Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia (AML) in Complete Remission

Leukemia, Myeloid, Acute Clinical Trial

— QUAZAR AML-001  

Official title:

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia in Complete Remission

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01757535
• Other study ID #: CC-486-AML-001
• Secondary ID: 2012-003457-28
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 24, 2013
• Est. completion date: December 31, 2024

Study information

• Verified date: January 2024
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study enrolled 472 participants, aged 55 or older, with a diagnosis of de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or chronic myelomonocytic leukemia (CMML), and who have achieved first complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) following induction with or without consolidation chemotherapy.

The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the investigator, to continue receiving oral azacitidine after unblinding by sponsor until the participant meets the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

Description:

This is an international, multicenter, placebo-controlled, Phase 3 study with a double-blind, randomized, parallel-group design in subjects with de novo AML or AML secondary to prior diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) aged ≥ 55 years, who are in first CR/CRi following induction therapy with or without consolidation chemotherapy. The study consists of 3 phases; the pre-randomization phase (screening phase), the treatment phase, and the follow-up phase.

The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the Investigator, to continue receiving oral azacitidine after unblinding by sponsor until they meet the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 472
• Est. completion date: December 31, 2024
• Est. primary completion date: July 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years and older

Eligibility

Key Inclusion Criteria:

1. Male or female participants = 55 years of age

2. Newly diagnosed, histologically confirmed de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or CMML (Chronic myelomonocytic leukemia)

3. First complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) with induction therapy with intensive chemotherapy with or without consolidation therapy within 4 months (+/- 7 days of achieving CR or CRi)

4. Eastern Cooperative Oncology Group (ECOG) performance status - 0, 1, 2, 3

Key Inclusion Criteria in the Extended Phase of the study:

At the Investigator's discretion and with approval of the sponsor, participants meeting all of the following eligibility criteria are eligible to enter the extension phase:

1. All participants randomized into the oral azacitidine or placebo arm and are continuing in either the treatment phase or follow-up phase of the CC-486-AML-001 study;

• Participants randomized to oral azacitidine treatment arm and continuing in the treatment phase demonstrating clinical benefit as assessed by the investigator are eligible to receive oral azacitidine in the extension phase (EP);

• Participants randomized into placebo arm of the study will not receive oral azacitidine in the EP, but will be followed for survival in the EP;

• Participants currently in the follow-up phase will continue to be followed for survival in the EP;

2. Participants who have signed the informed consent for the EP of the study;

3. Participants who do not meet any of the criteria for study discontinuation

Key Exclusion Criteria:

1. AML with inversion (inv)(16), translocation = t(8;21), t(16;16), t(15;17), or t(9;22) or molecular evidence of such translocations

2. Prior bone marrow or stem cell transplantation

3. Have achieved CR/CRi following therapy with hypomethylating agents

4. Diagnosis of malignant disease within the previous 12 months

5. Proven central nervous system (CNS) leukemia

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Oral Azacitidine
300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle.
• Placebo
Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.

Locations

Country	Name	City	State
Australia	Local Institution - 508	Adelaide	South Australia
Australia	Local Institution - 511	Bedford Park	South Australia
Australia	Local Institution - 503	Heidelberg
Australia	Local Institution - 502	Hobart
Australia	Local Institution - 507	Liverpool
Australia	Local Institution - 500	Melbourne
Australia	Local Institution - 505	Perth
Australia	Local Institution - 512	Perth
Australia	Local Institution - 509	South Brisbane	Queensland
Australia	Local Institution - 506	St Leonards
Australia	Local Institution - 510	Wollongong	New South Wales
Australia	Local Institution - 504	Woodville South	South Australia
Australia	Local Institution - 501	Woolloongabba
Austria	Local Institution - 271	Graz
Austria	Local Institution - 270	Salzburg
Austria	Local Institution - 273	Vienna
Austria	Local Institution - 274	Vienna
Austria	Local Institution - 272	Wien
Belgium	Local Institution - 300	Brugge
Belgium	Local Institution - 301	Charleroi
Belgium	Local Institution - 302	Mons
Brazil	Local Institution - 233	Curitiba	Paraná
Brazil	Local Institution - 231	Porto Alegre	Rio Grande Do Sul
Brazil	Local Institution - 232	Rio de Janeiro
Brazil	Local Institution - 230	Sao Paulo
Brazil	Local Institution - 234	São Paulo
Canada	Local Institution - 605	Edmonton	Alberta
Canada	Local Institution - 604	Halifax	Nova Scotia
Canada	Local Institution - 602	Montreal	Quebec
Canada	Local Institution - 608	Montreal	Quebec
Canada	Local Institution - 601	Saint John	New Brunswick
Canada	Local Institution - 603	St John's	Newfoundland and Labrador
Canada	Local Institution - 607	Toronto	Ontario
Canada	Local Institution - 600	Winnipeg	Manitoba
Czechia	Local Institution - 320	Brno	Jihomoravský Kraj
Czechia	Local Institution - 321	Praha
Czechia	Local Institution - 322	Praha
Finland	Local Institution - 361	Helsinki
Finland	Local Institution - 362	Tampere
Finland	Local Institution - 360	Turku
France	Local Institution - 456	Amiens
France	Local Institution - 465	Argenteuil
France	Local Institution - 457	Bobigny Cedex
France	Local Institution - 462	Boulognes Sur Mer
France	Local Institution - 460	Clamart Cedex
France	Local Institution - 452	Creteil
France	Local Institution - 458	Le Chesnay Cedex
France	Local Institution - 453	Lille
France	Local Institution - 461	Limoges Cedex
France	Local Institution - 450	Lyon cedex
France	Local Institution - 454	Paris
France	Local Institution - 463	Paris
France	Local Institution - 800	Paris Cedex 10
France	Local Institution - 464	Pontoise
France	Local Institution - 455	Rouen
France	Local Institution - 459	Saint-Cloud
France	Local Institution - 451	Villejuif CEDEX
Germany	Local Institution - 413	Berlin
Germany	Local Institution - 410	Bonn
Germany	Local Institution - 400	Dresden	Saxony
Germany	Local Institution - 406	Düsseldorf
Germany	Local Institution - 415	Erlangen
Germany	Local Institution - 404	Frankfurt am Main
Germany	Local Institution - 412	Goch
Germany	Local Institution - 405	Hannover
Germany	Local Institution - 408	Heilbronn
Germany	Local Institution - 414	Jena
Germany	Local Institution - 403	Keil
Germany	Local Institution - 402	Mannheim
Germany	Local Institution - 409	Muenchen
Germany	Local Institution - 411	München
Germany	Local Institution - 407	Oldenburg
Germany	Local Institution - 416	Schweiler
Germany	Local Institution - 401	Ulm
Ireland	Local Institution - 950	Dublin
Ireland	Local Institution - 951	Galway
Israel	Local Institution - 381	Beer Sheva
Israel	Local Institution - 380	Haifa
Israel	Local Institution - 383	Jerusalem
Israel	Local Institution - 382	Petach Tikva
Italy	Local Institution - 701	Alessandria
Italy	Local Institution - 721	Bari
Italy	Local Institution - 720	Bologna
Italy	Local Institution - 710	Cagliari
Italy	Local Institution - 702	Cremona
Italy	Local Institution - 708	Firenze
Italy	Local Institution - 712	Genova
Italy	Local Institution - 716	Lecce
Italy	Local Institution - 706	Milan
Italy	Local Institution - 726	Milano
Italy	Local Institution - 704	Monza
Italy	Local Institution - 717	Naples
Italy	Local Institution - 725	Naples
Italy	Local Institution - 705	Orbassano (TO)
Italy	Local Institution - 703	Palermo
Italy	Local Institution - 719	Palermo
Italy	Local Institution - 724	Pesaro
Italy	Local Institution - 700	Reggio Calabria
Italy	Local Institution - 709	Roma
Italy	Local Institution - 714	Roma
Italy	Local Institution - 723	Roma
Italy	Local Institution - 722	Rome
Italy	Local Institution - 715	Torino
Italy	Local Institution - 718	Torino
Italy	Local Institution - 711	Udine
Italy	Local Institution - 707	Varese
Korea, Republic of	Local Institution - 535	Busan
Korea, Republic of	Local Institution - 533	Daegu
Korea, Republic of	Local Institution - 530	Seoul
Korea, Republic of	Local Institution - 531	Seoul
Korea, Republic of	Local Institution - 532	Seoul
Korea, Republic of	Local Institution - 536	Seoul
Lithuania	Local Institution - 750	Klaipeda
Mexico	Local Institution - 252	Huixquilucan de Degollado
Mexico	Local Institution - 251	Mexico
Mexico	Local Institution - 250	Monterrey
Poland	Local Institution - 824	Bydgoszcz
Poland	Local Institution - 820	Gdansk
Poland	Local Institution - 822	Lodz
Poland	Local Institution - 821	Warsaw
Poland	Local Institution - 823	Wroclaw
Portugal	Local Institution - 841	Coimbra
Portugal	Local Institution - 840	Lisboa
Portugal	Local Institution - 843	Lisboa
Portugal	Local Institution - 842	Porto
Portugal	Local Institution - 844	Porto
Russian Federation	Local Institution - 971	Moscow
Russian Federation	Local Institution - 970	Nizhniy Novgorod
Russian Federation	Local Institution - 972	Saint Petersburg
Russian Federation	Local Institution - 973	St Petersburg
Spain	Local Institution - 869	Badalona (Barcelona)
Spain	Local Institution - 870	Barcelona
Spain	Local Institution - 871	Barcelona
Spain	Local Institution - 873	Caceres
Spain	Local Institution - 863	Cordoba
Spain	Local Institution - 867	La Coruna
Spain	Local Institution - 865	Madrid
Spain	Local Institution - 866	Madrid
Spain	Local Institution - 868	Madrid
Spain	Local Institution - 864	Oviedo
Spain	Local Institution - 872	Palma de Mallorca	Baleares
Spain	Local Institution - 861	Salamanca
Spain	Local Institution - 862	Sevilla
Spain	Local Institution - 860	Valencia
Taiwan	Local Institution - 599	Beitou District, Taipei City
Taiwan	Local Institution - 595	Niaosong District Kaohsiung City
Taiwan	Local Institution - 596	Taichung, Northern Dist.
Taiwan	Local Institution - 597	Tainan, Taiana
Taiwan	Local Institution - 598	Taipei, Zhongzheng Dist.
Turkey	Local Institution - 650	Ankara
Turkey	Local Institution - 653	Ankara
Turkey	Local Institution - 651	Istanbul
Turkey	Local Institution - 652	Samsun
United Kingdom	Local Institution - 907	Boston
United Kingdom	Local Institution - 903	Brighton East Sussex
United Kingdom	Local Institution - 902	Canterbury Kent
United Kingdom	Local Institution - 901	London
United Kingdom	Local Institution - 905	London
United Kingdom	Local Institution - 908	London
United Kingdom	Local Institution - 909	Maidstone
United Kingdom	Local Institution - 900	Manchester
United Kingdom	Local Institution - 904	Nottingham	Nottinghamshire
United Kingdom	Local Institution - 906	Romford, Essex
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Providence St Joseph Medical Center Cancer Center	Burbank	California
United States	Northwestern University Medical Center	Chicago	Illinois
United States	Local Institution - 016	Cleveland	Ohio
United States	University Of Texas Southwestern Medical Center	Dallas	Texas
United States	Rocky Mountain Cancer Center	Denver	Colorado
United States	City Of Hope	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Brooke-Army Medical Center	Fort Sam Houston	Texas
United States	University of California San Francisco Fresno Campus	Fresno	California
United States	University Of Florida	Gainesville	Florida
United States	Greenville Hospital System	Greenville	South Carolina
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	Franciscan St. Francis Health	Indianapolis	Indiana
United States	Indiana University Cancer Center	Indianapolis	Indiana
United States	Kansas City VA Medical Center University of Kansas Medical Center	Kansas City	Missouri
United States	Lancaster General Hospital	Lancaster	Pennsylvania
United States	Ucla	Los Angeles	California
United States	University of Southern California Norris Cancer Center	Los Angeles	California
United States	Norton Cancer Institute Louisville Oncology	Louisville	Kentucky
United States	University Of Louisville	Louisville	Kentucky
United States	Loyola University Chicago	Maywood	Illinois
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Froedtert Hospital BMT Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Sarah Cannon Research Inst	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Ochsner Medical Center - Jefferson Highway	New Orleans	Louisiana
United States	Tulane University Medical Center	New Orleans	Louisiana
United States	Columbia University Irving Medical Center	New York	New York
United States	Local Institution - 002	New York	New York
United States	Mt. Sinai Medical Center	New York	New York
United States	Cancer Care and Hematology Specialists of Chicagoland, P.C. - Niles, IL	Niles	Illinois
United States	University of Oklahoma Peggy and Charles Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	University Of Nebraska Medical Center	Omaha	Nebraska
United States	Local Institution - 050	Orange	California
United States	University of Florida Health Cancer Center at Orlando Health	Orlando	Florida
United States	Arizona Oncology Associates, P.C.	Phoenix	Arizona
United States	UPMC Cancer Pavillion	Pittsburgh	Pennsylvania
United States	Kaiser Permanente Northwest Oncology Hematology	Portland	Oregon
United States	VA Commonwealth University - Massey Cancer Center	Richmond	Virginia
United States	Local Institution - 037	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University School Of Medicine	Saint Louis	Missouri
United States	Cancer Care Centers of South Texas - Loop	San Antonio	Texas
United States	Methodist Hospital	San Antonio	Texas
United States	Sharp Memorial Hospital	San Diego	California
United States	Swedish Cancer Inst	Seattle	Washington
United States	The Hospital of Central Connecticut	Southington	Connecticut
United States	Stanford Cancer Center	Stanford	California
United States	Local Institution - 014	Valhalla	New York
United States	George Washington University Cancer Center	Washington	District of Columbia
United States	Kansas University Medical Center	Westwood	Kansas
United States	Innovative Clinical Research Institute	Whittier	California
United States	Local Institution - 025	Winston-Salem	North Carolina
United States	University of Massachusetts	Worcester	Massachusetts
United States	Yakima Valley Memorial Hospital/ North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Finland,  France,  Germany,  Ireland,  Israel,  Italy,  Korea, Republic of,  Lithuania,  Mexico,  Poland,  Portugal,  Russian Federation,  Spain,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (1)

Roboz GJ, Montesinos P, Selleslag D, Wei A, Jang JH, Falantes J, Voso MT, Sayar H, Porkka K, Marlton P, Almeida A, Mohan S, Ravandi F, Garcia-Manero G, Skikne B, Kantarjian H. Design of the randomized, Phase III, QUAZAR AML Maintenance trial of CC-486 (oral azacitidine) maintenance therapy in acute myeloid leukemia. Future Oncol. 2016 Feb;12(3):293-302. doi: 10.2217/fon.15.326. Epub 2016 Jan 19. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kaplan-Meier (K-M) Estimate for Overall Survival (OS)	Overall survival was defined as time from randomization to death from any cause; participants surviving at the end of the follow-up period, or who withdraw consent, or who were lost to follow up were censored at the date last known alive.	Day 1 (randomization) up to data cut off date of 15 July 2019; median follow-up for OS estimated by the reverse K-M method was 41.2 months for all participants.
Secondary	Kaplan-Meier Estimate of Relapse Free Survival (RFS)	RFS was defined as the time from the date of randomization to the date of documented relapse or death from any cause, whichever occurred first. Participants who were still alive without documented relapse, or who were lost to follow-up or withdrew consent without documented relapse, were censored at the date of their last bone marrow assessment, prior to receiving any other therapy for AML.; Documented relapse was defined as the earliest date of the following: = 5% bone marrow blasts (myeloblasts) from Central Pathology report, or; appearance of > 0% blasts in the peripheral blood with a later bone marrow confirmation (bone marrow blast [myeloblasts] = 5%) within 100 days, or; at least 2 peripheral blasts = 5% within 30 days.	From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months
Secondary	Kaplan-Meier Estimate of Time to Relapse	Time to relapse was defined as the interval (in months) from the date of randomization to the date of documented relapse. Estimates of relapse rate were based on the cumulative incidence function from a competing risk analysis with death as a competing risk for relapse from complete remission (CR)/ complete remission with incomplete blood count recovery (CRi).; Documented relapse was defined as, the earliest date of the following: = 5% bone marrow blasts (myeloblasts) from Central Pathology report, or; appearance of > 0% blasts in the peripheral blood with a later bone marrow confirmation (bone marrow blast [myeloblasts] = 5%) within 100 days, or; at least 2 peripheral blasts = 5% within 30 days.	Day 1 (randomization) to the date of the data cut off date of 15 July 2019; approximately 74 months
Secondary	Kaplan-Meier Estimates of Time to Discontinuation From Treatment	Time to discontinuation from treatment was assessed and defined as the interval from the date of randomization to the date of discontinuation from study drug. Participants who were receiving treatment at the time of study closure were censored at the date of last visit. Estimates of relapse rate were based on the cumulative incidence function from a competing risk analysis with death as a competing risk for relapse from CR/ CRi.	From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs)	TEAEs include AEs that started between first dose date and 28 days after the last dose of study drug.; A serious adverse event (SAE) is: Death; Life-threatening event; Inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Other important medical event The severity of AEs were assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0: Grade 1 (Mild): asymptomatic/mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-appropriate activities of daily living. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care Grade 4: Life-threatening; urgent intervention indicated. Grade 5: Death due to AE.	Day 1 (randomization) to the data cut off date of 15 July 2019; the median treatment duration was 11.6 months (range: 0.5 to 74.3 months) for the oral aza arm and 5.7 months (range: 0.7 to 68.5 months) for the placebo arm.
Secondary	Mean Change in the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale V 4.0) Score From Baseline	The functional assessment of chronic illness therapy (FACIT-Fatigue Scale V 4.0) is a subscale of the FACIT-F and has been validated in the oncology setting. The FACIT-Fatigue Scale is a short, 13-item, self-administered tool that measures the level of fatigue in an individual during usually daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all; 4 = very much. The scores range from 0 to 52, with higher scores indicating less fatigue. If there were missing items, but the participant answered at least 50% of the items, then subscores were prorated.	Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1
Secondary	Mean Change in the European Quality of Life-Five Dimensions-Three Levels (EQ-5D-3L) Score From Baseline	The EQ-5D-3L is a self-administered questionnaire consisting of 5 questions, pertaining to specific health dimensions (ie, mobility, self-care, pain, usual activities, and anxiety/depression) and a health status scale. Each question has 3 levels of severity, corresponding to no problems, moderate problems and severe problems. Canadian population sample weights were used to derive health utility scores. A higher utility score represents a better health state. A clinically meaningful improvement or worsening was defined as at least 0.08 points of improvement or 0.10 points of worsening from baseline, respectively, for the EQ-5D-3L Health Utility Index. The instrument is scored using the United Kingdom (UK) index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health; -0.594 is considered 'worse than death'.	Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1
Secondary	Percentage of Participants Experiencing a Clinically Meaningful Change (Improvement, No Change and Deterioration) in the FACIT-Fatigue Scale From Baseline	A clinically meaningful improvement or worsening was defined as at least 3 points of improvement or worsening from baseline, respectively, for FACIT-Fatigue. The functional assessment of chronic illness therapy (FACIT-Fatigue Scale V 4.0) is a subscale of the FACIT-F and has been validated in the oncology setting. The FACIT-Fatigue Scale is a short, 13-item, self-administered tool that measures the level of fatigue in an individual during usually daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all; 4 = very much. The scores range from 0 to 52, with higher scores indicating less fatigue. If there were missing items, but the participant answered at least 50% of the items, then subscores were prorated.	Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1
Secondary	Percentage of Participants Experiencing a Clinically Meaningful Change (Improvement, No Change and Deterioration) in the EQ-5D-3L Scale From Baseline	The EQ-5D-3L is a self-administered questionnaire consisting of 5 questions, pertaining to specific health dimensions (ie, mobility, self-care, pain, usual activities, and anxiety/depression) and a health status scale. Each question has 3 levels of severity, corresponding to no problems, moderate problems and severe problems. Canadian population sample weights were used to derive health utility scores. A higher utility score represents a better health state. A clinically meaningful improvement or worsening was defined as at least 0.08 points of improvement or 0.10 points of worsening from baseline, respectively, for the EQ-5D-3L Health Utility Index. The instrument is scored using the United Kingdom (UK) index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health; -0.594 is considered 'worse than death'.	Baseline to Cycle 2, Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1C3, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1, C21D1, C22D1, C23D1, C24D1, C25D1 and continued on day 1 at each cycle through C33D1
Secondary	Time to Definitive Clinically Meaningful Deterioration for = 2 Consecutive Visits as Measured Using the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale V 4.0)	Clinically meaningful deterioration was defined as at least 3 points of deterioration from baseline for at least 2 consecutive visits for the FACIT--Fatigue. The FACIT-Fatigue Scale V 4.0) is a subscale of the FACIT-F and has been validated in the oncology setting. The FACIT-Fatigue Scale is a short, 13-item, self-administered tool that measures the level of fatigue in an individual during usually daily activities over the past week. The level of fatigue is measured on a 5-point Likert scale (0 = not at all to 4 = very much. The scores that range from 0 to 52, with higher scores indicating less fatigue. If there were missing items, but the participant answered at least 50% of the items, subscores were prorated.	From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months
Secondary	Time to Definitive Clinically Meaningful Deterioration for = 2 Consecutive Visits as Measured Using the EQ-5D HRQoL Scale	Clinically meaningful deterioration was defined at least 0.10 point of deterioration from baseline for at least 2 consecutive visits for the EQ-5D Health Utility Index. The EQ-5D-3L is a self-administered questionnaire consisting of 5 questions, pertaining to specific health dimensions (ie, mobility, self-care, pain, usual activities, and anxiety/depression) and a health status scale. Each question has 3 levels of severity, corresponding to no problems, moderate problems and severe problems. Canadian population sample weights were used to derive health utility scores. A higher utility score represents a better health state. A clinically meaningful improvement or worsening was defined as at least 0.08 points of improvement or 0.10 points of worsening from baseline, respectively, for the EQ-5D-3L Health Utility Index. The EQ-5D-3L is scored using the UK index ranges from -0.594 to 1, where 0 equates to death and 1 equates to full health; -0.594 is considered 'worse than death'.	From day 1 (randomization) up to data cut off date of 15 July 2019; approximately 74 months
Secondary	Healthcare Resource Utilization (HRU): Rate of Hospital Events Per Person Year	HRU is defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU is a key component to understand treatment costs and budget impact of new treatments from a provider perspective.	Day 1 (randomization) to the date of the data cut off date of 15 July 2019; approximately 74 months
Secondary	Healthcare Resource Utilization (HRU): Number of Days Hospitalized Per Person-Year	HRU is defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU is a key component to understand treatment costs and budget impact of new treatments from a provider perspective.	Day 1 (randomization) to the date of the data cut off date of 15 July 2019; approximately 74 months

External Links

•   BMS Clinical Trial Information