EXHIBIT 2008
`
`EXHIBIT 2008
`
`Cephalon Exhibit 2008
`
`IPR2016-00026
`
`Agila V. Cephalon
`
`

`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the St Bartholomew’s Hospital,
`London; Christie Hospital, Manchester,
`United Kingdom; and Corixa Corp,
`South San Francisco, CA.
`
`Submitted June 13, 2003; accepted
`February 4, 2004.
`
`Supported by Corixa Corp (South San
`Francisco, CA), Cancer Research UK,
`Barts and the London NHS Trust, and
`Christie Hospital NHS Trust, United
`Kingdom.
`
`Authors’ disclosures of potential con-
`flicts of interest are found at the end of
`this article.
`
`Address reprint requests to A.J. Davies,
`BM, Cancer Research UK Medical On-
`cology Unit, Department of Medical
`Oncology, 45 Little Britain, St Bar-
`tholomew’s Hospital, London EC1A
`7BE, United Kingdom; e-mail:
`Andrew.J.Davies@cancer.org.uk.
`
`© 2004 by American Society of Clinical
`Oncology
`
`0732-183X/04/2208-1469/$20.00
`
`DOI: 10.1200/JCO.2004.06.055
`
`Tositumomab and Iodine I 131 Tositumomab for
`Recurrent Indolent and Transformed B-Cell Non-
`Hodgkin’s Lymphoma
`A.J. Davies, A.Z.S. Rohatiner, S. Howell, K.E. Britton, S.E. Owens, I.N. Micallef, D.P. Deakin,
`B.M. Carrington, J.A. Lawrance, S. Vinnicombe, S.J. Mather, J. Clayton, R. Foley, H. Jan, S. Kroll,
`M. Harris, J. Amess, A.J. Norton, T.A. Lister, and J.A. Radford
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`An open-label phase II study was conducted at two centers to establish the efficacy and safety of
`tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed
`indolent B-cell lymphoma.
`
`Patients and Methods
`A single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity
`required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts
`of 100 to 149 ⫻ 109/L). Forty of 41 patients received both infusions.
`Results
`Thirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or
`unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response
`rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration
`of remission was 1.3 years. The median duration of remission has not yet been reached for those
`patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6⫹ and 5.2⫹
`years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event.
`Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of
`patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed
`human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated
`thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient.
`
`Conclusion
`High overall and CR rates were observed after a single dose of tositumomab and iodine I 131
`tositumomab in this patient group. Toxicity was modest and easily managed.
`
`J Clin Oncol 22:1469-1479. © 2004 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`lymphocytic, and lym-
`Follicular, small
`phoplasmacytoid lymphomas1
`together
`comprise a group of diseases characterized
`clinically by a propensity for advanced stage
`at presentation and longer median survival
`than other histologic subtypes of B-cell non-
`Hodgkin’s lymphomas.2-8 Typically, patients
`respond to therapy but the clinical course is of
`multiple episodes of recurrence culminating
`in death as a result of disease (irrespective of
`whether transformation to large B-cell pathol-
`
`ogy has occurred) or complications of therapy.
`Treatment options at recurrence are increas-
`ingly broad,9,10 yet there has been little signif-
`icant impact on survival.11
`The CD20 antigen has become well
`established as a target
`for monoclonal
`antibody– directed therapy in B-cell lym-
`phoma. This transmembrane phosphopro-
`tein is expressed by more than 95% of B-cell
`lymphomas and is present on normal B cells
`except early progenitors and terminally dif-
`ferentiated plasma cells.12,13 Because there is
`little shedding into the circulation, no inter-
`
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`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
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`
`Davies et al
`
`nalization after antibody binding,14,15 and no antigenic
`16
`modulation, CD20 provides a
`After four weekly intravenous infusions of the chimeric
`anti-CD20 monoclonal antibody rituximab, responses are
`achieved in approximately 50% of patients. The complete
`remission (CR) rate, however, is low and the duration of
`response, in general, is short.17,18 Given the sensitivity of these
`lymphomas to external-beam irradiation, radioimmunocon-
`jugates directed against CD20 have been developed to over-
`come some of the deficiencies inherent in the use of cold
`antibodies.
`The murine immunoglobulin G2a anti-B1 antibody
`tositumomab targets the CD20 antigen.12 Covalently linked
`with iodine-131 (131I), tositumomab and iodine I 131 tosi-
`tumomab together comprise the BEXXAR therapeutic reg-
`imen (Corixa Corp, Seattle, WA, and GlaxoSmithKline,
`Philadelphia, PA). The dual-emission properties of 131I re-
`sult in delivery of high-energy beta particles over short
`distances, whereas measurements of gamma emissions may
`be made externally, allowing the determination of patient-
`specific pharmacokinetics. Encouraging results with tositu-
`momab and 131I tositumomab, hereafter referred to as 131I
`tositumomab, have been achieved in a series of studies
`during the last decade. In a phase I/II, single-center, dose-
`escalation study of 59 patients with B-cell lymphomas, the
`overall response rate (ORR) was 71%.19 A subsequent, mul-
`ticenter, phase II trial of 47 heavily pretreated patients (me-
`dian four prior therapies) with low-grade or transformed
`B-cell lymphoma reported an ORR of 57%, with 32% of
`patients achieving a CR.20 These findings were subsequently
`confirmed in a large expanded-access program.21 131I tosi-
`tumomab is effective in chemotherapy-refractory patients
`(ie, those in whom treatment has failed or those who have
`experienced disease recurrence within 6 months from their
`last chemotherapy regimen). In this group the ORR was
`65% (20% CR), in contrast with a response rate of only 28%
`and CR rate of 3% after their last regimen.22 Most strikingly,
`53% of patients had a longer remission duration after 131I
`tositumomab than after their previous regimen.
`On the basis of these promising results in a heavily
`pretreated population, this study was designed to investi-
`gate the safety and efficacy of 131I tositumomab when ad-
`ministered earlier in the clinical course of indolent or trans-
`formed indolent B-cell lymphoma.
`
`PATIENTS AND METHODS
`
`131I tositumomab in patients at first or second
`recurrence of indolent or transformed indolent B-cell non-
`Hodgkin’s lymphoma. Duration of response, progression-free
`survival (PFS), safety, and survival were the secondary end points.
`The study was conducted at two centers in the United Kingdom.
`Local research ethics committee approval was granted at both sites
`and patients gave written informed consent before study entry.
`
`Patient Eligibility
`Adult patients with a histologically confirmed diagnosis of
`CD20-positive B-cell follicular (grade 1 or 2), small lymphocytic,
`lymphoplasmacytoid/immunocytoma, or unclassifiable
`low-
`grade B-cell lymphoma1 were eligible for study entry. Patients with
`transformation from one of the above histologies to large B-cell
`lymphoma were also eligible. Histologic confirmation of transfor-
`mation was documented before therapy. Patients were treated at
`first or second recurrence and had experienced disease progres-
`sion after their last treatment. Patients were required to have a
`Karnofsky performance score ⱖ 60, adequate renal and hepatic
`function, bidimensionally measurable disease (ⱖ 2 ⫻ 2 cm by
`computed tomography scan), neutrophils ⱖ 1.5 ⫻ 109/L, platelets
`ⱖ 100 ⫻ 109/L, and no more than 25% of the intertrabecular bone
`marrow space infiltrated with lymphoma (determined by bone
`marrow trephine biopsy).
`Patients were excluded if they had received cytotoxic chemo-
`therapy, radiotherapy, or cytokine therapy within the previous 4
`weeks or had experienced disease progression in a field previously
`irradiated with more than 35 Gy within 1 year. Systemic cortico-
`steroids were discontinued at least 1 week before study entry.
`Patients were also excluded if they had previously received high-
`dose chemotherapy or radiotherapy with hematopoietic progeni-
`tor cell rescue; had prior exposure to either monoclonal or poly-
`clonal antibodies, known HIV infection, active hydronephrosis, CNS
`lymphoma, or any other malignancy diagnosed within 5 years; or if
`they were pregnant or breastfeeding. Previous radioimmunotherapy
`and allergy to iodine were also exclusions to study entry.
`
`Dosimetric and Therapeutic Doses
`Tositumomab was centrally radiolabeled with 131I (MDS
`Nordion Inc, Kanata, Canada) and shipped on a patient-specific
`basis. Administration was performed according to previously de-
`scribed methodology20 (Fig 1). Patients received 120 mg potas-
`sium iodide daily, as thyroid blockade, from at least 24 hours
`before administration of the dosimetric dose until 14 days after the
`therapeutic administration. Before drug administrations, patients
`were premedicated with paracetamol 500 mg and chlorphenira-
`mine 4 mg orally. After administration of the dosimetric dose, the
`effective half-life of total body clearance was calculated from
`gamma camera counts acquired at three time points. The patient-
`specific amount of radioactivity required to deliver the total-body
`therapeutic dose of 0.75 Gy was then calculated as previously
`described.23 For patients with platelet counts between 100 and 149
`⫻ 109/L, an attenuated total body dose of 0.65 Gy was adminis-
`tered, and for patients weighing more than 137% of their lean
`body mass, calculations were based on maximum effective mass.
`The therapeutic dose was administered 7 to 14 days after the
`dosimetric dose. Patients were hospitalized for this therapeutic
`phase and isolated in a dedicated facility until the total body
`activity was sufficiently low to permit discharge under current
`United Kingdom regulations.
`
`Response Evaluation
`The first response evaluation was performed 7 weeks after
`therapy and repeated at week 26 and every 3 months thereafter
`until disease progression or death. After 2 years, patients were
`observed every 6 months. A CR was defined as complete resolution
`of all disease-related radiologic abnormalities and the disappear-
`ance of all signs and symptoms related to the disease. Patients with
`bone marrow involvement at baseline were required to undergo a
`repeat bone marrow biopsy after therapy to confirm a CR. CR
`
`1470
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`JOURNAL OF CLINICAL ONCOLOGY
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`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`This was a single-arm, open-label, phase II study to establish the
`response rate to
`
`suitable and stable target.
`
`CEPHALON, INC. -- EXHIBIT 2008
`
`

`
`131I Tositumomab for Recurrent NHL
`
`Dosimetry
`(day 0)
`Dosimetry
`Dosimetry
`Dosimetry
`(day 0)
`(day 0)
`(day 0)
`
`450mg unlabelled
`tositumomab (over 1hr)
`450mg unlabelled
`450mg unlabelled
`450mg unlabelled
`then
`tositumomab (over 1hr)
`tositumomab (over 1hr)
`tositumomab (over 1hr)
`
`35mg (5mCi) iodine 1131
`then
`then
`then
`tositumomab
`(over 20 mins)
`35mg (5mCi) iodine 1131
`35mg (5mCi) iodine 1131
`35mg (5mCi) iodine 1131
`tositumomab
`tositumomab
`tositumomab
`(over 20 mins)
`(over 20 mins)
`(over 20 mins)
`
`gamma camera
`scans 1 hr post—
`dosimetric dose
`gamma camera
`gamma camera
`gamma camera
`scans 1 hr post—
`scans 1 hr post—
`scans 1 hr post—
`and
`dosimetric dose
`dosimetric dose
`dosimetric dose
`day 2, 3 or 4
`and
`and
`and
`and
`day 2, 3 or 4
`day 2, 3 or 4
`day 2, 3 or 4
`day 6 or 7
`and
`and
`and
`
`day 6 or 7
`day 6 or 7
`day 6 or 7
`
`—10.•
`
`—110-
`
`—110-
`—11116-
`
`Therapy
`(on a single day
`from day 8-14)
`Therapy
`Therapy
`Therapy
`(on a single day
`(on a single day
`(on a single day
`from day 8-14)
`from day 8-14)
`from day 8-14)
`
`450mg unlabelled
`tositumomab (over lhr)
`450mg unlabelled
`450mg unlabelled
`450mg unlabelled
`then
`tositumomab (over 1 hr)
`tositumomab (over 1 hr)
`tositumomab (over lhr)
`
`patient specific whole
`then
`then
`then
`body dose iodine 1131
`tositumomab
`patient specific whole
`patient specific whole
`patient specific whole
`(over 20 mins)
`body dose iodine 1131
`body dose iodine 1131
`body dose iodine 1131
`tositumomab
`tositumomab
`tositumomab
`(over 20 mins)
`(over 20 mins)
`(over 20 mins)
`
`Fig 1. Drug administration. The de-
`sired total body dose was 0.75 Gy and
`attenuated to 0.65 Gy for patients with
`platelet counts 100 to 149 ⫻ 109/L.
`
`unconfirmed [CR(u)] was defined as complete resolution of all
`disease-related symptoms but with residual focal abnormalities.
`Generally, these represented unchanging lesions of ⱕ 2 cm diam-
`eter by radiologic evaluation. The study was initiated before pub-
`lication of the International Workshop criteria,24 resulting in
`some difference in definition. Partial remission was defined as a
`greater than 50% reduction in the sum of products of the longest
`perpendicular diameters of all measurable lesions (SPPD); stable
`disease was defined as a less than 25% increase or less than 50%
`decrease in the SPPD with no new lesions. Progressive disease was
`defined as a ⱖ 25% increase of the SPPD from the nadir value. At
`disease progression, marker lesions were required to be more than
`2 ⫻ 2 cm diameter by radiographic evaluation, or more than 1 cm
`diameter by physical examination. Progressive disease also included
`the appearance of any new lesion. Response was investigator assessed.
`Duration of response was defined as the length of time from the day of
`first evaluation with a response to the first day of documented pro-
`gression. PFS was defined as the time from start of treatment (ie, the
`dosimetric dose) to first documented progression or death. Overall
`survival was defined from the date of start of therapy to death.
`
`Evaluation of Toxicity and Safety
`All adverse events from study entry through to week 13 were
`graded according to the National Cancer Institute Common Tox-
`icity Criteria (version 1.0). Any adverse event occurring after this
`period considered to be possibly or probably related to study drug
`was also recorded. Full blood counts were performed weekly from
`week 3 until week 9, or until grade 0 toxicity had been reached, and
`blood counts were repeated at weeks 13 and 26, and every 3
`months thereafter. The use of hematopoietic growth factors and
`blood products was at the discretion of the treating physician.
`History, physical examination, and hepatic, renal, and electrolyte
`studies were performed at weeks 3, 7, 13, and 26, and repeated
`every 3 months thereafter. Thyroid function tests (thyroid-
`stimulating hormone [TSH], free T4, and total T3) were per-
`formed at week 26 and repeated every 3 months thereafter. From 2
`years onward, patients were evaluated every 6 months, and data
`were collected for disease status, diagnosis of secondary myelodys-
`plasia or secondary acute myeloid leukemia, other secondary ma-
`lignancy, thyroid dysfunction, and use of thyroid medication.
`Serum human antimouse antibody (HAMA) and thyroid function
`analyses were also performed at these times.
`
`HAMA
`Detection of HAMA on serum samples was performed at each
`site using the ImmuSTRIP HAMA immunoglobulin G enzyme-
`linked immunosorbent assay test kit (Immunomedics Inc, Morris
`Plain, NJ). Samples were taken at baseline and at day 5 and evaluated
`before the administration of the dosimetric and therapeutic doses,
`respectively. Patients with a positive HAMA at baseline or on day 5
`did not receive subsequent 131I tositumomab therapy. HAMA assess-
`ment was repeated at weeks 7, 13, and 26, and as part of long-term
`follow-up. Independent central analysis also was performed (Co-
`vance Central Laboratory Services Inc, Indianapolis, IN).
`
`Statistical Analysis
`Data were analyzed through November 2003 for all patients who
`had received any study drug. Hematologic toxicity was analyzed only
`for those patients who received a therapeutic dose. The level of signif-
`icance for all comparative analyses was set at 0.05, with exact confi-
`dence limits calculated from binomial distributions. Analyses were
`performed using SAS version 6.12 (SAS Institute, Cary, NC). Dura-
`tion of response and survival data were analyzed using the censored
`data techniques of Kaplan-Meier.25 Differences in response rates
`across patient subgroups were tested for statistical significance by ␹2
`statistic (Yates corrected for two groups) and the log-rank test was
`used for duration of response by univariate analysis. The logistic
`regression model was used to perform multivariate analysis of re-
`sponse and the Cox proportional hazards model was used in multi-
`variate analysis of PFS. Cumulative incidence estimates incorporating
`the presence of competing risk were used for the proportion of pa-
`tients developing HAMA and hypothyroidism.26
`
`RESULTS
`
`Patient Characteristics
`Forty-four patients were enrolled onto this phase II
`study at two institutions between July 2, 1998, and February
`22, 2001. Three patients did not receive any study drug and
`are not included in the analysis (two patients had HAMA at
`baseline, in the absence of exposure to previous diagnostic
`or therapeutic murine proteins, and one patient withdrew
`consent before therapy). Thus, a total of 41 patients re-
`ceived a dosimetric dose of 131I tositumomab. One patient
`
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`
`1471
`
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`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
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`CEPHALON, INC. -- EXHIBIT 2008
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`

`
`Davies et al
`
`developed HAMA 12 days after dosimetry and did not
`receive the therapeutic dose. Clinical characteristics are
`documented in Table 1. The median age was 59 years
`(range, 36 to 90 years). Median follow-up of all patients is
`3.0 years (3.6 years for responders). The median activity
`administered to deliver a total body dose of 0.65 or 0.75 Gy
`was 95.1 mCi (range, 49.2 to 145.3 mCi; median, 3,519 MBq
`[range, 1,820 to 5,372 MBq]).
`
`Response to Treatment
`A response was observed in 31 (76%) of 41 patients.
`Twenty patients (49%) achieved either a CR (37%) or
`CR(u) (12%). At the earliest time of assessment, 7 weeks
`after the dosimetric dose, CR or CR(u) was only docu-
`mented in four of these 20 patients, indicating that time to
`maximal response may be slow. The median duration of
`remission for all responders was 1.3 years (95% CI, 0.7 years
`to not yet reached). For those in whom a CR or CR(u) was
`achieved, the median duration of remission has not yet been
`reached (95% CI, 1.1 year to not yet reached) but will
`exceed 2.5 years. Eleven (55%) of 20 patients continue in
`CR or CR(u) a median of 4.1 years (range, 2.6 to 5.2 years)
`after therapy. There was no difference in remission duration
`between CR and CR(u). The median PFS for all patients was
`0.8 years (95% CI, 0.5 years to not yet reached); for re-
`sponding patients, the median PFS was 1.7 years (95% CI,
`0.8 to 2.5 years; Figs 2 and 3).
`The highest overall response rate was seen in patients
`with follicular lymphoma (79%), with 59% achieving a CR
`or CR(u) (Table 2). The median duration of remission for
`patients with follicular lymphoma was 2.4 years (95% CI,
`0.9 years to not yet reached); for those patients achieving CR
`or CR(u), the median duration of remission was 3.4 years
`(95% CI, 1.3 years to not yet reached). There was no signif-
`icant difference in response rates between patients with
`disease transformation (71%) at the time of therapy and
`those without transformation (76%; P ⫽ .999); however,
`only seven patients were enrolled with transformed histol-
`ogy. Among the individuals with transformation, respond-
`ers included patients with large tumor volumes and ele-
`vated lactate dehydrogenase levels (Table 3).
`In univariate analysis, only lymph node diameter ⱖ 5
`cm was associated with a lower ORR and CR or CR(u) rate
`(P ⫽ .011; Table 4). A shorter duration of remission, how-
`ever, was not observed in these patients. Thrombocytopenia
`at baseline (and therefore attenuation of total body dose; P ⫽
`.002), elevated beta2-microglobulin at study entry (P ⫽ .004),
`and two or more prior chemotherapy regimens (P ⫽ .040)
`were associated with a statistically shorter median duration of
`remission. In an analysis for shorter PFS, elevated beta2-
`microglobulin (P ⫽ .007), receipt of two or more prior regi-
`mens (P ⫽ .005), and no response to last therapy (P ⫽ .005)
`were significant. In multivariate analysis, no variable signifi-
`cantly affected the ORR, CR or CR(u) rate, or PFS.
`
`Table 1. Patient Characteristics (N ⫽ 41)
`
`Characteristic
`
`No. of
`Patients %
`
`Age, years
`Median
`Range
`No. aged ⬎ 60
`Sex
`Male
`Female
`Karnofsky performance score
`Median
`Range
`Serum LDH
`Normal
`Elevated
`Beta2-microglobulin
`Normal
`Elevated
`Not recorded
`IPI
`0-1
`2
`3
`4-5
`Histology
`Follicular lymphoma
`Small lymphocytic lymphoma
`Lymphoplasmacytoid lymphoma
`Low-grade B unclassifiable
`Transformation to large B-cell lymphoma
`Maximum tumor diameter, cm
`ⱖ 5
`⬍ 5
`Bone marrow involvement
`Yes
`No
`Months from diagnosis to study entry
`Median
`Range
`Number of previous chemotherapy regimens
`1
`2
`⬎ 2
`Previous radiotherapy
`Yes
`No
`Response to last chemotherapy regimen
`CR or CR(u)
`PR
`SD
`PD
`Duration of response to most recent chemotherapy
`regimen, months
`Median
`Range
`Stage at study entry
`I or II
`III or IV
`
`59
`36-90
`
`39
`
`49
`51
`
`80
`60-100
`
`88
`12
`
`58
`37
`7
`
`49
`32
`15
`5
`
`71
`5
`5
`2
`17
`
`61
`39
`
`54
`46
`
`36
`10-246
`
`66
`41
`2
`
`17
`83
`
`46
`41
`7
`5
`
`20
`80
`
`9
`2-236
`
`16
`
`20
`21
`
`36
`5
`
`23
`15
`3
`
`20
`13
`6
`2
`
`29
`2
`2
`1
`7
`
`25
`16
`
`22
`19
`
`23
`17
`1
`
`7
`34
`
`19
`17
`3
`2
`
`8
`33
`
`Abbreviations: LDH, lactate dehydrogenase; IPI, International Prognostic
`Index; CR, complete remission; CR(u), unconfirmed complete remission;
`PR, partial remission; SD, stable disease; PD, progressive disease.
`
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`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
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`CEPHALON, INC. -- EXHIBIT 2008
`
`

`
`131I Tositumomab for Recurrent NHL
`
`1.1114
`
`I.
`
`L
`
`L
`
`I (cid:9) I (cid:9) Ili II (cid:9)
`
`II
`
`- Overall Survival
`Progression-Free Survival
`- Overall Survival
`- Overall Survival
`- Overall Survival
`Progression-Free Survival
`---- Progression-Free Survival
`---- Progression-Free Survival
`3 (cid:9)
`4 (cid:9)
`2
`5
`Time From Treatment (years)
`2
`3 (cid:9)
`4
`2 (cid:9)
`3 (cid:9)
`4
`2 (cid:9)
`3 (cid:9)
`4
`Fig 3. Progression-free and overall survival.
`Time From Treatment (years)
`Time From Treatment (years)
`Time From Treatment (years)
`
`1.0
`
`1.0
`1.0
`1.0
`0.8 -
`
`0.8 -
`0.8 -
`0.8 -
`0.6 -
`
`0.6 -
`0.6 -
`0.6 -
`0.4 -
`
`0.4 -
`0.4 -
`0.4 -
`0.2 -
`
`0.2 -
`0.2 -
`0.2 -
`
`0
`
`0
`0
`0
`
`Proportion Surviving
`
`Proportion Surviving
`Proportion Surviving
`Proportion Surviving
`
`111-
`1-,
`
`1
`1
`L__,
`
`- Complete Responders
`---- Partial Responders
`- Complete Responders
`- Complete Responders
`- Complete Responders
`---- Partial Responders
`---- Partial Responders
`---- Partial Responders
`
`1 (cid:9)
`
`4 (cid:9)
`3 (cid:9)
`2 (cid:9)
`Duration of Response (years)
`2 (cid:9)
`1 (cid:9)
`3 (cid:9)
`4 (cid:9)
`3 (cid:9)
`3 (cid:9)
`2 (cid:9)
`1 (cid:9)
`4 (cid:9)
`2 (cid:9)
`1 (cid:9)
`4 (cid:9)
`Fig 2. Duration of response by remission status.
`Duration of Response (years)
`Duration of Response (years)
`Duration of Response (years)
`
`5 (cid:9)
`
`5 (cid:9)
`5
`5
`
`6
`
`6
`
`1.0
`
`1.0
`1.0
`1.0 (cid:9)
`0.8
`
`
`
`0.8
`0.8 -
`0.8 -
`0.6 -
`
`0.6 -
`0.6 -
`0.6 -
`0.4 -
`
`0.4 -
`0.4 -
`0.4 -
`0.2 -
`
`0.2 -
`0.2 -
`0.2 -
`
`Proportion in Response
`
`Proportion in Response
`Proportion in Response
`Proportion in Response
`
`Toxicity
`A total of 295 adverse events (AEs) were reported, with
`36 (88%) of 41 patients experiencing an AE considered
`possibly or probably related to the study drug. Nonhema-
`tologic AEs occurring in more than 5% of patients are listed
`in Figure 4. These were typically mild and self-limiting.
`During both the dosimetric and therapeutic infusions,
`seven patients (18%) experienced an AE considered possi-
`bly or probably related to study drug. All of these were grade
`1 or 2, with somnolence occurring most frequently (7%).
`Toxicity was principally hematologic, with grade 3 or 4
`thrombocytopenia, neutropenia, and anemia occurring in
`32%, 45%, and 5% of patients, respectively (Fig 5). A platelet
`count below 10 ⫻ 109/L was documented in only 5% of pa-
`tients and neutropenia less than 0.5 ⫻ 109/L was documented
`in 20% of patients. The median time to platelet nadir was 31
`days (range, 18 to 64 days), median time to neutrophil nadir
`was 42 days (range, 10 to 53 days), and median time to hemo-
`globin nadir was 46 days (range, 13 to 95 days). The median
`nadir values were 78 ⫻109/L (range, 6 to 184 ⫻ 109/L) for
`platelets, 1.2 ⫻ 109/L (range, 0.1 to 4.5 ⫻ 109/L) for neutro-
`
`phils, and 11.3 g/dL (range, 6.6 to 14.8 g/dL) for hemoglobin.
`Only eight patients (20%) required blood product support:
`eight patients (20%) received a median of three platelet trans-
`fusions (range, one to five) and five patients (12.5%) received a
`median of two red cell transfusions (range, one to three).
`Growth factor support (granulocyte colony-stimulating fac-
`tor) was used in only two patients (5%). Abnormalities of
`serum chemistry were rare, although one patient developed
`grade 4 hypercalcemia in the context of progressive trans-
`formed follicular lymphoma.
`Forty-six AEs that may have been infection related were
`recorded, leading to hospitalization in six patients. Two pa-
`tients developed febrile neutropenia, one patient developed
`pneumonia, and one patient developed herpes zoster. A reac-
`tivation of herpes simplex type II occurred in one patient and
`one patient required admission with an unidentified self-
`limiting viral-type illness. HAMA developed in four patients
`(cumulative incidence at 2 years of 10%), with no apparent
`effect on response rate (P ⫽ .999) or remission duration (P ⫽
`.799). At the time of study entry, elevation of TSH was ob-
`served in three patients. In follow-up, five of 38 assessable
`
`Table 2. Response and Duration of Response According to Histology
`
`ORR
`
`CR
`
`CR(u)
`
`PR
`
`Failⴱ
`
`Median Duration of Response (months)
`
`Histology
`
`No. of
`Patients
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`No. of
`Patients %
`
`All
`Responders 95% CI
`
`Patients
`Achieving
`CR or CR(u)
`
`All
`Indolent
`Follicular
`Other
`Transformation to large
`B-cell lymphoma
`
`41
`34
`29
`5
`7
`
`31
`26
`23
`3
`5
`
`76
`76
`79
`60
`71
`
`15
`14
`13
`1
`1
`
`37
`41
`45
`20
`14
`
`5
`4
`4
`0
`1
`
`12
`12
`14
`0
`14
`
`11
`8
`6
`2
`3
`
`27
`24
`21
`40
`43
`
`10
`8
`6
`2
`2
`
`24
`24
`21
`40
`29
`
`15
`13
`28
`7
`41
`
`8 to NR
`8 to NR
`11 to NR
`4 to 8
`4 to NR
`
`NR
`40
`40
`8
`NR
`
`95% CI
`
`13 to NR
`13 to NR
`13 to NR
`
`NR to NR
`
`Abbreviations: ORR, overall response rate; CR, complete remission; CR(u), unconfirmed complete remission; PR, partial remission; Fail, treatment failure;
`NR, not yet reached.
`ⴱComprises stable and progressive disease.
`
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`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2008
`
`

`
`Davies et al
`
`Table 3. Patients With Transformation to Large B-Cell Lymphoma
`
`Duration of
`Response to
`Previous
`Chemotherapy
`(months)
`
`Stage at
`Study Entry
`
`Bone Marrow
`Involvement
`
`Maximal
`Tumor
`Diameter
`(cm)
`
`LDH at
`Study
`Entry
`
`Best
`Response
`
`Duration of
`Remission
`(months)
`
`Survival From
`Dosimetry
`(months)
`
`6
`
`3
`
`—
`
`2
`
`9
`
`—
`
`183
`
`III
`
`IV
`
`IV
`
`II
`
`II
`
`III
`
`IV
`
`No
`
`10
`
`604
`
`PD
`
`—
`
`⬍ 10% FL
`
`4
`
`453
`
`PR
`
`⬍ 5% FL
`
`12
`
`2,069
`
`PR
`
`4
`
`5
`
`No
`
`No
`
`No
`
`⬍ 10% FL
`
`5
`
`6
`
`9
`
`8
`
`285
`
`507
`
`596
`
`387
`
`CR(u)
`
`47⫹
`
`PR
`
`PD
`
`CR
`
`41
`
`—
`
`31⫹
`
`31
`
`7
`
`51⫹
`
`50⫹
`
`49⫹
`
`12
`
`33⫹
`
`Therapy at
`Recurrence After
`Iodine-131
`Tositumomab
`
`CHOP
`VP16/araC
`MTX
`LBCMVD-56
`nil
`
`CHOP
`VP16/araC
`BEAM ⫹ ASCT
`LBCMVD-56
`—
`
`Expectant
`(FL recurrence)
`CHOP
`RT
`MTX
`
`—
`
`Patient
`
`054018
`
`Previous
`Therapy
`CB3PR
`
`056018
`
`059018
`
`062018
`
`063018
`
`066018
`
`CB3PR
`FMD3PR
`CB3SD
`Pred3PR
`CB3SD
`
`CHOP3UK
`CEOP3CRⴱ
`CHOP3CR(u)ⴱ
`
`CB3PR
`FMD3PD
`
`073019
`
`VAC3CR
`
`Abbreviations: UK, outcome unknown; CB, chlorambucil; PR, partial response; FMD, fludarabine, mitoxantrone, and dexamethasone; SD, stable disease;
`CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisolone; CEOP, cyclophosphamide, epirubicin, vincristine, and prednisolone; CR, complete
`response; CR(u), unconfirmed complete remission; PD, progressive disease; VAC, vincristine, doxorubicin, and cyclophosphamide; MTX, methotrexate;
`VP16/araC, etoposide and cytarabine; LBCMVD-56, lomustine, daily subcutaneous bleomycin, chlorambucil, methotrexate, vinblastine, and dexamethasone;
`BEAM ⫹ ASCT, carmustine, etoposide, cytarabine, and melphalan with peripheral-blood stem-cell rescue; FL, follicular lymphoma; LDH,
`lactate
`dehydrogenase (normal range ⬍ 490 U/L).
`ⴱTherapy given for transformed disease (ie, iodine I 131 tositumobab given as second-line therapy after transformation).
`
`patients had an elevated TSH, with thyroxine treatment initi-
`ated in two patients. The cumulative incidence for hypothy-
`roidism or subclinical hypothyroidism was 14% at 2 years.
`With 123 patient-years of follow-up, one patient has de-
`veloped secondary myelodysplasia (therapy-related myelodys-
`plasia [t-MDS]; annualized incidence 0.8%/yr (95% CI, 0.1%
`to 5.8%/yr). This was diagnosed 53 months after therapy in a
`patient that had previously received two regimens (chloram-
`bucil and fludarabine plus mitoxantrone plus dexamethasone)
`before 131I tositumomab. Bone marrow morphology exami-
`nation, performed before therapy for recurrence, revealed in-
`filtration with follicular lymphoma and dysplastic features [cy-
`togenetics demonstrated del(13q) by fluorescent in situ
`hybridization, reported in follicular lymphoma and at a lower
`frequency in MDS]. The patient’s peripheral blood count re-
`mains normal 6 months after diagnosis.
`Survival
`The median survival from the dosimetric dose has not
`been reached (95% CI, 2.9 years to not yet reached). Sixteen
`patients have died, all as a result of progressive lymphoma (Fig
`3). Eight of these patients had responded to 131I tositumomab,
`including two patients who had achieved a CR after therapy;
`none of the eight patients, however, had a duration of response
`longer than 1 year. Twenty-four patients have received a me-
`dian of two (range, one to five) additional therapies after 131I
`
`tositumomab; in the minority of patients, dose reductions
`were necessary (Table 5).
`
`DISCUSSION
`
`This study provides evidence of the efficacy and safety of
`131I tositumomab at first or second recurrence of indolent
`or transformed indolent B-cell lymphoma. A single thera-
`peutic course of 131I tositumomab results in both a high
`ORR (76%) and CR rate (49%). These response rates fall
`between those observed in heavily pretreated individuals
`(ORR, 57%; CR or CR(u), 32%), after a median of four
`prior therapies,20 and those seen in newly diagnosed follic-
`ular lymphoma (ORR, 95%; CR 74%).27 Responses were
`noted in all subgroups; only in patients with tumor diame-
`ters ⱖ 5 cm was the response and CR rate statistically
`inferior. Activity was particularly notable in the follicular
`lymphoma subgroup (ORR, 79%; CR or CR(u), 59%),
`as has been previously reported with CD20-directed
`immunotherapy,28-30 although the number of patients treated
`with other histologies was small. Importantly, responses have
`proven to be durable, with 11 of 31 responding individuals
`remaining in CR or CR(u) a minimum of 2.6 years (median,
`4.1 years) after a single therapeutic dose. Consistent with data
`from patients treated with conventional chemotherapy,5 there
`
`1474
`
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`
`Downloaded from jco.ascopubs.org on July 27, 2015. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`CEPHALON, INC. -- EXHIBIT 2008
`
`

`
`131I Tositumomab for Recurrent NHL
`
`Table 4. Subgroup Analysis for Response and Duration of Response
`
`Characteristic
`
`No. of
`Patients
`
`% ORR
`
`Pⴱ
`
`% CR/
`CR(u)
`
`25
`16
`
`8
`33
`
`25
`16
`
`5
`36
`
`3
`15
`23
`
`76
`75
`
`75
`76
`
`60
`100
`
`60
`78
`
`100
`67
`78
`
`77
`74
`
`.999
`
`.999
`
`.011
`
`.755
`
`.677
`
`.999
`
`52
`44
`
`62
`45
`
`32
`75
`
`0
`56
`
`67
`33
`57
`
`41
`58
`
`Median
`Duration of
`Remission
`