A Study of Lenalidomide Versus Placebo in Subjects With Transfusion Dependent Anemia in Lower Risk Myelodysplastic Syndrome (MDS) Without Del 5q

Anemia Clinical Trial

— MDS-005  

Official title:

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study To Compare The Efficacy And Safety of Lenalidomide (Revlimid®) Versus Placebo In Subjects With Transufsion-Dependent Anemia Due to IPSS Low Or Imtermidate-1 Risk Myelodysplastic Syndromes Without Deletion 5Q(31) And Unresponsive Or Refractory To Erthropoiesis-Stimulating Agents

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01029262
• Other study ID #: CC-5013-MDS-005
• Status: Completed
• Phase: Phase 3
• Start date: January 26, 2010
• Est. completion date: May 9, 2018

Study information

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

Clinical Trial Summary

The purpose of this study is to investigate whether lenalidomide would reduce the number of red blood cell transfusions (RBC) needed in anemic (RBC transfusion-dependent) participants with low or intermediate-1 risk MDS without a deletion 5q chromosome abnormality. The study also investigated the safety of lenalidomide use in these participants. Two-thirds of the participants received oral lenalidomide and one-third of the participants received oral placebo.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 239
• Est. completion date: May 9, 2018
• Est. primary completion date: March 17, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years or older

• Diagnosis of low or intermediate-1 risk Myelodysplastic (MDS) with any chromosome karyotype except del 5q[31]

• Anemia that requires red blood cell transfusions

• Resistant to erythropoiesis stimulating agents (ESAs) or blood erythropoietin level > 500 mU/mL

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) = 2

• Must agree to follow pregnancy precautions as required by the protocol.

• Must agree to receive counseling related to teratogenic and other risks of lenalidomide

• Must agree not to donate blood or semen

• Must be willing to consent to two or more bone marrow aspirate procedures to be completed during study

Exclusion Criteria:

• Subjects previously receiving immunomodulating or immunosuppressive agents, or epigenetic or deoxyribonucleic acid (DNA) modulation agents

• Allergic reaction to thalidomide

• Renal insufficiency creatinine clearance (CrC1)<40 mL/min by Cockcroft-Gault method)

• Prior history of cancer, other than MDS, unless the subject has been free of the disease for = 5 years. (Basal cell carcinoma of the skin, carcinoma in situ of the cervix, or stage Tumor (T) 1a or T1b prostate cancer is allowed)

• Absolute neutrophil count (ANC) < 500/uL

• Platelets < 50,000/uL

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3X upper limit of normal

• Uncontrolled hyperthyroidism or hypothyroidism

• Significant neuropathy

• Prior stem cell transplantation

• Anemia due to reasons other than MDS

• History of deep venous thrombosis (DVT) or pulmonary embolus (PE) within past 3 years

• Significant active cardiac disease within the past 6 months

• Known Human Immunodeficiency Virus (HIV) infection; known Hepatitis C infection or active Hepatitis B infection

Related Conditions & MeSH terms

• Anemia
• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• Lenalidomide
One 10 mg Lenalidomide capsule + 2 placebo capsules or (3 placebo capsules) once daily for subjects with a creatinine clearance = 60 mL/min. Alternatively-one 5 mg Lenalidomide capsule + 2 placebo capsules (or 3 placebo capsules) once daily for subjects with a creatinine clearance between 40 and 60 mL/min. Subjects may take study drug for at least 168 days unless there are intolerable side effects or disease progresses. Subjects may continue study drug beyond 168 days if they have an erythroid response (increase in their hemoglobin levels and fewer transfusions administered than before starting study drug)

Other:
• Placebo
3 placebo capsules once daily. Subjects may take study drug for at least 168 days unless there are intolerable side effects or disease progresses. Subjects may continue study drug beyond 168 days if they have an erythroid response (increase in their hemoglobin levels and fewer transfusions administered than before starting study drug)

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital Institute of Medical and Veterinary Science	Adelaide	South Australia
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba
Austria	Medizinische Universitat Innsbruck	Innsbruck
Austria	Krankenhaus der Elisabethinen Linz, I Interne Abteilung	Linz
Austria	Universitatsklinik fur Innere Medizin Salzburg	Salzburg
Austria	Klinikum Wels-Grieskirchen GmbH	Weis
Austria	Wiener Gebietskrankenkasse-Hanusch-Krankenhaus	Wien
Belgium	AZ St-Jan Brugge Oostende AV	Brugge
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	Centre Hospitalier Universitaire de Liege	Liege
Belgium	Center Hospitalier Universitaire Ambroise Pare	Mons
Belgium	Cliniques Universitaires UCL de Mont-Godine	Namur
Canada	Tom Baker Cancer Center	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hopital du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Maisonneuve Rosemont	Montreal	Quebec
Canada	McGill University, Dept. Oncology Clinical Research Program	Montreal	Quebec
Canada	Princess Margaret Hospital and University of Toronto	Toronto	Ontario
Canada	Sunnybrook Regional Cancer Center	Toronto	Ontario
Canada	Cancer Care Manitoba	Winnepeg	Manitoba
Czechia	Fakultni nemocnice Brno	Brno
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Vseobecna Fakultni Nemocnice v Praze	Prague
Czechia	Ustav hematologie a krevni transfuze	Praha
France	CHU d'Angers	Angers
France	Hopital Avicenne	Bobigny Cedex
France	Hopital A. Michallon	La Tronche
France	CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang	Lille
France	Institut Paoli-Calmettes	Marseille cedex
France	Groupe hospitalier Cochin Saint-Vincent de Paul	Paris Cedex
Germany	BAG Freiberg-Richter, Jacobash, Illmer, Wolf	Dresden
Germany	Marien Hospital	Duesseldorf
Germany	Universitätsklinikum Düsseldorf	Düesseldorf
Germany	Sankt Johannes Hospital Duisburg	Duisberg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Klinikum Mannheim der Universitat Heidelberg	Heidelberg
Germany	Universitat zu Koln	Köln
Germany	Universitatsklinikum Mannheim	Mannheim
Germany	TU München - Klinikum rechts der Isar	München
Israel	Rabin Medical Center	Petach-Tikva
Israel	The Chaim Sheba Medical Center	Tel Hashomer
Israel	Tel-Aviv Sourasky Medical Center	Tel-Aviv
Italy	Az. Osp. SS.Antonio e Biagio - SC Ematologia	Alessandria
Italy	A.O.U. di Bologna Policlinico S.Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliero-Universitaria di Cagliari	Cagliari
Italy	P.O. Ospedale Roberto Binaghi (UNI CA/ASL 8)	Cagliari
Italy	Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	Azienda Ospedaliera Cardarelli	Naples
Italy	AOU San Luigi Gonzaga	Orbassano
Italy	IRCCS Centro di Riferimento Oncologico di Basilicata di Rionero in Vulture	Rionero in Vulture
Italy	Azienda Ospedaliera Universitaria Policlinico Tor Vergata	Roma
Italy	Azienda Policlinico Umberto I, Universita La Sapienzadi Roma	Roma
Italy	Policlinico Agostino Gemelli - Istituto di Ematologia	Roma
Italy	Policlinico Univeristario di Udine	Udine
Japan	Hiroshima University Hospital	Hiroshima
Japan	Tokai University School of Medicine	Isehara City, Kanagawa
Japan	Kameda General Hospital	Kamogawa
Japan	Kanazawa University Hospital	Kanazawa
Japan	Nagasaki Unversity Hospital	Nagasaki
Japan	National Hospital Organization Nagoya Medical Center	Nagoya
Japan	Osaka Red Cross Hospital	Osaka
Japan	Tohoku University Hospital	Sendai
Japan	Japanese Red Cross Medical Center	Shibuya
Japan	Jichi Medical University Hospital	Shimotsuke
Japan	Kanto Medical Center NTT EC	Shinagawa
Poland	Katedra i Klinika Hematologii i Transplantacji Szpiku - SLASKIEGO UNIWERSYTETU MEDYCZNEGO	Gdansk
Poland	Uniwersytet Medyczny w Lodzi	Lodz
Poland	Instytut Hematologii i Transfuzjologii, Klinika Hematologii	Warsaw
Portugal	Hospitais da Universidade de Coimbra	Coimbra
Portugal	Instituto Portugues de Oncologia de Lisboa	Lisboa
Portugal	Hospital Geral de Santo Antonio	Porto
Spain	Hospital Clinic Provincial de Barcelona	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Malaga
Spain	Hospital Son Llatzer	Palma de Mallorca
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen Del Rocio	Sevilla
Spain	Hospital Universitario La Fe	Valencia
Turkey	Gazi Universitesi Tip Fakltesi	Ankara
Turkey	Akdeniz Universitesi Tip Fakultesi	Antalya
Turkey	Istanbul Universitesi Istanbul	Istanbul
Turkey	Dokuz Eylul Universitesi Tip Faiultesi	Izimir
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Saint James University Hospital	Leeds
United Kingdom	Barts Cancer Institute, Queen Mary University of London, Charterhouse Square	London
United Kingdom	King's College Hospital	London
United Kingdom	Christie Hospital	Manchester
United Kingdom	John Radcliffe Hospital	Oxford
United States	Southern Illinois Hematology Oncology	Centralia	Illinois
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Dartmouth Hitchcock Medical Center Norris Cotton Cancer Center	Lebanon	New Hampshire
United States	University of California at Los Angeles	Los Angeles	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Columbia University Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czechia,  France,  Germany,  Israel,  Italy,  Japan,  Poland,  Portugal,  Spain,  Turkey,  United Kingdom, 

References & Publications (1)

Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, Mufti GJ, Buckstein R, Mittelman M, Platzbecker U, Shpilberg O, Ram R, Del Cañizo C, Gattermann N, Ozawa K, Risueño A, MacBeth KJ, Zhong J, Séguy F, Hoenekopp A, Beach CL, Fenaux P. Random — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for = 56 Days as Determined by an Independent Review Committee (IRC)	The percentage of participants who achieved the 56-day RBC transfusion independent (TI) response was defined as the absence of any RBC transfusions during any consecutive "rolling" 56-day interval within the double-blind treatment phase (ie, Days 2 (Day 1 is the first study drug day) to 57, Days 3 to 58, etcetera). The double-blind treatment phase was defined as the period between the 1st dosing up until 28 days after the last study drug dose	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Primary	Percentage of Participants With a Erythroid Gene Signature Who Achieved RBC Transfusion Independence for = 56 Days as Determined by an Independent Review Committee (IRC)	The percentage of participants who achieved the 56-day RBC TI response was defined as the absence of any RBC transfusions during any consecutive "rolling" 56-day interval within the double-blind treatment phase (ie, Days 2 (Day 1 is the first study drug day) to 57, Days 3 to 58, etcetera). A participant who achieved at least a 56-day RBC-transfusion-independent response was considered a 56-day RBC-TI responder.	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Secondary	Percentage of Participants Who Achieved RBC Transfusion Independence With a Duration of = 24 Weeks (168 Days) as Determined by the Sponsor	The 168-day RBC-transfusion-independent response was defined as the absence of any RBC transfusion during any consecutive "rolling" 168 days during the treatment period, for example Days 2 (Day 1 is the first study drug day) to 169, Days 3 to 170, Days 4 to 171, etcetera. A responder was defined as a participant who had a = 168 consecutive days of RBC-transfusion-free period after the first dose of study drug in the treatment phase.	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Secondary	Kaplan Meier Estimates of Duration of 56-day RBC Transfusion Independence Response as Determined by the Sponsor	The duration of the first 56-day RBC transfusion-independence response was calculated for those who achieved a response and was dependent on whether a subsequent RBC transfusion was given after the transfusion-free period (response): For those who received a subsequent RBC transfusion after the response starts, the duration of response was not censored, and was calculated as response duration = last day of response - first day of response +1 where the last day of response was defined as 1 day before the first RBC transfusion which was given at 56 days or more after the response starts.; For those who did not receive a subsequent RBC transfusion after the response started, the end day of the response was censored and duration of the response was calculated as response duration = date of last RBC transfusion assessment - first day of response+ 1. A responder was a participant who had a = 56 consecutive days of RBC-transfusion-free period after the first study drug treatment period	Response was assessed up to the end of treatment; up to the data cut-off date of 17 Mar 2014.
Secondary	Percentage of Participants Who Achieved an Erythroid Response Based on the Modified International Working Group (IWG) 2006 Criteria	A participant was considered as having achieved an erythroid response if the participant either: - had a hemoglobin (Hgb) increase =1.5 g/dL compared to baseline and confirmed by another central laboratory hemoglobin value at 4 to 8 weeks after the first Hgb measurement that also increased =1.5 g/dL. All Hgb values during this time interval must have had a = 1.5 g/dL increase (ie, no central laboratory Hgb increase during this timeframe could be less <1.5 g/dL) OR - had a 50% reduction in the number of the RBC transfusion units over any consecutive 56 days period compared to the baseline transfusion burden.; The baseline transfusion burden is the number of units over 112 days by the randomization divided by 2. Only transfusions given for a pre-transfusion Hgb value of 9 g/dL or less were used in this response assessment.	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Secondary	Time to 56-Day RBC-Transfusion-Independent (TI) Response as Determined by the Sponsor	The time to the first 56-day RBC-transfusion-independent response was calculated for participants who achieved a response. The day from the first dose of study drug to the date at which RBC-transfusion-independence starts was achieved and calculated using: Start date of the first response period - the date of the first study drug +1. A responder was defined as a participant who had a = 56 consecutive days of RBC-transfusion-free period after the first dose of study drug in the treatment phase.	From first dose of study drug until 28 days after the last dose of study drug, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Secondary	Kaplan Meier Estimates for Progression to Acute Myeloid Leukemia (AML)	Progression to AML is part of the natural course of MDS and is a manifestation of disease progression. The time to progress to AML was calculated from the day of randomization to the first day when AML was diagnosed. Participants who died without AML were censored at the date of death. The participants who were lost to follow-up were censored at the last known day when participants did not have AML. Participants who did not progress to AML at the last follow-up contact were censored at the day of the last follow-up contact.	From randomization to final data cut-off date of 03 Jul 2018; median follow up time for progression to AML was 2.3 years (range = 0 to 5.0 years) in the placebo arm and 2.6 years (range = 0 to 6.4 years) in the lenalidomide arm.
Secondary	Kaplan Meier Estimate for Overall Survival (OS)	Overall survival was assessed using the time between randomization and the date of death or date of censoring. Participants who were alive at a data cutoff date and participants who were lost to follow-up were censored at the last date when participants were known to be alive.	From randomization to final data cut-off date of 03 July 2018; maximum survival follow up was 6.4 years
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAE)	A TEAE was defined as an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug.; A serious adverse event (SAE) is any: Death; Life-threatening event; Any inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Any other important medical event; The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.	From the first dose of study drug through 28 days after discontinuation from the study treatment; up to the final data cut-off date of 03 July 2018; maximum exposure was 2100 days in the lenalidomide arm and 529 days in the placebo arm.
Secondary	Compliance Rates Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) From Baseline to Week 48	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A participant was considered compliant at a visit if at least 15 out of the QLQ-C30 items in the questionnaire were checked.	Baseline, Week 12, (±3 days), Week 24, (±3 days), Week 36, (±3 days), and Week 48 (±3 days); up to data cut-off of 17 Mar 2014
Secondary	Mean Change From Baseline in the EORTC QLQ-C30 Fatigue Domain at Week 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom).	Baseline and Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain at Week 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom).	Baseline and Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain at Week 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.	Baseline and Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (QOL) Domain at Week 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement.	Baseline and Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain at Week 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Domain was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.	Baseline and Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in Fatigue Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom).	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the Dyspnea Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom).	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the Physical Functioning Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Physical Functioning was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the Global Health Status/QoL Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Mean Change From Baseline in the Emotional Functioning Domain Associated With the EORTC QLQ-C30 Scale at Weeks 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Percentage of Participants With a Clinically Meaningful Improvement in QOL (EORTC QLQ-C-30 Scale) From Baseline in Fatigue Domain at Weeks 12 and 24	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. Improvement means at least 10 points better compared to baseline	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline in the Dyspnea Domain at Weeks 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). Improvement means at least 10 points better compared to baseline.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline Within the Physical Functioning Domain at Weeks 12 and 24	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A change of at least 10 points on the standardized domain scores was required for it to be considered clinically meaningful.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline in the Global Health Status/QOL Domain at Weeks 12 and 24	The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A change of at least 10 points on the standardized domain scores was required for it to be considered clinically meaningful.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline in the Emotional Functioning Domain at Weeks 12 and 24	The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Domain was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.	Baseline, Week 12, ±3 days and Week 24, ±3 days
Secondary	Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Related to Adverse Events Per Person Year	Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Secondary	Healthcare Resource Utilization (HRU): Duration of Hospitalizations Due to Adverse Events	Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.
Secondary	Healthcare Resource Utilization (HRU): Number of Days of Hospitalization Due to Adverse Events Per Person-Years	Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient	From first dose of study drug until 28 days after the last dose, as of the data cut-off date of 17 March 2014; median (minimum, maximum) duration of treatment was 168 (14, 449) and 164 (7, 1158) days in each treatment group respectively.