Diffuse Large B-cell Lymphoma
Conditions
Keywords
Diffuse Large B-Cell Lymphoma, Non Hodgkin's Lymphoma, relapsed, refractory, relapsed/refractory, DLBCL, Diffuse Large B Cell Lymphoma
Brief summary
The purpose of this study is to compare lenalidomide to a control drug and see which one delays Diffuse Large B-Cell Lymphoma (DLBCL) disease progression longer.
Detailed description
This research study is for patients who have been diagnosed with Diffuse Large B-cell Lymphoma (DLBCL) that did not respond to (refractory) or that has come back after chemotherapy treatment (relapsed). Lymphoma is a cancer of a type of blood cell called lymphocytes. DLBCL is just one type of lymphoma. Within DLBCL there are two different subtypes called Germinal Center B-cell (GCB) and non-GCB which can be determined by cell surface marker tests or by gene expression tests. Scientists can look at cells and genes in the laboratory and see that the two kinds are different, but they don't know yet what the difference means. To patients and doctors these two kinds seem the same. Right now doctors don't usually do tests to find out which kind a patient has because the treatment is the same for both. This study will have two stages, 1 and 2. The main purpose of Stage 1 is to separate patients by subtype and then test whether patients taking lenalidomide or any one of four other drugs have a better response. It is possible that lenalidomide will work better than one of the other drugs in zero, one, or both subtypes. Stage 2 will further test only the subtype(s) from Stage 1 that showed a good response to lenalidomide. The main purpose of Stage 2 is to test how long patients are disease free on lenalidomide compared to one of the four other drugs. On 29 January 2013 the enrolment goal for the Stage 1 portion of the study was met and enrollment was stopped. The final analysis for Stage 1 was performed as of the 04 Jul 2013 data cutoff date. According to the Stage 1 results as assessed by the independent response adjudication committee (IRAC), neither subtype met the pre specified requirement to be further studied in Stage 2. Additionally, a suitable assay for the selection of participants for the Stage 2 study was not available. Therefore, on 6 January 2014, Celgene decided to not open Stage 2.
Interventions
DRUGLenalidomide
Lenalidomide 25 mg orally for 21/28 days until Diffuse Large B-Cell Lymphoma (DLBCL) progressive disease. For patients with Creatinine Clearance ≥ 30 mL/min but \< 60 mL/min, lenalidomide 10 mg (max escalation is 15 mg).
DRUGGemcitabine
Suggested starting doses and regimens for Gemcitabine is 1,250 mg/m\^2 intravenous (IV) administration on days 1, 8, 15 every 28 days for 6 Cycles or 1,000 mg/m\^2 IV days 1 and 15 every 28 days for 6 Cycles
DRUGOxaliplatin
Suggested starting dose and regimen for Oxaliplatin is 100 mg/m\^2 IV day 1 for 21 days for 6 Cycles
DRUGRituximab
Suggested starting dose for Rituximab is 375 mg/m\^2 IV days 1, 8, 15, 22 during Cycle 1, and if stable disease at Week 12, also on Day 1 of Cycles 4, 6, 8, and 10 (CD20+ patients only)
DRUGEtoposide
Suggested starting doses for Etoposide are: 100 mg/m\^2 IV days 1-5 every 28 days for 6 Cycles, or 100 mg/m\^2 IV days 1-3 every 28 days for 6 Cycles, or 50 mg/m\^2 oral days 1-21 every 28 days for 6 Cycles, or 50 mg/m\^2 oral days 1-14 every 28 days for 6 Cycles, or 50 mg/m\^2 oral days 1-10 every 28 days for 6 Cycles
Sponsors
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven Diffuse Large B-Cell Lymphoma (DLBCL). * Relapsed or refractory to combination chemotherapy for DLBCL that contains rituximab and an anthracycline, and one additional combination chemotherapy or stem cell transplant. * Measurable DLBCL disease by computed tomograph (CT) / magnetic resonance imagining (MRI). * Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.
Exclusion criteria
* Diagnosis of lymphoma histologies other than DLBCL. * History of malignancies, other than DLBCL, unless the patient has been disease free for 3 years or more. * Eligible for autologous stem cell transplant. * Known seropositive for, or history of, active human immunodeficiency virus (HIV) hepatitis B virus (HBV), hepatitis C virus (HCV) * Neuropathy grade 4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | From the date of randomization to the data cut-off of 4 July 2013; when all patients reached the scheduled 16-week assessment or had progressed/died before the scheduled 16-week assessment); the median study duration was 27.0 and 19.7 weeks, respectively. | An overall response is a complete response (CR), unconfirmed complete response (CRu) or partial response (PR) and was evaluated by the IRAC. A CR = complete disappearance of disease and related symptoms. Lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and \> 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on exam, normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. 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 and hepatic nodules regressed by ≥ 50% in their SPD or for single nodules, in the greatest transverse diameter;no new disease. |
| Stage 1: Percentage of Participants With an Overall Response According to the IWG Response Criteria Based on the Investigators Assessment at the Final Data Cut During the Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | Response was defined as having a CR, CRu or PR, based on IWG 1999 Response Criteria for NHL as evaluated by the investigators. CR = complete disappearance of disease and disease related symptoms. All lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and \> 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical exam, normal size by imaging, and absence of nodules related to lymphoma. If BM was involved prior to therapy, infiltrate must have cleared on repeat biopsy. 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 the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 2: Overall Response Rate (ORR) | Approximately 3.5 years | ORR is defined as: Complete Response + Complete Response unconfirmed + Partial Response based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999). |
| Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | From first dose of study drug to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | A TEAE was defined as an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: * Death; * Life-threatening event; * Any inpatient hospitalization or prolongation of existing hospitalization; * Persistent or significant disability or incapacity; * Congenital anomaly or birth defect; * Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event.The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.03) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death |
| Stage 2: Duration of Response (DoR) | Approximately 3.5 years | Length of time of overall response (Complete Response + Complete Response unconfirmed + Partial Response) based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999). |
| Stage 2: Overall Survival (OS) | Approximately 3.5 years | Overall survival was defined as time from randomization until death of any cause. |
| Stage 2: Duration of Complete Response | Approximately 3.5 years | Length of time of complete response (Complete Response + Complete Response unconfirmed) based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999). |
| Stage 2: Overall Response Rate for With a Duration of Response Lasting ≥ 16 Weeks | Approximately 3.5 years | Complete Response + Complete Response unconfirmed + Partial Response for participants with a duration of response lasting ≥ 16 weeks based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999). |
| Stage 2: Time to Progression | Approximately 3.5 years | Length of time until disease progression occurs |
| Stage 2: Health Related Quality of Life Questionnaires | Approximately 3.5 years | Quality of Life based on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EQ-5D assessments |
Other
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Kaplan Meier Estimates of Duration of Complete Response (DoCR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | Duration of complete response was defined as the time from the first documented complete response (CR + CRu) until the first disease progression or death for participants who had a CR. |
| Stage 1: Kaplan Meier Estimates of Progression-Free Survival As Assessed By The Investigators At The Final Data Cut During The Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | Progression-free survival was defined as the time from randomization to the first documented disease progression or death due to any cause. |
| Stage 1: Kaplan Meier Estimates of Overall Survival As Assessed by the Investigators at the Final Data Cut During The Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | Overall survival was defined as time from randomization until death of any cause. |
| Stage 2: Progression-Free Survival | Approximately 3.5 years | Number of participants who survive without progressing based on the International Working Group Response Criteria \[IWG\]. |
| Stage 1: Percentage of Participants With a Complete Response According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | A complete response was defined as participants with a complete response (CR), or unconfirmed complete response (CRu) based on IWG 1999 Response Criteria for NHL as assessed by the investigator. A CR is a complete disappearance of all disease with the exception of nodes. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRu) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM. |
| Stage 1: Percentage of Participants With a Durable Overall Response (dORR) According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | Durable overall response rate was defined as the percentage of participants who maintained a response for at least 16 weeks after initial response. |
| Stage 1: Kaplan Meier Estimates of Duration of Overall Response (DoR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively. | Duration of overall response was calculated as the time of initial response (CR+CRu+PR) until documented disease progression determinted by computerized scan CT scan or MRI or death due to lymphoma, whichever occurred earlier, for participants who responded. |
Countries
Australia, Austria, Czechia, France, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Screening and enrollment occurred at 43 sites, including 10 in the United States, 9 in France, 7 in the United Kingdom; 4 in Spain, 4 in Italy, 3 each in Austria and Australia, 2 in the Czech Republic, and 1 in Sweden.
Pre-assignment details
Participants were stratified into Germinal center B-cell (GCB) or non-GCB subtypes and randomized 1:1 to receive lenalidomide or investigator's choice treatment (one of the single-agent reference therapies \[gemcitabine, rituximab, etoposide, or oxaliplatin)
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide Participants received lenalidomide 25 mg orally once daily for 21 days in each 28-day cycle until progressive disease. For participants with creatinine clearance ≥ 30 mL/min but \< 60 mL/min, lenalidomide 10 mg once daily for 21 days for 2 cycles. After Cycle 2 the dose may have been increased to a maximum of 15 mg lenalidomide once daily for 21 days in each 28-day cycle. Treatment was continued until disease progression, unacceptable toxicity, or voluntary withdrawal. | 51 |
| Investigators Choice (IC) Participants received a single agent reference therapy (either gemcitabine, oxaliplatin, rituximab or etoposide) based on published data for up to 6 cycles or until disease progression, unacceptable toxicity or withdrawal. Gemcitabine 1,250 mg/m\^2 Intravenous (IV) days 1, 8, 15 every 28 days for 6 Cycles or 1,000 mg/m\^2 IV days 1 and 15 in each 28- day cycle for 6 Cycles Oxaliplatin 100 mg/m\^2 IV day 1 in each 21-day cycle for 6 Cycles Rituximab is 375 mg/m\^2 IV days 1, 8, 15, 22 during Cycle 1, and if stable disease at Week 12, also on Day 1 of Cycles 4, 6, 8, and 10 (CD20+ patients only) Etoposide doses: 100 mg/m\^2 IV days 1-5 in each 28-day cycle for 6 Cycles, or 100 mg/m\^2 IV days 1-3 in each 28-day cycle for 6 Cycles, or 50 mg/m\^2 oral days 1-21 in each 28-day cycle for 6 Cycles, or 50 mg/m\^2 oral days 1-14 in each 28-day cycle for 6 Cycles, or 50 mg/m\^2 oral days 1-10 in each 28-day cycle for 6 Cycles | 51 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 8 |
| Overall Study | Death | 3 | 5 |
| Overall Study | Disease progression | 40 | 35 |
| Overall Study | Miscellaneous | 4 | 3 |
| Overall Study | Missing | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Lenalidomide | Total | Investigators Choice (IC) |
|---|---|---|---|
| Age, Continuous | 64.7 years STANDARD_DEVIATION 13.43 | 63.75 years STANDARD_DEVIATION 13.69 | 62.8 years STANDARD_DEVIATION 13.94 |
| Creatinine Clearance (CrCl) ≥ 30 but < 60 mL/min | 18 Participants | 25 Participants | 7 Participants |
| Creatinine Clearance (CrCl) ≥ 60 mL/min | 32 Participants | 75 Participants | 43 Participants |
| Creatinine Clearance (CrCl) Missing | 1 Participants | 2 Participants | 1 Participants |
| Diffuse Large B-Cell Lymphoma (DLBCL) Subtypes - Germinal Center B-Cell (GCB) and non-GCB Germinal Center B-Cell Type | 23 Participants | 48 Participants | 25 Participants |
| Diffuse Large B-Cell Lymphoma (DLBCL) Subtypes - Germinal Center B-Cell (GCB) and non-GCB Non-Germinal Center B-Cell Type | 28 Participants | 54 Participants | 26 Participants |
| Disease Stage of DLBCL at Enrollment IA | 1 Participants | 4 Participants | 3 Participants |
| Disease Stage of DLBCL at Enrollment IB | 1 Participants | 1 Participants | 0 Participants |
| Disease Stage of DLBCL at Enrollment IIA | 8 Participants | 15 Participants | 7 Participants |
| Disease Stage of DLBCL at Enrollment IIB | 3 Participants | 4 Participants | 1 Participants |
| Disease Stage of DLBCL at Enrollment IIIA | 13 Participants | 26 Participants | 13 Participants |
| Disease Stage of DLBCL at Enrollment IIIB | 2 Participants | 6 Participants | 4 Participants |
| Disease Stage of DLBCL at Enrollment IVA | 17 Participants | 31 Participants | 14 Participants |
| Disease Stage of DLBCL at Enrollment IVB | 6 Participants | 15 Participants | 9 Participants |
| Eastern Cooperative Oncology Performance Status (ECOG)] 0 = (Fully Active) | 18 Participants | 33 Participants | 15 Participants |
| Eastern Cooperative Oncology Performance Status (ECOG)] 1 (Restrictive but Ambulatory) | 24 Participants | 52 Participants | 28 Participants |
| Eastern Cooperative Oncology Performance Status (ECOG)] 2 (Ambulatory but Unable to Work) | 7 Participants | 15 Participants | 8 Participants |
| Eastern Cooperative Oncology Performance Status (ECOG)] 3 (Limited Self-Care) | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Performance Status (ECOG)] 4 (Completely Disabled) | 1 Participants | 1 Participants | 0 Participants |
| Eastern Cooperative Oncology Performance Status (ECOG)] Missing | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black/African American | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 9 Participants | 20 Participants | 11 Participants |
| Race/Ethnicity, Customized Other (Unspecified) | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 38 Participants | 74 Participants | 36 Participants |
| Sex: Female, Male Female | 21 Participants | 41 Participants | 20 Participants |
| Sex: Female, Male Male | 30 Participants | 61 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 48 / 54 | 51 / 55 |
| other Total, other adverse events | 53 / 54 | 52 / 55 |
| serious Total, serious adverse events | 31 / 54 | 42 / 55 |
Outcome results
Primary
Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC)
An overall response is a complete response (CR), unconfirmed complete response (CRu) or partial response (PR) and was evaluated by the IRAC. A CR = complete disappearance of disease and related symptoms. Lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and \> 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on exam, normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. 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 and hepatic nodules regressed by ≥ 50% in their SPD or for single nodules, in the greatest transverse diameter;no new disease.
Time frame: From the date of randomization to the data cut-off of 4 July 2013; when all patients reached the scheduled 16-week assessment or had progressed/died before the scheduled 16-week assessment); the median study duration was 27.0 and 19.7 weeks, respectively.
Population: The Modified Intent to Treat (mITT) population was defined as all participants randomized who had a diffuse large B-cell lymphoma (DLBCL) diagnosis and either germinal center B-cell subtype (GCB) or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenalidomide | Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | ORR for All Participants | 27.5 percentage of participants |
| Lenalidomide | Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | GCB Subtype | 26.1 percentage of participants |
| Lenalidomide | Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | Non-GCB | 28.6 percentage of participants |
| Investigators Choice (IC) | Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | GCB Subtype | 12.0 percentage of participants |
| Investigators Choice (IC) | Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | Non-GCB | 11.5 percentage of participants |
| Investigators Choice (IC) | Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC) | ORR for All Participants | 11.8 percentage of participants |
Comparison: Pertains to all participants; row 1p-value: 0.079Fisher Exact
Comparison: Pertains to GCB Subtype; row 2p-value: 0.279Fisher Exact
Comparison: Pertains to non-GCB Sub-type; row 3p-value: 0.179Fisher Exact
Primary
Stage 1: Percentage of Participants With an Overall Response According to the IWG Response Criteria Based on the Investigators Assessment at the Final Data Cut During the Core Treatment Phase
Response was defined as having a CR, CRu or PR, based on IWG 1999 Response Criteria for NHL as evaluated by the investigators. CR = complete disappearance of disease and disease related symptoms. All lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes \> 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and \> 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical exam, normal size by imaging, and absence of nodules related to lymphoma. If BM was involved prior to therapy, infiltrate must have cleared on repeat biopsy. 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 the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new disease.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: mITT was defined as all participants randomized who had a DLBCL diagnosis confirmed by central pathology, had either GCB or non-GCB subtype and received at least one dose of study drug or investigators choice regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Stage 1: Percentage of Participants With an Overall Response According to the IWG Response Criteria Based on the Investigators Assessment at the Final Data Cut During the Core Treatment Phase | 29.4 Percentage of participants |
| Investigators Choice (IC) | Stage 1: Percentage of Participants With an Overall Response According to the IWG Response Criteria Based on the Investigators Assessment at the Final Data Cut During the Core Treatment Phase | 13.7 Percentage of participants |
Comparison: Pertains to all participantsp-value: 0.091Fisher Exact
Secondary
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment
A TEAE was defined as an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: * Death; * Life-threatening event; * Any inpatient hospitalization or prolongation of existing hospitalization; * Persistent or significant disability or incapacity; * Congenital anomaly or birth defect; * Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event.The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.03) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death
Time frame: From first dose of study drug to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: Safety Population included all participants who received at least one dose of lenalidomide or IC regimen.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAEs | 54 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE | 49 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade ≥ 3 | 43 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade ≥ 4 | 29 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade 3 or 4 | 42 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE Grade ≥ 3 | 30 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE Grade 5 | 0 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE Grade 3 or 4 | 30 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Serious Adverse Events (SAEs) | 31 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any AE leading to stopping of study drug | 11 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any drug related AE leading to halt of study drug | 5 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any AE leading to dose interruption/reduct | 32 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade 5 | 9 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAEs Grade ≥ 4 | 15 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treated Related SAEs | 14 Participants |
| Lenalidomide | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any drug related AE leading to interruption/reduct | 27 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treated Related SAEs | 21 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAEs | 55 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE Grade 3 or 4 | 39 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any AE leading to stopping of study drug | 17 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade ≥ 3 | 53 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any drug related AE leading to halt of study drug | 4 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade 5 | 18 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAEs Grade ≥ 4 | 21 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade 3 or 4 | 52 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any AE leading to dose interruption/reduct | 34 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE Grade ≥ 3 | 39 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any drug related AE leading to interruption/reduct | 30 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE Grade 5 | 2 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Treatment Related TEAE | 45 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any TEAE Grade ≥ 4 | 36 Participants |
| Investigators Choice (IC) | Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment | Any Serious Adverse Events (SAEs) | 42 Participants |
Secondary
Stage 2: Duration of Complete Response
Length of time of complete response (Complete Response + Complete Response unconfirmed) based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999).
Time frame: Approximately 3.5 years
Population: Duration of CR was not analyzed; the Stage 1 results as assessed by the independent response adjudication committee (IRAC), demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Secondary
Stage 2: Duration of Response (DoR)
Length of time of overall response (Complete Response + Complete Response unconfirmed + Partial Response) based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999).
Time frame: Approximately 3.5 years
Population: DoR not analyzed; the Stage 1 results as assessed by the independent response adjudication committee (IRAC), demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Secondary
Stage 2: Health Related Quality of Life Questionnaires
Quality of Life based on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EQ-5D assessments
Time frame: Approximately 3.5 years
Population: Health Related Quality of Life Instruments were not analyzed; the Stage 1 results as assessed by the IRAC, demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Secondary
Stage 2: Overall Response Rate for With a Duration of Response Lasting ≥ 16 Weeks
Complete Response + Complete Response unconfirmed + Partial Response for participants with a duration of response lasting ≥ 16 weeks based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999).
Time frame: Approximately 3.5 years
Population: Overall Response Rate for with a Duration of Response Lasting ≥ 16 weeks was not analyzed: the Stage 1 results as assessed by the IRAC, demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Secondary
Stage 2: Overall Response Rate (ORR)
ORR is defined as: Complete Response + Complete Response unconfirmed + Partial Response based on the International Lymphoma Workshop Response Criteria \[IWRC\] (Cheson 1999).
Time frame: Approximately 3.5 years
Population: ORR not analyzed; the Stage 1 results as assessed by the independent response adjudication committee (IRAC), demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Secondary
Stage 2: Overall Survival (OS)
Overall survival was defined as time from randomization until death of any cause.
Time frame: Approximately 3.5 years
Population: OS not analyzed; the Stage 1 results as assessed by the independent response adjudication committee (IRAC), demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Secondary
Stage 2: Time to Progression
Length of time until disease progression occurs
Time frame: Approximately 3.5 years
Population: Time to progression was not analyzed; the Stage 1 results as assessed by the IRAC, demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.
Other Pre-specified
Stage 1: Kaplan Meier Estimates of Duration of Complete Response (DoCR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase
Duration of complete response was defined as the time from the first documented complete response (CR + CRu) until the first disease progression or death for participants who had a CR.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: For DoCR, the population included participants who had a CR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Stage 1: Kaplan Meier Estimates of Duration of Complete Response (DoCR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 66.4 Weeks |
| Investigators Choice (IC) | Stage 1: Kaplan Meier Estimates of Duration of Complete Response (DoCR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 179.3 Weeks |
p-value: 0.972Log Rank
Other Pre-specified
Stage 1: Kaplan Meier Estimates of Duration of Overall Response (DoR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase
Duration of overall response was calculated as the time of initial response (CR+CRu+PR) until documented disease progression determinted by computerized scan CT scan or MRI or death due to lymphoma, whichever occurred earlier, for participants who responded.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: For DoR, the population included participants who had an overall response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Stage 1: Kaplan Meier Estimates of Duration of Overall Response (DoR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 64.7 Weeks |
| Investigators Choice (IC) | Stage 1: Kaplan Meier Estimates of Duration of Overall Response (DoR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 63.1 Weeks |
p-value: 0.529Log Rank
Other Pre-specified
Stage 1: Kaplan Meier Estimates of Overall Survival As Assessed by the Investigators at the Final Data Cut During The Core Treatment Phase
Overall survival was defined as time from randomization until death of any cause.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: mITT was defined as all participants randomized who had a DLBCL diagnosis confirmed by central pathology, had either GCB or non-GCB subtype and received at least one dose of study drug or investigators choice regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Stage 1: Kaplan Meier Estimates of Overall Survival As Assessed by the Investigators at the Final Data Cut During The Core Treatment Phase | 31.0 Weeks |
| Investigators Choice (IC) | Stage 1: Kaplan Meier Estimates of Overall Survival As Assessed by the Investigators at the Final Data Cut During The Core Treatment Phase | 24.6 Weeks |
p-value: 0.211Log Rank
Other Pre-specified
Stage 1: Kaplan Meier Estimates of Progression-Free Survival As Assessed By The Investigators At The Final Data Cut During The Core Treatment Phase
Progression-free survival was defined as the time from randomization to the first documented disease progression or death due to any cause.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: mITT was defined as all participants randomized who had a DLBCL diagnosis confirmed by central pathology, had either GCB or non-GCB subtype and received at least one dose of study drug or investigators choice regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Stage 1: Kaplan Meier Estimates of Progression-Free Survival As Assessed By The Investigators At The Final Data Cut During The Core Treatment Phase | 9.6 Weeks |
| Investigators Choice (IC) | Stage 1: Kaplan Meier Estimates of Progression-Free Survival As Assessed By The Investigators At The Final Data Cut During The Core Treatment Phase | 7.1 Weeks |
p-value: 0.02Log Rank
Other Pre-specified
Stage 1: Percentage of Participants With a Complete Response According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase
A complete response was defined as participants with a complete response (CR), or unconfirmed complete response (CRu) based on IWG 1999 Response Criteria for NHL as assessed by the investigator. A CR is a complete disappearance of all disease with the exception of nodes. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRu) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: mITT was defined as all participants randomized who had a DLBCL diagnosis confirmed by central pathology, had either GCB or non-GCB subtype and received at least one dose of study drug or investigators choice regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Stage 1: Percentage of Participants With a Complete Response According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 13.7 percentage of participants |
| Investigators Choice (IC) | Stage 1: Percentage of Participants With a Complete Response According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 3.9 percentage of participants |
Comparison: Pertains to all participants; row 1p-value: 0.16Fisher Exact
Other Pre-specified
Stage 1: Percentage of Participants With a Durable Overall Response (dORR) According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase
Durable overall response rate was defined as the percentage of participants who maintained a response for at least 16 weeks after initial response.
Time frame: From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Population: mITT was defined as all participants randomized who had a DLBCL diagnosis confirmed by central pathology, had either GCB or non-GCB subtype and received at least one dose of study drug or investigators choice regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Stage 1: Percentage of Participants With a Durable Overall Response (dORR) According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 23.5 percentage of participants |
| Investigators Choice (IC) | Stage 1: Percentage of Participants With a Durable Overall Response (dORR) According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase | 9.8 percentage of participants |
p-value: 0.109Fisher Exact
Other Pre-specified
Stage 2: Progression-Free Survival
Number of participants who survive without progressing based on the International Working Group Response Criteria \[IWG\].
Time frame: Approximately 3.5 years
Population: PFS not analyzed; the Stage 1 results as assessed by the independent response adjudication committee (IRAC), demonstrated that neither subtype met the pre-specified requirement to be further studied in Stage 2. Study terminated after Stage 1 completed and before Stage 2 started.