V O L U M E 2 6 䡠 N U M B E R 3 0 䡠 O C T O B E R 2 0 2 0 0 8
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From Our Lady of Mercy Cancer Center,
`New York Medical College, Bronx, NY;
`Sylvester Comprehensive Cancer Center,
`University of Miami, Miami, FL; University
`of California, Davis Cancer Center, Sacra-
`mento; Pacific Coast Hematology/Oncol-
`ogy Medical Group, Fountain Valley, CA;
`University of Nebraska, Nebraska Medical
`Center, Omaha, NE; Gundersen Clinic, La
`Crosse, WI; BC Community Oncology Trial-
`ists, Burnaby, British Columbia, Canada;
`Instat Services, Chatham; Celgene Corpora-
`tion, Summit, NJ; and Mayo Clinic, Roches-
`ter, MN.
`
`Submitted November 16, 2007;
`accepted May 14, 2008; published
`online ahead of print at www.jco.org on
`July 7, 2008.
`
`Supported by Celgene Corporation,
`Summit, NJ. Editorial/writing support
`from Excerpta Medica (funded by
`Celgene).
`
`Presented in part as oral presentations at
`the 48th Annual Meeting of the American
`Society of Hematology, December 9-12,
`2006, Orlando, FL, and the 3rd International
`Conference of Innovative Therapies for
`Lymphoid Malignancies, September 28,
`2006, Palermo, Italy; and as poster presen-
`tations at the 48th Annual Meeting of the
`American Society of Hematology, Decem-
`ber 9-12, 2006, Orlando, FL, the 43rd
`Annual Meeting of the American Society of
`Clinical Oncology, June 1-5, 2007, Chicago,
`IL; and the Pan Pacific Lymphoma Confer-
`ence, June 11-15, 2007, Maui, HI.
`
`Authors’ disclosures of potential conflicts
`of interest and author contributions are
`found at the end of this article.
`
`Clinical Trials repository link available on
`JCO.org.
`
`Corresponding author: Thomas M.
`Habermann, MD, Mayo Clinic, 200 First
`St SW, Rochester, MN 55905; e-mail:
`habermann.thomas@mayo.edu.
`
`© 2008 by American Society of Clinical
`Oncology
`
`0732-183X/08/2630-4952/$20.00
`
`DOI: 10.1200/JCO.2007.15.3429
`
`Lenalidomide Monotherapy in Relapsed or Refractory
`Aggressive Non-Hodgkin’s Lymphoma
`Peter H. Wiernik, Izidore S. Lossos, Joseph M. Tuscano, Glen Justice, Julie M. Vose, Craig E. Cole, Wendy Lam,
`Kyle McBride, Kenton Wride, Dennis Pietronigro, Kenichi Takeshita, Annette Ervin-Haynes, Jerome B. Zeldis,
`and Thomas M. Habermann
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`The major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy.
`Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin’s
`lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the
`safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory
`aggressive NHL.
`Patients and Methods
`Patients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for
`52 weeks, until disease progression or intolerance. The primary end point was response;
`secondary end points included duration of response, progression-free survival (PFS), and safety.
`Results
`Forty-nine patients with a median age of 65 years received lenalidomide in this study. The most
`common histology was diffuse large B-cell lymphoma (53%), and patients had received a median
`of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49
`treated patients, including a 12% rate of complete response/unconfirmed complete response.
`Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell,
`follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease
`or partial response at first assessment, 25% improved with continued treatment. Estimated
`median duration of response was 6.2 months, and median PFS was 4.0 months. The most
`common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the
`most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and
`thrombocytopenia (12.2%).
`Conclusion
`Oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manage-
`able side effects.
`
`J Clin Oncol 26:4952-4957. © 2008 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`The natural history of diffuse large B-cell lymphoma
`(DLBCL) has been improved with the advent of
`immunochemotherapy. However, a significant
`number of patients experience disease progression
`or relapse or die from disease after initial therapy.1-3
`At 5 years, the expected overall survival rate is 60%,
`and the event-free survival rate is 50%.2,4 Currently,
`mantle-cell lymphoma (MCL), a rare type of non-
`Hodgkin’s lymphoma (NHL), is incurable with
`standard chemotherapy.5 Peripheral-blood stem
`cell transplantation has the potential to improve
`survival in patients with aggressive NHL, although
`patients might not respond to treatment or may
`develop disease progression.6 New drug develop-
`
`ment will be critical in further altering the natural
`history of aggressive NHL.
`Lenalidomide (Revlimid; Celgene Corpora-
`tion, Summit, NJ), an analog of thalidomide, is a
`promising new therapeutic agent. It has been hy-
`pothesized that the mechanism of action of
`lenalidomide includes immunomodulatory and
`nonimmunomodulatory activity.7 Lenalidomide
`monotherapy can enhance Th1-type cellular im-
`munity and natural killer T-cell cytotoxicity acti-
`vation markers
`in patients with advanced
`cancers.7,8 Lenalidomide also has direct antipro-
`liferative effects on hematopoietic tumors by in-
`hibiting the Akt pathway and increasing the
`expression of the p21 tumor suppressor protein,
`leading to G1 cell cycle arrest.9-11 In addition,
`
`4952
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`© 2008 by American Society of Clinical Oncology
`
`Downloaded from ascopubs.org by 104.129.194.118 on January 3, 2018 from 104.129.194.118
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1014, p. 1
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`

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`Lenalidomide Monotherapy in Relapsed or Refractory Aggressive NHL
`
`lenalidomide inhibits T regulatory cell function and has antiangio-
`genic effects on the tumor microenvironment.12,13
`Lenalidomide does not seem to cause significant somnolence,
`constipation, and neuropathy, which are usually dose-limiting for
`thalidomide.14 We report the results of a prospective phase II multi-
`center trial evaluating the safety and efficacy of oral lenalidomide
`monotherapy in relapsed or refractory aggressive NHL.
`
`PATIENTS AND METHODS
`
`Patients
`Institutional review boards or ethics committees at each participating
`center approved the study protocol. All patients provided written informed
`consent. The study was designed and conducted in accordance with the gen-
`eral ethical principles outlined in the Declaration of Helsinki, the International
`Conference on Harmonization Guidelines, and Title 21 of the United States
`Code of Federal Regulations.
`Key inclusion criteria were age ⱖ 18 years, biopsy-proven aggressive
`NHL (acceptable histologies: follicular center lymphoma grade 3, DLBCL,
`MCL, and transformed low-grade lymphoma) that has relapsed or is refrac-
`tory to previous therapy (with at least one prior treatment, such as radiation,
`immunotherapy, chemotherapy, or radioimmunotherapy), ineligibility or
`unwillingness to undergo autologous stem-cell transplantation, measurable
`disease on cross-sectional imaging that is ⱖ 2 cm in longest diameter, and
`Eastern Cooperative Oncology Group performance status score of ⱕ 2. Exclu-
`sion criteria included the presence of the following laboratory abnormalities:
`absolute neutrophil count less than 1,500 cells/␮L; platelets less than 100,000/
`␮L; serum creatinine more than 2.5 mg/dL; and serum AST or ALT levels more
`than 5⫻ the upper limit of normal. Patients with CNS lymphoma were not
`eligible for the trial unless the disease had been treated and the patient re-
`mained asymptomatic (for at least 6 months) with no active CNS lymphoma,
`as determined by lumbar puncture, computed tomography scan, or magnetic
`resonance imaging. In addition to the standard exclusion criteria (eg, preg-
`nancy, lactation), patients were ineligible to participate in the trial if they
`had experienced a grade ⱖ 3 prior allergic reaction or hypersensitivity to
`thalidomide or grade ⱖ 3 rash or any desquamation (blistering) while
`taking thalidomide.
`
`Study Design
`This single-arm, multicenter, open-label, phase II study was designed to
`evaluate the safety and efficacy of lenalidomide monotherapy in patients with
`relapsed or refractory aggressive NHL. The primary end point was response
`rate. Secondary end points were duration of response, progression-free sur-
`vival (PFS), and safety.
`Patients self-administered oral lenalidomide (25 mg once daily) on days
`1 to 21 of every 28-day cycle. Patients continued therapy for 52 weeks as
`tolerated or until disease progression. Lenalidomide was supplied as 25-mg
`and 5-mg capsules for oral administration. Patients were instructed to take
`lenalidomide at the same time each day. They were given enough capsules for
`each 21-day cycle and were required to return the study drug bottle (including
`any unused drug) on the next visit. At each scheduled study visit, lenalidomide
`capsule reconciliation was performed to monitor treatment compliance.
`A strict dose-modification schema was implemented in response to
`sustained (ie, lasting ⱖ 7 days) grade 3 neutropenia, grade ⱖ 3 neutropenia
`associated with fever, or grade 4 neutropenia; grade ⱖ 3 thrombocytopenia;
`grade ⱖ 3 desquamating rash or grade 4 nondesquamating rash; grade ⱖ 3
`erythema multiforme; grade ⱖ 2 neuropathy; grade ⱖ 2 sinus bradycardia or
`other cardiac arrhythmias; grade ⱖ 2 allergic reaction or hypersensitivity;
`grade ⱖ 1 constipation; grade ⱖ 3 venous thrombosis or embolism;
`grade ⱖ 3 nonhematologic drug-related toxicity; and grade ⱖ 2 hyperthy-
`roidism or hypothyroidism.
`Patients were encouraged to receive tumor lysis prophylaxis (with allo-
`purinol or equivalent) and to be well hydrated during the first 7 days of
`lenalidomide treatment in cycle 1 or as clinically indicated. To manage com-
`
`Table 1. Patient Demographics and Baseline Disease Characteristics (N ⫽ 49)
`
`Characteristic
`
`Age, years
`Median
`Range
`Male sex
`Time from diagnosis, years
`Median
`Range
`Time from last therapy, months
`Median
`Range
`No. of prior treatment regimens
`1
`2
`3
`4
`ⱖ 5
`Type of prior treatment regimensⴱ
`Rituximab plus combination chemotherapy, at
`least once
`Combination chemotherapy, at least once
`Rituximab, at least once
`Stem-cell transplantation
`Refractory to last therapy
`Rituximab refractory
`Refractory to last chemotherapy
`Histology
`Diffuse large B-cell lymphoma
`Follicular center lymphoma, grade 3
`Mantle-cell lymphoma
`Transformed low-grade lymphoma
`International prognostic index
`0-1
`2
`3
`4-5
`
`No. of
`Patients
`
`%
`
`65
`23-86
`
`25
`
`51.0
`
`2.7
`0.4-32
`
`3.9
`1-59
`
`4
`8
`12
`13
`12
`
`36
`
`29
`45
`14
`24
`25
`22
`
`26
`5
`15
`3
`
`8
`22
`13
`6
`
`8
`16
`24
`27
`24
`
`74
`
`59
`92
`29†
`56‡
`58§
`55储
`
`53.1
`10.2
`30.6
`6.1
`
`16.3
`44.9
`26.5
`12.2
`
`ⴱRituximab (R) plus combination chemotherapy included the following: cyclo-
`phosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); etoposide,
`prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH); dexa-
`methasone, cisplatin, and cytarabine (R-DHAP); etoposide, methylpred-
`nisolone, cytarabine, and cisplatin (R-ESHAP); ifosfamide, carboplatin, and
`etoposide (R-ICE); carmustine, etoposide, cytarabine, and melphalan (R-
`BEAM); cyclophosphamide, vincristine, and prednisolone (R-CVP); gemcitab-
`ine, dexamethasone, and cisplatin (R-GDP); fludarabine, mitoxantrone, and
`rituximab; rituximab, gemcitabine, and vinblastine; rituximab, cytarabine, and
`methotrexate; and rituximab, cytarabine, methotrexate, and leucovorin. Com-
`bination chemotherapy included: CHOP; EPOCH; DHAP; ESHAP; ICE; BEAM;
`Mini BEAM; CVP; GDP; Hyper CVAD (cyclophosphamide, doxorubicin, vincris-
`tine, dexamethasone, cytarabine, and methotrexate); cyclophosphamide, dexa-
`methasone, doxorubicin, mesna, and vincristine; carboplatin, ifosfamide, mesna,
`etoposide, dexamethasone, liposomal doxorubicin, and vinorelbine; bleomycin,
`cyclophosphamide, etoposide, prednisone, leucovorin, methotrexate, and vincris-
`tine; and cyclophosphamide, mitoxantrone, prednisone, and vincristine.
`†Forty-eight patients had information on stem-cell transplantation.
`‡Forty-three patients had sufficient information to characterize as refractory
`to last therapy or not.
`§Forty-three patients had sufficient information to characterize as refractory
`to rituximab or not.
`储Forty patients had sufficient information to characterize as refractory to last
`chemotherapy regimen or not.
`
`plications of the disease or treatment, other concomitant therapies (ie, antibi-
`otics, analgesics, antihistamines, growth factors, and transfusions of RBCs,
`platelets, or fresh-frozen plasma) were administered at the discretion of the
`treating physician. The concomitant use of other anticancer therapies was not
`
`www.jco.org
`
`© 2008 by American Society of Clinical Oncology
`
`4953
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`Downloaded from ascopubs.org by 104.129.194.118 on January 3, 2018 from 104.129.194.118
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
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`Apotex Ex. 1014, p. 2
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`

`

`Table 2. Adverse Events Reported in at Least 10% of Patients (N ⫽ 49)
`
`Table 3. All Grade 3 and 4 Adverse Events by Preferred Term (N ⫽ 49)
`
`Wiernik et al
`
`Adverse Event
`
`No. of Patients
`
`Neutropenia
`Thrombocytopenia
`Fatigue
`Anemia NOS
`Constipation
`Leukopenia NOS
`Rash NOS
`Diarrhea NOS
`Pyrexia
`Cough
`Nausea
`Arthralgia
`Dyspnea NOS
`Anorexia
`Hyperglycemia NOS
`Neuropathy NOS
`Edema peripheral
`Abdominal pain NOS
`Disease progression NOS
`Dizziness
`Infection NOS
`Insomnia
`Night sweats
`
`26
`26
`24
`20
`15
`14
`13
`12
`11
`9
`9
`7
`7
`6
`6
`6
`6
`5
`5
`5
`5
`5
`5
`
`%
`
`53.1
`53.1
`49.0
`40.8
`30.6
`28.6
`26.5
`24.5
`22.4
`18.4
`18.4
`14.3
`14.3
`12.2
`12.2
`12.2
`12.2
`10.2
`10.2
`10.2
`10.2
`10.2
`10.2
`
`Abbreviation: NOS, not otherwise specified.
`
`permitted, and previous anticancer therapies were discontinued for at least 28
`days before initiating lenalidomide treatment.
`Response and Safety Assessments
`Study visits were scheduled to occur every 28 days to coincide with the
`beginning of each new treatment cycle. Target and nontarget lesions were
`assessed at baseline and every 2 months using a chest x-ray, conventional or
`spiral computed tomography, and/or magnetic resonance imaging. Bone
`marrow biopsy was used to confirm a complete response (CR) in patients
`who had bone marrow involvement at baseline and who had achieved all
`other criteria for a CR. Response and progression were evaluated using the
`International Workshop Lymphoma Response Criteria.15 All patients who
`discontinued the treatment phase for any reason were observed until
`disease progression or administration of another lymphoma treatment.
`Patients who did not achieve a response (CR, unconfirmed CR [CRu], or
`partial response [PR]) to their last treatment regimen or last chemotherapy
`regimen were classified as refractory to last therapy or refractory to last
`chemotherapy, respectively. Patients with no response or a response lasting
`less than 6 months after their most recent rituximab-containing regimen
`were classified as rituximab refractory.
`Safety assessments included adverse events, blood pressure and pulse
`rate assessments, hematology and chemistry laboratory values, and serum
`thyroid function tests. In women of child-bearing potential, serum/urine
`beta-human chorionic gonadotropin levels were also evaluated to deter-
`mine pregnancy status.
`Statistical Analysis
`The primary end point was the objective response rate, defined as the
`proportion of patients assessable for response whose best response was PR,
`CRu, or CR. Secondary efficacy measures were duration of response, PFS, and
`safety. Duration of response was calculated as the time from at least a PR to
`progression of disease, including death owing to NHL. PFS was defined as the
`time from the start of lenalidomide therapy to the first observation of disease
`progression or death from any cause.
`PFS was censored for patients who had not experienced disease pro-
`gression or had not died at the time of last follow-up. The study had a
`
`Grade 3
`
`Grade 4
`
`Adverse Event
`
`No.
`
`Neutropenia
`Leukopenia
`Thrombocytopenia
`Fatigue
`Anemia
`Dyspnea NOS
`Febrile neutropenia
`Pain NOS
`Pneumonia NOS
`Acute myocardial infarction
`Alanine aminotransferase increased
`Aspartate aminotransferase increased
`Autoimmune hemolytic anemia NOS
`Blood bilirubin increased
`Cardiac failure congestive
`Cauda equina syndrome
`Cellulitis
`Chest pain
`Convulsions NOS
`Diarrhea NOS
`Diplegia
`Dysphagia
`Hematuria
`Hemolysis NOS
`Hyponatremia
`Jugular vein thrombosis
`Lymphopenia
`Malaise
`Mental status changes
`Nausea
`Osteomyelitis NOS
`Pain in foot
`Pneumonitis NOS
`Pulmonary embolism
`Rash NOS
`Sepsis NOS
`Spinal hematoma
`Sweating increased
`Urinary frequency
`
`12
`7
`6
`3
`2
`2
`2
`2
`2
`0
`1
`1
`1
`1
`1
`0
`1
`1
`1
`1
`0
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`0
`1
`1
`1
`1
`1
`
`Abbreviation: NOS, not otherwise specified.
`
`%
`
`24.5
`14.3
`12.2
`6.1
`4.1
`4.1
`4.1
`4.1
`4.1
`0
`2.0
`2.0
`2.0
`2.0
`2.0
`0
`2.0
`2.0
`2.0
`2.0
`0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`2.0
`0
`2.0
`2.0
`2.0
`2.0
`2.0
`
`No.
`
`4
`0
`4
`0
`1
`0
`1
`0
`0
`1
`0
`0
`0
`0
`0
`1
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`1
`1
`1
`0
`0
`0
`0
`
`%
`
`8.2
`0
`8.2
`0
`2.0
`0
`2.0
`0
`0
`2.0
`0
`0
`0
`0
`0
`2.0
`0
`0
`0
`0
`2.0
`0
`0
`0
`0
`0
`2.0
`0
`0
`0
`0
`0
`2.0
`2.0
`2.0
`0
`0
`0
`0
`
`two-stage design, with a target enrollment of approximately 40 patients.
`The study was to be halted if there were no responses among the first 20
`patients treated with lenalidomide (calculated based on the 0.88 probabil-
`ity of observing at least one response among 20 patients, if the true
`response rate was ⱖ 10%). If one or more of these 20 patients achieved
`response to lenalidomide, enrollment was to continue to reach the tar-
`get range.
`Univariate analyses using Fisher’s exact test were conducted to investi-
`gate and characterize associations of variables with response. Data from all
`patients treated with at least one dose of lenalidomide were included in the
`safety analysis. Adverse events and their severity were classified using the
`National Cancer Institute Common Toxicity Criteria. Results reported are
`based on data available on January 31, 2007. At this time, as per protocol, all
`patients had either experienced disease progression or completed six cycles of
`therapy. PFS and duration of response are based on data available on October
`31, 2007. As per protocol, at this time at least 80% of patients had discontin-
`ued treatment.
`
`4954
`
`© 2008 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from ascopubs.org by 104.129.194.118 on January 3, 2018 from 104.129.194.118
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1014, p. 3
`
`

`

`Lenalidomide Monotherapy in Relapsed or Refractory Aggressive NHL
`
`RESULTS
`
`From August 2005 to September 2006, 50 patients enrolled at eight
`centers in the United States. However, only 49 patients received lena-
`lidomide, because one patient was documented to have pathologic
`evidence of Hodgkin’s lymphoma and, therefore, received no treat-
`ment. The median age was 65 years (Table 1). The most common
`histology was DLBCL (53%). The median time from diagnosis to
`lenalidomide treatment was 2.7 years, and patients had received a
`median of four prior treatment regimens for NHL. The median time
`from last therapy was 3.9 months. Ninety-two percent of patients had
`received prior rituximab, and 58% were deemed to be rituximab
`refractory. Twenty-nine percent of the patients had undergone prior
`stem-cell transplantation.
`
`Safety
`The most common adverse events were hematologic, fatigue,
`gastrointestinal, and rash (Table 2). The most common grade 4 ad-
`verse events were neutropenia (8.2%) and thrombocytopenia (8.2%);
`the most common grade 3 adverse events were neutropenia (24.5%),
`leukopenia (14.3%), and thrombocytopenia (12.2%; Table 3).
`Eighteen patients (37%) had a total of 32 dose reductions (nine
`patients required one dose reduction to 20 mg, five patients required
`two dose reductions to 15 mg, three patients required three dose
`reductions to 10 mg, and one patient required four dose reductions to
`5 mg). Adverse events most commonly causing dose reduction were
`neutropenia (n ⫽ 15), thrombocytopenia (n ⫽ 5), and fatigue (n ⫽ 2).
`Hematologic events (neutropenia, thrombocytopenia, leukope-
`nia, and anemia) were manageable with dose reductions and resulted
`in only two patients discontinuing lenalidomide treatment (both ow-
`ing to thrombocytopenia). Other reasons for treatment discontinua-
`tion were cauda equina syndrome, rash, autoimmune hemolytic
`anemia, myocardial infarction, pneumonia, disease progression, and
`CNS lymphoma. Eight patients discontinued treatment because of
`adverse events.
`
`Response
`The overall response rate (ORR) was 35% (n ⫽ 17; Table 4). Two
`patients achieved CR, four patients achieved CRu, 11 patients
`achieved PR, and 11 patients had stable disease (SD). Patients with
`MCL achieved an ORR of 53%; this included one patient with CR
`(7%), one patient with CRu (7%), and six patients with PR (40%).
`Five of the 17 patients who responded to lenalidomide mono-
`therapy were refractory to their last prior therapy. They received a
`median number of four prior therapies. Three of these patients were
`
`refractory to autologous stem-cell transplantation, combination cy-
`clophosphamide plus vincristine plus prednisone, and tositumomab,
`and each achieved a CRu to lenalidomide; two patients were refractory
`to rituximab plus methlyprednisolone and SGN40, and each re-
`sponded to lenalidomide with a PR. Five of the 25 rituximab-
`refractory patients achieved a response to lenalidomide, whereas eight
`of 18 patients sensitive to their last rituximab-containing regimen had
`treatment response to lenalidomide. Four patients were rituximab
`naı¨ve, and of these, two patients achieved CR, one patient achieved PR,
`and one patient had SD.
`Median time to PR was 1.9 months (range, 1.2 to 3.7 months),
`and median time to CR/CRu was 4.3 months (range, 1.9 to 10.5
`months). Three (21%) of the 14 patients who had SD at the first
`assessment (cycle 2) exhibited a response (one CRu and two PRs) with
`continued treatment. Likewise, four (31%) of 13 patients with an
`initial PR after cycle 2 eventually achieved a CR/CRu with continued
`lenalidomide treatment.
`The estimated median duration of response was 6.2 months
`(range, 0 to 12.8 months), and median PFS was 4.0 months (range, 0 to
`14.5 months; Fig 1).
`
`DISCUSSION
`
`In this phase II study, lenalidomide produced an ORR of 35% in 49
`patients with relapsed or refractory aggressive NHL. Responses were
`observed in each aggressive histologic subtype tested (DLBCL, follic-
`ular center lymphoma grade 3, MCL, and transformed low-grade
`lymphoma). The 53% ORR seen in patients with relapsed or refrac-
`tory MCL treated with lenalidomide, along with a manageable toxicity
`profile, suggests that lenalidomide is a potential treatment option for
`these patients. Twenty-five percent of patients with SD or PR at first
`assessment had improved responses with continued treatment. With a
`median follow-up of 3.7 months, the estimates for median duration of
`response and PFS were 6.2 and 4.0 months, respectively. The adverse
`events were predominantly hematologic, manageable, and consistent
`with lenalidomide therapy in patients with other diseases.
`The population evaluated in this study had advanced disease,
`were heavily pretreated, and had limited treatment options. Overall,
`29% of patients had undergone prior stem-cell transplantation, and
`58% were refractory to rituximab-containing regimens. All except one
`patient had received prior chemotherapy regimens. This patient had
`previously undergone renal transplantation and had received thalid-
`omide monotherapy after developing DLBCL. Also, this patient had a
`
`Table 4. Objective Response of Patients Receiving Lenalidomide Therapy by Histology Type (N ⫽ 49)
`
`Histology
`
`No. of Patients
`
`Aggressive NHL
`Diffuse large B-cell lymphoma
`Follicular center lymphoma, grade 3
`Mantle-cell lymphoma
`Transformed low-grade lymphoma
`
`49
`26
`5
`15
`3
`
`CR
`
`2
`1
`0
`1
`0
`
`CRu
`
`4
`2
`1
`1
`0
`
`PR
`
`11
`2
`2
`6
`1
`
`SD
`
`11
`7
`0
`2
`2
`
`PD
`
`21
`14
`2
`5
`0
`
`ORR (%)
`
`35
`19
`60
`53
`33
`
`Abbreviations: NHL, non-Hodgkin’s lymphoma; CR, complete response; CRu, unconfirmed CR; PR, partial response; SD, stable disease; PD, progressive disease;
`ORR, overall response rate.
`
`www.jco.org
`
`© 2008 by American Society of Clinical Oncology
`
`4955
`
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
`
`Apotex Ex. 1014, p. 4
`
`

`

`Wiernik et al
`
`Patients
`Censored
`
`aggressive NHL and warrant further investigation of lenalidomide
`therapy, alone or in combination, in the treatment of patients with
`aggressive NHL.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest that is relevant to the subject
`matter under consideration in this article. Certain relationships marked
`with a “U” are those for which no compensation was received; those
`relationships marked with a “C” were compensated. For a detailed
`description of the disclosure categories, or for more information about
`ASCO’s conflict of interest policy, please refer to the Author Disclosure
`Declaration and the Disclosures of Potential Conflicts of Interest section in
`Information for Contributors.
`Employment or Leadership Position: Kenton Wride, Celgene Corp (C);
`Dennis Pietronigro, Celgene Corp (C); Kenichi Takeshita, Celgene Corp
`(C); Annette Ervin-Haynes, Celgene Corp (C); Jerome B. Zeldis, Celgene
`Corp (C) Consultant or Advisory Role: Peter H. Wiernik, Celgene Corp
`(U); Kyle McBride, Celgene Corp (C) Stock Ownership: Kenton Wride,
`Celgene Corp; Dennis Pietronigro, Celgene Corp; Kenichi Takeshita,
`Celgene Corp; Annette Ervin-Haynes, Celgene Corp; Jerome B. Zeldis,
`Celgene Corp Honoraria: Peter H. Wiernik, Celgene Corp; Joseph M.
`Tuscano, Celgene Corp Research Funding: Peter H. Wiernik, Celgene
`Corp; Julie M. Vose, Celgene Corp Expert Testimony: Jerome B. Zeldis,
`Celgene Corp (C) Other Remuneration: None
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Peter H. Wiernik, Dennis Pietronigro,
`Kenichi Takeshita, Annette Ervin-Haynes, Jerome B. Zeldis,
`Thomas M. Habermann
`Financial support: Jerome B. Zeldis
`Administrative support: Craig E. Cole, Dennis Pietronigro,
`Jerome B. Zeldis
`Provision of study materials or patients: Peter H. Wiernik, Izidore S.
`Lossos, Joseph M. Tuscano, Glen Justice, Craig E. Cole, Wendy Lam,
`Dennis Pietronigro, Thomas M. Habermann
`Collection and assembly of data: Peter H. Wiernik, Izidore S. Lossos,
`Glen Justice, Dennis Pietronigro, Annette Ervin-Haynes,
`Thomas M. Habermann
`Data analysis and interpretation: Peter H. Wiernik, Izidore S. Lossos,
`Joseph M. Tuscano, Julie M. Vose, Kyle McBride, Kenton Wride,
`Dennis Pietronigro, Annette Ervin-Haynes, Jerome B. Zeldis,
`Thomas M. Habermann
`Manuscript writing: Peter H. Wiernik, Izidore S. Lossos, Joseph M.
`Tuscano, Julie M. Vose, Dennis Pietronigro, Kenichi Takeshita, Annette
`Ervin-Haynes, Jerome B. Zeldis, Thomas M. Habermann
`Final approval of manuscript: Peter H. Wiernik, Izidore S. Lossos,
`Joseph M. Tuscano, Glen Justice, Julie M. Vose, Craig E. Cole, Wendy
`Lam, Kyle McBride, Kenton Wride, Dennis Pietronigro, Kenichi
`Takeshita, Annette Ervin-Haynes, Jerome B. Zeldis,
`Thomas M. Habermann
`
`100
`
`75
`
`50
`
`25
`
`0
`
`Patients (%)
`
`5.0
`10.0
`Progression-Free Survival Time (months)
`
`15.0
`
`Fig 1. Kaplan-Meier plot of progression-free survival.
`
`CR for 40 months after treatment with thalidomide and a CR with
`lenalidomide in the current trial, which continued at 7.6 months.
`The responses to lenalidomide monotherapy compare favorably
`to that observed for other monotherapies evaluated in similar patient
`populations. Goy et al16 reported an ORR of 32% with bortezomib
`monotherapy in patients with relapsed or refractory, indolent, and
`aggressive NHL. The ORR reported with gemcitabine monotherapy in
`rituximab-naı¨ve patients was 20% (all PRs), and the median duration
`of response was 6 months.17 Treatment with rituximab monotherapy
`in 54 patients with relapsed or refractory, aggressive, rituximab-naı¨ve
`NHL yielded an ORR of 31% (33% in MCL and 37% in DLBCL) and
`a median time to progression of at least 105 days.18 In the present
`study, three of four patients with rituximab-naı¨ve disease had an
`objective response.
`Lenalidomide, a known immunomodulatory drug, may control
`aggressive NHL by enhancing the immune system.7,8,12,19-21 It was
`recently reported that when used in combination, lenalidomide and
`rituximab produce a robust response rate in relapsed or refractory
`MCL.22 Other activities that might be relevant to the activity of lena-
`lidomide in NHL, apart from its immunomodulatory activity, include
`its direct antiproliferative effect on the tumor and its pro-apoptotic
`effects via p21, as well as its inhibition of angiogenesis.9-11,13
`Ongoing and future studies of lenalidomide in NHL include the
`use of lenalidomide as monotherapy and in combination with ritux-
`imab in indolent lymphoma and in combination with bortezomib
`in MCL.23-25
`The results from this phase II study demonstrate the activity of
`oral lenalidomide monotherapy in patients with relapsed or refractory
`
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`JOURNAL OF CLINICAL ONCOLOGY
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`Copyright © 2018 American Society of Clinical Oncology. All rights reserved.
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