Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

Breast Cancer Clinical Trial

— tnAcity  

Official title:

A Phase 2/3, Multi-Center, Open-Label, Randomized Study of Weekly Nab®-Paclitaxel in Combination With Gemcitabine or Carboplatin, Compared to Gemcitabine/Carboplatin, as First Line Treatment in Subjects With ER, PgR, and HER2 Negative (Triple Negative) Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01881230
• Other study ID #: ABI-007-MBC-001
• Secondary ID: 2013-000113-20
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: September 26, 2013
• Est. completion date: October 28, 2016

Study information

• Verified date: February 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the safety and efficacy of nab-paclitaxel in combination with either gemcitabine or carboplatin to the combination of gemcitabine and carboplatin as first line treatment in female subjects with triple negative metastatic breast cancer (TNMBC) or metastatic triple negative breast cancer.

Description:

ABI-007-MBC- 001 is a Phase 2/3, multicenter, open-label, randomized, study that will compare the safety and efficacy of weekly nab-paclitaxel in combination with gemcitabine or carboplatin to the combination of gemcitabine and carboplatin as first line therapy in female subjects with Estrogen Receptor (ER), Progesterone Receptor (PgR), and human epidermal growth factor receptor 2 (HER2) negative (triple negative) metastatic breast cancer (TNMBC) or metastatic triple negative breast cancer. In the phase 2 portion of the study, the combinations of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus carboplatin will be evaluated, and a comparator arm of gemcitabine combined with carboplatin will be used. In the phase 3 portion of the study, the selected nab-paclitaxel combination treatment will be compared to gemcitabine combined with carboplatin to evaluate progression free survival, safety and tolerability, overall survival, disease control rate and duration of response in women with metastatic triple negative breast cancer.

Due to changes in the treatment landscape since the initiation of this trial, the decision was made not to proceed to the Phase 3 portion of the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 191
• Est. completion date: October 28, 2016
• Est. primary completion date: October 28, 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of the following criteria are met:

1. Female subjects, age = 18 years at the time informed consent is signed

2. Pathologically confirmed adenocarcinoma of the breast

3. Pathologically confirmed as triple negative, source documented, defined as both of the following

1. Estrogen Receptor (ER) and Progesterone Receptor (PgR) negative: < 1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PgR (positive intrinsic controls)

2. Human Epidermal Growth Factor Receptor 2 (HER2) negative as per American Society of Clinical Oncology - College of American Pathologists (ASCO/CAP) guidelines i. Immunohistochemistry (IHC) 0 or 1 Fluorescence In Situ Hybridization (FISH) negative (or equivalent negative test). Subjects with IHC 2 must have a negative by Fluorescence In Situ Hybridization (FISH),, (or equivalent negative test).

4. Subjects with prior breast cancer history of different phenotypes (ie, ER/PgR/HER2 positive) must have pathologic confirmation of triple negative disease in at least one of the current sites of metastasis

5. Subjects must have received prior adjuvant or neoadjuvant anthracycline therapy; unless (a) anthracycline treatment was not indicated or was not the best treatment option for the subject in the opinion of the treating physician; and (b) anthracycline treatment remains not indicated or, in the opinion of the treating physician, is not the best treatment option for the subject's metastatic disease.

a. Newly diagnosed subjects presenting with TNMBC are eligible for the study if anthracycline treatment is not indicated or is not the best treatment option for the subject in the opinion of the treating physician.

6. Subjects with measurable metastatic disease, defined by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) guidelines

7. Life expectancy = 16 weeks from randomization

8. No prior cytotoxic chemotherapy for metastatic breast cancer. Prior immunotherapy and/or monoclonal antibody therapy are acceptable. Prior treatments must have been discontinued at least 30 days prior to start of study treatment and all related toxicities must have resolved to Grade 1 or less.

9. Prior neoadjuvant or adjuvant chemotherapy, if given, must have been completed at least 6 months before randomization with all related toxicities resolved, and documented evidence of disease progression per RECIST 1.1 guidelines is required.

a. If prior neoadjuvant or adjuvant chemotherapy contained taxane, gemcitabine, or platinum agents, the treatment must have completed at least 12 months before randomization

10. Prior radiotherapy must have completed before randomization, with full recovery from acute radiation side effects. At least one measurable lesion must be completely outside the radiation portal or there must be unequivocal radiologic or clinical exam proof of progressive disease within the radiation portal, in accordance with RECIST 1.1 guidelines

11. At least 30 days from major surgery before randomization, with full recovery

12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

13. Subject has the following blood counts at screening:

• Absolute Neutrophil Count (ANC) = 1500/mm^2 ;

• Platelets = 100,000/mm^2 ;

• Hemoglobin (Hgb) = 9 g/dL

14. Subject has the following blood chemistry levels at screening:

• Aspartate aminotransferase (AST) Serum glutamic-oxaloacetic transaminase (SGOT), Alanine Aminotransferase (ALT ) Serum Glutamic Pyruvate Transaminase (SGPT) = 2.5 x upper limit of normal range (ULN); if hepatic metastases present = 5.0 x ULN

• Total serum bilirubin = ULN; or total bilirubin = 3.0 × ULN with direct bilirubin within normal range in subjects with documented Gilbert's Syndrome

• Creatinine clearance > 60 mL/min (by Cockcroft-Gault)

15. Females of child-bearing potential [defined as a sexually mature women who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)] must:

• Demonstrate a negative serum pregnancy test result at screening (performed by central lab) confirmed by local negative urine pregnancy dipstick within 72 hours prior to the first dose of IP); pregnancy test with sensitivity of at least 25 mIU/mL; and

• Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, two physician approved effective contraception methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) without interruption for 28 days or longer as required by local guidelines, prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of the study or longer as required by local guidelines

16. Females must abstain from breastfeeding starting at randomization, during study participation and for 28 days or longer as required by local guidelines, after IP discontinuation

17. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted

18. Able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Male subjects

2. Concurrent chemotherapy or any other anti tumor therapy for breast cancer. Prior immunotherapy & monoclonal antibody therapy are acceptable.

3. Subjects who received prior cytotoxic chemotherapy after incomplete resection of locoregional recurrent disease

4. History of, or known current evidence of brain metastasis, including leptomeningeal involvement.

5. Subjects with bone as the only site of metastatic disease

6. Subjects with regional lymph node as the only site of metastatic disease

7. Serious intercurrent medical or psychiatric illness, including serious active infection

8. History of class II-IV congestive heart failure or myocardial infarction within 6 months of randomization

9. History of other primary malignancy in the last 5 years prior to randomization. Subjects with prior breast cancer history are eligible, however, the most recently obtained biopsy must demonstrate triple negative disease (source documented). Subjects with prior history of in situ cancer or basal or localized squamous cell skin cancer are eligible.

10. Subjects with a history of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple uncontrolled or unstable allergies which, in the opinion of the investigator, may lead to serious complications

11. Peripheral neuropathy Grade = 2 by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

12. Subjects who have received an investigational product within the previous 4 weeks prior to randomization

13. Subject is currently enrolled, or will enroll in a different clinical study in which investigational therapeutic procedures are performed or investigational therapies are administered while participating in this study

14. Pregnant or nursing women

15. Subjects with prior hypersensitivity to nab-paclitaxel, gemcitabine, carboplatin or any other platin, or nucleoside analogue agents

16. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study

17. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if she were to participate in the study

18. Any condition that confounds the ability to interpret data from the study

19. History of seropositive human immunodeficiency virus (HIV)

20. Subjects who are receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the investigator, increase the risk of serious neutropenic complications

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Breast Tumor
• Cancer of the Breast
• Estrogen Receptor- Negative Breast Cancer
• HER2- Negative Breast Cancer
• Metastatic Breast Cancer
• Progesterone Receptor- Negative Breast Cancer
• Recurrent Breast Cancer
• Stage IV Breast Cancer
• Triple Negative Breast Neoplasms
• Triple-negative Breast Cancer
• Triple-negative Metastatic Breast Cancer

Intervention

Drug:
• nab-Paclitaxel
nab-Paclitaxel 125 mg/m^2 by IV administration over 30 minutes on Days 1 and 8 of each 21-day treatment cycle.
• Carboplatin
Carboplatin at an AUC of 2 on Days 1 and 8 of each 21-day cycle by IV administration
• Gemcitabine
Gemcitabine 1000 mg/m^2 on Days 1 and 8 of each 21-day treatment cycle.

Locations

Country	Name	City	State
Australia	Frankston Hospital Oncology Research	Frankston	Victoria
Australia	Canberra Hospital	Garran	Australian Capital Territory
Australia	Sir Charles Gairdner Hospital	Nedlands
Australia	Border Medical Oncology	Wodonga	Victoria
Austria	Universitaetsklinik Innsbruck	Innsbruck
Austria	Salzburger Landkliniken St. Johanns-Spital	Salzburg
Austria	Medizinische Universitat Wien	Vienna
Brazil	Fundacao Pio XII - Hospital de Cancer de Barretos	Barretos	São Paulo
Brazil	Liga Paranaense de Combate Ao Cancer	Curitiba	Paraná
Brazil	ONCOCLINIC Clinica de Oncologia LTDA	Fortaleza
Brazil	Hospital Dr. Amaral Carvalho/ Hospital Amaral Carvalho Jaú	Jau/SP	São Paulo
Brazil	Associacao Hospitalar Moinhos de Vento Hospital Moinhos de Vento	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital Sao Lucas - PUCRS	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital das Clinicas da Faculdade de Medicina da USP	Ribeirao Preto
Brazil	Instituto Ribeiraopretano de Combate Ao Cancer	Ribeirao Preto
Brazil	Instituto Nacional de Cancer - INCA	Rio De Janerio	Rio De Janeiro
Brazil	Hospital Bruno Born	Rio Grande Do Sul
Brazil	Centro de Oncologia Da Bahia	Salvador	Bahia
Brazil	Hospital de Base Da Faculdade de Medicina de	Sao Jose Do Rio Preto
Brazil	Hospital Albert Einstein Sociedade Beneficente Israelita Brasileira	Sao Paulo
Brazil	Instituto Brasileiro de Controle Do Cancer IBCC	São Paulo
Brazil	Sociedade Beneficente de Senhoras Hospital Sirio Libanes	São Paulo
Canada	CHUM - Notre Dame	Montreal	Quebec
Canada	Ottawa General Hospital	Ottawa	Ontario
Canada	Hospital du Saint Scarement Sacrement Laboratory	Quebec City	Quebec
Canada	Alan Blair Cancer Centre at Pasqua Hosptial	Regina	Saskatchewan
Canada	CSSS de Rimouski Neigette	Rimouski	Quebec
France	Centre Jean Perrin	Clermont-Ferrand
Germany	Sankt Gertrauden-Krankenhaus	Berlin
Germany	Facharztpraxis fur Gynakologie und Geburtshilfe	Bonn
Germany	Agaplesion Markus Krankenhaus	Frankfurt
Germany	Praxis fur interdisziplinare Onkologie & Hamatologie	Freiburg
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Frauenarzte am Bahnhofsplatz	Hildesheim
Germany	Schwerpunktpraxis fur Gynakologische Onkologie	Köln
Germany	LMU Klinikum der Universitat	München
Germany	Krankenanstalt Mutterhaus der Borromaerinnen	Trier
Germany	Universitatsklinikum Ulm	Ulm
Greece	IASO General	Athens
Greece	University of Athens Medical school - Regional General Hospital	Athens
Greece	Metropolitan Hospital	Faliro
Greece	University General Hospital of Heraklion	Heraklion
Greece	University General Hospital of Patras	Rio Patras
Italy	Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi	Bologna, Emilia-Romagna
Italy	Azienda Ospedaliero-Universitaria di Ferrara Arcispedale Sant' Anna	Ferrara
Italy	IRCCS AziendaOspedaliera Universitaria San Martino	Genova
Italy	Presidio Ospedaliero della Misericordia	Grosseto
Italy	Azienda Ospedaliera Ospedali Riuniti Papardo-Piemonte	Messina
Italy	Azienda Ospedaliera San Gerardo	Monza
Italy	Azienda Ospedaliera Universitaria Federico II	Napoli, Campania
Italy	Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale	Napoli, Campania
Italy	Istituto Oncologico Veneto	Padova
Italy	Arcispedale Santa Maria Nuova	Reggio Emilia
Italy	Azienda Ospedaliera Sant Andrea	Roma
Italy	Istituto Nazionale Tumori Regina Elena	Roma
Italy	Policlinico Universitario A Gemelli	Roma
Italy	Istituto Clinico Humanitas	Rozzano (MI)
Italy	Azienda Ospedaliera Citta della Salute e della Scienza di Torino	Torino, Piemonte
Italy	Azienda Ospedaliera Treviglio-Caravaggio	Treviglio
Portugal	Hospital Espirito Santo	Evora
Portugal	Hospital Da Luz	Lisboa
Portugal	Hospital de Santa Maria	Lisboa
Portugal	Instituto Portugues de Oncologia do Porto, Francisco Gentil	Porto
Spain	Clinic Barcelona Hospital Universitari	Barcelona
Spain	Hospital Universitario Vall D Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Hospital General Gregorio Maranon	Madrid
Spain	Onkologikoa - Kutxaren Institutu Onkologikoa	San Sebastian
Spain	Hospital Clinico Universitario de Santiago	Santiago de Compostela
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Hospital Universitario Miguel Servet	Zaragoza
United Kingdom	Royal United Hospital	Bath
United Kingdom	Sarah Cannon Research Institute UK	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	The East and North Hertfordshire NHS Trust	Middlesex
United Kingdom	Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield South Yorkshire
United States	Pacific Cancer Medical Center Inc	Anaheim	California
United States	University of Maryland School of Med	Baltimore	Maryland
United States	Center for Cancer and Blood Disorders, PC	Bethesda	Maryland
United States	Center for Hematology-Oncology	Boca Raton	Florida
United States	Alamance Regional Medical Cancer Center	Burlington	North Carolina
United States	Ironwood Cancer and Research Center	Chandler	Arizona
United States	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee
United States	Oncology Hematology Care	Cincinnati	Ohio
United States	University of Cincinnatti	Cincinnati	Ohio
United States	South Carolina Oncology Associates	Columbia	South Carolina
United States	Mark H Zangmeister Center	Columbus	Ohio
United States	North Bend Medical Center	Coos Bay	Oregon
United States	Texas Oncology, PA	Dallas	Texas
United States	Texas Oncology, PA- Dallas	Dallas	Texas
United States	Henry Ford Medical Center - New Center One	Detroit	Michigan
United States	Hematology Oncology Associates of CNY	East Syracuse	New York
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	California Cancer Associates for Research and Excellence cCARE	Escondido	California
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	The Center for Cancer and Blood Disorders	Fort Worth	Texas
United States	Hematology Oncology Associates of Fredericksburg	Fredericksburg	Virginia
United States	Arizona Center for Cancer Care	Glendale	Arizona
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Memorial Breast Cancer Center	Hollywood	Florida
United States	New Hampshire Oncology Hematology	Hooksett	New Hampshire
United States	UT Physicians General Medicine	Houston	Texas
United States	Edwards Comprehensive Cancer Center	Huntington	West Virginia
United States	Investigative Clinical Research of Indiana, LLC	Indianapolis	Indiana
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	Joliet Oncology-Hematology Associates, Ltd	Joliet	Illinois
United States	Midwest Physicians Group	Kansas City	Missouri
United States	University of California San Diego Moores Cancer Center	La Jolla	California
United States	Wilshire Oncology Medical Group, Inc	La Verne	California
United States	University of South Alabama Mitchell Cancer Institute	Lafayette	Louisiana
United States	NYU Langone Arena Oncology	Lake Success	New York
United States	St Mary Medical Center	Langhorne	Pennsylvania
United States	Cancer Centers of Southwest Oklahoma	Lawton	Oklahoma
United States	Dartmouth Hitchcock Medical Center Norris Cotton Cancer Center	Lebanon	New Hampshire
United States	Translational Research Management	Los Angeles	California
United States	University of Miami School of Medicine	Miami	Florida
United States	Columbia St Marys Cancer Center	Milwaukee	Wisconsin
United States	Minnesota Oncology Hematology, PA	Minneapolis	Minnesota
United States	Sarah Cannon Cancer Center	Nashville	Tennessee
United States	Clinical Research Alliance	New York	New York
United States	Magee Women's Hospital	Pittsburgh	Pennsylvania
United States	Northwest Cancer Specialists, P.C. - Hoyt	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Delta Hematologyoncology Associates	Portsmouth	Virginia
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Florida Cancer Specialists	Saint Petersburg	Florida
United States	Cancer Care Centers of South Texas - Loop	San Antonio	Texas
United States	Coastal Integrative Cancer Care	San Luis Obispo	California
United States	Central Coast Medical Oncology Corporation	Santa Maria	California
United States	Redwood Regional Medical Group, INC	Santa Rosa	California
United States	Florida Cancer Specialists	Sarasota	Florida
United States	Arizona Cancer Research Alliance	Scottsdale	Arizona
United States	Mayo Clinic Arizona	Scottsdale	Arizona
United States	Medical Oncology Associates	Spokane	Washington
United States	Toledo Community Oncology Program	Toledo	Ohio
United States	Texas Oncology P.A.- Tyler	Tyler	Texas
United States	Carle Cancer Center	Urbana	Illinois
United States	Florida Cancer Specialists	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Brazil,  Canada,  France,  Germany,  Greece,  Italy,  Portugal,  Spain,  United Kingdom, 

References & Publications (1)

Yardley DA, Brufsky A, Coleman RE, Conte PF, Cortes J, Glück S, Nabholtz JM, O'Shaughnessy J, Beck RM, Ko A, Renschler MF, Barton D, Harbeck N. Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial. Trials. 2015 Dec 16;16:575. doi: 10.1186/s13063-015-1101-7. Erratum in: Trials. 2016;17:63. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kaplan-Meier Estimates of Progression-Free Survival (PFS) Based on Investigator Assessment.	PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause on or prior to the data cutoff date for the statistical analysis, whichever occurred earlier. Tumor responses were assessed every 6 weeks using, Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and defined as: Complete response (CR) is the disappearance of all target lesions; Partial response (PR) occurs when at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable disease is neither sufficient shrinkage to qualify for a PR nor sufficient increase of lesions to qualify for Progressive disease (PD); Progressive Disease- is at least a 20% increase in the sum of diameters of target lesions from nadir.	From date of randomization to data cut-off date of 16 December 2016; total length of time on study was 31 months for Arm A, 34 months for Arm B and 35 months for Arm C
Secondary	Percentage of Participants With an Objective Complete or Partial Overall Response by Investigator Assessment.	Percentage of participants with an Objective Complete or Partial Overall Response according to RECIST 1.1 and defined as: Complete response-disappearance of all target lesions; partial response at least a 30% decrease in the sum of diameters of target lesions from baseline; stable disease-neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for Progressive disease (PD)• Progressive Disease- At least a 20% increase in the sum of diameters of target lesions from nadir.	Disease response was assessed every 6 weeks; from date of randomization to data cut-off date of 16 December 2016; total length of time on study was 31 months for Arm A, 34 months for Arm B and 35 months for Arm C
Secondary	Percentage of Participants Who Initiated Cycle 6 Receiving Doublet Combination Therapy	The percentage of participants who initiated Cycle 6 receiving doublet combination therapy regardless of the need for dose modifications.	Cycle 6
Secondary	Kaplan-Meier Estimates of Overall Survival	Overall survival was defined as the time from the date of randomization to the date of death (from any cause).	From date of randomization to data cut-off date of 16 December 2016; total length of time on study was 31 months for Arm A, 34 months for Arm B and 35 months for Arm C
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Treatment-emergent adverse events (TEAEs) were defined as any AEs that began or worsened with the onset date on or after the date of the first dose of IP through 28 days after the last dose. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was graded based on the participant's symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity as follows: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death.	From randomization through to 28 days after the last dose of IP; up to data cut off date of 16 Dec 2016; maximum treatment duration of study drug exposure was 108.3 weeks for Arm A, 83 weeks for Arm B, 110.1 weeks for Arm C
Secondary	Percentage of Participants Experiencing Dose Modifications (Reductions and Interruptions)	The number of participants with dose modifications occurring during the treatment period. Dose reductions and interruptions are typically caused by clinically significant laboratory abnormalities and /or treatment emergent adverse events/toxicities.	From randomization through to 28 days after the last dose of IP; up to data-cut off of date of 16 Dec 2016; maximum treatment duration of study drug exposure was 108.3 weeks for Arm A, 83 weeks for Arm B, 110.1 weeks for Arm C
Secondary	Percentage of Participants Who Discontinued From All Study Treatment Due to TEAEs	Treatment-emergent adverse events (TEAEs) were defined as any AEs that begin or worsen with an onset date on or after the date of the first dose of IP through 28 days after the last dose.	From randomization through to 28 days after the last dose of IP; up to data-cut off of date of 16 Dec 2016; maximum treatment duration of study drug exposure was 108.3 weeks for Arm A, 83 weeks for Arm B, 110.1 weeks for Arm C