1	0/181 (0%)	0
PYELONEPHRITIS	2/2002 (0.1%)	2	0/181 (0%)	0
PYELONEPHRITIS ACUTE	1/2002 (0%)	1	0/181 (0%)	0
PYELONEPHRITIS CHRONIC	1/2002 (0%)	2	0/181 (0%)	0
RESPIRATORY TRACT INFECTION	1/2002 (0%)	1	0/181 (0%)	0
RESPIRATORY TRACT INFECTION VIRAL	1/2002 (0%)	1	0/181 (0%)	0
SEPSIS	9/2002 (0.4%)	9	0/181 (0%)	0
SEPTIC SHOCK	1/2002 (0%)	1	0/181 (0%)	0
SKIN INFECTION	1/2002 (0%)	1	0/181 (0%)	0
SOFT TISSUE INFECTION	1/2002 (0%)	1	0/181 (0%)	0
STAPHYLOCOCCAL BACTERAEMIA	1/2002 (0%)	1	0/181 (0%)	0
STAPHYLOCOCCAL INFECTION	2/2002 (0.1%)	2	0/181 (0%)	0
STAPHYLOCOCCAL SEPSIS	2/2002 (0.1%)	2	0/181 (0%)	0
STREPTOCOCCAL INFECTION	1/2002 (0%)	1	0/181 (0%)	0
TRACHEOBRONCHITIS	1/2002 (0%)	1	0/181 (0%)	0
UPPER RESPIRATORY TRACT INFECTION	3/2002 (0.1%)	4	0/181 (0%)	0
URINARY TRACT INFECTION	11/2002 (0.5%)	12	0/181 (0%)	0
VASCULAR DEVICE INFECTION	3/2002 (0.1%)	3	0/181 (0%)	0
VIRAL INFECTION	1/2002 (0%)	1	0/181 (0%)	0
VIRAL UPPER RESPIRATORY TRACT INFECTION	1/2002 (0%)	2	0/181 (0%)	0
VULVAL ABSCESS	1/2002 (0%)	1	0/181 (0%)	0
Injury, poisoning and procedural complications
ANASTOMOTIC ULCER	1/2002 (0%)	1	0/181 (0%)	0
ANKLE FRACTURE	2/2002 (0.1%)	2	0/181 (0%)	0
FALL	1/2002 (0%)	1	0/181 (0%)	0
FEMORAL NECK FRACTURE	4/2002 (0.2%)	4	0/181 (0%)	0
FEMUR FRACTURE	8/2002 (0.4%)	8	0/181 (0%)	0
FOREARM FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
HAND FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
HEAD INJURY	3/2002 (0.1%)	3	0/181 (0%)	0
HIP FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
HUMERUS FRACTURE	2/2002 (0.1%)	2	0/181 (0%)	0
INFUSION RELATED REACTION	2/2002 (0.1%)	6	0/181 (0%)	0
INTENTIONAL OVERDOSE	1/2002 (0%)	1	0/181 (0%)	0
LUMBAR VERTEBRAL FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
PELVIC FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
POST PROCEDURAL HAEMORRHAGE	1/2002 (0%)	1	0/181 (0%)	0
RADIATION NECROSIS	1/2002 (0%)	1	0/181 (0%)	0
RIB FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
ROAD TRAFFIC ACCIDENT	1/2002 (0%)	1	0/181 (0%)	0
SKELETAL INJURY	1/2002 (0%)	1	0/181 (0%)	0
SPLENIC INJURY	1/2002 (0%)	1	0/181 (0%)	0
SUBDURAL HAEMATOMA	1/2002 (0%)	2	0/181 (0%)	0
THERMAL BURN	1/2002 (0%)	1	0/181 (0%)	0
UPPER LIMB FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
WRIST FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED	2/2002 (0.1%)	2	0/181 (0%)	0
AMYLASE INCREASED	1/2002 (0%)	1	0/181 (0%)	0
ASPARTATE AMINOTRANSFERASE INCREASED	3/2002 (0.1%)	4	0/181 (0%)	0
BLOOD BILIRUBIN INCREASED	2/2002 (0.1%)	2	1/181 (0.6%)	1
ECG SIGNS OF MYOCARDIAL ISCHAEMIA	1/2002 (0%)	1	0/181 (0%)	0
GAMMA-GLUTAMYLTRANSFERASE INCREASED	1/2002 (0%)	1	0/181 (0%)	0
HEPATIC ENZYME INCREASED	3/2002 (0.1%)	3	0/181 (0%)	0
LIVER FUNCTION TEST ABNORMAL	3/2002 (0.1%)	3	0/181 (0%)	0
LIVER FUNCTION TEST INCREASED	0/2002 (0%)	0	1/181 (0.6%)	1
NEUTROPHIL COUNT DECREASED	1/2002 (0%)	1	0/181 (0%)	0
PLATELET COUNT DECREASED	2/2002 (0.1%)	2	8/181 (4.4%)	12
TRANSAMINASES INCREASED	0/2002 (0%)	0	1/181 (0.6%)	1
Metabolism and nutrition disorders
DECREASED APPETITE	2/2002 (0.1%)	2	0/181 (0%)	0
DEHYDRATION	3/2002 (0.1%)	3	0/181 (0%)	0
FAILURE TO THRIVE	1/2002 (0%)	1	0/181 (0%)	0
HYPERCALCAEMIA	3/2002 (0.1%)	3	0/181 (0%)	0
HYPERURICAEMIA	1/2002 (0%)	1	0/181 (0%)	0
HYPOGLYCAEMIA	1/2002 (0%)	1	0/181 (0%)	0
HYPOKALAEMIA	1/2002 (0%)	1	1/181 (0.6%)	2
HYPONATRAEMIA	1/2002 (0%)	1	0/181 (0%)	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA	2/2002 (0.1%)	2	0/181 (0%)	0
BACK PAIN	1/2002 (0%)	1	0/181 (0%)	0
BONE LESION	1/2002 (0%)	1	0/181 (0%)	0
BONE PAIN	2/2002 (0.1%)	2	0/181 (0%)	0
HAEMATOMA MUSCLE	1/2002 (0%)	1	0/181 (0%)	0
INTERVERTEBRAL DISC PROTRUSION	1/2002 (0%)	1	0/181 (0%)	0
KYPHOSIS	1/2002 (0%)	1	0/181 (0%)	0
MOBILITY DECREASED	1/2002 (0%)	1	0/181 (0%)	0
MUSCULAR WEAKNESS	1/2002 (0%)	1	0/181 (0%)	0
MUSCULOSKELETAL CHEST PAIN	3/2002 (0.1%)	3	0/181 (0%)	0
OSTEONECROSIS OF JAW	1/2002 (0%)	1	0/181 (0%)	0
PAIN IN EXTREMITY	2/2002 (0.1%)	2	0/181 (0%)	0
PATHOLOGICAL FRACTURE	1/2002 (0%)	1	0/181 (0%)	0
SPINAL PAIN	2/2002 (0.1%)	2	0/181 (0%)	0
SYSTEMIC LUPUS ERYTHEMATOSUS	1/2002 (0%)	1	0/181 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	1/2002 (0%)	1	0/181 (0%)	0
BENIGN NEOPLASM	1/2002 (0%)	1	0/181 (0%)	0
BREAST CANCER METASTATIC	1/2002 (0%)	1	0/181 (0%)	0
CANCER PAIN	3/2002 (0.1%)	3	0/181 (0%)	0
MALIGNANT MELANOMA	1/2002 (0%)	1	0/181 (0%)	0
MENINGIOMA	1/2002 (0%)	1	0/181 (0%)	0
METASTASES TO BONE	1/2002 (0%)	1	0/181 (0%)	0
METASTATIC UTERINE CANCER	1/2002 (0%)	1	0/181 (0%)	0
NAEVUS HAEMORRHAGE	1/2002 (0%)	1	0/181 (0%)	0
SARCOMA	1/2002 (0%)	1	0/181 (0%)	0
SKIN NEOPLASM BLEEDING	1/2002 (0%)	1	0/181 (0%)	0
Nervous system disorders
APHASIA	2/2002 (0.1%)	4	0/181 (0%)	0
ATAXIA	1/2002 (0%)	1	0/181 (0%)	0
BRAIN OEDEMA	6/2002 (0.3%)	7	0/181 (0%)	0
CENTRAL NERVOUS SYSTEM NECROSIS	1/2002 (0%)	1	0/181 (0%)	0
CEREBRAL HAEMORRHAGE	4/2002 (0.2%)	8	1/181 (0.6%)	2
CEREBRAL ISCHAEMIA	2/2002 (0.1%)	2	0/181 (0%)	0
CEREBROVASCULAR ACCIDENT	1/2002 (0%)	2	0/181 (0%)	0
DIZZINESS	3/2002 (0.1%)	4	0/181 (0%)	0
EPILEPSY	8/2002 (0.4%)	15	0/181 (0%)	0
HAEMORRHAGE INTRACRANIAL	3/2002 (0.1%)	6	0/181 (0%)	0
HAEMORRHAGIC STROKE	1/2002 (0%)	2	0/181 (0%)	0
HEADACHE	1/2002 (0%)	1	0/181 (0%)	0
HEMIPARESIS	5/2002 (0.2%)	5	0/181 (0%)	0
IIIRD NERVE PARESIS	1/2002 (0%)	1	0/181 (0%)	0
LEUKOENCEPHALOPATHY	2/2002 (0.1%)	2	0/181 (0%)	0
MIGRAINE	1/2002 (0%)	1	0/181 (0%)	0
MOTOR DYSFUNCTION	1/2002 (0%)	1	0/181 (0%)	0
NERVOUS SYSTEM DISORDER	1/2002 (0%)	1	0/181 (0%)	0
PARTIAL SEIZURES	1/2002 (0%)	1	0/181 (0%)	0
PRESYNCOPE	2/2002 (0.1%)	2	0/181 (0%)	0
SCIATICA	2/2002 (0.1%)	2	0/181 (0%)	0
SEIZURE	7/2002 (0.3%)	11	0/181 (0%)	0
TRANSIENT ISCHAEMIC ATTACK	1/2002 (0%)	1	0/181 (0%)	0
VOCAL CORD PARALYSIS	1/2002 (0%)	1	0/181 (0%)	0
Product Issues
DEVICE BREAKAGE	1/2002 (0%)	1	0/181 (0%)	0
DEVICE EXTRUSION	1/2002 (0%)	1	0/181 (0%)	0
DEVICE LOOSENING	1/2002 (0%)	1	0/181 (0%)	0
Psychiatric disorders
AGITATION	1/2002 (0%)	1	0/181 (0%)	0
ANXIETY	2/2002 (0.1%)	2	0/181 (0%)	0
COMPLETED SUICIDE	1/2002 (0%)	1	0/181 (0%)	0
CONFUSIONAL STATE	4/2002 (0.2%)	4	0/181 (0%)	0
DEPRESSION	3/2002 (0.1%)	4	0/181 (0%)	0
HALLUCINATION	1/2002 (0%)	1	0/181 (0%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY	1/2002 (0%)	1	0/181 (0%)	0
HAEMATURIA	2/2002 (0.1%)	4	0/181 (0%)	0
NEPHROLITHIASIS	1/2002 (0%)	1	0/181 (0%)	0
RENAL COLIC	2/2002 (0.1%)	2	0/181 (0%)	0
RENAL FAILURE	4/2002 (0.2%)	4	0/181 (0%)	0
RENAL INJURY	1/2002 (0%)	1	0/181 (0%)	0
URINARY TRACT OBSTRUCTION	1/2002 (0%)	1	0/181 (0%)	0
Reproductive system and breast disorders
CYSTOCELE	1/2002 (0%)	1	0/181 (0%)	0
METRORRHAGIA	1/2002 (0%)	1	0/181 (0%)	0
UTERINE HAEMORRHAGE	1/2002 (0%)	1	0/181 (0%)	0
UTERINE POLYP	1/2002 (0%)	1	0/181 (0%)	0
VAGINAL HAEMORRHAGE	1/2002 (0%)	1	1/181 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA	1/2002 (0%)	1	0/181 (0%)	0
ASPIRATION	1/2002 (0%)	1	0/181 (0%)	0
ASTHMATIC CRISIS	1/2002 (0%)	1	0/181 (0%)	0
CHOKING	1/2002 (0%)	1	0/181 (0%)	0
DYSPNOEA	7/2002 (0.3%)	24	0/181 (0%)	0
EPISTAXIS	7/2002 (0.3%)	8	0/181 (0%)	0
HAEMOPTYSIS	1/2002 (0%)	1	0/181 (0%)	0
INTERSTITIAL LUNG DISEASE	4/2002 (0.2%)	4	0/181 (0%)	0
PLEURAL EFFUSION	3/2002 (0.1%)	4	0/181 (0%)	0
PLEURITIC PAIN	2/2002 (0.1%)	2	0/181 (0%)	0
PNEUMONITIS	6/2002 (0.3%)	6	0/181 (0%)	0
PNEUMOTHORAX	5/2002 (0.2%)	5	0/181 (0%)	0
PULMONARY ALVEOLAR HAEMORRHAGE	1/2002 (0%)	1	0/181 (0%)	0
PULMONARY EMBOLISM	3/2002 (0.1%)	3	0/181 (0%)	0
PULMONARY FIBROSIS	1/2002 (0%)	1	0/181 (0%)	0
PULMONARY OEDEMA	1/2002 (0%)	1	0/181 (0%)	0
RESPIRATORY DISTRESS	2/2002 (0.1%)	2	0/181 (0%)	0
RESPIRATORY FAILURE	1/2002 (0%)	1	1/181 (0.6%)	1
RESPIRATORY TRACT HAEMORRHAGE	1/2002 (0%)	1	0/181 (0%)	0
SLEEP APNOEA SYNDROME	1/2002 (0%)	1	0/181 (0%)	0
Skin and subcutaneous tissue disorders
SPIDER NAEVUS	1/2002 (0%)	2	0/181 (0%)	0
Surgical and medical procedures
BREAST CONSERVING SURGERY	1/2002 (0%)	1	0/181 (0%)	0
SCAR EXCISION	1/2002 (0%)	1	0/181 (0%)	0
Vascular disorders
CIRCULATORY COLLAPSE	1/2002 (0%)	3	0/181 (0%)	0
EMBOLISM	1/2002 (0%)	1	0/181 (0%)	0
HAEMATOMA	2/2002 (0.1%)	2	0/181 (0%)	0
HYPOTENSION	1/2002 (0%)	3	0/181 (0%)	0
ORTHOSTATIC HYPOTENSION	1/2002 (0%)	1	0/181 (0%)	0
VENA CAVA THROMBOSIS	1/2002 (0%)	1	0/181 (0%)	0
VENOUS THROMBOSIS LIMB	1/2002 (0%)	1	0/181 (0%)	0
Other (Not Including Serious) Adverse Events
	Trastuzumab Emtansine (All Participants)		Trastuzumab Emtansine (Asian Participants)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1734/2002 (86.6%)		170/181 (93.9%)
Blood and lymphatic system disorders
ANAEMIA	173/2002 (8.6%)	231	27/181 (14.9%)	49
LEUKOPENIA	19/2002 (0.9%)	23	15/181 (8.3%)	69
NEUTROPENIA	79/2002 (3.9%)	151	17/181 (9.4%)	72
THROMBOCYTOPENIA	165/2002 (8.2%)	257	47/181 (26%)	157
Gastrointestinal disorders
ABDOMINAL PAIN	139/2002 (6.9%)	182	6/181 (3.3%)	8
ABDOMINAL PAIN UPPER	135/2002 (6.7%)	163	5/181 (2.8%)	5
CONSTIPATION	394/2002 (19.7%)	568	10/181 (5.5%)	38
DIARRHOEA	252/2002 (12.6%)	376	9/181 (5%)	9
DRY MOUTH	283/2002 (14.1%)	303	7/181 (3.9%)	13
GINGIVAL BLEEDING	83/2002 (4.1%)	96	14/181 (7.7%)	19
NAUSEA	651/2002 (32.5%)	1204	28/181 (15.5%)	45
STOMATITIS	160/2002 (8%)	213	4/181 (2.2%)	6
VOMITING	294/2002 (14.7%)	408	17/181 (9.4%)	24
General disorders
ASTHENIA	491/2002 (24.5%)	828	18/181 (9.9%)	44
FATIGUE	556/2002 (27.8%)	846	12/181 (6.6%)	17
INFLUENZA LIKE ILLNESS	107/2002 (5.3%)	161	3/181 (1.7%)	3
OEDEMA PERIPHERAL	102/2002 (5.1%)	115	6/181 (3.3%)	10
PAIN	85/2002 (4.2%)	92	10/181 (5.5%)	11
PYREXIA	339/2002 (16.9%)	1599	47/181 (26%)	243
Infections and infestations
NASOPHARYNGITIS	136/2002 (6.8%)	195	8/181 (4.4%)	13
UPPER RESPIRATORY TRACT INFECTION	80/2002 (4%)	107	14/181 (7.7%)	18
URINARY TRACT INFECTION	157/2002 (7.8%)	230	4/181 (2.2%)	4
Investigations
ALANINE AMINOTRANSFERASE INCREASED	86/2002 (4.3%)	100	58/181 (32%)	133
ASPARTATE AMINOTRANSFERASE INCREASED	136/2002 (6.8%)	156	77/181 (42.5%)	143
BLOOD ALKALINE PHOSPHATASE INCREASED	52/2002 (2.6%)	52	14/181 (7.7%)	16
BLOOD BILIRUBIN INCREASED	89/2002 (4.4%)	171	30/181 (16.6%)	85
GAMMA-GLUTAMYLTRANSFERASE INCREASED	84/2002 (4.2%)	94	21/181 (11.6%)	31
NEUTROPHIL COUNT DECREASED	36/2002 (1.8%)	58	20/181 (11%)	84
PLATELET COUNT DECREASED	91/2002 (4.5%)	124	55/181 (30.4%)	191
TRANSAMINASES INCREASED	27/2002 (1.3%)	28	18/181 (9.9%)	39
WEIGHT DECREASED	106/2002 (5.3%)	109	8/181 (4.4%)	8
WHITE BLOOD CELL COUNT DECREASED	11/2002 (0.5%)	13	20/181 (11%)	85
Metabolism and nutrition disorders
DECREASED APPETITE	320/2002 (16%)	398	16/181 (8.8%)	23
HYPOALBUMINAEMIA	13/2002 (0.6%)	13	11/181 (6.1%)	14
HYPOKALAEMIA	73/2002 (3.6%)	91	19/181 (10.5%)	37
Musculoskeletal and connective tissue disorders
ARTHRALGIA	265/2002 (13.2%)	349	6/181 (3.3%)	7
BACK PAIN	199/2002 (9.9%)	226	5/181 (2.8%)	5
MUSCLE SPASMS	124/2002 (6.2%)	154	1/181 (0.6%)	1
MUSCULOSKELETAL PAIN	135/2002 (6.7%)	150	3/181 (1.7%)	3
MYALGIA	205/2002 (10.2%)	279	8/181 (4.4%)	11
PAIN IN EXTREMITY	148/2002 (7.4%)	169	3/181 (1.7%)	3
Nervous system disorders
DIZZINESS	117/2002 (5.8%)	137	11/181 (6.1%)	17
HEADACHE	454/2002 (22.7%)	650	19/181 (10.5%)	32
PARAESTHESIA	128/2002 (6.4%)	139	4/181 (2.2%)	5
PERIPHERAL SENSORY NEUROPATHY	113/2002 (5.6%)	132	0/181 (0%)	0
Psychiatric disorders
INSOMNIA	118/2002 (5.9%)	134	11/181 (6.1%)	13
Respiratory, thoracic and mediastinal disorders
COUGH	220/2002 (11%)	256	23/181 (12.7%)	28
DYSPNOEA	211/2002 (10.5%)	705	2/181 (1.1%)	6
EPISTAXIS	402/2002 (20.1%)	669	30/181 (16.6%)	43
Vascular disorders
HYPERTENSION	96/2002 (4.8%)	113	12/181 (6.6%)	17

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.