EXHIBIT 2015
`
`EXHIBIT 2015
`
`Cephalon Exhibit 2015
`
`IPR2016-00026
`
`Agila V. Cephalon
`
`

`
`VOLUME 26 䡠 NUMBER 27 䡠 SEPTEMBER 20 2008
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the QE II Health Sciences Centre,
`Halifax, Nova Scotia; Ottawa General
`Hospital, Ottawa; Northeastern Ontario
`Regional Cancer Centre, Sudbury,
`Ontario; Hospital Notre-Dame Du
`Chum, Montreal, Quebec, Canada;
`University of Virginia Health System,
`Charlottesville, VA; Georgetown Univer-
`sity Hospital, Washington, DC; Univer-
`sity of Southern California/Norris Cancer
`Hospital, Los Angeles, CA; and West
`Cancer Clinic, Memphis, TN.
`
`Submitted March 7, 2008; accepted
`May 21, 2008; published online ahead
`of print at www.jco.org on July 14,
`2008.
`
`Supported by Cephalon, Inc.
`
`Preliminary results were presented at
`the 48th Annual Meeting of the Ameri-
`can Society of Hematology, December
`9-12, 2006, Orlando, FL.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical Trials repository link available on
`JCO.org
`
`Corresponding author: Bruce D.
`Cheson, MD, Georgetown University
`Hospital, 3800 Reservoir Rd, NW,
`Washington, DC 20007-2197; e-mail:
`bdc4@georgetown.edu.
`
`© 2008 by American Society of Clinical
`Oncology
`
`0732-183X/08/2627-4473/$20.00
`
`DOI: 10.1200/JCO.2008.17.0001
`
`Phase II Multicenter Study of Bendamustine Plus Rituximab
`in Patients With Relapsed Indolent B-Cell and Mantle Cell
`Non-Hodgkin’s Lymphoma
`K. Sue Robinson, Michael E. Williams, Richard H. van der Jagt, Philip Cohen, Jordan A. Herst, Anil Tulpule,
`Lee S. Schwartzberg, Bernard Lemieux, and Bruce D. Cheson
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`is a bifunctional mechlorethamine derivative with clinical activity in the
`Bendamustine HCl
`treatment of non-Hodgkin’s lymphoma. This study evaluated bendamustine plus rituximab in 67
`adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to
`prior rituximab.
`Patients and Methods
`Patients received rituximab 375 mg/m2 intravenously on day 1 and bendamustine 90 mg/m2
`intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of
`rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six
`patients (median age, 60 years) received at least one dose of both drugs.
`Results
`Overall response rate was 92% (41% complete response, 14% unconfirmed complete response,
`and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24
`months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months).
`Outcomes were similar for patients with indolent or mantle cell histologies. The combination was
`generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia,
`36%; grade 3 or 4 thrombocytopenia, 9%).
`Conclusion
`Bendamustine plus rituximab is an active combination in patients with relapsed indolent and
`mantle cell lymphoma.
`
`J Clin Oncol 26:4473-4479. © 2008 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`In 2008, non-Hodgkin’s lymphoma (NHL) will be
`diagnosed in 66,120 patients, and 20,510 patients
`will die of the disease.1 Significant gains in response
`and survival have been achieved with chemoimmu-
`notherapy, particularly with the introduction of rit-
`uximab (Rituxan; Genentech,
`Inc, South San
`Francisco, CA).2
`Data from the National LymphoCare Study in-
`dicate that, although a variety of regimens are used
`as initial therapy for follicular lymphomas, ritux-
`imab plus chemotherapy is the most frequent choice
`(51%).3,4 Given the relapsing nature of indolent
`lymphomas, patients require re-treatment, and
`most ultimately become refractory to rituximab
`and/or various chemotherapies.5 Thus, despite
`availability of active therapies, indolent B-cell and
`mantle cell lymphomas remain incurable for most
`
`patients. A significant unmet need remains for effec-
`tive and well-tolerated treatment.
`Mantle cell
`lymphoma represents approxi-
`mately 6% of all NHL and is among the more aggres-
`sive subtypes, with a response duration of 1 to 3
`years after initial treatment and a median survival
`time of 3 to 5 years.6 A variety of chemoimmuno-
`therapy approaches have been used in the front-line
`and relapsed settings, but refractoriness to treatment
`and the presence of comorbid illness in this typically
`older population often limit effective therapy.7
`Bendamustine (Treanda; Cephalon, Inc, Frazer,
`PA) is a novel agent consisting of a mechlorethamine
`(nitrogen mustard) group, a benzimidazole ring,
`and a butyric acid side chain. In vitro studies
`demonstrate rapid production of DNA cross-
`links and strand breaks after bendamustine expo-
`sure.8 In addition to direct DNA damage and
`apoptosis, other mechanisms include inhibition
`
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
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`

`
`Robinson et al
`
`of mitotic checkpoints and induction of mitotic catastrophe.9
`These characteristics may explain the activity of bendamustine in
`drug-resistant cancer cells9 and refractory lymphoma patients.10
`Benzimidazole acts as a purine antagonist in experimental models;
`the contribution of this structure to the overall antitumor activity
`of bendamustine is unknown.
`In vitro testing in CD20-positive lymphoma cell lines has
`demonstrated synergy between bendamustine and rituximab, evi-
`denced by a reduction in the bendamustine concentration required
`to induce apoptosis in 50% of tumor cells after the addition of
`rituximab.11 Rituximab has previously been shown to increase the
`sensitivity of NHL cells to other chemotherapeutic agents.12 Cross
`resistance has not been observed between rituximab and chemo-
`therapeutic agents. Considering these findings and the widespread
`use of rituximab in NHL patients, we evaluated the efficacy and
`safety of bendamustine plus rituximab in patients with indolent
`B-cell or mantle cell lymphoma experiencing relapse after chemo-
`therapy or chemoimmunotherapy.
`
`PATIENTS AND METHODS
`
`Study Design and Objectives
`We conducted this multicenter, open-label, single-arm, phase II clinical
`trial to determine the overall response rate (ORR) to bendamustine plus
`rituximab in patients with relapsed indolent B-cell or mantle cell lymphoma.
`ORR was defined as a complete response (CR), unconfirmed complete re-
`sponse (CRu), or partial response (PR) during the study period. Secondary
`objectives included safety, progression-free survival (PFS), and duration of
`response (DR). The institutional review board approved the protocol at each
`site, and an institutional review board–approved consent form was signed
`before study participation.
`
`Eligibility
`Patients age ⱖ 18 years with a WHO performance status of 0 to 2 were
`eligible if they had documented relapsed, CD20-positive mantle cell lym-
`phoma or indolent B-cell (follicular, small lymphocytic, lymphoplasmacytic,
`or marginal zone) lymphoma. Patients were required to have bidimensionally
`measurable disease with at least one lesion measuring ⱖ 2 cm in a single
`dimension. A maximum of three prior, unique chemotherapy regimens was
`allowed. Prior rituximab was allowed if the patient was not refractory (disease
`progression during or within 6 months of the last dose of rituximab or achieve-
`ment of less than a PR to a rituximab-containing regimen). Adequate hema-
`tologic function (absolute neutrophil count ⱖ 1,000 cells/␮L and platelets ⱖ
`100,000 cells/␮L) was required unless patients demonstrated more than 50%
`marrow involvement. Study entry required adequate renal (creatinine clear-
`ance ⬎ 30 mL/min) and hepatic function (ⱕ 2.5⫻ the upper limit of labora-
`tory normal for AST and ALT and ⱕ 1.5⫻ the upper limit of laboratory
`normal for total bilirubin).
`Patients were excluded if they were refractory to rituximab, had
`received prior radioimmunotherapy or prior high-dose chemotherapy
`with allogeneic stem-cell support, or had concurrent treatment with ther-
`apeutic doses of systemic corticosteroids. Patients were also excluded if
`they had an active malignancy other than lymphoma, malignant effusions,
`or evidence of serious infection, or had not recovered from prior
`treatment-related adverse effects.
`
`Treatment
`Baseline evaluation included medical history and physical examination,
`CBC, serum electrolytes and clinical chemistry, bone marrow aspiration/
`biopsy, and tumor staging using contrast-enhanced computed tomography or
`magnetic resonance imaging. Patients received rituximab 375 mg/m2 on day 1,
`followed by bendamustine 90 mg/m2 by intravenous infusion over 30 to 60
`
`minutes on days 2 and 3 every 28 days for four cycles. Additional doses of
`rituximab were administered 7 days before the first cycle and 28 days after the
`last cycle. Patients could receive up to six cycles if disease regression was evident
`between the second and fourth cycles. If grade 3 nonhematologic or grade 4
`hematologic toxicity occurred, as determined by the Common Terminology
`Criteria for Adverse Events (version 3.0),13 the dose of bendamustine was
`reduced to 60 mg/m2 in the subsequent cycle. If a similar severity of toxicity
`occurred at the reduced dose, study treatment was discontinued. Primary
`prophylactic use of granulocyte colony-stimulating factor or granulocyte-
`macrophage colony-stimulating factor was discouraged; however, treatment
`was allowed for prolonged neutropenia (grade 4 leukopenia ⱖ 1 week, failure
`of WBCs to recover to at least grade 1 by the next scheduled dose, or febrile
`neutropenia in a prior treatment cycle). Bendamustine was postponed if
`toxicities remained at ⱖ grade 2. Except for patients with more than 50% bone
`marrow involvement, recovery to absolute neutrophil count ⱖ 1,000/␮L and
`platelet count ⱖ 75,000/␮L was required before starting the second and sub-
`sequent cycles. If recovery was not evident within 2 weeks of a scheduled
`treatment, the patient was re-evaluated for continued treatment.
`
`Response Criteria
`Response was assessed after the second cycle, at the end of treatment
`(within 8 weeks after the last dose of rituximab), and then every 3 months for
`a minimum of 2 years until death, disease progression, or alternate treatment.
`Response and progression were based on International Working Group Re-
`sponse Criteria for NHL,14 using the same imaging method (computed
`tomography or magnetic resonance imaging) used to establish baseline
`tumor measurements.
`Patients were classified by best tumor response (CR, CRu, PR, stable
`disease, or progressive disease). PFS was calculated as the time from first dose
`of study drug to first documentation of disease progression or death. DR was
`calculated as the time from first documentation of best response (CR, CRu, or
`PR) to first documentation of disease progression or death. Laboratory assess-
`ments were performed at baseline and on day 1 of each cycle. The severity of
`adverse events was determined using Common Terminology Criteria for
`Adverse Events version 3.0.13
`
`Statistical Methods
`We hypothesized that bendamustine plus rituximab would produce
`an ORR ⱖ 70%.15 On the basis of prior studies indicating an ORR of 50%
`after single-agent rituximab,16 a sample size of 60 patients was planned to
`yield more than 80% power (using an overall, two-sided, 5% significance
`level) to detect an increase of 20% in ORR after treatment with bendamus-
`tine plus rituximab.
`ORR was calculated as the number of patients achieving a best response
`of CR, CRu, or PR divided by the number of patients treated with at least one
`dose of bendamustine. Patients without at least one response assessment were
`treated as nonresponders. A two-sided 95% exact CI for ORR was calculated
`using the binomial distribution. The Kaplan-Meier method was used to esti-
`mate median DR and PFS, and two-sided 95% CIs were calculated using the
`Brookmeyer-Crowley nonparametric method.17
`Absolute dose-intensity of bendamustine and rituximab (mg/m2/wk)
`was calculated for each patient as the sum of doses administered divided by the
`number of weeks in the treatment period. Relative dose-intensity for each
`agent (%) was then calculated as the dose-intensity divided by the weekly
`intended dose and then multiplied by 100.
`
`RESULTS
`
`Patient Disposition and Characteristics
`The study enrolled 67 patients at 22 sites in the United States,
`Canada, and Australia from April 2004 to December 2005. One
`patient withdrew consent after the first dose of rituximab, did not
`receive bendamustine, and was excluded from further analyses.
`Patient characteristics are listed in Table 1. Fifty-six percent of
`
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`© 2008 by American Society of Clinical Oncology
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2015
`
`

`
`Bendamustine Plus Rituximab in Relapsed Lymphoma
`
`Table 1. Patient Demographics and Disease Characteristics
`
`Characteristic
`
`Age, years
`Median
`Range
`Sex
`Male
`Female
`Years since NHL diagnosis
`Median
`Range
`Stage
`I-II
`III-IV
`WHO performance status
`0-1
`2
`Histologic subtypes
`Indolent
`Follicular center cell
`Small lymphocytic
`Lymphoplasmacytic/Waldenström
`Marginal zone
`Mantle cell
`Prior chemotherapy or biologic therapy
`Prior chemotherapy
`Prior alkylator
`Prior purine analog
`Prior anthracycline
`No. of prior chemotherapy regimens
`Any
`1
`2
`3
`⬎ 3
`Mean
`Median
`Range
`Prior rituximab-containing treatment
`No. of prior rituximab regimens
`Any
`1
`2
`3
`Mean
`Median
`Range
`FLIPI risk category
`Low (score ⫽ 0-1)
`Intermediate (score ⫽ 2)
`High (score ⬎ 2)
`Unknown
`
`No. of
`Patients
`(N ⫽ 66)
`
`60
`40-84
`
`3.4
`0.25-17.0
`
`63
`3
`
`54
`40
`10
`2
`2
`12
`66
`64
`56
`15
`38
`
`64
`36
`21
`4
`3
`
`37
`
`37
`27
`8
`2
`
`40
`13
`13
`13
`1
`
`1.6
`1.0
`1.0-4.0
`
`1.3
`1.0
`1.0-3.0
`
`%
`
`59
`41
`
`18
`82
`
`82
`61
`15
`3
`3
`18
`100
`97
`85
`23
`58
`
`100
`56
`33
`6
`5
`
`56
`
`100
`73
`22
`5
`
`33
`33
`33
`3
`
`Abbreviations: NHL, non-Hodgkin’s lymphoma; FLIPI, Follicular Lymphoma
`International Prognostic Index.
`
`patients had received prior rituximab; 44% were rituximab naive.
`Sixty-four patients (97%) received prior chemotherapy; these pa-
`tients received a median of one prior chemotherapy regimen
`(range, one to four regimens). Two patients (3%) received prior
`rituximab without chemotherapy. Although three patients re-
`
`ceived more than three prior chemotherapy regimens, these occur-
`rences did not constitute protocol violations because two patients
`received repeated treatment with the same regimen and the third
`patient received cyclophosphamide, doxorubicin, vincristine, and
`prednisone (CHOP) and, later, cyclophosphamide, vincristine,
`and prednisone, which was counted as one unique regimen.
`
`Safety
`Sixty-one patients (92%) received at least four cycles of treat-
`ment; 41 patients (62%) received six cycles of treatment (Table 2). Of
`the total 346 patient-cycles administered, 43 (12%) were delayed; 74%
`of these delays were ⱕ 14 days in duration. The mean relative dose-
`intensities for bendamustine and rituximab were 93% and 95%, re-
`spectively. Six patients discontinued bendamustine treatment before
`completing four cycles as a result of adverse events (n ⫽ 2), disease
`progression (n ⫽ 1), patient/investigator decision (n ⫽ 2), or loss to
`follow-up (n ⫽ 1).
`
`Table 2. Patient Disposition
`
`Measure
`
`Patients enrolled
`Patients treated
`No. of cycles completed
`Mean
`Median
`Range
`Completed No. of cycles
`2
`3
`4
`5
`6
`7
`Rituximab dose-intensity
`Planned, mg/m2/wk
`Absolute, mg/m2/wk
`Median
`Range
`Relative, %†
`Median
`Range
`Bendamustine dose-intensity
`Planned, mg/m2/wk
`Absolute, mg/m2/wk
`Median
`Range
`Relative, %†
`Median
`Range
`Reasons for study drug discontinuation in
`patients receiving ⬍ four cycles
`Adverse event
`Consent withdrawn
`Disease progression
`Lost to follow-up
`
`No. of
`Patients
`
`%
`
`5.2
`6.0
`2.0-7.0
`
`93.75
`
`93.3
`72.2-95.5
`
`99.3
`76.0-101.5
`
`45
`
`43.7
`29.6-45.8
`
`97.1
`65.7-101.8
`
`67
`66
`
`2
`3
`15
`4
`41
`1
`
`6
`
`2
`2
`1
`1
`
`3
`5
`23
`6
`62
`2ⴱ
`
`3
`3
`1
`1
`
`ⴱOne patient received an extra cycle of bendamustine in error.
`†Relative dose-intensity is a measure of the amount of drug received in an
`actual treatment period, expressed as a percentage of the amount of drug
`planned for the realized treatment period.
`
`www.jco.org
`
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
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`

`
`Robinson et al
`
`Table 3. Hematologic Adverse Events in 66 Patients Receiving Bendamustine Plus Rituximab
`
`Event
`
`No. of Patients
`
`All Grades
`
`Leukopenia
`Neutropenia
`Febrile neutropenia
`Thrombocytopenia
`Anemia
`
`62
`52
`4
`41
`51
`
`%
`
`94
`79
`6
`62
`77
`
`Grade 3
`
`No. of Patients
`
`18
`15
`3
`5
`1
`
`%
`
`27
`23
`5
`8
`2
`
`Grade 4
`
`No. of Patients
`
`2
`9
`1
`1
`0
`
`%
`
`3
`14
`2
`2
`0
`
`NOTE. Severity was determined from postbaseline laboratory results using Common Terminology Criteria for Adverse Events, version 3.0, available at
`http://ctep.cancer.gov/reporting/ctc.html.
`
`The combination of bendamustine and rituximab was well
`tolerated (Tables 3 and 4). The primary toxicity was reversible
`myelosuppression; grade 3 or 4 neutropenia was reported in 24
`patients (36%), including four patients (6%) with febrile neutro-
`penia. Other grade 3 or 4 hematologic toxicities included throm-
`bocytopenia (9%) and anemia (2%). Growth factor or blood
`product support was administered during 43 (9%) of 463 cycles.
`Ten patients (15%) received RBC growth factors (darbapoetin or
`epoetin-alfa), and eight patients (12%) received granulocyte growth
`factors (pegfilgrastim, filgrastim, or sargramostim). Up to cycle 4,
`growth factor support increased with the number of treatment cycles
`administered. Four patients (6%) received transfusions of platelets,
`plasma, or other blood products during the study. There was no clear
`trend for an increase in the frequency of transfusions administered
`over time. No secondary malignancies were reported.
`Nonhematologic adverse events attributed to bendamustine
`included (all grades) nausea (70%),
`infection (64%), fatigue
`
`(59%), constipation (44%), diarrhea (36%), headache (36%), and
`vomiting (29%; Table 4). Most events were grade 1 or 2 in severity.
`Sixty-two patients (94%) received antiemetics. Ten grade 3 or 4
`infections were reported in six patients (diverticulitis, fungal respi-
`ratory tract infection, herpes simplex, herpes zoster, neutropenic
`infection [n ⫽ 2], oropharyngeal candidiasis, pneumonia, pseudo-
`monal sepsis, and grade 4 cytomegalovirus infection). Other grade
`4 nonhematologic toxicities included compartment syndrome,
`pulmonary edema, and toxic epidermal necrolysis (one patient
`each). Events commonly attributed to rituximab by investigators
`included fatigue (45%) and nausea (30%). There was no evidence
`of cardiac, renal, or hepatic toxicity. Grade 1 alopecia was reported
`in one patient (2%).
`Infusion-related or injection site reactions were associated
`with bendamustine and rituximab in 10 (15%) and 13 patients
`(20%), respectively. These were mostly mild to moderate in sever-
`ity, consisting of chills, fever, phlebitis, and rash. Two patients
`
`Table 4. Nonhematologic Adverse Events Occurring With a Frequency of ⱖ 15% in 66 Patients Receiving Bendamustine Plus Rituximab
`
`All Grades
`
`Grade 3
`
`Grade 4
`
`Event
`
`No. of Patients
`
`Nausea
`Infectionⴱ
`Fatigue
`Constipation
`Diarrhea
`Headache
`Vomiting
`Cough
`Chills
`Rash
`Pruritus
`Abdominal pain
`Stomatitis
`Dyspnea
`Peripheral edema
`Insomnia
`Infusion-related reaction
`Pyrexia
`Asthenia
`
`46
`42
`39
`29
`24
`24
`19
`18
`13
`13
`12
`11
`11
`11
`11
`11
`10
`10
`10
`
`%
`
`70
`64
`59
`44
`36
`36
`29
`27
`20
`20
`18
`17
`17
`17
`17
`17
`15
`15
`15
`
`No. of Patients
`
`%
`
`No. of Patients
`
`%
`
`0
`5
`3
`0
`2
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`2
`0
`2
`
`0
`8
`5
`0
`3
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`3
`0
`3
`
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`2
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`NOTE. Two deaths occurred that were unrelated to disease progression; one was a result of toxic epidermal necrolysis and was considered to be possibly related to
`rituximab or bendamustine, and the other death was a result of compartment syndrome and pulmonary edema and was considered to be unrelated to study treatment.
`ⴱGrade 3 and 4 infections included diverticulitis, fungal respiratory tract infection, herpes simplex, herpes zoster, neutropenic infection, oropharyngeal candidiasis,
`pneumonia, and pseudomonal sepsis; one patient also experienced a grade 4 cytomegalovirus infection. The most common grade 1 and 2 infections included
`nasopharyngitis, sinusitis, herpes simplex, urinary tract infection, pneumonia, and herpes zoster.
`
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`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2015
`
`

`
`Bendamustine Plus Rituximab in Relapsed Lymphoma
`
`Pathologic Subtype and Rituximab Exposure Status
`
`No. of Patients
`
`ORR (%)
`
`CR (%)
`
`CRu (%)
`
`PRⴱ (%)
`
`SD (%)
`
`PD (%)
`
`Table 5. Treatment Response in All Patients by Pathologic Subtype and by Prior Rituximab Exposure
`
`Total
`Pathologic subtype
`Indolent lymphoma
`Mantle cell lymphoma
`Rituximab exposure
`Prior rituximab
`No prior rituximab
`
`66
`
`54
`12
`
`37
`29
`
`92
`
`93
`92
`
`87
`100
`
`41
`
`41
`42
`
`35
`48
`
`14
`
`13
`17
`
`14
`14
`
`38
`
`39
`33
`
`38
`38
`
`8
`
`7
`8
`
`14
`0
`
`0
`
`0
`0
`
`0
`0
`
`Abbreviations: ORR, overall response rate; CR, complete response; CRu, complete response unconfirmed; PR, partial response; SD, stable disease; PD,
`progressive disease.
`
`tion of 21 months. CR occurred less frequently in patients previously
`treated with rituximab compared with rituximab-naive patients (35%
`v 48%, respectively). One additional notable finding was a high rate of
`durable responses in the mantle cell lymphoma patients (ORR, 92%;
`median DR, 19 months).
`These results are comparable to those from a German study
`conducted in a similar population of lymphoma patients receiving
`
`61
`Number of subjects
`41% (25)
`Event
`59% (36)
`Censored
`Median Duration of Response (95% CI) 21.04 (18.25 to 24.46)
`
`5
`10
`15
`20
`Duration of Response (months)
`
`25
`
`Number of subjects
`Event
`Censored
`Median PFS (95% CI)
`
`66
`44% (29)
`56% (37)
`22.92 (20.28 to 26.30)
`
`5
`10
`15
`20
`25
`Progression-Free Survival (months)
`
`30
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`A
`
`Distribution Function
`Response Duration
`
`B
`
`Distribution Function
`
`Survival
`
`Fig 1. Kaplan-Meier curves of (A) duration of response to bendamustine plus
`rituximab in patients exhibiting a complete, complete unconfirmed, or partial
`response (n ⫽ 61) and (B) progression-free survival (PFS) in all patients (N ⫽ 66)
`receiving treatment with bendamustine and rituximab. Patients who were alive
`and without disease progression or lost to follow-up at the time of analysis were
`censored at the last assessment for tumor response.
`
`experienced grade 3 infusion reactions attributed to rituximab.
`There were no infusion-related reactions specifically attributed
`to bendamustine.
`Five deaths reported during the study included three attrib-
`uted to disease progression, one attributed to compartment syn-
`drome and pulmonary edema, and one attributed to toxic
`epidermal necrolysis. All but the latter event were considered un-
`related to bendamustine or rituximab. Toxic epidermal necrolysis
`was considered possibly related to rituximab or bendamustine,
`although the patient received multiple other medications that
`could have contributed.
`
`Efficacy
`ORR was 92%, including 41% CR, 14% CRu, and 38% PR
`(Table 5). Median follow-up time was 20 months (range, 19 to 22
`months). Median DR was 21 months (95% CI, 18 to 24 months; Fig
`1A). Median PFS time was 23 months (95% CI, 20 to 26 months;
`Fig 1B). ORR among 37 patients who had prior rituximab exposure
`was 86% (95% CI, 71% to 95%), and ORR in 29 patients who
`were rituximab naive was 100% (95% CI, 88% to 100%); corre-
`sponding CR rates were 35% (95% CI, 20% to 53%) and 48%
`(95% CI, 29% to 67%), respectively (P ⫽ .32). Median DR in 32
`patients with prior rituximab exposure (21 months) was similar
`to the overall population. Among 21 patients who had received
`two or more previous chemotherapy regimens, the extent of
`prior treatment did not influence the response rate, and the
`median DR was 19 months.
`Twelve patients with mantle cell lymphoma exhibited an ORR of
`92%, including 42% CR, 17% CRu, and 33% PR. Median DR for the
`mantle cell population was 19 months (95% CI, 12 to 24 months).
`
`DISCUSSION
`
`Bendamustine is a cytotoxic compound that acts primarily as an
`alkylating agent inducing extensive and durable DNA breaks. Its benz-
`imidazole ring structure may explain differences between bendamus-
`tine and other alkylating agents, such as slower repair of damaged
`DNA, activity against multidrug-resistant cells, and only partial cross
`resistance with other alkylating agents.8 In this study, the response to
`bendamustine plus rituximab was high, with an ORR of 92% and a CR
`rate of 41%. These responses were also durable, with a median dura-
`
`www.jco.org
`
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
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`
`

`
`Robinson et al
`
`bendamustine plus rituximab.15 In that study, previous rituximab
`was not allowed, whereas in the present study, 56% of patients
`received prior rituximab. Otherwise, the overall history of previous
`treatment was similar in the two study populations. In the German
`study (N ⫽ 63), ORR was 90% (v 92% in the present study), with a
`median PFS time of 24 months (v 23 months in the present study).
`The CR rate was higher in the German study compared with the
`present study (60% v 41%, respectively), possibly because of dif-
`ferences in prior rituximab treatment. The safety profile of com-
`bined bendamustine-rituximab was also similar in the two studies,
`with a relatively low incidence of grade 3 or 4 hematologic and
`nonhematologic adverse events.
`Bendamustine has also been administered in combination
`with mitoxantrone and rituximab.18 In a study of 54 patients with
`relapsed and refractory CD20-positive indolent malignancies, mi-
`toxantrone (10 mg/m2 on day 1) and bendamustine (90 mg/m2 on
`days 1 and 2) were followed by four weekly doses of rituximab (375
`mg/m2); bendamustine and mitoxantrone were repeated every 4
`weeks for five additional cycles. Grade 3 or 4 adverse events in-
`cluded anemia (7%), thrombocytopenia (14%), and leukopenia
`(50%); no cardiotoxicity was reported. ORR was 96%, including a
`CR rate of 41%, similar to the present study. Among patients with
`indolent lymphoma, median time to progression had not been
`reached after a median observation time of 27 months.
`Results from the present study compare favorably with other
`established treatments for relapsed indolent lymphoma, including
`rituximab monotherapy and radioimmunotherapy.19,20 A recent
`phase III study of CHOP versus rituximab plus CHOP (R-CHOP)
`in 474 patients with relapsed/refractory follicular lymphoma
`showed an ORR of 85% for R-CHOP and a CR rate of 29%.21 PFS
`for patients treated with R-CHOP was longer than in the present
`study, but the comparison is complicated by the use of rituximab
`maintenance after the completion of R-CHOP and because prior
`treatment with rituximab was not allowed.
`The efficacy outcomes associated with bendamustine and rit-
`uximab in the subgroup of patients with mantle cell lymphoma are
`particularly good for this relatively poorly responsive population
`after initial relapse. Although the number of patients treated is
`small (n ⫽ 12), the ORR of 92% and median PFS time of 23 months
`compare favorably with the ORR of 58% and median PFS time of 8
`months reported for 24 relapsed mantle cell patients treated with
`rituximab plus fludarabine, cyclophosphamide, and mitox-
`antrone regimen.22
`Given the efficacy of bendamustine demonstrated in the re-
`lapsed setting, Rummel et al23 are currently comparing the benda-
`mustine plus rituximab combination and R-CHOP as initial
`therapy in a multicenter, randomized phase III trial. Interim re-
`sults in 315 assessable patients with indolent (80%) and mantle cell
`(20%) lymphomas show similar rates of response (ORR, 93% for
`bendamustine plus rituximab v 94% R-CHOP) between treat-
`ments. After a median 18-month observation period, median PFS
`time is 39 months for R-CHOP–treated patients and has not been
`reached for bendamustine/rituximab-treated patients. Bendamus-
`tine plus rituximab, compared with R-CHOP, was associated with
`lower incidences of myelosuppression (grade 3 or 4 leukopenia,
`16% v 41%, respectively), infection (23% v 41%, respectively), and
`alopecia (0% v 94%, respectively).
`
`Tolerability of treatment is an important consideration for
`patients with relapsed lymphoma. Large studies of alternative com-
`bination regimens, such as rituximab plus fludarabine, cyclophos-
`phamide, and mitoxantrone22; R-CHOP21; and rituximab plus
`cyclophosphamide, vincristine, and prednisone,24 demonstrate fre-
`quencies of nonhematologic toxicities similar to the bendamustine
`and rituximab combination with two exceptions. First, severe nausea
`and vomiting were not observed in the present study but were re-
`ported for a small proportion of chemotherapy-naive patients receiv-
`ing R-CHOP for follicular NHL.25 Whether this difference is
`meaningful is not clear because antiemetic use may differ between
`protocols. A second major difference was in the incidence of alopecia.
`This was reported for only one patient in the present study (grade 1),
`whereas the majority of patients receiving R-CHOP experience grade
`3 or 4 alopecia.25
`The hematologic toxicities observed in the present study seem
`similar to those reported for other rituximab plus chemotherapy
`combinations, although no comparative studies have been con-
`ducted. The observed incidence of grade 3 or 4 neutropenia and
`thrombocytopenia is lower than in the previous study of benda-
`mustine monotherapy in rituximab-refractory indolent NHL pa-
`tients.10 This finding may be related to a higher dose-intensity of
`the monotherapy regimen (120 mg/m2 on days 1 and 2 every 21
`days) and a more heavily pretreated population with more ad-
`vanced disease. However, the incidence of grade 3 or 4 lymphope-
`nia was higher with combined bendamustine-rituximab compared
`with bendamustine alone, likely reflecting the contribution of rit-
`uximab to the combination regimen.
`Results of this study support the efficacy of combined benda-
`mustine and rituximab for patients with relapsed indolent and
`mantle cell NHL. This combination elicited durable responses
`without evidence of additive toxicity and a low incidence of severe
`and life-threatening events. High response rates were observed in
`all subgroups; response rates and PFS for patients with mantle cell
`lymphoma were similar to those in patients with follicular NHL.
`This combination represents an effective and tolerable treatment
`option in patients with relapsed indolent and mantle cell 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: None Consultant or Advisory Role:
`None Stock Ownership: None Honoraria: Philip Cohen, Genentech Research
`Funding: Michael E. Williams, Cephalon Inc, Genentech, Biogen Idec; Richard
`H. van der Jagt, Cephalon Inc; Philip Cohen, Cephalon Inc, Genentech; Jordan
`A. Herst, Salmedix Inc; Anil Tulpule, Salmedix Inc Expert Testimony: None
`Other Remuneration: Richard H. van der Jagt, Cephalon Inc
`
`4478
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2008 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2015
`
`

`
`Bendamustine Plus Rituximab in Relapsed Lymphoma
`
`AUTHOR CONTRIBUTION