A Study to Determine the Efficacy and Safety of Lenalidomide in Patients With Mantle Cell NHL Who Have Relapsed or Progressed After Treatment With Bortezomib or Are Refractory to Bortezomib. The "EMERGE" Trial

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00737529
• Collaborator: (none)
• Enrollment: 134
• Locations: 70
• Arm: 1
• Actual Duration (Months): 106.5
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To evaluate the safety and efficacy of Lenalidomide (Revlimid (R)) in subjects with mantle cell lymphoma who have relapsed, progressed or are refractory to bortezomib.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: lenalidomide	Phase 2

Detailed Description

Follow up phase will continue until either 100% of the patients have died, are lost to follow up or have withdrawn consent or a maximum of 4 years from the last patient enrolled, whichever comes first. All other efficacy and safety endpoints will be updated at this time. In the unlikely event that the study will be closed and patients are still responding to treatment at this time, Celgene will discuss with the treating physicians options to provide further treatment to the patient after study closure in line with local regulation.

Follow up for second primary malignancies and OS will continue until 100% of the patients have died, are lost to follow up, have withdrawn consent, or a maximum of 5 years from the last patient enrolled, whichever comes first.

10 October 2017: In regard to the last subject last visit date/study completion date, the prolongation of timelines is due to the bridging of a treatment gap for a patient responding to study medication until non-study medication is available.

Study Design

• Study Type: Interventional
• Actual Enrollment: 134 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Single-Arm, Open-Label Study To Determine The Efficacy And Safety Of Single-Agent Lenalidomide (Revlimid®) In Patients With Mantel Cell NHL Who Have Relapsed Or Progressed After Treatment With Bortezomib Or Are Refractory To Bortezomib
• Actual Study Start Date: Dec 22, 2008
• Actual Primary Completion Date: Apr 6, 2016
• Actual Study Completion Date: Nov 8, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lenalidomide Single agent Lenalidomide Lenalidomide: 10mg or 25 mg oral capsules on days 1 to 21 of each 28 day cycle and dependent on renal function; Participants with normal renal function (defined as Creatinine Clearance(CrCl)) of ≥ 60 mL/min in this study) received 25 mg of lenalidomide daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10-mg dose. Participants could continue to receive treatment until disease progression, development of unacceptable AEs, or voluntary withdrawal.

Drug: lenalidomide; 25mg oral capsules continuous days 1-21 each of a 28 day cycle; Other Names: Revlimid

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieved an Overall Response According to the Independent Review Committee (IRC) [From Day 1 of study treatment to progession or early treatment discontinuation; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days.]

   Overall Response Rate (ORR) was defined as the percentage of participants whose best response was Complete Response, Complete Response unconfirmed or Partial Response. Participants who had discontinued before any response has been observed, or changed to other anti-lymphoma treatments before response had been observed, were considered as non-responders. Tumor Response was assessed by a modification of the International Lymphoma Workshop Response Criteria, IWRC, Cheson, 1999); CR is defined as the disappearance of all clinical and radiographic evidence of disease; CRu is defined as a CR, with a 1) residual lymph node mass >1.5 cm that has decreased by 75% in the sum of the product of the diameters (SPD). Individual nodes previously confluent decreased by more than 75% in the SPD compared with original mass; 2) indeterminate bone marrow; PR = is defined ≥50% decrease in 6 largest nodes or nodal masses.

2. Kaplan Meier Estimate of Duration of Response (DoR) According to the Independent Review Committee [From Day 1 of study drug to progression or early treatment discontinuation; up to data cut-off date of 06 April 2016; Median duration of treatment was 94.5 days.]

   Kaplan Meier estimate for the duration of response (DoR) was calculated from the date of the first occurrence of initial response for responders (demonstrating evidence of at least a PR) to the date of first documented disease progression (any new lesion or increase by ≥ 50% of previously involved sites from nadir) or death (without documented progression) for participants who responded; participants who had not progressed (or died) were censored at the last valid assessment.

Secondary Outcome Measures

1. Percentage of Participants With a Complete Response (CR) /Complete Response Unconfirmed (CRu) According to the Independent Review Committee [From Day 1 of study drug to progression or early treatment discontinuation; up to data cut-off date of 06 April 2016; Median duration of treatment was 94.5 days]

   The percentage of participants whose best response was CR or CRu. Participants who had discontinued before CR/CRu was observed, or changed to other anti-lymphoma treatments before a CR/CRu response had been observed, were considered as non-responders. CR is defined as the disappearance of all clinical and radiographic evidence of disease; CRu is defined as a CR, with a 1) residual lymph node mass >1.5 cm that has decreased by 75% in the sum of the product of the diameters (SPD). Individual nodes previously confluent decreased by more than 75% in the SPD compared with original mass; 2) indeterminate bone marrow.

2. Kaplan Meier Estimate of Duration of Complete Response (DoCR) (CR+CRu) According to the Independent Review Committee [From Day 1 of study drug to progression or early discontinuation; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months]

   Kaplan Meier estimates for the duration of CR/CRu was calculated from the date of the first occurrence of CR/CRu to the date of documented disease progression or death (without documented progression) for participants who obtained a CR/CRu; participants who had not progressed (or died) were censored at the last valid assessment.

3. Kaplan-Meier Estimate of Progression-Free Survival (PFS) According to the Independent Review Committee [From Day 1 of study drug to first documented date of disease progression; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months]

   Kaplan Meier estimates of PFS was defined as the start of study drug therapy to the first observation of disease progression or death due to any cause, whichever comes first. If a participant had not progressed or died, PFS was censored at the time of last adequate assessment when the participant was known not to have progressed. For participants who received other anti-lymphoma therapy with no evidence of progression, PFS was censored at time of last adequate tumor assessment with no evidence of progression prior to the start of new anti-lymphoma treatment.

4. Kaplan Meier Estimate of Time to Progression (TTP) According to the Independent Review Committee [From Day 1 of study drug to first documented time of progression; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months]

   Kaplan Meier estimate of time to progression was calculated as time from the start of the study drug therapy to the first observation of disease progression. Participants who died without progression were censored at the date of death; otherwise, the censoring rules presented above for PFS applied to the analysis of TTP. Progressive Disease(PD): Appearance of new lesion or increase by ≥50% from previously involved sites from nadir

5. Kaplan-Meier Estimate of Time to Treatment Failure (TTF) According to the Independent Review Committee [From Day 1 of study drug to first documented time of treatment failure; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days]

   Time to treatment failure (TTF) was calculated from the start of study drug therapy to early discontinuation from treatment due to any cause, including disease progression, toxicity, or death and was based on site-reported data.

6. Time to Response (TTR) [From Day 1 of study drug to time of first documented PR or better; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days]

   Time to Response was defined as the time from first dose of study drug to the date of the first response (having at least a PR) and was calculated only for responding participants.

7. Time to Complete Response (CR+CRu) According to the Independent Review Committee [From Day 1 of study drug to first documented CR/CRu or better; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days]

   Time to Complete Response (CR+CRu) was defined as the time from the first dose of study drug to the date of the first occurrence of at least CRu and was calculated only for participants with CR or CRu.

8. Overall Survival (OS) [From Day 1 of study drug to first documented date of progressive disease or death; up to the final data cut-off date of 30 March 2017; median duration of follow-up for surviving participants was 62.94 months]

   Kaplan Meier estimate of overall survival was calculated from the time the first dose of study drug to death from any cause. Participants who had not died were censored at the last date the participant was known to be alive.

9. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From the first dose of lenalidomide through 28 days after the last dose during the follow-up phase; median (minimum, maximum) duration of treatment was 94.0 (1.0, 1950 days)]

   Adverse events were assessed using National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3: according to the following scale: Grade 1 = Mild Adverse Event (AE), Grade 2 = Moderate AE, Grade 3 = Severe and Undesirable AE, Grade 4 = Life-threatening or Disabling AE, and Grade 5 = Death; Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. after the first dose of study drug and within 28 days after the last dose. A TEAE is defined as any AE occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Biopsy proven mantle cell lymphoma

• Patients must have documents relapsed, refractory or PD after treatment with bortezomib

• Must have measureable disease on cross sectional imaging by CT

• Eastern Cooperative Oncology Group (ECOG) performance score 0,1 or 2

• Willing to follow pregnancy precautions

Exclusion Criteria:

• Any of the following laboratory abnormalities

• Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L)

• Platelet count < 60,000/mm3 (60 x 109/L)

• Serum aspartate transaminase/Serum glutamic oxaloacetic transaminase(AST/SGOT) or alanine transaminase/Serum glutamic pyruvic transaminase (ALT/SGPT) > 3.0 x upper limit of normal (ULN), except in patients with documented liver involvement by lymphoma.

• Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert's Syndrome and documented liver involvement by lymphoma.

• Calculated creatinine clearance (Cockcroft-Gault formula) of < 30 mL /min

• Patients who are candidates for high dose chemotherapy/allogeneic stem cell transplant are not eligible

• History of active central nervous system (CNS) lymphoma within the previous 3 months

• Subjects not willing or unable to take deep vein thrombosis (DVT) prophylaxis

• Prior history of malignancies, other than MCL, unless the patient has been free of the disease for ≥ 3 years

• Positive Human immunodeficiency virus (HIV) or active Hepatitis B or C

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
2	UCSD Moores Cancer Center	La Jolla	California	United States	92093
3	Loma Linda University Medical Center	Loma Linda	California	United States	92354
4	Tower Cancer Research Foundation	Los Angeles	California	United States	90211
5	Boca Raton Community Hospital, Inc., Research Dept.	Boca Raton	Florida	United States	33486
6	Pasco Hernando Oncology Associates, PA	Brooksville	Florida	United States	34613
7	Broward General Medical Center	Fort Lauderdale	Florida	United States	33316
8	MD Anderson Cancer Center, Orlando Regional Healthcare	Orlando	Florida	United States	32806
9	Lake County Oncology and Hematology	The Villages	Florida	United States	32159
10	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
11	Northwestern University	Chicago	Illinois	United States	60611
12	Loyola University Medical Center - Smith	Maywood	Illinois	United States	60153
13	Indiana University Cancer Center	Indianapolis	Indiana	United States	46202
14	Alvin and Lois Lapidus Cancer Institute Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
15	Tufts Medical Center	Boston	Massachusetts	United States	02111
16	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
17	University of Massachusetts Medical Center	Worcester	Massachusetts	United States	01655
18	Karmanos Cancer Institute	Detroit	Michigan	United States	48201-2014
19	Mayo Clinic	Rochester	Minnesota	United States	55905
20	Washington University Siteman Cancer Center	Saint Louis	Missouri	United States	63110
21	University of Nebraska	Omaha	Nebraska	United States	68198-7680
22	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
23	NYU School of Medicine	New York	New York	United States	10016
24	University of Rochester Cancer Center, James P. Wilmot Cancer Center	Rochester	New York	United States	14642
25	Presbyterian Hospital	Charlotte	North Carolina	United States	28204
26	Temple University School of Medicine	Philadelphia	Pennsylvania	United States	19140
27	Hillman Cancer Institute at UPMC	Pittsburgh	Pennsylvania	United States	15232
28	South Carolina Cancer Specialists	Hilton Head Island	South Carolina	United States	29926
29	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
30	University of Tennessee Cancer Institute	Memphis	Tennessee	United States	38104
31	University of Virginia Cancer Center Clinical Trials Office	Charlottesville	Virginia	United States	22908
32	Universitaetsklinik Innsbruck	Innsbruck		Austria	6020
33	Landeskrankenhaus Salzburg	Salzburg		Austria	5020
34	Medical University of Vienna	Vienna		Austria	1090
35	AZ Sint-Jan AV Brugge	Brugge		Belgium	8000
36	UZ Gent	Gent		Belgium	9000
37	Universitair Ziekenhuis Leuven, Campus Gasthuisberg	Leuven		Belgium	3000
38	Hospital Universitario San Ignacio	Bogota		Colombia
39	Oncologos del occidente S.A.	Pereira		Colombia
40	Hopital Sud, CHU d'Amiens	Amiens		France	80054
41	Institut Bergonie	Bordeaux		France	33076
42	Hopital Henri Mondor	Créteil		France	94010
43	Hopital Emile Muller	Mulhouse		France	68070
44	Hopital Cochin	Paris		France	75014
45	Institut Curie	Paris		France	75248
46	Hopital Robert Debre	Reims Cedex		France	51092
47	Institut de Cancerologie de la Loire	Saint Jean Priest En Jarez		France	42277
48	Hopital Hautepierre	Strasbourg		France	67098
49	University Hospital Wuerzburg	Wuerzburg		Germany	97080
50	Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum	Debrecen		Hungary	4032
51	University of Debrecen, DEOEC, Institute of Internal Medicine	Debrecen		Hungary	4032
52	Petz Aladar Megyei Oktato Korhaz,II. Belgyogyaszat	Gyor		Hungary	9024
53	Kaposi Mor Oktato Korhaz	Kaposvar		Hungary	7400
54	Rambam Medical Center	Haifa		Israel	35254
55	Hadassah Medical Center	Jerusalem		Israel	91120
56	Rabin Medical Center	Petch Tikva		Israel	49100
57	Sheba Medical Center	Tel Hashomer		Israel	52621
58	Universita Federico II di Napoli Nuovo Policlinico	Napoli		Italy	80131
59	Ospedale Civile dello Spirito Santo	Pescara		Italy	65124
60	Universita Cattololica del Sacro Cuore	Roma		Italy	00168
61	Centro De Cancer, Hospital Espanol Auxilio De Puerto Rico	San Juan		Puerto Rico	00919
62	Singapore General Hospital	Singapore		Singapore	169608
63	Hospital General De Elche	Alicante		Spain	03203
64	Duran i Reynals Institut Catala d'Oncologia	L'Hospitalet de Llobregat		Spain	08907
65	Hospital Clinico Universitario de Salamanca	Salamanca		Spain	37003
66	Hospital Universitario La Fe	Valencia		Spain	46009
67	Gazi Universitesi	Besevler Ankara		Turkey	06500
68	Istanbul Universitesi Istanbul	Istanbul		Turkey	34390
69	Ankara Universitesi Tip Fakultesi	Sihhiye Ankara		Turkey	06100
70	Royal Cornwall Hospitals Trust	Truro		United Kingdom	TR1 3LJ

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Lei Zhang, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Publications

• Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, Zhang L, Cicero S, Fu T, Witzig TE. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013 Oct 10;31(29):3688-95. doi: 10.1200/JCO.2013.49.2835. Epub 2013 Sep 3.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00737529
• Other Study ID Numbers: CC-5013-MCL-001
• First Posted: Aug 19, 2008
• Last Update Posted: Dec 13, 2018
• Last Verified: Dec 1, 2018

• Keywords provided by Celgene: Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; CC-5013; Revlimid; Lenalidomide
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Lenalidomide

Study Results

Participant Flow

Recruitment Details	Participants were enrolled and treated at 42 centers in 12 countries: US/ Puerto Rico, France, Israel, Belgium, Spain, Turkey, Austria, Hungary, Italy, Colombia, Germany, and Singapore.
Pre-assignment Detail	All participants were required to have local histologic confirmation of Mantle Cell Lymphoma (MCL) for entry into the study.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Period Title: Overall Study
STARTED	134
COMPLETED	1
NOT COMPLETED	133

Baseline Characteristics

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Overall Participants	134
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	67.2 (8.38)
Age, Customized (Count of Participants)
<65	49 36.6%
≥ 65	85 63.4%
Sex: Female, Male (Count of Participants)
Female	26 19.4%
Male	108 80.6%
Race/Ethnicity, Customized (Count of Participants)
White or Caucasian	128 95.5%
Asian	3 2.2%
Black or African American	1 0.7%
Other	2 1.5%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 = (Fully Active)	43 32.1%
1 = (Restrictive but ambulatory)	73 54.5%
2 = (Ambulatory but unable to work)	17 12.7%
3 = (Limited self care)	1 0.7%
4 = (Completely Disabled)	0 0%
Renal function at baseline (Count of Participants)
Normal (CrCl > = 60 mL/min)	99 73.9%
Moderate Renal Insufficiency (CrCl ≥ 30 and < 60mL	28 20.9%
Severe Renal Insufficiency (CrCl < 30 mL/min)	1 0.7%
Missing	6 4.5%
Duration of Mantle Cell Lymphoma (years) [Number]
<3 years	52
≥ 3 years	82
MCL (Ann Arbor) Stage at Diagnosis (Count of Participants)
I	2 1.5%
II	5 3.7%
III	19 14.2%
IV	105 78.4%
Missing	3 2.2%
MCL International Prognostic Index (MIPI) Score Group at Enrollment (Count of Participants)
Low	39 29.1%
Intermediate	51 38.1%
High	39 29.1%
Missing	5 3.7%
Prior Bone Marrow Assessment (Count of Participants)
Positive	55 41%
Negative	52 38.8%
Indeterminate	8 6%
Missing	19 14.2%
Tumor Burden (Count of Participants)
High = having 1 lesion ≥ 5 cm or 3 lesions ≥ 3cm	78 58.2%
Low = < 5cm lesions	54 40.3%
Missing = unable to characterize	2 1.5%
Bulky Disease (Count of Participants)
Yes	44 32.8%
No	88 65.7%
Missing	2 1.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved an Overall Response According to the Independent Review Committee (IRC)
Description	Overall Response Rate (ORR) was defined as the percentage of participants whose best response was Complete Response, Complete Response unconfirmed or Partial Response. Participants who had discontinued before any response has been observed, or changed to other anti-lymphoma treatments before response had been observed, were considered as non-responders. Tumor Response was assessed by a modification of the International Lymphoma Workshop Response Criteria, IWRC, Cheson, 1999); CR is defined as the disappearance of all clinical and radiographic evidence of disease; CRu is defined as a CR, with a 1) residual lymph node mass >1.5 cm that has decreased by 75% in the sum of the product of the diameters (SPD). Individual nodes previously confluent decreased by more than 75% in the SPD compared with original mass; 2) indeterminate bone marrow; PR = is defined ≥50% decrease in 6 largest nodes or nodal masses.
Time Frame	From Day 1 of study treatment to progession or early treatment discontinuation; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days.

Outcome Measure Data

Analysis Population Description

ITT population defined as all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Number (95% Confidence Interval) [percentage of participants]	29.9 22.3%

2. Primary Outcome

Title	Kaplan Meier Estimate of Duration of Response (DoR) According to the Independent Review Committee
Description	Kaplan Meier estimate for the duration of response (DoR) was calculated from the date of the first occurrence of initial response for responders (demonstrating evidence of at least a PR) to the date of first documented disease progression (any new lesion or increase by ≥ 50% of previously involved sites from nadir) or death (without documented progression) for participants who responded; participants who had not progressed (or died) were censored at the last valid assessment.
Time Frame	From Day 1 of study drug to progression or early treatment discontinuation; up to data cut-off date of 06 April 2016; Median duration of treatment was 94.5 days.

Outcome Measure Data

Analysis Population Description

Includes participants from the ITT population who achieved a PR or better.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	40
Median (95% Confidence Interval) [months]	16.64

3. Secondary Outcome

Title	Percentage of Participants With a Complete Response (CR) /Complete Response Unconfirmed (CRu) According to the Independent Review Committee
Description	The percentage of participants whose best response was CR or CRu. Participants who had discontinued before CR/CRu was observed, or changed to other anti-lymphoma treatments before a CR/CRu response had been observed, were considered as non-responders. CR is defined as the disappearance of all clinical and radiographic evidence of disease; CRu is defined as a CR, with a 1) residual lymph node mass >1.5 cm that has decreased by 75% in the sum of the product of the diameters (SPD). Individual nodes previously confluent decreased by more than 75% in the SPD compared with original mass; 2) indeterminate bone marrow.
Time Frame	From Day 1 of study drug to progression or early treatment discontinuation; up to data cut-off date of 06 April 2016; Median duration of treatment was 94.5 days

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Number (95% Confidence Interval) [percentage of participants]	9.0 6.7%

4. Secondary Outcome

Title	Kaplan Meier Estimate of Duration of Complete Response (DoCR) (CR+CRu) According to the Independent Review Committee
Description	Kaplan Meier estimates for the duration of CR/CRu was calculated from the date of the first occurrence of CR/CRu to the date of documented disease progression or death (without documented progression) for participants who obtained a CR/CRu; participants who had not progressed (or died) were censored at the last valid assessment.
Time Frame	From Day 1 of study drug to progression or early discontinuation; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months

Outcome Measure Data

Analysis Population Description

Includes participants from the ITT population who achieved a CRu or better.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	12
Median (95% Confidence Interval) [months]	24.43

5. Secondary Outcome

Title	Kaplan-Meier Estimate of Progression-Free Survival (PFS) According to the Independent Review Committee
Description	Kaplan Meier estimates of PFS was defined as the start of study drug therapy to the first observation of disease progression or death due to any cause, whichever comes first. If a participant had not progressed or died, PFS was censored at the time of last adequate assessment when the participant was known not to have progressed. For participants who received other anti-lymphoma therapy with no evidence of progression, PFS was censored at time of last adequate tumor assessment with no evidence of progression prior to the start of new anti-lymphoma treatment.
Time Frame	From Day 1 of study drug to first documented date of disease progression; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population defined as all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Median (95% Confidence Interval) [months]	4.01

6. Secondary Outcome

Title	Kaplan Meier Estimate of Time to Progression (TTP) According to the Independent Review Committee
Description	Kaplan Meier estimate of time to progression was calculated as time from the start of the study drug therapy to the first observation of disease progression. Participants who died without progression were censored at the date of death; otherwise, the censoring rules presented above for PFS applied to the analysis of TTP. Progressive Disease(PD): Appearance of new lesion or increase by ≥50% from previously involved sites from nadir
Time Frame	From Day 1 of study drug to first documented time of progression; up to data cut-off date of 06 April 2016; median time in follow-up was 16.34 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population was defined as all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Median (95% Confidence Interval) [months]	5.46

7. Secondary Outcome

Title	Kaplan-Meier Estimate of Time to Treatment Failure (TTF) According to the Independent Review Committee
Description	Time to treatment failure (TTF) was calculated from the start of study drug therapy to early discontinuation from treatment due to any cause, including disease progression, toxicity, or death and was based on site-reported data.
Time Frame	From Day 1 of study drug to first documented time of treatment failure; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days

Outcome Measure Data

Analysis Population Description

Intent to Treat population was defined as all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Median (95% Confidence Interval) [months]	3.75

8. Secondary Outcome

Title	Time to Response (TTR)
Description	Time to Response was defined as the time from first dose of study drug to the date of the first response (having at least a PR) and was calculated only for responding participants.
Time Frame	From Day 1 of study drug to time of first documented PR or better; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days

Outcome Measure Data

Analysis Population Description

Included participants from the ITT population who achieved a PR or better.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	40
Median (Full Range) [months]	3.5

9. Secondary Outcome

Title	Time to Complete Response (CR+CRu) According to the Independent Review Committee
Description	Time to Complete Response (CR+CRu) was defined as the time from the first dose of study drug to the date of the first occurrence of at least CRu and was calculated only for participants with CR or CRu.
Time Frame	From Day 1 of study drug to first documented CR/CRu or better; up to data cut-off date of 06 April 2016; median duration of treatment was 94.5 days

Outcome Measure Data

Analysis Population Description

Included participants from the ITT population who achieved a CRu or better.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	12
Median (Full Range) [months]	3.9

10. Secondary Outcome

Title	Overall Survival (OS)
Description	Kaplan Meier estimate of overall survival was calculated from the time the first dose of study drug to death from any cause. Participants who had not died were censored at the last date the participant was known to be alive.
Time Frame	From Day 1 of study drug to first documented date of progressive disease or death; up to the final data cut-off date of 30 March 2017; median duration of follow-up for surviving participants was 62.94 months

Outcome Measure Data

Analysis Population Description

Intent to Treat population defined as all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Median (95% Confidence Interval) [months]	19.50

11. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	Adverse events were assessed using National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3: according to the following scale: Grade 1 = Mild Adverse Event (AE), Grade 2 = Moderate AE, Grade 3 = Severe and Undesirable AE, Grade 4 = Life-threatening or Disabling AE, and Grade 5 = Death; Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. after the first dose of study drug and within 28 days after the last dose. A TEAE is defined as any AE occurring or worsening on or after the first dose of study drug and within 28 days after the last dose of study drug.
Time Frame	From the first dose of lenalidomide through 28 days after the last dose during the follow-up phase; median (minimum, maximum) duration of treatment was 94.0 (1.0, 1950 days)

Outcome Measure Data

Analysis Population Description

The safety population received at least one dose of lenalidomide was used for all safety analysis. This was identical to the ITT population.

Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
Measure Participants	134
Any TEAE	132 98.5%
Any TEAE Related to Investigational Product (IP)	118 88.1%
Any TEAE Grade 3-5 AE	106 79.1%
Any TEAE Grade 3 AE	101 75.4%
Any TEAE Grade 4 AE	57 42.5%
Any TEAE Grade 5 AE	18 13.4%
Any Grade 3-5 AE Related to IP	90 67.2%
Any Grade 3 AE Related to IP	88 65.7%
Any Grade 4 AE Related to IP	41 30.6%
Any Grade 5 AE Related to IP	2 1.5%
Any TEAE Serious Adverse Event (SAE)	70 52.2%
Any SAE Related to IP	30 22.4%
Any TEAE Leading to Stopping of IP	28 20.9%
Any Treatment Related AE Leading to Stopping IP	16 11.9%
Any AE Leading to Dose Reduction	55 41%
Any AE Leading to IP Interruption	81 60.4%
Any Treatment Related AE Leading to Dose Reduction	52 38.8%
Treatment Related AE Leading to IP Interruption	66 49.3%

Adverse Events

Time Frame	From the first dose of 1enalidomide through 28 days after the last dose of lenalidomide; (maximum duration of study drug was 1940 days).
Arm/Group Title	Lenalidomide
Arm/Group Description	Participants received lenalidomide 10 mg or 25 mg oral capsules on days 1 to 21 of each 28-day cycle and was dependent on renal function; Participants with normal renal function (defined as creatinine clearance (CrCl)) of ≥ 60 mL/min) received 25 mg of lenalidomide by mouth (PO) daily, and those with moderate renal insufficiency (CrCl) ≥ 30 mL/min but < 60 mL/min) were started at a 10 mg daily dose. Participants could continue to receive treatment until disease progression, development of unacceptable adverse events (AEs), or voluntary withdrawal.
All Cause Mortality
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	106/134 (79.1%)
Serious Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	70/134 (52.2%)
Blood and lymphatic system disorders
ANAEMIA	2/134 (1.5%)
FEBRILE NEUTROPENIA	7/134 (5.2%)
LEUKOCYTOSIS	1/134 (0.7%)
LYMPH NODE PAIN	1/134 (0.7%)
LYMPHOCYTOSIS	1/134 (0.7%)
NEUTROPENIA	1/134 (0.7%)
THROMBOCYTOPENIA	2/134 (1.5%)
Cardiac disorders
ATRIAL FIBRILLATION	1/134 (0.7%)
BRADYCARDIA	1/134 (0.7%)
CARDIAC FAILURE CONGESTIVE	2/134 (1.5%)
SUPRAVENTRICULAR TACHYCARDIA	2/134 (1.5%)
Gastrointestinal disorders
ABDOMINAL PAIN	4/134 (3%)
ASCITES	1/134 (0.7%)
CONSTIPATION	1/134 (0.7%)
DIARRHOEA	2/134 (1.5%)
ENTERITIS	1/134 (0.7%)
FAECES DISCOLOURED	1/134 (0.7%)
GASTRIC HAEMORRHAGE	1/134 (0.7%)
GASTROINTESTINAL HAEMORRHAGE	1/134 (0.7%)
INTESTINAL ISCHAEMIA	1/134 (0.7%)
INTRA-ABDOMINAL HAEMORRHAGE	1/134 (0.7%)
LOWER GASTROINTESTINAL HAEMORRHAGE	1/134 (0.7%)
NAUSEA	2/134 (1.5%)
PANCREATITIS	1/134 (0.7%)
VOMITING	2/134 (1.5%)
General disorders
ASTHENIA	3/134 (2.2%)
DEATH	1/134 (0.7%)
GENERAL PHYSICAL HEALTH DETERIORATION	3/134 (2.2%)
MUCOSAL INFLAMMATION	1/134 (0.7%)
NON-CARDIAC CHEST PAIN	1/134 (0.7%)
PYREXIA	6/134 (4.5%)
SUDDEN DEATH	1/134 (0.7%)
Hepatobiliary disorders
CHOLECYSTITIS	1/134 (0.7%)
Infections and infestations
ATYPICAL PNEUMONIA	1/134 (0.7%)
BACTERAEMIA	2/134 (1.5%)
BACTERIAL SEPSIS	1/134 (0.7%)
BRONCHITIS	1/134 (0.7%)
BRONCHOPNEUMONIA	1/134 (0.7%)
BRONCHOPULMONARY ASPERGILLOSIS	2/134 (1.5%)
CELLULITIS	3/134 (2.2%)
CLOSTRIDIUM DIFFICILE COLITIS	2/134 (1.5%)
ENTEROCOCCAL SEPSIS	1/134 (0.7%)
ENTEROCOLITIS INFECTIOUS	1/134 (0.7%)
H1N1 INFLUENZA	1/134 (0.7%)
INFLUENZA	1/134 (0.7%)
LOBAR PNEUMONIA	1/134 (0.7%)
PNEUMONIA	8/134 (6%)
PNEUMONIA BACTERIAL	4/134 (3%)
PNEUMONIA KLEBSIELLA	1/134 (0.7%)
PNEUMONIA STREPTOCOCCAL	2/134 (1.5%)
PSEUDOMONAL SEPSIS	1/134 (0.7%)
RESPIRATORY TRACT INFECTION	1/134 (0.7%)
SEPSIS	3/134 (2.2%)
SEPTIC SHOCK	1/134 (0.7%)
STAPHYLOCOCCAL SEPSIS	2/134 (1.5%)
STREPTOCOCCAL BACTERAEMIA	1/134 (0.7%)
URINARY TRACT INFECTION	3/134 (2.2%)
UROSEPSIS	1/134 (0.7%)
Injury, poisoning and procedural complications
ANKLE FRACTURE	2/134 (1.5%)
FALL	1/134 (0.7%)
SUBDURAL HAEMATOMA	1/134 (0.7%)
Investigations
CREATININE RENAL CLEARANCE DECREASED	1/134 (0.7%)
Metabolism and nutrition disorders
DEHYDRATION	4/134 (3%)
FAILURE TO THRIVE	1/134 (0.7%)
GOUT	1/134 (0.7%)
HYPERCALCAEMIA	1/134 (0.7%)
Musculoskeletal and connective tissue disorders
BACK PAIN	1/134 (0.7%)
MUSCULAR WEAKNESS	3/134 (2.2%)
NECK PAIN	1/134 (0.7%)
PAIN IN EXTREMITY	1/134 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	3/134 (2.2%)
MANTLE CELL LYMPHOMA	6/134 (4.5%)
MENINGIOMA	1/134 (0.7%)
METASTATIC SQUAMOUS CELL CARCINOMA	1/134 (0.7%)
MYELODYSPLASTIC SYNDROME	1/134 (0.7%)
SQUAMOUS CELL CARCINOMA OF SKIN	6/134 (4.5%)
Nervous system disorders
HEADACHE	1/134 (0.7%)
MIGRAINE	1/134 (0.7%)
TRANSIENT GLOBAL AMNESIA	1/134 (0.7%)
Renal and urinary disorders
BLADDER NECK OBSTRUCTION	1/134 (0.7%)
HAEMATURIA	1/134 (0.7%)
RENAL FAILURE	2/134 (1.5%)
URINARY RETENTION	1/134 (0.7%)
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	3/134 (2.2%)
DYSPNOEA	4/134 (3%)
OBSTRUCTIVE AIRWAYS DISORDER	1/134 (0.7%)
PLEURAL EFFUSION	2/134 (1.5%)
PNEUMONITIS	1/134 (0.7%)
PULMONARY EMBOLISM	1/134 (0.7%)
RESPIRATORY DISTRESS	2/134 (1.5%)
RESPIRATORY FAILURE	1/134 (0.7%)
Skin and subcutaneous tissue disorders
SKIN TOXICITY	1/134 (0.7%)
Vascular disorders
DEEP VEIN THROMBOSIS	2/134 (1.5%)
HYPOTENSION	7/134 (5.2%)
ORTHOSTATIC HYPOTENSION	1/134 (0.7%)
Other (Not Including Serious) Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	125/134 (93.3%)
Blood and lymphatic system disorders
ANAEMIA	42/134 (31.3%)
LEUKOPENIA	22/134 (16.4%)
LYMPHOPENIA	10/134 (7.5%)
NEUTROPENIA	68/134 (50.7%)
THROMBOCYTOPENIA	51/134 (38.1%)
Gastrointestinal disorders
ABDOMINAL PAIN	10/134 (7.5%)
CONSTIPATION	21/134 (15.7%)
DIARRHOEA	45/134 (33.6%)
NAUSEA	41/134 (30.6%)
VOMITING	16/134 (11.9%)
General disorders
ASTHENIA	18/134 (13.4%)
CHILLS	8/134 (6%)
FATIGUE	47/134 (35.1%)
OEDEMA PERIPHERAL	22/134 (16.4%)
PYREXIA	30/134 (22.4%)
Infections and infestations
NASOPHARYNGITIS	8/134 (6%)
PNEUMONIA	8/134 (6%)
RESPIRATORY TRACT INFECTION	9/134 (6.7%)
SINUSITIS	9/134 (6.7%)
UPPER RESPIRATORY TRACT INFECTION	20/134 (14.9%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	7/134 (5.2%)
BLOOD CREATININE INCREASED	7/134 (5.2%)
WEIGHT DECREASED	20/134 (14.9%)
Metabolism and nutrition disorders
DECREASED APPETITE	21/134 (15.7%)
DEHYDRATION	8/134 (6%)
HYPOCALCAEMIA	7/134 (5.2%)
HYPOKALAEMIA	19/134 (14.2%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	12/134 (9%)
BACK PAIN	19/134 (14.2%)
MUSCLE SPASMS	17/134 (12.7%)
PAIN IN EXTREMITY	9/134 (6.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR FLARE	13/134 (9.7%)
Nervous system disorders
DIZZINESS	7/134 (5.2%)
DYSGEUSIA	8/134 (6%)
HEADACHE	8/134 (6%)
NEUROPATHY PERIPHERAL	9/134 (6.7%)
Psychiatric disorders
ANXIETY	11/134 (8.2%)
INSOMNIA	8/134 (6%)
Respiratory, thoracic and mediastinal disorders
COUGH	41/134 (30.6%)
DYSPHONIA	9/134 (6.7%)
DYSPNOEA	24/134 (17.9%)
OROPHARYNGEAL PAIN	14/134 (10.4%)
PLEURAL EFFUSION	8/134 (6%)
Skin and subcutaneous tissue disorders
DRY SKIN	10/134 (7.5%)
NIGHT SWEATS	8/134 (6%)
PRURITUS	23/134 (17.2%)
RASH	30/134 (22.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Single center publications may not be submitted until after multicenter publication is submitted (or 1 year after study completion), whichever comes first. The investigator may then publish results provided that Celgene receive a copy of any proposed publication/presentation at least 30 days in advance of submission, delete any confidential information & delay the submission for up to 60 additional days for patent filing. Multicenter publications must include input from investigators & Celgene.