Guadecitabine (SGI-110) vs Treatment Choice in Adults With MDS or CMML Previously Treated With HMAs

Myelodysplastic Syndromes Clinical Trial

Official title:

A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) Previously Treated With Hypomethylating Agents

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02907359
• Other study ID #: SGI-110-07
• Secondary ID: 2015-005257-12
• Status: Completed
• Phase: Phase 3
• Start date: January 13, 2017
• Est. completion date: November 30, 2020

Study information

• Verified date: April 2023
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the efficacy and safety of guadecitabine in participants with MDS or CMML who failed or relapsed after adequate prior treatment with azacitidine, decitabine, or both. This global study will be conducted in approximately 15 countries. Approximately 408 participants from approximately 100 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine (approximately 272 participants) or Treatment Choice (approximately 136 participants). The study consists of a 21-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last more than 2 years, and the duration of individual participant participation will vary. Participants may continue to receive treatment for as long as they continue to benefit.

Description:

Multicenter, randomized, open-label, parallel-group study of guadecitabine vs Treatment Choice (TC). Approximately 408 participants will be randomly assigned 2:1 to either guadecitabine or TC. - Guadecitabine: approximately 272 participants. - TC: approximately 136 participants. Before randomization, the investigator will assign each participant to one of the following TC options: - Low dose cytarabine (LDAC). - Standard Intensive Chemotherapy (IC) of a 7+3 regimen. - Best Supportive Care (BSC) only. BSC will be provided to all participants as per standard and institutional practice. Participants randomized to TC will not be allowed to cross over to guadecitabine. Data will be reviewed by an independent Data Monitoring Committee at regular intervals, primarily to evaluate safety during study conduct. Randomization will be stratified by disease category (MDS vs CMML), bone marrow (BM) blasts (BM blasts >10% vs BM blasts ≤10%), TC option (LDAC vs IC vs BSC), and study center region. Guadecitabine: 60 milligrams per square meter (mg/m^2) given subcutaneously (SC) daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as the participant continues to benefit. BSC should be given according to standard and institutional practice. Treatment Choice (TC): Before randomization, the investigator will assign each participant to one of the following TC options: - Low dose cytarabine (LDAC) given as 20 mg/m^2 SC or intravenously (IV) once daily for 14 days in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 4 cycles in the absence of disease progression or unacceptable toxicity. - Standard Intensive Chemotherapy (IC) of a 7+3 regimen: given as cytarabine 100-200 mg/m^2/day given as continuous infusion for 7 days and an anthracycline given as per institutional standard practice such as daunorubicin (45-60 mg/m^2/day), or idarubicin (9-12 mg/m^2/day), or mitoxantrone (8-12 mg/m^2/day) by intravenous infusion for 3 days. - Best Supportive Care (BSC) only: given according to standard and institutional practice. BSC includes, but is not limited to blood transfusions (Red blood cells [RBCs] or platelets), growth factors including erythropoiesis stimulating agents (ESA), granulocyte stimulating factors (GSFs), iron chelating therapy, and broad-spectrum antibiotics and/or antifungals.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 417
• Est. completion date: November 30, 2020
• Est. primary completion date: March 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult participants =18 years of age who are able to understand and comply with study procedures and provide written informed consent before any study-specific procedure.
• Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
• Performance status (ECOG) of 0-2.
• Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high

risk MDS or CMML whose disease progressed or relapsed as follows:

1. Participant received HMA for at least 6 cycles and was still transfusion dependent.

2. Participant received HMA for at least 2 complete cycles and had disease progression prior to Cycle 6 defined as i. =50% increase in bone marrow blasts from pre-HMA-treatment levels or from nadir post-HMA-treatment levels to >5% (for participants with pretreatment or nadir blasts =5%) or to >10% (for participants with pretreatment or nadir blasts >5%), and/or ii. Transfusion dependent and =2 gram/deciliter (g/dL) reduction of Hgb from pre-HMA-treatment levels. Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.

• Participants must have either:

1. Bone marrow blasts >5% at randomization, OR

2. Transfusion dependence, defined as having had transfusion (in the setting of active disease) of 2 or more units of RBC or platelets within 8 weeks prior to randomization.

• Creatinine clearance or glomerular filtration rate =30 milliliter/minute (mL/min) estimated by the Cockroft-Gault (C-G) or other medically acceptable formulas such as MDRD (Modification of Diet in Renal Disease) or CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration).
• Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control and must agree not to become pregnant or father a child (a) while receiving treatment with guadecitabine and for at least 3 months after completing treatment and (b) while receiving treatment with LDAC or IC and for at least 6 months after completing treatment or for the duration specified in local prescribing information, whichever is longer.

Exclusion Criteria:

• Participants who have been diagnosed as having AML with peripheral blood or bone marrow blasts of =20%.
• Participants who may still be sensitive to repeated treatment with decitabine or azacitidine such as participants who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
• Prior treatment with guadecitabine.
• Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
• Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
• Treated with any investigational drug within 2 weeks of the first dose of study treatment.
• Total serum bilirubin >2.5 × upper limit of normal (ULN) (except for participants with Gilbert's Syndrome for whom direct bilirubin is <2.5×ULN), or liver cirrhosis or chronic liver disease Child-Pugh Class B or C.
• Known active HIV, HBV, or HCV infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
• Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the participant to high risk of noncompliance with the protocol.
• Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring >2 liters per minute oxygen.
• Life expectancy of less than one month
• Participants with TP53 mutations

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelomonocytic, Chronic
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Guadecitabine

Other:
• Treatment Choice
BSC: according to standard/institutional practice; included RBC or platelet transfusions; growth factors, i.e. erythropoiesis stimulating agents, granulocyte stimulating factors, iron chelating therapy; broad spectrum antibiotics and/or antifungals. LDAC: 20 mg/m^2 SC or IV once daily (QD) for 14 days in 28-day cycles. Other schedules were allowed per institutional practice. Treatment for =4 cycles absent disease progression/toxicity. BSC per institutional/standard practice. Standard Intensive Chemotherapy: recommended regimen of 7+3 was given as cytarabine 100-200 mg/m^2/day continuous infusion for 7 days and an anthracycline for 3 days. Anthracyclines per institutional practice included daunorubicin (45-60 mg/m^2/day) or idarubicin (9-12 mg/m^2/day) or mitoxantrone (8-12 mg/m^2/day) by IV infusion. Participants with complete or partial response after IC induction received =1 additional cycles with reduced cytotoxic doses then BSC per standard /institutional practice.

Locations

Country	Name	City	State
Belgium	Ziekenhuis Netwerk Antwerpen Stuivenberg	Antwerp
Belgium	Algemeen Ziekenhuis Sint-Jan Brugge-Oostende	Brugge
Belgium	Grand Hôpital de Charleroi - Notre Dame	Charleroi
Canada	Royal Victoria Regional Health Centre	Barrie	Ontario
Canada	Burnaby Hospital	Burnaby
Canada	Tom Baker Cancer Center	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Juravinski Cancer Centre	Hamilton	Ontario
Canada	Moncton Hospital	Moncton
Canada	Maisonneuve-Rosemont Hôpital Service d'Hematologie et d'Oncologie Medicale	Montréal
Canada	Saskatchewan Cancer Agency	Regina
Canada	Princess Margaret Hospital	Toronto	Ontario
Czechia	Fakultní nemocnice Brno	Brno
Czechia	Fakultni Nemocnice Hradec Králové	Hradec Králové
Czechia	Fakultní nemocnice Ostrava	Ostrava
Czechia	Fakultní Nemocnice Královské Vinohrady	Praha
Czechia	Onkologická klinika Všeobecná fakultní nemocnice v Praze a 1	Praha 2
Denmark	Aalborg Universitetshospital	Aalborg
Denmark	Aarhus Universitetshospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Denmark	Odense University Hospital	Odense
France	Centre Hospitalier Universitaire	La Tronche
France	Hôpital Dupuytren	Limoges
France	GHR Mulhouse Sud-Alsace	Mulhouse Cedex
France	Hôpital Hôtel-Dieu	Nantes
France	Centre Antoine Lacassagne	Nice
France	Hôpital Saint Louis	Paris
France	Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Centre Hospitalier Universitaire de Toulouse	Toulouse
Germany	Städtisches Klinikum Braunschweig	Braunschweig
Germany	Marien Hospital Düsseldorf	Düsseldorf
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Universitätsklinikum Halle	Halle
Germany	Universitätsklinikum Ulm	Ulm
Italy	Azienda Ospedaliera SS. Antonio E. Biagio E. Cesare Arrigo di Alessandria	Alessandria
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze
Italy	Azienda Ospedaliera Universitaria San Martino	Genova
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	AORN A. Cardarelli	Napoli
Italy	Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara	Novara
Italy	Azienda Ospedaliera Ospedali Riuniti Marche Nord	Pesaro
Italy	Ospedale S. Eugenio	Roma
Japan	Nippon Medical School Hospital	Bunkyo-Ku	Tokyo
Japan	National Hospital Organization Kyushu	Fukuoka
Japan	Fukushima Medical University	Fukushima
Japan	Chugoku Central Hospital	Fukuyama-shi	Hiroshima
Japan	Gifu Municipal Hospital	Gifu
Japan	Kansai Medical University Hirakata	Hirakata	Osaka
Japan	Tokai University Hospital	Isehara	Kanagawa
Japan	Saitama Medical Center	Kawagoe	Saitama
Japan	The Cancer Institute Hospital of Japanese Foundation for Cancer Research	Koto	Tokyo
Japan	National Hospital Organization Kumamoto Medical Center	Kumamoto
Japan	Japanese Red Cross Kyoto Daini Hospital	Kyoto
Japan	University Hospital-Kyoto Prefectural University of Medicine	Kyoto
Japan	Nagasaki University Hospital	Nagasaki	Nagasaki-shi
Japan	NHO Nagoya Medical Center	Nagoya-shi	Aichi
Japan	Narita Red Cross Hospital	Narita	Chiba
Japan	Kindai University Hospital	Osakasayama-shi	Osaka
Japan	Kitasato University Hospital	Sagamihara-shi	Kanagawa
Japan	NTT Medical Center Tokyo	Shinagawa	Tokyo
Japan	National Hospital Organization Disaster Medical Center	Tachikawa	Tokyo
Japan	Yamagata University Hospital	Yamagata
Japan	Yokohama Municipal Citizen's Hospital	Yokohama	Kanagawa
Japan	University of Fukui Hospital	Yoshida	Fukui
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul Saint Mary's Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Poland	Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie	Lublin
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Poland	Samodzielny Publiczny Centralny Szpital Kliniczny	Warszawa
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitari Germans Trias i Pujol	Badalona
Spain	Fundació Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital San Pedro de Alcantara	Cáceres
Spain	Hospital de León	León
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramón Y Cajal	Madrid
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Sweden	Sahlgrenska Universitetssjukhuset, Östra sjukhuset	Göteborg
Sweden	Universitetssjukhuset Örebro	Örebro
United Kingdom	Medway NHS Foundation Trust	Gillingham
United Kingdom	The Leeds Teaching Hospitals NHS Trust	Leeds
United Kingdom	Chelsea and Westminster Hospital NHS Foundation Trust	London
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United States	University of Michigan Cancer Center	Ann Arbor	Michigan
United States	University of Maryland	Baltimore	Maryland
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	City of Hope	Duarte	California
United States	Duke Cancer Center	Durham	North Carolina
United States	North Shore Medical Center	Evanston	Illinois
United States	Cancer Specialists of North Florida	Fleming Island	Florida
United States	Bon Secours Saint Francis Hospital	Greenville	South Carolina
United States	John Theurer Cancer Center	Hackensack	New Jersey
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	West Virginia University Mary Babb Randolph Cancer Center	Morgantown	West Virginia
United States	Weill Cornell Medical College	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Desert Hematology Oncology Medical Group, Inc.	Rancho Mirage	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Swedish Cancer Institute	Seattle	Washington
United States	Stony Brook University Medical Center	Stony Brook	New York

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Poland,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	OS was defined as the number of days from the day the participant was randomized to the date of death due to any cause. Survival time was censored on the last date the participant is known alive with no event of death. OS time will be estimated using the Kaplan-Meier method.	From randomization up to death (up to approximately 38.6 months)
Secondary	Percentage of Participants With Transfusion Independence for Any 8 Consecutive Weeks	Transfusion independence rate was calculated as the number of participants with neither RBC nor platelet transfusion for any period of 8 weeks after the initiation of treatment (or cycle 1 day 1 { C1D1} visit date for participants randomized to BSC or randomization date for participants not treated) and up to treatment discontinuation (or 180 days for participants discontinuing the treatment within 6 months), while maintaining haemoglobin (Hgb) =8 gram per deciliter (g/dL) and platelets =20×10^9/liter (L) divided by the total number of participants included in the efficacy analysis. RBC or Platelet transfusion independence rate was defined similarly as above. Percentage of participants are rounded off to the single decimal point.	Up to approximately 46.6 months
Secondary	Percentage of Participants With Marrow Complete Response (mCR) Along With Transfusion Independence Rate	mCR was defined as per 2006 Myelodysplastic Syndromes International Council for Harmonisation (MDS IWG) criteria as reduction of bone marrow (BM) blasts to =5% and decrease by 50% or more with or without normalization of peripheral counts. Transfusion independence rate was calculated as the number of participants with neither RBC nor platelet transfusion for any period of 8 weeks after the initiation of treatment (or C1D1 visit date for participants randomized to BSC or randomization date for participants not treated) and up to treatment discontinuation (or 180 days for participants discontinuing the treatment within 6 months), while maintaining Hgb =8 g/dL and platelets =20×10^9/L divided by the total number of participants included in the efficacy analysis. The percentage of participants who achieved mCR and transfusion independence simultaneously in the same period were calculated for each group. Percentage of participants are rounded off to the single decimal point.	Up to approximately 46.6 months
Secondary	Survival Rate at 1 Year After Randomization	One year survival rate was defined as the percentage of participants that survived at the end of the first year from randomization. Participants who did not have death in record were censored on the last date known to be alive. Percentage of participants are rounded off to the nearest whole number.	From randomization up to 12 months
Secondary	Leukemia-free Survival	Leukemia-free survival was defined as the number of days from randomization to the earliest date when participants have bone marrow (BM) or peripheral blood (PB) blasts =20%, conversion to acute myeloid leukemia (AML) or death of any cause. Participants with no events in leukemia-free survival were censored on the last date of BM or PB blasts assessment, whichever is later. Survival time will be estimated using the Kaplan-Meier method.	From randomization up to 46.6 months
Secondary	Number of Days Alive and Out of the Hospital (NDAOH)	The date of each hospital admission and discharge was collected for each participant for up to 6 months, unless the participant died or withdrew consent prior to that time. Duration of each hospital stay in days was calculated as date of discharge minus date of admission. The NDAOH within first 6 month period was calculated as: NDAOH 6M=180 -total duration of all hospital stays within 180 days from the first treatment -number of death days before Day 180. For participants who were lost to follow-up within 6 months, the NDAOH was calculated conservatively assuming that the participant would have died the day after the last contact day.	Up to 6 months
Secondary	Disease Response (DR) Rate	DR: Complete Response(CR), Partial Response(PR),Marrow Complete Response(mCR), and Hematological Improvement(HI) including HI with Erythroid (HI-E), HI with Neutrophil (HI-N), or HI with Platelet (HI-P) based on IWG 2006 criteria. CR: BM:=5% myeloblasts, Peripheral blood: Hgb=11g/dL, Platelets(PLTs)=100x10^9/L, Neutrophils=1.0x10^9/L, Blasts 0%. PR: All CR criteria if abnormal before treatment except BM blasts decreased =50% over pretreatment but still>5%, Cellularity, morphology not relevant. HI responses:1) HI-E: Hgb increase =1.5g/dL, Relevant reduction of RBC units transfusions by absolute =4 RBC transfusions/8 week(wk) compared with pretreatment transfusion number previous 8wk. Only RBC transfusions given for Hgb=9.0g/dL. 2) HI-P: Absolute increase=30x10^9/L starting>20x10^9/L PLTs; Increase from<20x10^9/L to>20x10^9/L and by=100%. 3) HI-N: =100% increase, absolute increase>0.5x10^9/L.	Up to approximately 46.6 months
Secondary	Duration of Complete Response (CR)	Duration of complete response (in number of days) was calculated from the first time a CR was observed to the date of the earliest of the following three events: 1) relapse/disease progression, 2) start of alternative therapy (except Hematopoietic Cell Transplant [HCT]) or 3) death. In the absence of any event, the duration of CR was censored at the last available time point (BM assessment, PB assessment, or safety/long-term follow-up visit) at which an event was not observed. Duration of complete response was analysed using a Kaplan-Meier method for participants who achieved a CR during the study. CR: BM: =5% myeloblasts (all cell lines normal maturation), Peripheral blood: Hgb =11g/dL, PLTs =100x10^9/L, Neutrophils =1.0x10^9/L, Blasts 0%.	Up to approximately 46.6 months
Secondary	Time to First Response, Complete Response (CR) and Best Response	Time to first response was the time(days) from randomization to first date when any response was achieved. Time to CR was the time(days) from randomization to first date when CR was achieved. Time to best response was the time(days) from randomization to first date when participant's best response (CR,PR,mCR or HI) was achieved. CR:BM:=5% myeloblasts, Peripheral blood:Hgb=11g/dL,PLTs=100x10^9/L,Neutrophils=1.0x10^9/L,Blasts 0%. PR: All CR criteria except BM blasts decreased=50% over pretreatment but still >5%,Cellularity,morphology not relevant. mCR: Reduction of BM blasts to=5%; decrease =50% with/without normalization of peripheral counts. HI responses:1)HI-E:Hgb increase=1.5 g/dL, Relevant reduction of RBC units transfusions by absolute=4 RBC transfusions/8wk compared with pretreatment transfusion number previous 8wk. 2)HI-P:Absolute increase=30x10^9/L starting>20x10^9/L PLTs; Increase from=20 to>20x10^9/L and by=100% 3)HI-N:=100% granulocyte increase, absolute increase>0.5x10^9/L.	From study Day 1 to the earliest date that a response was first documented (up to approximately 46.6 months)
Secondary	Number of Red Blood Cell (RBC) and Platelet Transfusions	The total number of RBCs transfused or, separately, the total number of platelets transfused up to the 6-month time point for each participant was counted from the date of randomization to Day 180, the date of last contact, or date of death, whichever occurred earlier. One RBC or platelet transfusion was defined as one unit, and a single bag of RBCs or platelets was considered one unit. The mean total number of RBC or platelet units transfused per participant is presented.	Up to 6 months
Secondary	Change From Baseline in Health-related Quality of Life (QOL) By EuroQol 5-level 5-dimension (EQ-5D-5L) Summary Index	The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L, first component is a descriptive system five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a second component visual analogue scale (VAS) that measures health state. Each dimension comprises 5 levels with corresponding numeric scores, where 1 indicates no problems, and 5 indicates extreme problems. The health status is converted to an index value using the country-specific weighted scoring algorithm for England. The summary index value for the England ranges from a worst score of -0.281 to a best score of 1. An increase in the EQ-5D-5L total score indicates improvement.	Baseline to Month 6
Secondary	Change From Baseline in Health-related QOL: EuroQOL Visual Analogue Scale (EQ-VAS) Score	The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. The second component, EQ VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine).	Baseline to Month 6
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. An SAE is defined any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization; results in persistent or significant disability; is congenital anomaly; is suspected transmission of any infectious agent via a medicinal product or is medically important. Treatment emergent AEs which are those with onset date on or after the date of the first dose of study drug on C1D1 until 30 days after the last dose of study treatment, or the start of an alternative anticancer treatment, whichever occurs first.	From first dose through end of study (up to approximately 46.6 months)
Secondary	30-day and 60-day All-cause Mortality	Number of deaths, regardless of cause, within 30 or 60 days from the first study dose divided by the total number of participants included in the Safety Analysis Set. Participants who died within 30 days were also included in the 60-day mortality calculations.	From first dose until 60 days after study treatment initiation