Efficacy and Safety Study of Lenalidomide Plus R-CHOP Chemotherapy Versus Placebo Plus R-CHOP Chemotherapy in Untreated ABC Type Diffuse Large B-cell Lymphoma

Lymphoma, Large B-Cell, Diffuse Clinical Trial

— ROBUST  

Official title:

Phase 3 Randomized, Double-Blind, Placebo Controlled, Multicenter Study to Compare the Efficacy and Safety of Lenalidomide (CC-5013) Plus R-CHOP Chemotherapy (R2-CHOP) Versus Placebo Plus R-CHOP Chemotherapy in Subjects With Previously Untreated Activated B-cell Type Diffuse Large B-cell Lymphoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02285062
• Other study ID #: CC-5013-DLC-002
• Secondary ID: 2013-004054-21
• Status: Completed
• Phase: Phase 3
• Start date: February 17, 2015
• Est. completion date: July 28, 2022

Study information

• Verified date: May 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the efficacy and safety of lenalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R2-CHOP) chemotherapy versus placebo, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) chemotherapy in patients who have previously untreated ABC type DLBCL.

Description:

This research study is for patients with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL) of the activated B-cell (ABC) type who have not yet been treated. DLBCL is a cancer of a type of blood cell called B-lymphocytes. B lymphocytes are part of the body's immune system. There are different types of DLBCL. About a third of newly diagnosed DLBCL cancers are the ABC type. It has been observed that treatment does not work as well for patients with the ABC type compared to patients with other DLBCL types who receive standard treatment. However, at this time both ABC type and other DLBCL type patients receive the same standard treatments.

Patients with DLBCL who are otherwise healthy are usually treated first with the chemotherapy drug combination called R-CHOP. The drugs in this combination are "R" for rituximab, "C" for cyclophosphamide, "H" for doxorubicin which has a chemical name of hydroxydaunomycin, "O" for vincristine which has a trade name of oncovin, and "P" for prednisone. Depending on the local practice where you are treated, R-CHOP may be given for 6 or 8 cycles. A cycle could lasts for 14 or 21 days. The R-CHOP drug combination is approved for the treatment of DLBCL of all types, including ABC type. R-CHOP is standard care.

This study will test the standard R-CHOP21 against R-CHOP21 plus lenalidomide. The purpose is to see whether adding lenalidomide works better and is as safe as R-CHOP by itself. This study is only for patients with ABC type DLBCL who have not yet been treated. Lenalidomide is not approved for use in DLBCL. Its use in this disease is experimental. In this study, the experimental treatment is lenalidomide + R-CHOP21 x 6.

This study will use a gene expression profile (GEP) test to see if a patient has the ABC type. The results of this GEP test affect whether you may be treated on this study. Because the performance of this test has not been proven, it is for investigational use only, and is still under development. This means the GEP test is an experimental test.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 570
• Est. completion date: July 28, 2022
• Est. primary completion date: March 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Histologically proven Diffuse Large B-Cell Lymphoma of the Activated B-Cell type

2. Newly diagnosed, previously untreated Diffuse Large B-Cell Lymphoma

3. Measurable Diffuse Large B-Cell Lymphoma disease by Computed Tomography (CT) / Magnetic Resonance Imagining (MRI) scans

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

5. Age 18 - 80 years; age > 80 allowed at investigator discretion if performance status = 1; and each organ system score = 2 using cumulative illness rating scale (CIRS)

Exclusion Criteria:

1. Diagnosis of lymphoma histologies other than Diffuse Large B-Cell Lymphoma

2. History of malignancies, other than Diffuse Large B-Cell Lymphoma, unless the patient has been disease free for 5 years or more

3. Known seropositive for, or history of, active Human Immunodeficiency Virus (HIV) Hepatitis B Virus (HBV), Hepatitis C Virus (HCV)

4. Contraindication to any drug in the chemotherapy regimen, and specifically: LVEF (Left Ventricular Ejection Fraction) < 45% or peripheral neuropathy grade 2

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Drug:
• lenalidomide

• Placebo

• Rituximab

• Cyclophosphamide

• Doxorubicin

• prednisone

• vincristine

Locations

Country	Name	City	State
Australia	Local Institution - 004	Albury	New South Wales
Australia	Local Institution - 008	Clayton	Victoria
Australia	Local Institution - 003	Frankston
Australia	Local Institution - 002	Geelong	Victoria
Belgium	Local Institution - 301	Brussels
Belgium	Local Institution - 307	Liege
Belgium	Local Institution - 305	Roeselare
Belgium	Local Institution - 303	Sint-Niklaas
Canada	Local Institution - 368	Calgary	Alberta
Canada	Local Institution - 362	Greenfield Park	Quebec
Canada	Local Institution - 365	Montreal	Quebec
Canada	Local Institution - 366	Saint John	New Brunswick
Canada	Local Institution - 373	Surrey	British Columbia
China	Local Institution - 200	Beijing
China	Local Institution - 206	Beijing
China	Local Institution - 209	Beijing
China	Local Institution - 215	Beijing
China	Local Institution - 211	Changchun
China	Local Institution - 210	Chengdu
China	Local Institution - 213	Chongqing
China	Local Institution - 202	Fuzhou
China	Local Institution - 217	Guangzhou, Guangdong
China	Local Institution - 204	Hangzhou
China	Local Institution - 207	Harbin, Heilongjiang
China	Local Institution - 212	Nanjing
China	Local Institution - 205	Nanjing, Jiangsu
China	Local Institution - 214	Shanghai
China	Local Institution - 219	Suzhu
China	Local Institution - 221	Tianjin
China	Local Institution - 203	Wuhan
Czechia	Local Institution - 376	Brno
Czechia	Local Institution - 377	Hradec Kralove
Czechia	Local Institution - 379	Olomouc
Czechia	Local Institution - 380	Prague 10
Czechia	Local Institution - 378	Praha
France	Local Institution - 576	Bayonne
France	Local Institution - 585	Bordeaux
France	Local Institution - 583	Montpellier
France	Local Institution - 582	Paris
France	Local Institution - 588	Pessac Cedex
France	Local Institution - 587	Toulose
France	Local Institution - 581	Vandoeuvre les Nancy
Ireland	Local Institution - 893	Dublin 4
Ireland	Local Institution - 894	Galway
Israel	Local Institution - 273	Beer-Sheva
Israel	Local Institution - 274	Haifa
Israel	Local Institution - 272	Jerusalem
Israel	Local Institution - 275	Kfar-Saba
Israel	Local Institution - 277	Petach Tikva
Israel	Local Institution - 278	Tel-Aviv
Israel	Local Institution - 270	Zerifin
Italy	Local Institution - 659	Allessandria
Italy	Local Institution - 658	Brescia
Italy	Local Institution - 674	Cuneo
Italy	Local Institution - 664	Firenze
Italy	Local Institution - 652	Genova
Italy	Local Institution - 667	Ivrea
Italy	Local Institution - 684	Meldola
Italy	Local Institution - 653	Milano
Italy	Local Institution - 666	Milano
Italy	Local Institution - 676	Milano
Italy	Local Institution - 657	Napoli, Campania
Italy	Local Institution - 655	Novara
Italy	Local Institution - 685	Padova
Italy	Local Institution - 686	Pagani
Italy	Local Institution - 651	Pavia
Italy	Local Institution - 679	Ravenna
Italy	Local Institution - 668	Reggio Emilia
Italy	Local Institution - 683	Rimini
Italy	Local Institution - 673	Roma
Italy	Local Institution - 689	Roma
Italy	Local Institution - 694	Roma
Italy	Local Institution - 656	Rome
Italy	Local Institution - 690	Terni	Umbria
Italy	Local Institution - 662	Torino
Italy	Local Institution - 671	Torino
Italy	Local Institution - 681	Tricase
Italy	Local Institution - 692	Udine
Italy	Local Institution - 682	Verona
Italy	Local Institution - 672	Vicenza
Japan	Local Institution - 513	Akita-shi
Japan	Local Institution - 508	Chuo-ku	Tokyo
Japan	Local Institution - 511	Fukuoka
Japan	Local Institution - 505	Isehara City, Kanagawa
Japan	Local Institution - 501	Kashiwa
Japan	Local Institution - 509	Koto-ku	Tokyo
Japan	Local Institution - 510	Kyoto-City
Japan	Local Institution - 506	Minami-Ku, Fukuoka
Japan	Local Institution - 502	Minato-ku	Tokyo
Japan	Local Institution - 507	Nagoya
Japan	Local Institution - 515	Sendai-city
Japan	Local Institution - 504	Yamagata
Korea, Republic of	Local Institution - 830	Gyeonggi-do
Korea, Republic of	Local Institution - 826	Seoul
Korea, Republic of	Local Institution - 828	Seoul
Korea, Republic of	Local Institution - 829	Seoul
Netherlands	Local Institution - 358	Amsterdam
Netherlands	Local Institution - 359	Breda
Netherlands	Local Institution - 357	Hoofddorp
Netherlands	Local Institution - 354	Leeuwarden
Netherlands	Local Institution - 353	s-Hertogenbosch
Netherlands	Local Institution - 350	Schiedam
New Zealand	Local Institution - 240	Christchurch
New Zealand	Local Institution - 243	Palmerston
Portugal	Local Institution - 730	Figueira da Foz
Portugal	Local Institution - 729	Lisboa
Portugal	Local Institution - 732	Lisboa
Portugal	Local Institution - 727	Pragal
Puerto Rico	Local Institution - 115	San Juan
Russian Federation	Local Institution - 050	Kazan
Russian Federation	Local Institution - 052	Moscow
Russian Federation	Local Institution - 051	St. Petersburg
Spain	Local Institution - 776	Barcelona
Spain	Local Institution - 780	Barcelona
Spain	Local Institution - 796	Caceres
Spain	Local Institution - 783	Madrid
Spain	Local Institution - 785	Madrid
Spain	Local Institution - 787	Madrid
Spain	Local Institution - 788	Madrid
Spain	Local Institution - 797	Salamanca
Spain	Local Institution - 790	Sevilla
Spain	Local Institution - 800	Sevilla
Spain	Local Institution - 793	Valencia
Spain	Local Institution - 802	Valencia
Switzerland	Local Institution - 323	Bellinzona
Switzerland	Local Institution - 320	Geneva
Switzerland	Local Institution - 321	Winterthur
Taiwan	Local Institution - 253	Niao-Sung Hsiang Kaohsiung County
Taiwan	Local Institution - 255	Taichung City
Taiwan	Local Institution - 252	Taipei, Zhongzheng Dist.
Turkey	Local Institution - 429	Adana
Turkey	Local Institution - 431	Ankara
Turkey	Local Institution - 430	Antalya
Turkey	Local Institution - 435	Denizli
Turkey	Local Institution - 428	Edirne
Turkey	Local Institution - 432	Istanbul
United States	McFarland Clinic	Ames	Iowa
United States	Center For Cancer And Blood Disorders	Bethesda	Maryland
United States	Local Institution - 151	Dallas	Texas
United States	Local Institution - 951	Dallas	Texas
United States	Local Institution - 103	Durham	North Carolina
United States	Local Institution - 905	Edmonds	Washington
United States	Local Institution - 143	Fairway	Kansas
United States	Local Institution - 177	Fayetteville	Arkansas
United States	Local Institution - 128	Hollywood	Florida
United States	Local Institution - 903	Issaquah	Washington
United States	Local Institution - 101	Minneapolis	Minnesota
United States	Local Institution - 138	Minneapolis	Minnesota
United States	Local Institution - 169	New Haven	Connecticut
United States	Local Institution - 136	Orange	California
United States	Local Institution - 161	Philadelphia	Pennsylvania
United States	Local Institution - 112	Rochester	Minnesota
United States	Local Institution - 127	Sacramento	California
United States	Local Institution - 146	Salt Lake City	Utah
United States	Local Institution - 162	Seattle	Washington
United States	Local Institution - 904	Seattle	Washington
United States	Local Institution - 158	Shreveport	Louisiana
United States	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  Czechia,  France,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  New Zealand,  Portugal,  Puerto Rico,  Russian Federation,  Spain,  Switzerland,  Taiwan,  Turkey, 

References & Publications (1)

Nowakowski GS, Chiappella A, Witzig TE, Spina M, Gascoyne RD, Zhang L, Flament J, Repici J, Vitolo U. ROBUST: Lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Future Oncol. 2016 Jul;12(13):1553-63. doi: 10.2217/fon-2016-0130. Epub 2016 Apr 18. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kaplan-Meier Estimate of Progression Free Survival (PFS)	Progression free survival was defined as the time (months) from the date of randomization to the date of disease progression or death (any cause), whichever occurred earlier and was assessed by the Independent Response Adjudication Committee (IRAC). Relapse from complete response (CR) was considered as disease progression throughout the study. Disease progression was determined based on the Revised Response Criteria for Malignant Lymphoma. The PFS analysis was based on the censoring rules using the Food and Drug Administration (FDA) Guidance. Participants who did not experience disease progression and who did not die before the clinical data cutoff date were censored at the date of last adequate response assessment.	From the date of randomization up to the data cut off date of 15 March 2019; median follow-up of 24.5 months
Secondary	Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS)	EFS was defined as the time (months) from randomization until occurrence of one of the following events, whichever occurred first: • Disease progression • Initiation of subsequent systemic anti-lymphoma therapy • Death due to any cause The assessment of EFS was conducted by the IRAC using the International Working Group (IWG) criteria for NHL. Pre-specified optional therapies such as the extra 2 doses of single agent rituximab after Cycle 6 or consolidation radiotherapy did not count as an EFS event (initiation of subsequent systemic anti-lymphoma therapy) if the decision to treat and the location to be treated was determined prior to randomization. Participants who did not experience any of the events defined in the categories above before the clinical data cutoff date were censored at date last known alive.	From the date of randomization up to the data cut off date of 15 March 2019; median follow-up was 24.5 months
Secondary	K-M Estimate of Overall Survival (OS)	Overall survival was assessed by the Independent Response Adjudication Committee (IRAC) and defined as time from randomization until death due to any cause. Participants who withdrew consent were censored at the time of withdrawal. Participants who were still alive before the clinical data cutoff date and participants who were lost to follow-up were censored at date last known alive.	From randomization until death due to any cause (up to approximately 86 months)
Secondary	Percentage of Participants Who Achieved a Complete Response (CR)	The percentage of participants who achieved a CR after initiation of the study treatment and prior to initiation of subsequent systemic antilymphoma therapy as assessed by the IRAC. A CR = complete metabolic response; target nodes/nodal masses regressed on computed tomography to (= 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy. Regressed to normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, no evidence of fluorodeoxyglucose avid disease in marrow per International Working Group (IWG) 2014 for Non-Hodgkin's Lymphoma (NHL). Participants who did not have any adequate response assessments during this period were not considered as responders.	From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months
Secondary	Percentage of Participants Who Achieved an Objective Response	An objective response = percentage of participants who achieved a complete response or partial response after initiation of the treatment and prior to initiation of subsequent systemic anti-lymphoma therapy. A CR = complete metabolic response; Target nodes/nodal masses regressed on computed tomography to (= 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy. Regressed to normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, no evidence of fluorodeoxyglucose avid disease in marrow. PR = = 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in other nodes, liver, or spleen. Splenic nodules regressed by = 50% in their SPD or for single nodules, in the greatest transverse diameter; no new lesions. Participants who did not have any adequate response assessments during this period were not considered as responders.	From randomization date up to the data cut off date of 15 March 2019; median total treatment duration was 18.10 weeks for both treatment arms; range = 1.6 to 29.0 weeks for R2-CHOP arm and 0.3 to 22.9 weeks for placebo-R-CHOP arm
Secondary	K-M Estimate of Duration of Complete Response	Duration of complete response was calculated for complete responders only and was defined as the time from documented initial complete response prior to initiation of subsequent systemic antilymphoma therapy until documented disease progression or death, whichever occurred earlier. Participants who had not progressed or died at the time of the analysis were censored at the date of last response assessment demonstrating no disease progression. Participants who changed treatment without evidence of disease progression were censored at the last assessment showing no progression prior to treatment change.	From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months.
Secondary	K-M Estimate of Time to Next Lymphoma Therapy (TTNLT)	Time to next lymphoma therapy was defined as the time from randomization to the time of treatment change for the next lymphoma treatment. Participants without treatment change were censored at date last known alive. Pre-specified optional therapies such as the extra 2 doses of single agent rituximab after Cycle 6 or consolidation radiotherapy did not count as treatment change for the next lymphoma therapy if the decision to treat and the location to be treated were determined prior to randomization.	From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months
Secondary	Percentage of Participants Who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire	The completion rate for FACT-Lym assessments was judged by looking at the number of completed FACT-Lym assessments at each time point. The FACT-Lym was considered completed if at least 1 calculable score was present. Completion rates were calculated as the number and percentage of participants out of the total number of patients in the ITT population and summarized by visit/cycle and treatment group. The FACT-Lym is a health related quality of life (HRQoL) questionnaire targeted to the management of chronic illness, predominantly within oncology and is considered an extension of the FACT-General questionnaire.	Screening, Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Percentage of Participants Who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire	The completion rate for EQ-5D assessments was judged by looking at the number of completed assessments at each time point. Completion rates were calculated as the number and percentage of participants out of the total number of patients in the ITT population and summarized by visit/cycle and treatment group. The EQ-5D-3L is a generic, self-reported preference-based measure of health across five dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has three levels of 'severity' corresponding to "no problems", "some problems" and "extreme problems". The instrument is scored using the United Kingdom (UK) index ranges from -0.594 - 1, where 0 equates to death and 1 equates to full health -0.594 is considered 'worse than death'.	Screening, Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Mean Change From Baseline in the FACT-Lym Physical Well-Being Subscale	The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from "not at all" (0) to "very much" (4). The physical well-being subscale ranges from 0 to 28, where higher scores reflect better HRQoL.	Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Mean Change From Baseline in the FACT-Lym Additional Concerns Subscale	The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms such as pain, itching, night sweats,trouble sleeping, fatigue and trouble concentrating and concerns regarding lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. All questions are answered on a 5-point scale ranging from "not at all" (0) to "very much" (4). The Additional Concerns subscale ranges from 0 to 60, where higher scores reflect better HRQoL.	Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Mean Change From Baseline in the FACT-Lym Functional Well-Being Subscale	The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from "not at all" (0) to "very much" (4). The functional well-being subscale ranges from 0 to 28, where higher scores reflect better HRQoL.	Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Mean Change From Baseline in the FACT-Lym Trial Outcome Index (TOI)	The FACT-Lym questionnaire is a validated instrument for assessing the impact of lymphoma on HRQL and contains 42 questions covering HRQL and common lymphoma symptoms and treatment side-effects. It begins with the Functional Assessment of Cancer Therapy - General (FACT-G), which contains 27 questions covering four core subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 questions) used to assess NHL-related symptoms and concerns. All questions are answered on a 5-point scale ranging from "not at all" (0) to "very much" (4). The FACT-Lym TOI is calculated by summing the Physical Well-being, Functional Well-being and Additional Concerns scores and has a range of 0 to 116. Higher scores reflect better HRQoL or fewer symptoms.	Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Mean Change From Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score	The EQ-5D-3L is a generic, self-reported preference-based measure of health across five dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has three levels of 'severity' corresponding to "no problems", "some problems" and "extreme problems". The instrument is scored as a single summary index using one of the available EQ-5D-3L value sets; in this study the UK scoring weights 9 were used. 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').	Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34
Secondary	Mean Change From Baseline in the EQ-5D-3L Visual Analogue Scale (VAS)	The EQ-5D-3L questionnaire includes a visual analogue scale which records the respondent's self-rated health on a vertical, 0-100 scale where 100 = "Best imaginable health state" and 0 = "Worst imaginable health state". Higher scores again indicate better HRQoL and positive change scores indicate that post screening values were higher than those observed at screening. The EQ-5D-3L is a generic, self-reported preference-based measure of health across five dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has three levels of 'severity' corresponding to "no problems", "some problems" and "extreme problems".	Baseline and Midcycle = after Cycle 3 but before Cycle 4, Cycle 6 Day 1 (C6D1), End of Treatment (C6,D21), and Follow-Up Period up to Week 34

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