A Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Participants With HER2-Positive Early Breast Cancer

Early Breast Cancer Clinical Trial

— FeDeriCa  

Official title:

A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Patients With HER2-Positive Early Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03493854
• Other study ID #: WO40324
• Secondary ID: 2017-004897-32
• Status: Completed
• Phase: Phase 3
• Start date: June 14, 2018
• Est. completion date: June 2, 2023

Study information

• Verified date: June 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab and trastuzumab for subcutaneous (SC) administration in combination with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the neoadjuvant/adjuvant setting.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 500
• Est. completion date: June 2, 2023
• Est. primary completion date: July 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Ability to comply with the study protocol, in the investigator's judgment

• Eastern Cooperative Oncology Group (ECOG) Performance Status =1

• Female and male patients with Stage II - IIIC (T2-T4 plus any N, or any T plus N1-N3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer

• Primary tumor >2 cm in diameter, or node-positive disease (clinically or on imaging, and node positivity confirmed with cytology and/or histopathology)

• HER2-positive breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on pretreatment breast biopsy material.

• Hormone receptor status of the primary tumor, centrally confirmed

• Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy

• Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for central confirmation of HER2 and hormone receptor status and additional biomarker research

• Baseline left ventricular ejection fraction (LVEF) =55% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)

• For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent or use one highly effective non-hormonal contraceptive method with a failure rate of <1% per year, or two effective non-hormonal contraceptive methods during the treatment period and for 7 months after the last dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this same period

• For men: men must remain abstinent or use a condom with a spermicidal product during the treatment period and for 7 months after the last dose of HER2-targeted therapy to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

• A negative serum pregnancy test must be available prior to randomization for WOCBP, unless they have undergone surgical sterilization

• No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment

Exclusion Criteria:

• Stage IV (metastatic) breast cancer

• Patients with a history of invasive breast cancer

• Patients with a history of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix, colon, and skin

• Patients who have received any previous systemic therapy for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer

• Patients who have a past history of ductal carcinoma in situ or lobular carcinoma in situ if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast

• Patients with high-risk for breast cancer who have received chemo-preventative drugs in the past are not allowed to enter the study

• Patients with multicentric breast cancer, unless all tumors are HER2-positive

• Patients with bilateral breast cancer

• Patients who have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes

• Axillary lymph node dissection prior to initiation of neoadjuvant therapy

• Sentinel lymph node biopsy prior to neoadjuvant therapy

• Treatment with any investigational drug within 28 days prior to randomization

• Serious cardiac illness or medical conditions

• Inadequate bone marrow function, renal function or impaired liver function

• Current severe, uncontrolled systemic disease that may interfere with planned treatment

• Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of HER2-targeted therapy

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

• Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis

• Concurrent, serious, uncontrolled infections, or known infection with HIV

• Known hypersensitivity to study drugs, excipients, and/or murine proteins

• Current chronic daily treatment with corticosteroids

• History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma

• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome

Related Conditions & MeSH terms

• Breast Neoplasms
• Early Breast Cancer

Intervention

Drug:
• Cyclophosphamide
Cyclophosphamide 600 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of ddAC Q2W or AC Q3W) for Cycles 1-4.
• Doxorubicin
Doxorubicin 60 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of either ddAC Q2W or AC Q3W) for Cycles 1-4.
• Docetaxel
As part of one of the two investigator's choices of chemotherapy (AC followed by docetaxel), docetaxel 75 mg/m2 will be administered IV on Day 1 of Cycle 5 and then 100 mg/m2 IV at the discretion of the investigator for Cycles 6-8 (Q3W), if no dose-limiting toxicity occurs.
• Paclitaxel
As part of one of the two investigator's choices of chemotherapy (ddAC followed by paclitaxel), paclitaxel 80 mg/m2 will be administered IV QW for 12 weeks.
• Pertuzumab IV
Pertuzumab will be administered as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W.
• FDC of Pertuzumab and Trastuzumab SC
The FDC of pertuzumab and trastuzumab will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.
• Trastuzumab IV
Trastuzumab will be administered as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W.
• Trastuzumab SC
After surgery (from Cycle 9 onwards), participants in Arm A will be allowed to switch from trastuzumab IV to trastuzumab SC, at the discretion of the investigator, in the countries where trastuzumab SC is routinely used. For participants who switch, a fixed dose of 600 mg trastuzumab SC (irrespective of the patient's weight) will be administered in the adjuvant phase.

Procedure:
• Surgery
Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.

Radiation:
• Post-operative Radiotherapy
If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).

Drug:
• Hormone Therapy
For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.

Locations

Country	Name	City	State
Argentina	Fundación CENIT para la Investigación en Neurociencias	Buenos Aires
Argentina	Centro Oncologico Riojano Integral (CORI)	La Rioja
Argentina	COIBA	Provincia De Buenos Aires
Belgium	Institut Jules Bordet	Anderlecht
Belgium	GHdC Site Notre Dame	Charleroi
Belgium	UZ Antwerpen	Edegem
Belgium	Jessa Zkh (Campus Virga Jesse)	Hasselt
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	Clinique Ste-Elisabeth	Namur
Brazil	Hospital Araujo Jorge; Departamento de Ginecologia E Mama	Goiania	GO
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Hospital Perola Byington	Sao Paulo	SP
Canada	Royal Victoria Hospital	Barrie	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Lakeridge Health Center; R. S. MacLaughlin Durham Regional Cancer Center	Oshawa	Ontario
Canada	The Ottawa Hospital Cancer Centre	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont	Sherbrooke	Quebec
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Multiscan s.r.o.	Pardubice
France	ICO Paul Papin; Oncologie Medicale.	Angers
France	Institut Sainte Catherine	Avignon
France	CHRU Besançon	Besançon
France	Institut Bergonie; Oncologie	Bordeaux
France	Centre Léon Bérard	Lyon
France	APHP - Hospital Saint Louis	Paris
France	Institut Curie; Oncologie Medicale	Paris
France	ICO - Site René Gauducheau	Saint Herblain
Germany	Klinikum Augsburg; Frauenklinik	Augsburg
Germany	Hochwaldkrankenhaus; Abt.Gynäkologie Geburtshilfe u.Senologie	Bad Nauheim
Germany	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin
Germany	St. Johannes-Hospital	Dortmund
Germany	Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum	Essen
Germany	Kooperatives Mammazentrum Hamburg Krankenhaus Jerusalem	Hamburg
Germany	Sana Klinikum Offenbach GmbH; Klinik für Gynäkologie & Geburtshilfe	Offenbach
Germany	Gynäkologie Kompetenzzentrum; Praxis Dr. med. Carsten Hielscher	Stralsund
Italy	Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica	Aviano	Friuli-Venezia Giulia
Italy	Uni Degli Studi Di Genova ; Clinica Di Medicina Interna Ad Indirizzo Oncologico	Genova	Liguria
Italy	ASST DI LECCO; Oncologia Medica	Lecco	Lombardia
Italy	Istituto Nazionale Tumori Irccs Fondazione g. PASCALE;U.O.C. Oncologia Medica Senologica	Napoli	Campania
Italy	Università degli Studi Federico II; Clinica di Oncologia Medica	Napoli	Campania
Italy	IOV - Istituto Oncologico Veneto - IRCCS; Oncologia Medica II	Padova	Veneto
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	Fukushima Medical University Hospital	Fukushima
Japan	Gifu University Hospital	Gifu
Japan	Hiroshima City Hiroshima Citizens Hospital	Hiroshima
Japan	Hiroshima University Hospital	Hiroshima
Japan	National Hospital Organization Hokkaido Cancer Center	Hokkaido
Japan	Hyogo Medical University Hospital	Hyogo
Japan	Sagara Hospital	Kagoshima
Japan	Kanagawa Cancer Center	Kanagawa
Japan	Tokai University Hospital	Kanagawa
Japan	Niigata Cancer Center Hospital	Niigata
Japan	Okayama University Hospital	Okayama
Japan	Osaka International Cancer Institute	Osaka
Japan	Saitama Medical University International Medical Center	Saitama
Japan	St. Luke's International Hospital	Tokyo
Japan	The Cancer Institute Hospital of JFCR	Tokyo
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Ulsan University Hosiptal	Ulsan
Mexico	Iem-Fucam	D.f.	Mexico CITY (federal District)
Mexico	Centro Médico Zambrano Hellion	Monterrey	Nuevo LEON
Mexico	Oncologico Potosino	San Luis Potosí	SAN LUIS Potosi
Poland	Bialostockie Centrum Onkologii im. Marii Sklodowskiej - Curie	Bialystok
Poland	Narodowy Inst.Onkol.im.Sklodowskiej-Curie Panstw.Inst.Bad Gliwice; Centr.Diagn.i Lecz.Chor.Piersi	Gliwice
Poland	Szpital Uniwersytecki w Krakowie; Oddzial Kliniczny Onkologii i Poradnia Onkologiczna	Kraków
Poland	Zachodniopomorskie Centrum Onkologii, Osrodek Innowacyjnosci, Rozwoju i Badan Klinicznych	Szczecin
Poland	Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr	Warszawa
Poland	Dolnoslaskie Centrum Onkologii	Wroclaw
Russian Federation	Arkhangelsk Regional Clinical Oncology Dispensary	Arkhangelsk	Arhangelsk
Russian Federation	Ivanovo Regional Oncology Dispensary	Ivanovo
Russian Federation	Clinical Oncology Dispensary of Ministry of Health of Tatarstan	Kazan	Tatarstan
Russian Federation	Moscow City Oncology Hospital #62	Moscovskaya Oblast	Moskovskaja Oblast
Russian Federation	Omsk Region Clinical Oncology Dispensary; 1St Sergical Department	Omsk
Russian Federation	S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)	Saint-Petersburg	Sankt Petersburg
Spain	Hospital de Cruces; Servicio de Oncología Médica	Barakaldo	Vizcaya
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Institut Catala d Oncologia Hospital Duran i Reynals	Barcelona
Spain	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Princesa	Madrid
Spain	Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia	Santiago de Compostela	LA Coruña
Spain	Hospital Universitario Virgen del Rocio; Servicio de Oncologia	Sevilla
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
Taiwan	China Medical University Hospital; Surgery	Taichung
Taiwan	VETERANS GENERAL HOSPITAL; Department of General Surgery	Taipei
Taiwan	Chang Gung Medical Foundation - Linkou; Dept of Surgery	Taoyuan
Thailand	Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital; Department of Surgery/Head Neck and Breast Unit; Clinical Trial	Chiang Mai
Thailand	Songklanagarind Hospital; Department of Surgery	Songkla
Ukraine	Chemotherapy SI Dnipropetrovsk MA of MOHU	Dnipropetrovsk
Ukraine	Municipal Noncommercial Institution Regional Center of Oncology	Kharkiv	Kharkiv Governorate
Ukraine	National Cancer Institute MOH of Ukraine	Kiev
Ukraine	Lviv State Oncology Regional Treatment and Diagnostic Centre	Lviv
Ukraine	RCI Sumy Regional Clinical Oncological Dispensary	Sumy
United Kingdom	Brighton and Sussex Univ Hosp	Brighton
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	St Georges University Hospitals NHS Foundation Trust	London
United Kingdom	Christie Hospital NHS Trust	Manchester
United Kingdom	Freeman Hospital	Newcastle upon Tyne
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Peterborough City Hospital	Peterborough
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	Northwest Medical Specialties	Lakewood	Washington
United States	Maryland Oncology Hematology	Rockville	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  Czechia,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Mexico,  Poland,  Russian Federation,  Spain,  Taiwan,  Thailand,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Trough Serum Concentration (Ctrough) of Pertuzumab During Cycle 7 (Pre-Dose Cycle 8)	The observed pertuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.	Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
Secondary	Ctrough of Trastuzumab During Cycle 7 (Pre-Dose Cycle 8)	The observed trastuzumab trough serum concentration (Ctrough) at Cycle 7 was assessed following 3 cycles of pertuzumab IV and trastuzumab IV or the fixed-dose combination (FDC) of pertuzumab and trastuzumab SC. The Per Protocol Pharmacokinetics (PK) analysis population includes all enrolled participants who adhered to the protocol. Exclusions from the Per Protocol PK analysis population were made for the following reasons: participants were missing the Ctrough pre-dose Cycle 8 PK sample, participants with a Ctrough sample collected with at least 2 days deviation from the planned date on Day 21 (i.e., before Day 19 or after Day 23), participants given a dose amount that deviated from the planned dose by >20% within 3 cycles (from Cycle 5), participants with a dose delay of more than 7 days, a subcutaneous injection site other than thigh was used, if the Cycle 8 pre-dose and post-dose samples were switched, and an assay error impacting Ctrough measurement.	Pre-dose on Cycle 8, Day 1 (up to 21 weeks)
Secondary	Percentage of Participants With Total Pathological Complete Response (tpCR), According to Local Pathologist Assessment	Total pCR (tpCR) was defined as eradication of invasive disease in the breast and axilla; that is, ypT0/is ypN0, according to the local pathologists' assessment. Pathologic response to therapy was determined at the time of surgery. The tpCR rate is the percentage of participants in the ITT population who achieved a tpCR. Participants with missing data for tpCR (i.e., do not undergo surgery or have an invalid pCR assessment) were included in the analysis and classified as non-responders. Rates of tpCR were calculated in each treatment arm and were assessed using the difference between the Arm B: Pertuzumab and Trastuzumab FDC SC and the Arm A: Pertuzumab IV and Trastuzumab IV tpCR rates and corresponding 95% Clopper-Pearson confidence intervals (CIs). The difference between the tpCR rates along with corresponding 95% Hauck-Anderson CIs were calculated. The lower bound of the CI will reliably reflect the largest tpCR difference that can be considered unlikely.	Following completion of surgery (up to 33 weeks)
Secondary	Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Invasive Disease-Free Survival (iDFS; Excluding Second Primary Non-Breast Cancer [SPNBC]) Criteria	iDFS (excluding SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.	Up to 5 years
Secondary	Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to iDFS (Including SPNBC) Criteria	Invasive disease-free survival (iDFS) including second primary non-breast cancer (SPNBC) is defined as the time from the first date of no disease (i.e., the date of primary surgery) to the first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence; ipsilateral local-regional invasive breast cancer reccurrence; distant recurrence; contralateral invasive breast cancer; or death attributable to any cause. It also includes SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).	Up to 5 years
Secondary	Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Event-Free Survival (EFS; Excluding SPNBC) Criteria	Event-free survival (EFS) excluding second primary non-breast cancer (SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. Ipsilateral or contralateral in situ disease and SPNBC (including in situ carcinomas and non-melanoma skin cancers) will not be counted as progressive disease or relapse.	Up to 5 years
Secondary	Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to EFS (Including SPNBC) Criteria	Event-free survival (EFS) including second primary non-breast cancer (SPNBC) is defined as the time from enrollment to the first occurrence of one of the following events: breast cancer progression; breast cancer recurrence; or death from any cause. It also includes SPNBC as an event (with the exception of non-melanoma skin cancers and in situ carcinoma of any site).	Up to 5 years
Secondary	Kaplan-Meier Estimate of the Percentage of Participants Who Are Event-Free According to Distant Recurrence-Free Interval (DRFI) Criteria	The distant recurrence-free interval (DRFI) is defined as the time between randomization and the date of distant breast cancer recurrence.	Up to 5 years
Secondary	Kaplan-Meier Estimate of the Percentage of Participants in Overall Survival	Overall survival is defined as the time from randomization to death from any cause.	Up to 5 years
Secondary	Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (NCI CTCAE v4)	The adverse event (AE) severity grading scale for the NCI CTCAE v4.0 was used for assessing AE severity. Any AEs that were not specifically listed in the NCI CTCAE, v4.0 were graded per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline until the primary completion date (up to 1 year, 1 month)
Secondary	Number of Participants With a Primary Cardiac Event	A primary cardiac event is defined as the occurrence of either of the following events: - Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%; or - Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).	From Baseline until the primary completion date (up to 1 year, 1 month)
Secondary	Number of Participants With a Secondary Cardiac Event	A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as a left ventricular ejection fraction (LVEF) decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks	From Baseline until the primary completion date (up to 1 year, 1 month)
Secondary	Number of Participants With Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline	Clinical laboratory tests were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest (worst) severity grade (according to NCI-CTCAE v4.0) post-baseline. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a medical intervention or a change in concomitant therapy. For a participant with multiple post-baseline abnormalities, only the highest (worst) grade for a given laboratory test is reported. 'Any Grade' indicates the total number of participants with a post-baseline abnormality of any grade for the specified test. Abs. = absolute count; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate transaminase; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine transaminase	Day 1 of Cycles 1 to 8 (up to 21 weeks)
Secondary	Summary of the Number of Participants With at Least One Adverse Event, Severity Determined According to NCI CTCAE v4, Over the Course of the Entire Study	The adverse event (AE) severity grading scale for the NCI CTCAE v4.0 was used for assessing AE severity. Any AEs that were not specifically listed in the NCI CTCAE, v4.0 were graded per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline until end of study (up to 5 years)
Secondary	Number of Participants With a Primary Cardiac Event Over the Course of the Entire Study	A primary cardiac event is defined as the occurrence of either of the following events: - Incidence of a symptomatic ejection fraction decrease (heart failure) of New York Heart Association (NYHA) Class III or IV and a drop in left ventricular ejection fraction (LVEF) of at least 10-percentage points from baseline and to below 50%; or - Cardiac death, defined as: Definite cardiac death (due to heart failure, myocardial infarction, or documented primary arrhythmia); or, Probable cardiac death (sudden unexpected death within 24 hours of a definite or probable cardiac event [e.g., syncope, cardiac arrest, chest pain, infarction, arrhythmia] without documented etiology).	From Baseline until end of study (up to 5 years)
Secondary	Number of Participants With a Secondary Cardiac Event Over the Course of the Entire Study	A secondary cardiac event is defined as asymptomatic or mildly symptomatic Left Ventricular Systolic Dysfunction (LVSD) of NYHA Class II, defined as a left ventricular ejection fraction (LVEF) decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% confirmed by a second assessment within approximately 3 weeks	From Baseline until end of study (up to 5 years)
Secondary	Number of Participants With Laboratory Test Abnormalities at the Highest NCI CTCAE v4 Grade Post-Baseline Over the Course of the Entire Study	Clinical laboratory tests were performed at local laboratories; any abnormal values (High or Low) were based on local laboratory normal ranges. Laboratory abnormalities are presented by the highest (worst) severity grade (according to NCI-CTCAE v4.0) post-baseline. Not every abnormal laboratory value qualified as an adverse event, only if it met any of the following criteria: clinically significant (per investigator); accompanied by clinical symptoms; resulted in a change in study treatment; or required a medical intervention or a change in concomitant therapy. For a participant with multiple post-baseline abnormalities, only the highest (worst) grade for a given laboratory test is reported. 'Any Grade' indicates the total number of participants with a post-baseline abnormality of any grade for the specified test.	Day 1 of Cycles 1 to 22 (1 cycle is 3 weeks), during treatment-free follow-up every 3 months for 1 year, then every 6 months until end of study (up to 5 years)