EXHIBIT 2008
`
`EXHIBIT 2008
`
`

`
`VOLUME 27 䡠 NUMBER 26 䡠 SEPTEMBER 10 2009
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Department of Hematology/
`Oncology, Onkologische Praxis, Frank-
`furt; Onkologische Gemeinschaftspraxis,
`Leipzig; Onkologische Schwerpunktpraxis,
`Minden; Department of Hematology,
`University Hospital, Jena; DSH Statistical
`Services, Rohrbach; Oncology Consult-
`ing, Miesbach, Germany; Hematology &
`Transfusion Medicine, National Hemato-
`logical Center, Sofia; Department of
`Hematology, University Hospital, Varna;
`Department of Hematology, University
`Hospital, Plovdiv, Bulgaria; Department of
`Oncology, Universita degli Studi, Perugia;
`Ematologia, Ospedale Niguarda
`Ca’Granda, Milano; Dip. Ematologia,
`Universita “La Sapienza,” Roma, Italy;
`Department of Hematology, Hopital de la
`Princesa, Madrid, Spain; Hematology &
`Oncology, Hopital Universitaire Hautepi-
`erre, Strasbourg; Department of Hema-
`tology, Hopital Purpan, Toulouse, France;
`Department of Hematology, University
`Hospital, Lund, Sweden; Ludwig Boltz-
`mann Institute–Applied Cancer Research
`and Applied Cancer Research–Institute
`for Translational Research VIEnna Kaiser
`Franz Josef-Spital, Vienna, Austria; and
`the Cephalon Research Data Manage-
`ment & Programming, Frazer, PA.
`
`Submitted November 18, 2008;
`accepted May 6, 2009; published online
`ahead of print at www.jco.org on
`August 3, 2009.
`
`Supported by grants from Ribosepharm
`GmbH, Germany. and Mundipharma
`International, United Kingdom.
`
`Presented in part at the Annual Meeting
`of the American Society of Hematology,
`Atlanta, GA, December 6-9, 2008, and San
`Francisco, CA, December 8-11, 2007.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Corresponding author: Wolfgang Knauf,
`MD, PhD, Onkologische Gemein-
`schaftspraxis, Frankfurter Diakonie
`Kliniken, Im Pruefling 17-19, 60389
`Frankfurt, Germany; e-mail:
`wolfgang.knauf@telemed.de.
`
`The Acknowledgment and Appendix
`are included in the full-text version
`of this article; they are available
`online at www.jco.org. They are
`not included in the PDF version
`(via Adobe® Reader®).
`
`© 2009 by American Society of Clinical
`Oncology
`
`0732-183X/09/2726-4378/$20.00
`
`DOI: 10.1200/JCO.2008.20.8389
`
`Phase III Randomized Study of Bendamustine Compared
`With Chlorambucil in Previously Untreated Patients With
`Chronic Lymphocytic Leukemia
`Wolfgang U. Knauf, Toshko Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht,
`Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin Becker, Hans-Joerg Fricke,
`Francoise Huguet, Ilaria Del Giudice, Peter Klein, Lothar Tremmel, Karlheinz Merkle, and Marco Montillo
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`This randomized, open-label, parallel-group, multicenter study was designed to compare the
`efficacy and safety of bendamustine and chlorambucil
`in previously untreated patients with
`advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL).
`Patients and Methods
`Patients (ⱕ 75 years of age) were randomly assigned to receive bendamustine 100 mg/m2/d
`intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca’s normal weight) orally on days 1
`and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response
`to treatment was assessed according to National Cancer Institute Working Group criteria, and the
`final determination of response was made by a blinded independent review committee.
`Results
`A total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete
`or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157
`chlorambucil-treated patients (P ⬍ .0001). More patients showed complete responses with
`bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6
`months with bendamustine and 8.3 months with chlorambucil (P ⬍ .0001). Bendamustine was
`also associated with an improvement in duration of remission, compared with chlorambucil
`(median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria
`grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil
`(occurring in 40% v 19% of patients). Severe infections (grade 3 to 4) occurred in 8% of
`bendamustine-treated patients and 3% of chlorambucil-treated patients.
`Conclusion
`Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity
`profile, when used as first-line therapy in patients with advanced CLL.
`
`J Clin Oncol 27:4378-4384. © 2009 by American Society of Clinical Oncology
`
`Chronic lymphocytic leukemia (CLL) is the most
`common form of adult leukemia in the Western
`world.1 Although patients with early-stage disease
`have a life expectancy of longer than 10 years, those
`who progress or have advanced disease (Binet stage
`B or C or Rai stage II to IV) have a median survival of
`approximately 2 to 7 years.2,3 First-line treatment is
`frequently conducted with chlorambucil, fludara-
`bine, or fludarabine plus cyclophosphamide, either
`alone or in combination with rituximab. Fludara-
`bine has been reported to produce higher response
`rates, a longer duration of remission, and longer
`progression-free survival than chlorambucil in pre-
`viously untreated younger patients with CLL, but
`
`without affecting overall survival.4,5 However, there
`remains a need for new treatment options in pa-
`tients with advanced CLL.
`Bendamustine is a novel agent, synthesized
`with the intent of combining the alkylating proper-
`ties of mechlorethamine and the purine antimetab-
`olite properties of benzimidazole.6,7 This agent,
`alone or in combination with other chemotherapeu-
`tic agents, has been shown to produce good clinical
`efficacy and acceptable tolerability in patients with
`non-Hodgkin’s lymphoma8,9 and multiple myelo-
`ma.10 In phase I/II trials in patients with advanced
`relapsed or refractory CLL, bendamustine has
`been shown to produce overall response rates
`(ORR) similar to or higher than those achieved with
`chlorambucil.11-14 Therefore, a phase III trial was
`
`4378
`
`© 2009 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 © 2009 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2008 0001
`
`

`
`Bendamustine v Chlorambucil in CLL
`
`investigator to the same maximum of six cycles. Patients with progressive
`disease were withdrawn. After the last treatment cycle, patients were moni-
`tored for response and survival at 3-month intervals. Final assessment of best
`response was performed in a blinded fashion by an Independent Committee
`for Response Assessment (ICRA) and classified as CR, PR, PR with nodular
`involvement, stable disease, or progressive disease based on the National
`Cancer Institute Working Group criteria.15
`Primary end points were the overall response rate and progression-free
`survival. Secondary end points included time to progression, duration of
`remission, and overall survival. Safety end points were infection rates and
`adverse events.
`Statistical Methods and Sample Size Calculation
`The statistical analysis was performed on the intention-to-treat (ITT)
`patient population. The safety population consisted of all patients who re-
`ceived at least one dose of study medication.
`Statistical analysis of the primary end points was performed by means of
`an a priori–sequenced hypothesis testing and an adaptive group sequential test
`procedure. Overall remission rate was analyzed by means of Fisher’s exact test,
`stratified by Binet stage; progression-free survival was analyzed by log-rank
`test, stratified by Binet stage. All tests were two tailed with a multiple signifi-
`cance level of ␣⫽ 5%.
`A five-stage adaptive group sequential procedure with Pocock cut-offs of
`⫽ .016 was used, with a maximum of four planned interim analyses, of
`which three were performed (first analysis after treated 85 patients with a
`follow-up of at least 5 months; second analysis after 158 patients; third analysis
`after 264 patients). In each interim analysis, ORR was tested first, while
`progression-free survival was tested only if the first was significant, thus con-
`trolling for multiple testing.17 The P values of the individual sequences were
`combined using the ␸⫺1 method17; since patients included in each interim
`
`␣i
`
`Table 1. Demographic Characteristics of the Intention-to Treat Population
`
`BEN
`
`CLB
`
`Characteristic
`
`No. of patients
`Sex
`Female
`Male
`WHO performance status
`Missing
`0
`1
`2
`Age, years
`Mean
`SD
`Min-Max
`Median
`Q1-Q3
`Binet stage
`B
`C
`B symptoms
`Yes
`No
`Unknown
`LDH
`Normal
`Out of normal ranges
`Not done
`
`No.
`
`162
`
`60
`102
`
`3
`113
`43
`3
`
`%
`
`37.0
`63
`
`1.9
`69.8
`26.5
`1.9
`
`No.
`
`157
`
`62
`95
`
`5
`102
`45
`5
`
`%
`
`39.5
`60.5
`
`3.2
`65.0
`28.7
`3.2
`
`63.0
`7.5
`45.0-77.0
`63.0
`58.0-70.0
`
`63.6
`8.8
`35.0-78.0
`66.0
`59.0-70.0
`
`116
`46
`
`80
`81
`1
`
`84
`73
`5
`
`71.6
`28.4
`
`49.4
`50.0
`0.6
`
`51.9
`45.1
`3.1
`
`111
`46
`
`79
`74
`4
`
`80
`66
`6
`
`70.7
`29.3
`
`50.3
`47.1
`2.5
`
`51.0
`42.0
`3.8
`
`Abbreviations: BEN, bendamustine; CLB, chlorambucil; SD, standard devia-
`tion; LDH, lactate dehydrogenase.
`
`undertaken to compare the efficacy and tolerability of bendamustine
`with that of chlorambucil in previously untreated patients with CLL.
`
`PATIENTS AND METHODS
`
`The study was a randomized, open-label, parallel-group, phase III trial con-
`ducted at 45 centers in Austria, Bulgaria, France, Germany, Italy, Spain, Swe-
`den, and the United Kingdom. The protocol was approved by local ethics
`committees at all participating centers, and the study was conducted in accor-
`dance with the International Conference on Harmonization Good Clinical
`Practice guidelines and the Declaration of Helsinki.
`Patients
`Previously untreated patients up to 75 years of age with Binet stage B (ie,
`ⱖ 3 lymph node regions involved including hepatomegaly and splenomegaly)
`or Binet stage C (ie, anemia and/or thrombocytopenia regardless of the num-
`ber of lymph node regions) CLL confirmed by demonstration of coexpression
`of CD5, CD23, and either CD19, CD20, or both, and in need for treatment15,16
`were included. All patients were required to have a WHO performance status
`of 0 to 2 and a life expectancy of at least 3 months. Women of childbearing
`potential were required to use adequate contraception for at least 6 months
`after treatment. Patients with a second malignancy other than cured basal cell
`carcinoma or cured cervical cancer were excluded, as were patients with
`manifest immune hemolysis or thrombocytopenia that could be treated with
`corticosteroids alone, and patients with Richter’s syndrome or transformation
`to prolymphocytic leukemia. Other exclusion criteria were hepatic dysfunc-
`tion (bilirubin ⬎ 2.0 mg/dL, transaminases ⬎ 3⫻ upper limit of normal, or
`both), renal dysfunction (calculated creatinine clearance ⬍ 30 mL/min), sig-
`nificant medical or mental disorders, known HIV infection, pregnancy or
`lactation, hypersensitivity to study drugs, major surgery within 30 days before
`the start of the trial, and participation in another clinical trial within 4 weeks
`before the study. Written informed consent was obtained from all patients
`before inclusion in the study.
`Recruitment started in November 2002 and was stopped in Novem-
`ber 2006.
`Study Design and Treatment
`Patients were randomly assigned in a 1:1 ratio to receive bendamustine
`or chlorambucil, and stratified by center and Binet stage. Bendamustine (Ri-
`bosepharm, Munich, Germany) was administered by intravenous infusion
`over 30 minutes at a dose of 100 mg/m2/d on days 1 to 2 every 4 weeks.
`Chlorambucil (GlaxoSmithKline, Uxbridge, United Kingdom) was given
`orally at a dose of 0.8 mg/kg (Broca’s normal weight in kg: the body weight for
`the dose being the height of the patient in cm minus 100) on days 1 and 15 (or
`as divided doses on days 1 to 2 and 15 to 16 for patient comfort in some
`individual cases) every 4 weeks. Treatment was to be suspended if platelet
`counts decreased to below 20 ⫻ 109/L, hemoglobin decreased to below 7 g/dL,
`or the absolute neutrophil count decreased to lower than 0.5 ⫻ 109/L. Doses
`were to be modified according to the National Cancer Institute Working
`Group guidelines15 if hematologic toxicities developed. For Common Toxicity
`Criteria grade 3 nonhematologic toxicities other than nausea and vomiting or
`alopecia, the dose was to be reduced by 50% or the patient withdrawn from the
`study, depending on the investigator’s judgment; if any grade 4 toxicity devel-
`oped, the patient was to be withdrawn. Patients for whom dose reduction was
`necessary could have the dose restored to the original level if they had tolerated
`the reduced dose. Prophylactic hyperuricemic treatment was recommended to
`prevent uric acid-induced nephropathy. Nonprotocol antineoplastic drugs
`were not allowed. The study protocol did not provide recommendations for
`the prophylactic use of antibiotics or antiemetics. The use of hematopoietic
`growth factors was discouraged.
`Patients were assessed for response after three cycles of treatment. Two
`additional cycles were recommended for patients with complete response
`(CR) or partial response (PR), up to a maximum limit of six cycles in total. The
`response criteria according to the National Cancer Institute Sponsored Work-
`ing Group guidelines for CLL15 had to be met for at least 8 weeks. Patients with
`no change were allowed to receive additional cycles at the discretion of the
`
`www.jco.org
`
`© 2009 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 © 2009 American Society of Clinical Oncology. All rights reserved.
`
`4379
`
`CEPHALON, INC. -- EXHIBIT 2008 0002
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`

`
`Knauf et al
`
`Table 2. Quality of Response According to Independent Committee for Response Assessment: Intention-to-Treat Population
`
`B
`
`Binet Stage
`
`C
`
`B ⫹ C
`
`BEN
`
`CLB
`
`BEN
`
`CLB
`
`BEN
`
`CLB
`
`Variable
`
`No. of patients overall
`Complete response
`Nodular partial response
`Partial response
`Overall response rate
`
`No.
`
`116
`41
`14
`27
`82
`
`%
`
`35
`12
`23
`71
`
`No.
`
`111
`3
`4
`31
`38
`
`%
`
`3
`4
`28
`34
`
`No.
`
`46
`9
`3
`16
`28
`
`%
`
`20
`7
`35
`61
`
`No.
`
`46
`0
`0
`10
`10
`
`%
`
`0
`0
`22
`22
`
`No.
`
`162
`50
`17
`43
`110
`
`%
`
`31
`11
`27
`68
`
`No.
`
`157
`3
`4
`41
`48
`
`%
`
`2
`3
`26
`31
`
`Abbreviations: BEN, bendamustine; CLB, chlorambucil.
`
`in the chlorambucil group required at least one dose reduction. The
`principal reasons for dose reduction in both groups were neutropenia
`and thrombocytopenia.
`Overall, 110 bendamustine-treated patients (68%), and 48
`(31%) chlorambucil-treated patients achieved a CR or PR as deter-
`mined by the ICRA (P ⬍ .0001). The proportion of patients with CR
`or PR is summarized in Table 2. The proportion of patients with a CR
`was higher with bendamustine than with chlorambucil (31% v 2%), as
`was the proportion with nodular PR (11% v 3%). Patients with stage C
`disease showed a higher likelihood of CR with bendamustine: nine
`patients (20%) with bendamustine showed a CR, whereas no
`chlorambucil-treated patient did so.
`The median observation time was 35 months (range, 1 to 68) at
`the time of the analysis presented here. The median progression-free
`survival was 21.6 months in the bendamustine group and 8.3 months
`in the chlorambucil group (P ⬍ .0001; Fig 1). This difference was
`evident in patients with Binet stage B disease (bendamustine: median
`21.4 months; chlorambucil: median 9.0 months) as well as in stage C
`disease (bendamustine: median 25.4 months; chlorambucil: median
`6.3 months).
`The median duration of response in the bendamustine and
`chlorambucil groups was 21.8 months and 8.0 months, respectively.
`
`BEN (N = 162; median, 21.6)
`CLB (N = 157; median, 8.3)
`Censored observations
`
`+
`
`I%
`I (cid:9)
`1...
`t
`it
`
`+++4.
`
`+14-
`
`1++ 1-
`+ +4+
`
`6
`
`I.
`12
`18
`24
`30
`36
`42
`48
`Time Since Treatment (months)
`
`54
`
`60
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`
`0
`
`Progression-Free Survival
`
`No. left:
`BEN
`CLB
`
`00
`
`30
`
`70
`
`162
`157
`
`116
`59
`
`94
`29
`
`73
`6
`
`54
`2
`
`42
`1
`
`23
`1
`
`10
`0
`
`Fig 1. Progression-free survival based on the assessment of Independent
`Committee for Response Assessment: intention-to-treat population. BEN, ben-
`damustine; CLB, chlorambucil.
`
`analysis were still under observation, these values were not definitive, and
`were used only to determine whether to continue the study with the new
`sample size or to terminate the study. After each interim analysis the safety
`and efficacy data were reviewed by an independent data monitoring com-
`mittee who decided about study continuation. After the third interim
`analysis, the independent data monitoring committee recommended
`the termination of the recruitment and the final analysis to be per-
`formed with the available data. Thus, the enrollment of patients
`stopped in November 2006.
`Sample size calculations were based on data from a study comparing
`fludarabine and chlorambucil in previously untreated CLL patients,4 which
`suggesting a 30% difference in overall remission rate between treatments, and
`a 6-month difference in median progression-free survival. From this, it was
`calculated that approximately 42 patients per group would be required to
`achieve 80% power to show a significant difference in overall response rate,
`assuming a two-sided level of statistical significance of ␣⫽ .05. For the second
`primary end point— progression-free survival—it was calculated that a total
`of 326 patients would be required if no interim analyses were to be performed.
`Since it was uncertain whether the assumptions based on the data from the
`previous study4 would apply to this study, the adaptive group sequential
`procedure described above was used. Using this approach, the final sample size
`was estimated to be approximately 350 patients.
`
`RESULTS
`
`Between November 2002 and November 2006, 319 patients were
`randomly assigned,162 to bendamustine and 157 to chlorambucil. Six
`patients randomly assigned to chlorambucil and one to bendamustine
`were not treated. The ITT population includes all 319 randomly as-
`signed patients and the safety population includes 312 treated patients.
`Demographic characteristics of the ITT population are sum-
`marized in Table 1. Overall, patient characteristics were well bal-
`anced between the groups. One hundred sixteen (72%) in the
`bendamustine group and 111 (71%) in the chlorambucil group
`had Binet stage B disease, while 46 (28%) and 46 (29%), respec-
`tively, had stage C disease. The mean time from initial diagnosis to
`registration in the trial was 18.8 months (standard deviation [SD],
`32.3) in the bendamustine group and 24.6 months (SD, 33.9) in the
`chlorambucil group (P ⫽ .12).
`
`Efficacy
`The median number of treatment cycles per patient was six in
`both arms. The mean number of treatment cycles per patient was 4.9
`(SD, 1.7) with bendamustine and 4.9 (SD, 1.7) with chlorambucil.
`Overall, 54 patients (34%) in the bendamustine group and 46 (31%)
`
`4380
`
`JOURNAL OF CLINICAL ONCOLOGY
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`Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
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`CEPHALON, INC. -- EXHIBIT 2008 0003
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`

`
`Bendamustine v Chlorambucil in CLL
`
`The adherence to the dosing schedule was high in both treatment
`arms. In total, 90% of the planned bendamustine dose and 95% of the
`planned chlorambucil dose were administered.
`Severe infections of grade 3 or 4 occurred in 8% and 3% of treated
`patients in the bendamustine and chlorambucil arm, respectively,
`with one singular grade 4 infection in the chlorambucil arm.
`Fifty-eight patients (36%) in the bendamustine group and six
`patients (4%) in the chlorambucil group received antiemetic therapy.
`Antiemetics were given as preventive therapy in 46 of the 58 patients in
`the bendamustine group and in two of six patients in the chloram-
`bucil group.
`There was a single report of a new malignancy during follow-up;
`a bronchial carcinoma in a patient who had received bendamustine
`was detected 12 months after the patient has finished treatment
`with bendamustine.
`There were two reports on tumor lysis syndrome, both in pa-
`tients who had received their first cycle of bendamustine. However,
`these events were not fatal and the two patients continued treatment.
`
`DISCUSSION
`
`This study has shown that bendamustine induces significantly higher
`response rates and longer progression-free survival than chlorambucil
`in first-line therapy in patients with CLL. Chlorambucil was chosen as
`the comparator because it was approved for first-line use in CLL in all
`participating countries when the trial was planned in 2001. Further-
`more, chlorambucil exhibits a favorable toxicity profile that makes this
`agent suitable in the elderly CLL patients.4,18
`The cumulative dose of chlorambucil was carefully considered
`and was at the higher end compared to doses used in other random-
`ized trials (Table 4). The cumulative dose of chlorambucil in this study
`was similar to that used in a recently completed trial.19
`The response rate achieved with chlorambucil is comparable
`with that achieved in another trial4 with this agent, in which the total
`dose per cycle was below 100 mg/cycle. A higher response rate of 59%
`was reported by Eichhorst et al18 in an elderly study population,
`however, without external monitoring and without independent re-
`sponse assessment. In our trial, ORR achieved with chlorambucil
`assessed by the treating physician was 40%, while with the rigorous
`ICRA assessment, ORR was 31%.
`The overall response rate achieved with bendamustine was com-
`parable with that obtained with fludarabine4,20-22 or cladribine.23 The
`31% CR rate achieved with bendamustine is higher than those recently
`reported for fludarabine alone.18,24,25 However, other studies with
`fludarabine monotherapy have reported CR rates up to 40%.4,20 Sim-
`ilar or higher CR rates have been reported with combinations of
`fludarabine with cyclophosphamide22,24,25 or rituximab26 or with
`both.27-29 Nevertheless, the high CR rate with bendamustine is an
`important finding because there is evidence that the CR is associated
`with longer progression-free survival.28-31
`Progression-free survival was significantly longer with benda-
`mustine than with chlorambucil, and similar to that reported with
`fludarabine,22,25 and alemtuzumab.19 This represents a valuable
`clinical benefit since prolonged progression-free survival is as-
`sumed to be associated with improved quality of life. The median
`progression-free survival in chlorambucil-treated patients was
`lower than in other trials.4,18,19,24 In addition to methodologic
`
`CR-BEN (N = 50; median, 29.3)
`CR-CLB (N = 3; median, 8)
`PR-BEN (N = 60; median, 17.4)
`PR-CLB (N = 45; median, 8)
`Censored observations
`
`6
`
`12
`
`18
`24
`30
`Time (months)
`
`36
`
`42
`
`48
`
`2010
`
`5020
`
`7040
`
`13
`
`091
`
`25
`0
`17
`1
`
`31
`0
`25
`3
`
`50
`3
`60
`45
`
`46
`2
`49
`28
`
`42
`0
`34
`8
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`
`0
`
`Patients in Remission
`
`(proportion)
`
`No. left:
`CR-BEN
`CR-CLB
`PR-BEN
`PR-CLB
`
`Fig 2. Duration of responses according to Independent Committee for Re-
`sponse Assessment: intention-to-treat population. BEN, bendamustine; CLB,
`chlorambucil; CR, complete response; PR, partial response.
`
`The median duration of CR (Fig 2) in bendamustine-treated patients
`was 29.3 months. The median duration of PR was 17.4 months with
`bendamustine and 8.0 months with chlorambucil.
`Further follow-up is required to comment on survival. Overall,
`72 patients (31 in the bendamustine group, 41 in the chlorambucil
`group) died during follow-up. Death due to CLL was reported for 13
`patients in the bendamustine group and 21 patients in the chloram-
`bucil group. So far, no significant differences in overall survival have
`become evident.
`
`Safety
`A total of 23 patients—18 from the bendamustine and five from
`the chlorambucil group—were withdrawn from the study due to
`unacceptable toxicity or the risk/benefit assessment was no longer
`acceptable. The most frequent adverse events (AEs) leading to termi-
`nation of the study were hypersensitivity reactions including skin and
`subcutaneous tissue (nine patients treated with bendamustine, two
`treated with chlorambucil). Two patients in the bendamustine arm
`but none in the chlorambucil arm experienced grade 3 hypersensitiv-
`ity reactions. Grade 4 hypersensitivity was not observed at all (Table 3).
`AE s were reported in 143 (89%) of 161 patients in the bendamustine
`group and 122 (81%) of 151 in the chlorambucil group. Most fre-
`quently occurring AEs were hematologic with the number of events
`being higher in the bendamustine arm (neutropenia in 27%, throm-
`bocytopenia in 25%, and anemia in 22% of patients) than in the
`chlorambucil arm (neutropenia in 14%, thrombocytopenia in 21%,
`and anemia in 14% of patients). GI events (nausea, vomiting, and
`diarrhea) were also more frequent under bendamustine than under
`chlorambucil (Table 3). Neutropenia of National Cancer Institute
`Working Group grade 3 or 4 occurred in 37 bendamustine-treated
`patients (23%) and 16 chlorambucil-treated patients (11%), granulo-
`cyte colony-stimulating factors were used on the discretion of the
`investigators in 23 (3%) of 783 cycles in the bendamustine and in two
`(0.3%) of 733 cycles in the chlorambucil arm. Erythropoetin was used
`in 0.5% and 0.3% of all cycles in the bendamustine and chlorambucil
`arms, respectively.
`
`www.jco.org
`
`© 2009 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 © 2009 American Society of Clinical Oncology. All rights reserved.
`
`4381
`
`CEPHALON, INC. -- EXHIBIT 2008 0004
`
`

`
`Knauf et al
`
`Table 3. Summary of Adverse Events Occurring in At Least 5% of Patients by System Organ Class and Preferred Terms
`
`BEN (n ⫽ 161)
`
`CLB (n ⫽ 151)
`
`All Grades
`
`Grade 3/4
`
`All Grades
`
`Grade 3/4
`
`System Organ Class Preferred Term by Disorder
`
`No.
`
`Blood and lymphatic system
`Neutropenia/granulocytopenia
`Thrombocytopenia
`Anemia
`Leukopenia
`Lymphopenia
`
`GI
`
`44
`40
`35
`28
`10
`
`31
`25
`16
`
`40
`14
`14
`9
`
`8
`
`%
`
`27.3
`24.8
`21.7
`17.4
`6.2
`
`19.3
`15.5
`9.9
`
`24.8
`8.7
`8.7
`5.6
`
`5.0
`
`No.
`
`37
`19
`4
`23
`10
`
`1
`2
`2
`
`3
`0
`2
`0
`
`2
`
`%
`
`23.0
`11.8
`2.5
`14.3
`6.2
`
`0.6
`1.2
`1.2
`
`1.9
`0.0
`1.2
`0.0
`
`1.2
`
`No.
`
`21
`31
`21
`5
`1
`
`21
`10
`6
`
`8
`7
`7
`2
`
`3
`
`11
`2
`
`%
`
`13.9
`20.5
`13.9
`3.3
`0.7
`
`13.9
`6.6
`4.0
`
`5.3
`4.6
`4.6
`1.3
`
`2.0
`
`7.3
`1.3
`
`No.
`
`16
`12
`0
`2
`0
`
`1
`0
`0
`
`2
`0
`0
`0
`
`0
`
`0
`0
`
`%
`
`10.6
`7.9
`0.0
`1.3
`0.0
`
`0.7
`0.0
`0.0
`
`1.3
`0.0
`0.0
`0.0
`
`0.0
`
`0.0
`0.0
`
`Nausea
`Vomiting
`Diarrhea
`General disorders and administration site conditions
`Pyrexia
`Asthenia
`Fatigue
`Chills
`Immune system
`Hypersensitivity
`Infection and infestation
`Nasopharyngitis
`Infection
`Investigation
`Weight decreased
`Metabolism and nutrition disorders
`Hyperuricemia
`Respiratory, thoracic, and mediastinal
`Cough
`Skin and subcutaneous tissue
`Rash
`Pruritus
`
`Abbreviations: BEN, bendamustine; CLB, chlorambucil.
`
`11
`10
`
`9
`
`12
`
`10
`
`15
`8
`
`6.8
`6.2
`
`5.6
`
`7.5
`
`6.2
`
`9.3
`5.0
`
`0
`3
`
`0
`
`3
`
`1
`
`4
`0
`
`0.0
`1.9
`
`0.0
`
`1.9
`
`0.6
`
`2.5
`0.0
`
`5
`
`2
`
`7
`
`7
`4
`
`3.3
`
`1.3
`
`4.6
`
`4.6
`2.6
`
`1
`
`0
`
`1
`
`3
`0
`
`0.7
`
`0.0
`
`0.7
`
`2.0
`0.0
`
`differences (ie, external monitoring, blinded assessment) this may
`be due to differences in the patient population. These other studies
`have included patients with Binet stage A (ie, ⬍ 3 lymph node
`regions involved, corresponding in part to Rai stages 0 to 1) disease
`who have a better prognosis.3
`Toxicity of bendamustine was manageable and of short dura-
`tion. Severe infections are of particular interest since they are a
`major cause of morbidity and mortality in CLL patients.32 Com-
`mon Toxicity Criteria grade 3 to 4 infections occurred in 8% of
`patients with bendamustine and 3% with chlorambucil. Notably,
`
`grade 3 to 4 infection rates of 11% and 15% have been recently
`reported for fludarabine22 and fludarabine with cyclophospha-
`mide28 in similar populations. The difference may be explained by
`different etiologies. Infections occurring during bendamustine
`treatment may be related to transient neutropenia, whereas flu-
`darabine is associated with prolonged T-cell depletion.33
`There are anecdotal reports on transient hemolysis in two pa-
`tients treated with bendamustine and one treated with chlorambucil.
`All of these patients had positive DAT at study entry. At the end of
`therapy active hemolysis was apparent in none of these patients.
`
`Table 4. Comparison of Total Doses Chlorambucil in Different Trials Based on an Average Patient (70 kg/1.75 m/1.85 m2)
`
`Study
`
`Knauf/02CLLIII
`Eichhorst18
`Hillmen19
`Rai4
`Catovsky24
`
`Regimen
`0.8 mg/kg d1 ⫹ 15
`0.4-0.8 (ø 0.5) mg/kg days 1 and 15
`40 mg/m2 every day 28
`40 mg/m2 every day 28
`10 mg/m2 days 1-7
`
`Abbreviation: NA, not available.
`
`Total per Cycle
`
`Per m2 per Cycle
`
`Median Cumulative
`
`Dose (mg)
`
`112
`56-112 (ø 70)
`74
`74
`130
`
`60
`30-60 (ø 38)
`40
`40
`70
`
`522
`455
`515
`NA
`NA
`
`4382
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2009 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 © 2009 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2008 0005
`
`

`
`Bendamustine v Chlorambucil in CLL
`
`The two reports on tumor lysis syndrome during the first cycle of
`treatment with bendamustine merit particular attention. Tumor lysis
`syndrome is reported as a rare but potentially fatal event in fludarabine
`treatment of CLL and to occur predominantly in high-risk patients
`presenting with high lymphocyte counts and hepatosplenomegaly.34
`Both affected patients in our trial presented with a high tumor burden.
`At least in such cases it is urgently recommended to administer pro-
`phylactic therapy against hyperuricemia and to provide the patients
`with adequate fluid intake during the initial phase of treatment.
`Meanwhile, the combination of bendamustine with rituximab
`was reported to be feasible.35 This combination may offer an addi-
`tional option for treatment of patients with CLL.
`In conclusion, this study has shown that bendamustine offers
`significantlygreaterefficacythanchlorambucil,andamanageabletoxicity
`profile, when used as first-line therapy in patients with advanced CLL. In
`March 2008, the US Food and Drug Administration approved benda-
`mustine for the treatment of CLL with regard to data of this trial.
`
`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: Wolfgang U. Knauf, Ribosepharm, Germany and Mundipharma,
`Germany (C); Hans-Joerg Fricke, Ribosepharm, Germany (C); Karlheinz
`Merkle, Ribosepharm and Mundipharma (C) Stock Ownership: None
`Honoraria: Wolfgang U. Knauf, Ribosepharm, Germany and
`Mundipharma, Germany Hans-Joerg Fricke, Ribosepharm, Germany;
`Marco Montillo, Mundipharma Italy Research Funding: Peter Klein,
`Ribosepharm, Germany; Marco Montillo, Mundipharma International
`Expert Testimony: Gunnar Juliusson, Swedish National CLL Group (U)
`Other Remuneration: Gunnar Juliusson, Bayer Schering, Roche
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Wolfgang U. Knauf, Karlheinz Merkle
`Administrative support: Karlheinz Merkle
`Provision of study materials or patients: Wolfgang U. Knauf, Toshko
`Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul
`Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan
`Goranov, Martin Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del
`Guidice, Marco Montillo
`Collection and assembly of data: Wolfgang U. Knauf, Toshko
`Lissichkov, Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul
`Herbrecht, Gunnar Juliusson, Gerhard Postner, Liana Gercheva, Stefan
`Goranov, Martin Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del
`Guidice, Karlheinz Merkle, Marco Montillo
`Data analysis and interpretation: Wolfgang U. Knauf, Peter Klein,
`Lothar Tremmel, Karlheinz Merkle
`Manuscript writing: Wolfgang U. Knauf, Gunnar Juliusson, Peter Klein,
`Karlheinz Merkle
`Final approval of manuscript: Wolfgang U. Knauf, Toshko Lissichkov,
`Ali Aldaoud, Anna Liberati, Javier Loscertales, Raoul Herbrecht, Gunnar
`Juliusson, Gerhard Postner, Liana Gercheva, Stefan Goranov, Martin
`Becker, Hans-Joerg Fricke, Francoise Huguet, Ilaria Del Guidice, Peter
`Klein, Lothar Tremmel, Karlheinz Merkle, Marco Montillo
`