EXHIBIT 2009
`
`EXHIBIT 2009
`
`Cephalon Exhibit 2009
`
`Fresenius v. Cephalon IPR2016-00098
`
`

`
`Cancer Therapy: Clinical
`
`Phase II Trial of Short-Course CHOP-R Followed by 90Y-ibritumomab
`Tiuxetan and Extended Rituximab in Previously Untreated
`Follicular Lymphoma
`Samuel A. Jacobs,1Steven H. Swerdlow,2 Jeffrey Kant,2 Kenneth A. Foon,1Rachel Jankowitz,1
`Stephanie R. Land,5 Nicholas DeMonaco,6 Judith Joyce,3 Jennifer L. Osborn,1Terry L. Evans,1
`Patricia M. Schaefer,4 and The Minh Luong5
`
`Abstract Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL),
`including rituximab-refractory FL. This study was designed to determine the CR rate with short-
`course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone,
`and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab
`as first-line treatment.
`Experimental Design: Between March 2004 and February 2007, 60 patients with stage II to IV
`symptomatic or bulky FL from a single institution supported by a large community net-
`work entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT
`followed by four additional weekly treatments with rituximab. Response was determined using
`fusion [18 F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography
`(CT) imaging.
`Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy.
`The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis,
`the complete response (CR) rate after CHOP-R, as assessed by CTand PET imaging, was 40%
`and 46%, respectively. After RIT, the CR rate improved, as assessed by CTand PET imaging, to
`82% and 89%, respectively. Ten patients have progressed, including eight from best response
`of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with
`3 of 37 patients who were PET negative (P = 0.010).
`Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course
`chemoimmunotherapy and consolidation RITand extended rituximab resulted in a high CR rate.
`Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.
`
`After three decades with little advance in the outcome for
`patients with follicular lymphoma (FL), the addition of the
`anti-CD20 chimeric monoclonal antibody, rituximab, dramat-
`ically changed the overall response rates (ORR) and may be
`affecting survival (1). As a single agent, rituximab was shown in
`a nonrandomized pivotal trial of 166 patients with relapsed
`
`Authors’ Affiliations: Departments of 1Medicine, 2Pathology, and 3Radiology,
`4Clinical Research Services, University of Pittsburgh Medical Center Cancer
`Centers, 5Department of Biostatistics, Graduate School of Public Health, NSABP
`and University of Pittsburgh Cancer Institute, and 6Oncology-Hematology
`Associates, Pittsburgh, Pennsylvania
`Received 4/11/08; revised 5/28/08; accepted 6/29/08.
`Grant support: BiogenIdec Pharmaceuticals and National Cancer Institute CCSG/
`IRAT P30 CA 047904. The trial is registered at http://www.clinicaltrials.gov
`(identifier: NCT00177554.)
`The costs of publication of this article were defrayed in part by the payment of page
`charges. This article must therefore be hereby marked advertisement in accordance
`with 18 U.S.C. Section 1734 solely to indicate this fact.
`Requests for reprints: Samuel A. Jacobs, Department of Medicine, University of
`Pittsburgh Medical Center Cancer Centers, 5150 Centre Avenue, Suite 510,
`University of Pittsburgh Medical Center Cancer Pavilion, Pittsburgh, PA 15232.
`Phone: 412-235-1278; Fax: 412-623-4655; E-mail: jacobssa@upmc.edu.
`F 2008 American Association for Cancer Research.
`doi:10.1158/1078-0432.CCR-08-0529
`
`low-grade lymphoma to have an ORR of 48% and a complete
`response (CR) of 6% (2). Lacking significant myelosuppres-
`sion, investigators immediately recognized that rituximab was
`an ideal agent to combine with chemotherapy. Phase II studies
`combining chemotherapy with rituximab in relapsed and
`previously untreated patients with FL showed impressive ORR
`and CR rates of 90% to 100% and 50% to 70%, respectively
`(3, 4). Subsequently, two large randomized trials confirmed the
`benefit of combining chemotherapy with immunotherapy
`with CR rates of 41% and 20% compared with 10% and 17%
`with chemotherapy alone, significantly longer duration of
`response, and possibly, a survival advantage (5, 6).
`Radioimmunotherapy is a promising new therapy demon-
`strating complete and partial responses in chemotherapy and
`rituximab refractory patients. As early as 1996, a phase II study
`using single agent 131-iodine (I) tositumomab (Bexxar; Glaxo-
`SmithKline), in previously untreated patients with FL, resulted
`in an ORR of 95% and a CR rate of 75% (7). In 2002, 90-
`yttrium(Y) ibritumomab tiuxetan (RIT; Zevalin; Biogen Idec)
`was approved by the Food and Drug Administration for
`the treatment of relapsed and refractory low-grade FL. RIT
`received approval based on ORR of 73% to 83% and CR rates
`of 15% to 51% depending upon the previous number and type
`of prior therapies (8, 9). Several small studies have reported
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`

`
`CHOP-R Followed by RITas First-LineTherapy in Follicular Lymphoma
`
`Translational Relevance
`
`The optimal treatment of advanced stage follicular
`lymphoma remains to be determined. With the addition of
`immunotherapy and radioimmunotherapy, the overall and
`complete response rates have improved. Furthermore,
`there is suggestive evidence that overall survival may be
`improved. In this study, we have sequenced a short-course
`of chemoimmunotherapy, cyclophosphamide, doxorubicin,
`vincristine, prednisone, and rituximab  3 cycles, followed
`by radioimmunotherapy, 90-Y ibritumomab tiuxetan, and
`immunotherapy. Using fusion [18 F] fluorodeoxyglucose-
`positron emission tomography ^ computed tomography
`scans to determine response rate, a complete response
`was seen in 96% of patients who completed the thera-
`peutic regimen. The progression-free survival and overall
`survival for patients completing all protocol therapy with a
`median follow-up of 19.7 months were 78% and 100%.
`Much longer follow-up will be necessary to determine
`the durability of these responses. This and additional
`studies will be necessary to define the appropriate place
`for radioimmunotherapy in the therapeutic algorithm for
`advanced follicular lymphoma.
`
`sequencing chemotherapy with or without rituximab fol-
`lowed by radioimmunotherapy as first-line therapy. The ORRs
`were 90% to 100% and CR rates ranging from 69% to 86%
`(10 – 15).
`Based on these developments, we designed a phase II trial
`to take advantage of the exquisite sensitivity of FL to RIT and
`to decrease the amount of exposure to cytotoxic drugs. We
`reduced the number of cycles of standard dose cyclophos-
`phamide, doxorubicin, vincristine, prednisone, and rituximab
`(CHOP-R) from 6 to 3 and followed with RIT and extended
`rituximab. The primary end points were safety and efficacy.
`Fusion [18 F] fluorodeoxyglucose-positron emission tomogra-
`phy (PET)-computed tomography (CT) imaging was used to
`determine CR.
`
`Materials and Methods
`
`Patients. This phase II, nonrandomized study, was carried out at a
`single institution supported by a large community oncology network.
`Radioimmunotherapy was administered at the central academic hub,
`the Hillman Cancer Center, but over half
`the patients received
`chemoimmunotherapy and follow-up at community offices. Between
`March 2004 through February 2007, 60 patients were enrolled.
`Eligibility criteria were as follows: FL grade of 1, 2, and 3 by WHO
`criteria; age of z18 y; no prior chemotherapy or monoclonal antibody
`therapy; prior radiation therapy was allowed if <25% of active bone
`marrow was exposed; Ann Arbor stages of
`II
`to IV with either
`symptomatic or bulky disease (>5 cm); performance status of 0 to 2;
`and measurable disease. A baseline MUGA scan within the institutional
`reference range was required. Patients with known HIV-related
`lymphoma were excluded. All patients signed a written informed
`consent approved by the University of Pittsburgh Institutional Review
`Board. Each patient received a FLIPI score based on age, stage,
`hemoglobin level, number of nodal sites of disease, and serum lactate
`dehydrogenase level and was classified as either asymptomatic,
`symptomatic, or with B symptoms. The largest cross-sectional dia-
`meter of a nodal mass was recorded as either <5 cm, from 5 to 10 cm,
`
`or >10 cm. A baseline PET-CT scan was recorded as either positive or
`negative for fluorodeoxyglucose uptake.
`Drug administration. CHOP-R was administered at 21-d intervals.
`Rituximab 375 mg/m2 i.v was given on day 1 of each cycle. Standard
`Eastern Cooperative Oncology Group doses of CHOP were used (16).
`Doses were not modified, but use of growth factor and/or prophy-
`lactic antibiotics was allowed. For an absolute neutrophile count
`of <1,500/mm3 or a platelet count of <100,000/mm3 on day 1 of
`subsequent cycles, chemotherapy was delayed 1 wk. A 2-wk delay
`was allowed for neutropenic fever. After three cycles of CHOP-R,
`patients were restaged with fusion PET-CT scan and bone marrow
`biopsy before receiving the RIT regimen. To proceed with RIT, bone
`marrow recovery was required as evidenced by an absolute neutrophile
`count of z1,500/mm3, a platelet of z100,000/mm3, bone marrow
`cellularity of z15%, and lymphoma infiltration of <25%. The details
`of RIT have been described elsewhere (17). Within 1 to 2 wk of
`receiving RIT, patients began an additional 4-wk course of rituximab
`375 mg/m2 on days 1, 8, 15, and 22.
`Clinical response criteria. Disease response and progression were
`determined by physical examination and fusion PET-CT scan done
`before therapy, 3 to 4 wk after 3 cycles of CHOP-R, at 12 wk post-
`RIT therapy to minimize posttherapy inflammatory changes (18, 19),
`and thereafter at 6-mo intervals. Bone marrow biopsy was done at
`baseline, after 3 cycles of CHOP-R, at 12 wk post-RIT therapy if either
`of the prior biopsies were positive. A CR included the following:
`resolution of all palpable peripheral adenopathy, a normocellular
`bone marrow without evidence of lymphomatous infiltration by histo-
`logy or flow cytometry, the CT portion of the PET-CT scan meeting the
`international working group criteria, or the PET portion read visually
`as negative (18, 20). Partial response, stable disease, and progressive
`disease were determined by international working group criteria (20).
`Assessment of molecular response. Quantitative PCR was done as
`described (21) using FAM-labeled forward primers directed toward
`BCL2 mbr or mcr sequences and a reverse consensus primer for the IgH
`joining region. Copies of t(14;18)-positive DNA were calculated from
`standard curves of serially diluted plasmids containing inserts of either
`mbr or mcr BCL2/IgH joining region translocation regions from
`t(14;18)-positive patients. Because this aspect of the study required
`potentially serial bone marrows, participation was optional.
`Toxicity. Adverse events were summarized for all patients who
`began any study therapy using the Common Toxicity Criteria of the
`National Cancer Institute version 3.0. All serious adverse events were
`discussed at a monthly disease center meeting. Serious adverse events
`that were either related, possibly or probably related to study treatment,
`but unexpected, were reported to the Institutional Review Board.
`Statistical analysis. Follow-up time was computed using Kaplan-
`Meier with reverse censoring for deaths (22). We compared CR rates by
`disease characteristics with Fisher’s exact tests. Progression-free survival
`(PFS) was calculated as the time from the start of treatment to the date
`of lymphoma progression or death from any cause. Overall survival
`(OS) was computed as the time from the start of treatment to death
`from any cause. PFS and OS were computed based on all patients with
`follow-up information. Statistical analyses were done with S-Plus
`version 7.0 (Insightful Corp.).
`
`Results
`
`Patient characteristics. Sixty patients met eligibility criteria
`and are included in baseline characteristics, safety, and re-
`sponse calculations (Table 1). Five patients did not complete
`protocol therapy and follow-up (Fig. 1). The median age was
`57 years (range, 27-78 years). The histologic or cytologic
`features included follicular grade 1 (28%), grade 2 (45%), and
`grade 3 (22%), and for 3 patients (5%),
`the grade was
`undetermined as the diagnosis was made on fine needle
`aspirate. The FLIPI risk groups included were as follows: low,
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`
`Cancer Therapy: Clinical
`
`Table 1. Clinical characteristics of 60 patients
`enrolled on study
`
`Age (y)
`<60
`z60
`Gender
`Male
`Female
`Histologic grade
`1
`2
`3
`Undetermined
`Stage
`II
`III
`IV
`FLIPI risk
`Low
`Intermediate
`High
`Bone marrow
`Negative
`Positive
`Bulk lesion
`<5 cm
`5-10 cm
`>10 cm
`
`39 (65%)
`21 (35%)
`
`32 (53%)
`28 (47%)
`
`17 (28%)
`27 (45%)
`13 (22%)
`3 (5%)
`
`6 (10%)
`19 (32%)
`35 (58%)
`
`15 (25%)
`20 (33%)
`25 (42%)
`
`25 (42%)
`35 (58%)
`
`30 (50%)
`21 (35%)
`9 (15%)
`
`with 0 to 1 risk factors (25%); intermediate, with 2 risk factors
`(33%); and high, with 3 to 5 risk factors (42%). Bulky nodal
`disease was <5 cm in 30 patients (50%), 5 to 10 cm in 21
`(35%), and >10 cm in 9 (15%). There were 30 (50%)
`asymptomatic patients, 12 (20%) with symptoms such as pain
`or excessive fatigue, and 18 (30%) with frank B symptoms.
`Bone marrow was considered positive if there was unequivocal
`involvement by histology and/or flow cytometry; equivocal or
`‘‘suspicious’’ involvement was considered to be negative. Base-
`line bone marrow positivity was recorded as either <25% or
`>25% of the marrow space infiltrated with lymphoma. Thirty-
`five patients (58%) had positive bone marrow and 10 (17%)
`had >25% involvement. The baseline fluorodeoxyglucose PET
`scan was positive in 59 of 60 patients.
`BCL2 gene translocation determination was measured in
`bone marrow specimens at baseline in 31 patients. Twelve of
`these 31 samples were tested at our institution, and 4 were
`positive. Twenty-eight of these samples were then sent to an
`outside laboratory and 6 were positive (US LABS).
`Toxicity. The expected CHOP-R related toxicities are shown
`in Table 2. Two patients died during the CHOP-R phase. One of
`these patients developed neutropenic sepsis during CHOP-R
`and presented to the hospital with hypotension and multisys-
`tem organ dysfunction. The other patient had a history of
`alcoholic cirrhosis and esophageal varices but was clinically
`compensated at
`the start of
`treatment. He had a lethal
`gastrointentestinal bleed 48 hours after the start of chemother-
`apy. A third patient withdrew from the study after cycle 1 of
`CHOP-R because of decreased performance status, generalized
`weakness, and myopathy. One patient was removed from the
`study when a metastatic colon cancer was diagnosed after cycle
`3 of CHOP-R. One patient was withdrawn from the study
`because of noncompliance. Grade 3 to 4 neutropenia occurred
`in 23 (39%) patients, and grade 3 to 4 thrombocytopenia
`
`occurred in 3 (5%) patients. There were a total of 3 (5%) hos-
`pitalizations due to neutropenic fever.
`frequent
`Radioimmunotherapy-related toxicities. The most
`toxicity associated with RIT was myelosuppression (Table 2).
`Grade 3 to 4 neutropenia occurred in 28 (51%) patients.
`However, there was only one hospitalization for neutropenic
`fever. The incidence of grade 3 and 4 thrombocytopenia
`was 44%. One patient experienced a prolonged episode of
`serum sickness-like toxicity. This case has been described
`elsewhere (23).
`Second malignancies. Three patients were diagnosed with
`second malignancies. One patient was diagnosed with meta-
`static colon cancer on the PET-CT imaging study done after
`cycle 3 of CHOP-R. Another patient developed a PET-positive
`pelvic mass, which was diagnosed as an endometrial cancer
`11 months after completing therapy. A third patient was found
`on routine mammography, 9 months after protocol therapy,
`to have an early stage breast cancer. In retrospect, two of the
`malignancies were likely present at the time of the diagnosis of
`FL. The finding of a solid tumor malignancy is not unexpected
`in this age group in the general population (24). There has not
`been any case of MDS or acute myelogenous leukemia observed
`in our patients.
`Clinical outcomes. Of the 60 patients entering this trial, 56
`were evaluable for response after 3 cycles of CHOP-R (Fig. 1).
`There were 55 patients who completed all protocol therapy.
`According to intent-to-treat analysis of 60 patients consented,
`the CR rate after CHOP-R as determined by CT and PET
`imaging was 40% and 44%, and increased to 82% and 89%
`after RIT and extended rituximab, respectively. For the 55
`patients who completed both CHOP-R and RIT and extended
`rituximab, the CR rate was 44% (CT) and 67% (PET), and
`increased to 89% (CT) and 96% (PET), respectively. In specific
`
`Assessed for
`Assessed for
`eligibility (n=61)
`eligibility (n=61)
`
`Consented (n=60)
`Consented (n=60)
`
`
`CHOP-R Therapy CHOP-R Therapy
`
`(n=60) (n=60)
`
`PET neg
`PET neg
`
`(n=37) (n=37)
`
`PET pos
`PET pos
`
`(n=19) (n=19)
`
`r
`r
`
`
`RIT Therapy RIT Therapy
`
`(n= 8) (n= 8)
`
`Excluded — Not
`Excluded — Not
`meeting eligibility
`meeting eligibility
`
`criteria (n=1) criteria (n=1)
`
`Discontinued CHOP-R
`Discontinued CHOP-R
`Non-compliant (n=1)
`Non-compliant (n=1)
`Septic death (n=1)
`Septic death (n=1)
`GI bleed (n=1)
`GI bleed (n=1)
`Neuropathy (n=1)
`Neuropathy (n=1)
`
`
`Colon ca diagnosis Colon ca diagnosis
`
`(n=1) (n=1)
`
`
`PET neg PET neg
`
`(n=16) (n=16)
`
`
`PET pos PET pos
`
`(n=2) (n=2)
`
`
`Progressed Progressed
`
`(n=5, 31%) (n=5, 31%)
`
`
`Progressed Progressed
`
`(n=2, 100%) (n=2, 100%)
`
`
`RIT Therapy RIT Therapy
`
`(n=37) (n=37)
`
`
`
`ri ri
`
`PET neg
`PET neg
`(n=37)
`(n=37)
`
`
`Progressed Progressed
`
`(n=3, 8%) (n=3, 8%)
`
`Fig. 1. Study enrollment, treatment, and clinical outcomes.
`
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`
`CHOP-R Followed by RITas First-LineTherapy in Follicular Lymphoma
`
`Table 2. Toxicity associated with CHOP-R and RIT
`
`Toxicity
`
`CHOP-R (n = 60)
`
`RIT (n = 55)
`
`Hemorrhage, GI
`Serum sickness
`Anemia
`Neutropenia
`Febrile neutropenia
`Thrombocytopenia
`Muscle weakness
`Hyperglycemia
`
`Grade 3
`
`Grade 4
`
`10 (17%)
`2 (3%)
`3 (5%)
`1 (1.6%)
`
`13 (22%)
`
`1 (1.6%)
`
`Grade 5
`
`1 (1.6%)
`
`1 (1.6%)
`
`Abbreviation: GI, gastrointestinal.
`
`Grade 3
`
`Grade 4
`
`Grade 5
`
`1 (1.8%)
`1 (1.8%)
`17 (31%)
`1 (1.8%)
`13 (24%)
`
`11 (20%)
`
`11 (20%)
`
`regard to the PET responses in the 55 patients who completed
`both phases of the study, after CHOP-R, 37 (67%) patients
`were PET negative and 18 (33%) were PET positive. After RIT,
`another 16 patients became PET-negative for a total PET CR rate
`of 96%. PET CR rate by stage, FLIPI score, bulk disease,
`histologic grade, and bone marrow status is shown in Table 3.
`The mean estimated follow-up for all 60 patients was 19
`months (median, 19.7-35.9 months). Ten patients progressed
`(eight whose best response was CR, one from partial response,
`and one from stable disease). Among these 10 patients who
`progressed (Table 4), 7 were PET positive after CHOP-R. Two
`patients did not achieve PET-negative status after RIT and
`progressed within 6 months. Seven of the 18 patients who
`remained PET-positive after three cycles of CHOP-R and who
`then received RIT progressed, compared with only 3 of 37
`patients who were PET negative after CHOP-R (P = 0.010). All
`of the progressed patients had stage IV disease with bone
`
`marrow involvement. Four patients who progressed had >25%
`marrow involvement at baseline. Biopsy material was available
`for 8 of the 10 patients at the time of relapse. One patient had
`transformation to a diffuse large B-cell lymphoma, whereas
`the others continued to have a follicular pattern. On an intent-
`to-treat basis, the PFS and OS at 24 months were 73% and
`94.8%, respectively. The PFS and OS for patients completing
`all protocol therapy at 24 months were 78.4% and 100%
`(Fig. 2A and B).
`
`Discussion
`
`This study was designed based on the favorable experience
`using I-131 tositumomab as a single agent
`in previously
`untreated patients with FL (7). In that study, the ability to
`achieve a CR was significantly decreased in patients with a
`maximal nodal mass of >5 cm and bone marrow involvement.
`
`Table 3. CR rate by patient characteristic
`
`Characteristic
`
`n = 60 (intent to treat, all patients)
`
`n = 55 (patients who completed study protocol and RIT)
`
`CR by PET
`
`Statistical significance
`
`CR by PET
`
`Statistical significance
`
`Number
`
`%
`
`Number
`
`%
`
`Stage
`II
`III
`IV
`FLIPI
`Low
`Intermediate
`High
`Bulk
`<5 cm
`5-10 cm
`>10 cm
`Grade
`1
`2
`3
`Undetermined
`BM
`Negative
`Positive
`
`6/6
`19/21
`28/33
`
`15/15
`18/19
`20/26
`
`29/30
`19/22
`5/8
`
`16/17
`23/27
`11/13
`3/3
`
`23/25
`30/35
`
`100%
`90%
`85%
`
`100%
`95%
`77%
`
`97%
`86%
`63%
`
`94%
`85%
`85%
`100%
`
`92%
`86%
`
`All P values from Fisher’s exact test.
`
`0.726
`
`0.063
`
`0.031
`
`0.772
`
`0.688
`
`6/6
`19/19
`28/30
`
`15/15
`18/18
`20/22
`
`29/29
`19/20
`5/6
`
`16/16
`23/24
`11/12
`3/3
`
`23/23
`30/32
`
`100%
`100%
`93%
`
`100%
`100%
`91%
`
`100%
`95%
`83%
`
`100%
`96%
`92%
`100%
`
`100%
`94%
`
`0.616
`
`0.329
`
`0.091
`
`0.741
`
`0.775
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`
`Cancer Therapy: Clinical
`
`Table 4. Characteristics of progressed patients
`
`Relapsed Pt # Age Bone marrow Stage
`
`Grade
`
`FLIPI risk PET post-CHOP PET post-RIT Bulk (cm) Relapse biopsy
`
`2
`6
`9
`13
`16
`17
`33
`45
`48
`53
`
`46
`70
`59
`42
`61
`62
`60
`51
`51
`66
`
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`
`IV
`IV
`IV
`IV
`IV
`IV
`IV
`IV
`IV
`IV
`
`2
`2
`3
`3
`1
`1
`Undetermined
`2
`1
`2
`
`2
`3
`2
`3
`3
`3
`3
`4
`2
`3
`
`Pos
`Pos
`Pos
`Pos
`Neg
`Neg
`Neg
`Pos
`Pos
`Pos
`
`Neg
`Neg
`Neg
`Pos
`Neg
`Neg
`Neg
`Pos
`Neg
`Neg
`
`3.4
`5.8
`14
`13.5
`4.8
`6
`4.2
`7.4
`7
`3.8
`
`Follicular
`Follicular
`Follicular
`Follicular
`N/A
`Follicular
`N/A
`Large cell
`Follicular
`Follicular
`
`Abbreviations: Pos, positive; neg, negative; N/A, not available.
`
`For all patients, PFS at a median follow-up of nearly 8 years was
`50%; however, for partial responders, median PFS was 1 year,
`and for complete responders, which includes 75% of patients,
`median PFS has not been reached at 8 years (25). Therefore,
`this suggested that in the subset of patients who did not achieve
`a CR, radioimmunotherapy alone might be insufficient to
`achieve long-term remissions. The design of our study was to
`take advantage of the expected synergy of combining a short-
`course of chemoimmunotherapy as a debulking therapy,
`followed by consolidation of the remission with RIT and
`extended rituximab, thus decreasing the duration of therapy
`and possibly decreasing the potential long-term toxicities of
`chemotherapy. Although the rationale for extended rituximab
`was based on the superior event-free survival in chemotherapy-
`naBve patients treated with eight doses of rituximab compared
`with the standard four doses without chemotherapy (26), the
`extended rituximab does potentially confound the precise
`contribution of RIT. Our study included patients with high-
`risk characteristics, including grade 3 histology (22%), inter-
`mediate and high FLIPI risk (75%), bulky disease of z5 cm
`(50%), B symptoms (30%), and baseline bone marrow
`involvement of >25% (17%). Nonetheless,
`this regimen
`
`resulted in a CR rate by PET imaging of 96% in those patients
`completing protocol therapy.
`Since the publication of the international working group
`criteria for response assessment of lymphoma (20), CT has been
`the predominant imaging study for judging response rate.
`Shortcomings of determining a CR by CT are well-known,
`including relatively minor differences in the measurement of the
`size of a node and the inability to determine if residual enlarged
`nodes by size criteria contain viable lymphoma. PET has gained
`widespread use as a functional imaging tool for staging and
`response assessment in lymphomas (27– 29). Correlation with
`response by PET and outcome has been suggested for diffuse
`large B-cell lymphoma and Hodgkin lymphoma but remains
`less well-established for other histologies. In aggressive lympho-
`ma and Hodgkin lymphoma,
`the failure to achieve early
`fluorodeoxyglucose-PET negativity after two to three cycles of
`combination chemotherapy was predictive of relapse, even if
`imaging studies became negative after completion of a full course
`of chemotherapy (30– 32). In our study, patients who remained
`PET-positive after three cycles of CHOP-R were significantly
`more likely to progress. The potential for early prediction of
`failure has not been previously reported for FL.
`
`IIIIII (cid:9) II
`IIIIII (cid:9) I (cid:9)
`
`IN (cid:9) II (cid:9) 1111 (cid:9)
`
`I (cid:9)
`
`F
`
`All consented patients
`All consented patients
`All patients who received RIT
`All patients who received RIT
`95% CI fon all consented patients
`95% CI for all consented patients
`
`
`
`5 (cid:9)5 (cid:9)
`
`
`
`10 (cid:9)10 (cid:9)
`
`
`
`15 15
`
`
`
`20 20
`
`months
`months
`
`II (cid:9)
`II (cid:9)
`
`I
`I
`
`'Er-171-111
`
`III (cid:9)
`
`-
`-
`-
`-
`
`-
`-
`
`All consented patients
`All consented patients
`All patients who received RIT
`All patients who received RIT
`PET-positive after CHOP-R
`PET-positive after CHOP-R
`PET-negative after CHOP-R
`PET-negative after CHOP-R
`
`5
`
`
`
`10 (cid:9)10 (cid:9)
`
`
`
`15 15
`
`
`
`20 20
`
`months
`months
`
`0?
`0
`42 0)
`Cs
`
`C co. C
`O o
`0
`
`—
`
`csi 0
`0
`
`0
`0
`
`
`
`0 (cid:9)0 (cid:9)
`
`
`
`A 0 A .
`
` O
`
`C a)
`• oc..
`O e — e
`
`"c7) N
`
`2 • 0 G
`2 • 0 —
`0
`C
`C
`O
`O
`•tr
`o
`O d
`0.
`
`2 2
`O
`O
`
`N
`cs1
`
`0 - 0 -
`
`0
`0
`
`o — 0
`
`
`
`(7 0
`
`Fig. 2. Kaplan-Meier analysis for PFS and OS. A, PFS shown for all consented patients, all patients who received RIT, PET-positive after CHOP-R, and PET negative
`after CHOP-R. B, OS shown for all consented patients, all patients who received RIT, and 95% confidence interval for all consented patients.
`
`7092
`www.aacrjournals.org
`Clin Cancer Res 2008;14(21) November 1, 2008
`on July 27, 2015. © 2008 American Association for Cancer
`clincancerres.aacrjournals.org Downloaded from
`
`Research.
`
`CEPHALON, INC. -- EXHIBIT 2009 0005
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`CHOP-R Followed by RITas First-LineTherapy in Follicular Lymphoma
`
`Transformation of FL to diffuse large B-cell lymphoma occurs
`in approximately one-third of patients diagnosed with FL. Some
`investigators prefer to keep anthracylines in reserve should
`transformation occur. However, in a study using anthracycline-
`based chemotherapy upfront, it seemed that aggressive initial
`therapy might actually decrease the incidence of transformation
`(33). In our study, only one relapsed patient was documented to
`have transformed to diffuse large-cell histology.
`The major toxicity associated with RIT was myelosuppres-
`sion. Both grade 4 neutropenia and thrombocytopenia
`occurred in 20% of patients. There was only one episode of
`febrile neutropenia after RIT. In comparison to post-CHOP
`treatment with 131-I tositumomab (10), myelosuppression
`seems to be slightly greater with RIT. Although it is most likely
`attributable to RIT, rituximab may have contributed. However,
`all 55 patients who received RIT had normal white blood
`counts and platelet counts by week 12 post-RIT.
`In our design of this study, we hypothesized that we would be
`able to measure an increased depth of complete remission by
`adding PET scanning and molecular assessment of response to
`the standard use of CT imaging. Of the 31 patients who had bone
`marrow samples available for baseline testing for the BCL2 gene
`rearrangement, only 9 were positive and thus precluded a formal
`analysis. This is a much lower rate of BCL2 positivity than
`generally reported in the literature (34). These results point out
`the need for a reproducible, standardized, and universally
`accepted assay before BCL2 gene rearrangement can be pros-
`pectively evaluated and compared with PET imaging for mea-
`surement of response and as a predictor of durability of response.
`A number of studies have shown that chemoimmunotherapy
`results in a higher CR rate than chemotherapy alone. In one
`large randomized trial, the CR rate for R-CVP was 41% (5, 24)
`and in another trial,
`the rate for CHOP-R was 20% (6).
`
`Although these CR rates are much lower than phase II studies of
`chemoimmunotherapy and in studies incorporating chemo-
`immunotherapy followed by first-line radioimmunotherapy,
`the wide range of CR rates serves to emphasize the importance
`of patient selection and study design, and thereby underscores
`the need for large randomized studies before a paradigm shift
`in therapy can occur. A pivotal study is being conducted by the
`intergroup mechanism, comparing six cycles of CHOP-R with
`six cycles of CHOP followed by 131-I tositumomab. This study
`may establish the role of upfront radioimmunotherapy; how-
`ever, the superiority of CHOP-R over CHOP alone may limit
`the benefit of radioimmunotherapy in this trial. Although there
`is a theoretical concern that rituximab may block potential
`binding sites for radio-labeled monoclonal antibodies, we saw
`a significant number of patients (29%) convert from partial
`responders after CHOP-R to complete responders after RIT,
`suggesting that RIT was not blocked by rituximab. Additional
`randomized studies comparing the optimal chemoimmuno-
`therapy regimen with sequential chemoimmunotherapy and
`RIT may be needed.
`PET positivity after three cycles of CHOP-R seems to be an
`indicator of more resistant disease and predictive of relapse.
`This suggests intrinsic differences between patients who achieve
`early response and those with more resistant disease. Studies in
`lymphoma cell lines have shown that there are differences in
`cell signaling pathways that predict sensitivity and resistance to
`both chemotherapy and rituximab. Analysis of these pathways
`in patient tissues may be the next critical step in understanding
`and optimizing targeted therapy (35, 36).
`
`Disclosure of Potential Conflicts of Interest
`
`No potential conflicts of interest were disclosed.
`
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