Trial Outcomes & Findings for Study of Lenalidomide to Evaluate Safety and Effectiveness in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) (NCT NCT01197560)

NCT ID: NCT01197560

Last Updated: 2019-11-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

111 participants

Primary outcome timeframe

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.

Results posted on

2019-11-25

Participant Flow

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.

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)

Participant milestones

Participant milestones
Measure	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.	Investigators Choice (Control Arm) 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. Participants with documented progressive disease had the option to receive crossover lenalidomide at the same dosage as participants randomized to lenalidomide.
Overall Study STARTED	54	57
Overall Study Received ≥ One Dose Study Drug	54	55
Overall Study Lenalidomide Crossover	0	29
Overall Study Discontinued Treatment After ≥ 6 Cycles	14	0
Overall Study COMPLETED	0	4
Overall Study NOT COMPLETED	54	53

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	Investigators Choice (Control Arm) 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. Participants with documented progressive disease had the option to receive crossover lenalidomide at the same dosage as participants randomized to lenalidomide.
Overall Study Adverse Event	6	8
Overall Study Death	3	5
Overall Study Withdrawal by Subject	1	1
Overall Study Disease progression	40	35
Overall Study Miscellaneous	4	3
Overall Study Missing	0	1

Baseline Characteristics

The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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	Total n=102 Participants Total of all reporting groups
Age, Continuous	64.7 years STANDARD_DEVIATION 13.43 • n=5 Participants	62.8 years STANDARD_DEVIATION 13.94 • n=7 Participants	63.75 years STANDARD_DEVIATION 13.69 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	20 Participants n=7 Participants	41 Participants n=5 Participants
Sex: Female, Male Male	30 Participants n=5 Participants	31 Participants n=7 Participants	61 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Black/African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	38 Participants n=5 Participants	36 Participants n=7 Participants	74 Participants n=5 Participants
Race/Ethnicity, Customized Missing	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Race/Ethnicity, Customized Other (Unspecified)	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Eastern Cooperative Oncology Performance Status (ECOG)] 0 = (Fully Active)	18 Participants n=5 Participants	15 Participants n=7 Participants	33 Participants n=5 Participants
Eastern Cooperative Oncology Performance Status (ECOG)] 1 (Restrictive but Ambulatory)	24 Participants n=5 Participants	28 Participants n=7 Participants	52 Participants n=5 Participants
Eastern Cooperative Oncology Performance Status (ECOG)] 2 (Ambulatory but Unable to Work)	7 Participants n=5 Participants	8 Participants n=7 Participants	15 Participants n=5 Participants
Eastern Cooperative Oncology Performance Status (ECOG)] 3 (Limited Self-Care)	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Eastern Cooperative Oncology Performance Status (ECOG)] 4 (Completely Disabled)	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Eastern Cooperative Oncology Performance Status (ECOG)] Missing	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Creatinine Clearance (CrCl) ≥ 60 mL/min	32 Participants n=5 Participants	43 Participants n=7 Participants	75 Participants n=5 Participants
Creatinine Clearance (CrCl) ≥ 30 but < 60 mL/min	18 Participants n=5 Participants	7 Participants n=7 Participants	25 Participants n=5 Participants
Creatinine Clearance (CrCl) Missing	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IA	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IB	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IIA	8 Participants n=5 Participants	7 Participants n=7 Participants	15 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IIB	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IIIA	13 Participants n=5 Participants	13 Participants n=7 Participants	26 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IIIB	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IVA	17 Participants n=5 Participants	14 Participants n=7 Participants	31 Participants n=5 Participants
Disease Stage of DLBCL at Enrollment IVB	6 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants
Diffuse Large B-Cell Lymphoma (DLBCL) Subtypes - Germinal Center B-Cell (GCB) and non-GCB Germinal Center B-Cell Type	23 Participants n=5 Participants • The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).	25 Participants n=7 Participants • The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).	48 Participants n=5 Participants • The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).
Diffuse Large B-Cell Lymphoma (DLBCL) Subtypes - Germinal Center B-Cell (GCB) and non-GCB Non-Germinal Center B-Cell Type	28 Participants n=5 Participants • The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).	26 Participants n=7 Participants • The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).	54 Participants n=5 Participants • The Modified Intent to Treat (mITT ) population was defined as all participants randomized who had a DLBCL diagnosis and either Germinal Center B-cell subtype or non-GCB subtype confirmed by central pathology, and who received at least one dose of study drug (lenalidomide or investigator's choice).

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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
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 Interval 15.9 to 41.7	11.8 percentage of participants Interval 4.4 to 23.9
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 Interval 10.2 to 48.4	12.0 percentage of participants Interval 2.5 to 31.2
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 Interval 13.2 to 48.7	11.5 percentage of participants Interval 2.4 to 30.2

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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
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 Interval 17.5 to 43.8	13.7 Percentage of participants Interval 5.7 to 26.3

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Lenalidomide n=54 Participants 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.	Investigators Choice (IC) n=55 Participants 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
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any TEAEs	54 Participants	55 Participants
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any Treatment Related TEAE	49 Participants	45 Participants
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any TEAE Grade ≥ 3	43 Participants	53 Participants
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any TEAE Grade ≥ 4	29 Participants	36 Participants
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any TEAE Grade 5	9 Participants	18 Participants
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	52 Participants
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	39 Participants
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	21 Participants
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	2 Participants
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	39 Participants
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any Serious Adverse Events (SAEs)	31 Participants	42 Participants
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment Any Treated Related SAEs	14 Participants	21 Participants
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	17 Participants
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	4 Participants
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	34 Participants
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	30 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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
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 Interval 12.8 to 37.5	9.8 percentage of participants Interval 3.3 to 21.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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
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 Interval 5.7 to 26.3	3.9 percentage of participants Interval 0.5 to 13.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=15 Participants 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.	Investigators Choice (IC) n=7 Participants 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
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 Interval 29.1 to 141.6	63.1 Weeks Interval 15.3 to 79.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=7 Participants 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.	Investigators Choice (IC) n=2 Participants 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
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 Interval 22.1 to No estimable due to that the estimated upper 97.5% survival curve does not reach 50%.	179.3 Weeks Interval 63.1 to 295.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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
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 Interval 7.6 to 17.1	7.1 Weeks Interval 6.0 to 8.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Lenalidomide n=51 Participants 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.	Investigators Choice (IC) n=51 Participants 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
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 Interval 16.6 to 43.7	24.6 Weeks Interval 12.7 to 34.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Number of participants who survive without progressing based on the International Working Group Response Criteria \[IWG\].

Outcome measures

Outcome data not reported

Adverse Events

Lenalidomide

Serious events: 31 serious events

Other events: 53 other events

Deaths: 48 deaths

Investigator's Choice

Serious events: 42 serious events

Other events: 52 other events

Deaths: 51 deaths

Serious adverse events

Other adverse events

Additional Information

Anne McClain

Celgene

Phone: 1-888-260-1599

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 days. Investigator must delete confidential information before submission or defer publication to permit patent applications.
Publication restrictions are in place

Restriction type: OTHER