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Trial record 1 of 4 for:    lenalidomide R-CHOP | Lymphoma | Italy
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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 (ROBUST)

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ClinicalTrials.gov Identifier: NCT02285062
Recruitment Status : Active, not recruiting
First Posted : November 6, 2014
Results First Posted : March 30, 2020
Last Update Posted : March 31, 2020
Sponsor:
Information provided by (Responsible Party):
Celgene

Tracking Information
First Submitted Date  ICMJE November 4, 2014
First Posted Date  ICMJE November 6, 2014
Results First Submitted Date  ICMJE March 13, 2020
Results First Posted Date  ICMJE March 30, 2020
Last Update Posted Date March 31, 2020
Actual Study Start Date  ICMJE January 21, 2015
Actual Primary Completion Date March 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2020)
Kaplan-Meier Estimate of Progression Free Survival (PFS) [ Time Frame: From the date of randomization up to the data cut off date of 15 March 2019; median follow-up of 24.5 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2014)
Progression Free Survival [ Time Frame: Up to 5 years from the time the last patient is randomized ]
Number of participants who survive without progressing
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2020)
  • Kaplan-Meier (K-M) Estimate of Event Free Survival (EFS) [ Time Frame: From the date of randomization up to the data cut off date of 15 March 2019; median follow-up was 24.5 months ]
    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.
  • K-M Estimate of Overall Survival (OS) [ Time Frame: From the date of randomization up to the data cut off date of 15 March 2019; median follow-up was 24.5 months ]
    Overall survival was assessed by the IRAC and defined as time from randomization until death of 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.
  • Percentage of Participants Who Achieved a Complete Response (CR) [ Time Frame: From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months ]
    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.
  • Percentage of Participants Who Achieved an Objective Response [ Time Frame: 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 ]
    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.
  • K-M Estimate of Duration of Complete Response [ Time Frame: From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months. ]
    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.
  • K-M Estimate of Time to Next Lymphoma Therapy (TTNLT) [ Time Frame: From randomization date up to the data cut off date of 15 March 2019; median follow-up was 24.5 months ]
    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.
  • Number of Participants With a Treatment Emergent Adverse Event (TEAE) [ Time Frame: From the first dose of study treatment up to 28 days after the last dose of LEN/placebo or any component of R-CHOP including the optional 2 additional doses of rituximab if administered; up to 15 March 2019; maximum treatment duration = 29 months ]
    A TEAE was defined as an AE that begins or worsens in intensity or 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 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death
  • Percentage of Participants Who Completed the Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) Questionnaire [ Time Frame: 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 ]
    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.
  • Percentage of Participants Who Completed the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Health Related Quality of Life (HR-QoL) Questionnaire [ Time Frame: 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 ]
    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'.
  • Mean Change From Baseline in the FACT-Lym Physical Well-Being Subscale [ Time Frame: 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 ]
    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.
  • Mean Change From Baseline in the FACT-Lym Additional Concerns Subscale [ Time Frame: 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 ]
    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.
  • Mean Change From Baseline in the FACT-Lym Functional Well-Being Subscale [ Time Frame: 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 ]
    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.
  • Mean Change From Baseline in the FACT-Lym Trial Outcome Index (TOI) [ Time Frame: 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 ]
    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.
  • Mean Change From Baseline in the Euroqol 5-Dimension 3-Level (EQ-5D-3L) Index Score [ Time Frame: 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 ]
    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').
  • Mean Change From Baseline in the EQ-5D-3L Visual Analogue Scale (VAS) [ Time Frame: 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 ]
    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".
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2014)
  • Overall Survival [ Time Frame: Up to 5 years from the time the last patient is randomized ]
    Proportion of patients who survive
  • Complete Response Rate [ Time Frame: Up to 5 years from the time the last patient is randomized ]
    Proportion of patients who have a complete response prior to any treatment change
  • Duration of Complete Response [ Time Frame: Up to 5 years from the time the last patient is randomized ]
    Calculated only for patients who have a complete response. Time from the first complete response prior to treatment change to the first event of disease progression or death
  • Time to Next Lymphoma Treatment [ Time Frame: Up to 5 years from the time the last patient is randomized ]
    Time from randomization to the time of treatment change to the next lymphoma treatment
  • Objective Response Rate [ Time Frame: Up to 5 years from the time the last patient is randomized ]
    Proportion of patients who have either a complete or partial response before any treatment change
  • Health Related Quality of Life [ Time Frame: Up to 5 years from the time the last patient is randomized ]
    Differences in health related quality of life will be compared between the two treatment groups
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Lymphoma, Large B-Cell, Diffuse
Intervention  ICMJE
  • Drug: lenalidomide
  • Drug: Placebo
  • Drug: Rituximab
  • Drug: Cyclophosphamide
  • Drug: Doxorubicin
  • Drug: prednisone
  • Drug: vincristine
Study Arms  ICMJE
  • Experimental: R2-CHOP
    Lenalidomide plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
    Interventions:
    • Drug: lenalidomide
    • Drug: Rituximab
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: prednisone
    • Drug: vincristine
  • Active Comparator: R-CHOP
    Placebo plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
    Interventions:
    • Drug: Placebo
    • Drug: Rituximab
    • Drug: Cyclophosphamide
    • Drug: Doxorubicin
    • Drug: prednisone
    • Drug: vincristine
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 27, 2017)
570
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2014)
560
Estimated Study Completion Date  ICMJE August 3, 2022
Actual Primary Completion Date March 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   Australia,   Belgium,   Canada,   China,   Czechia,   France,   Ireland,   Israel,   Japan,   Korea, Republic of,   Netherlands,   New Zealand,   Poland,   Portugal,   Puerto Rico,   Russian Federation,   Spain,   Switzerland,   Taiwan,   Turkey,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02285062
Other Study ID Numbers  ICMJE CC-5013-DLC-002
2013-004054-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene
Study Sponsor  ICMJE Celgene
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Stacey Kalambakas, M.D Celgene Corporation
PRS Account Celgene
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP