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002 CELLTRION EX. 1028

OF CLINICAL ONCOLOGY Official Journa,l of the American Society of Clinical Oncology

Vol22, No 23 CONTENTS December 1, 2004

Editorials e Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects? K. Kian Ang (see articl e on page 4665) ......................................................................................................................................................................... 4657

' e Adjuvant Chemotherapy for Elderly Women With Hormone Receptor-Positive Breast ~ }

Cancer: An Old(er)l Problem ,, Anne Schott and Daniel F. Hayes (see article on page 4674) ............................................................................................................ ij ..... 4660

e Profiling the Perpetrator Beth Karlan (see article on page 4700) ......................................................................................................................................................................... 4663

Original Repo1rts HEAD AND NECK CANCER

e Concomitant Cisplatin Significantly Improves Locoregional Control in Advanced Head and Neck Cancers: Treated With Hyperfractionated Radiotherapy Pia Huguenin, Karl T. Beer, Abdelkarim Allal, Kaspar Rufibach, Corinne Friedli, Jacques Bernard Davis, Bernhard Pestalozzi, Stephan Schmid, Armin Thoni, Mahmut Ozsahin, Jacques Bernier, Michael Topfer, Roger Kann, Urs Richard Meier, Peter Thurn, Sabine Bieri, Markus Notter, Norbert Lombriser, and Christoph Glanzrnann (see editorial on page 4657) ................................................................................................................................. 4665

~

BREAST CANCER

e Disease-Free SUirvival Advantage of Weekly Epirubicin Plus Tamoxifen Versus Tamoxifen Alone J's Adjuvant Treatment of Operable, Node-Positive, Elderly Breast Cancer Patients: 6-Year Follow-Up Results of the French Adjuvant Study Group 08 Trial Pierre Fargeot, Jacquos Bonneterre, Henri Roche, Alain Lortholary, Mario Campone, Isabelle Van Praagh, Alain Monnier, Mo'ise Namer, Simon Schraub, Jean-Claude Barats, Jean-Paul Guastalla, Marie-Josephe Goudi•9r, and Isabelle Chapelle-Marcillac (see editorial on page 4660) ........................................................ 4674

Randomized Phaso Ill Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperati\fe Oncology Group Trial E2196 Joseph A. Sparano, Patricia Bernardo, Patricia Stephenson, William J. Gradishar, James N. Ingle, Stanley Zucker, and Nancy E. Davidson ...................................................................................................................................................................... 4683

(continued on following page)

/oltm41ofCiinical Oncologr (ISSN 0732- 183X) is published 24 times a year, twice monthly, by Am~rican Soci~ryofCiinical Oncology, 1900 Duke St, Suite 200, Alexandria, VA 22314. Periodicals postag~ >Spaid at VA, and at additional mailing offices. Publication Mail Agrttmenl Number 863289.

Editorial correspondence should be to Danid G. HaU~r. MD, Journal ofOiniaJI Oncology, 330 John CarlyiA: St, Suit~ 300, AIA:undria, VA 22314. Triq>ho~ (703) 797-1900; Fax: (703) 684-8720. E-mail: lnlttn~: www.jco.org.

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2005 annual subscription Sept~mber I, 2004: United Stales and possessions: individual, $.421; single issue, $35. International: individual, $587;single issue, $45. lllltitutions: Ti~r 1: $580 US, Tier 2: $675 US, $915 lnt'l; Tier 3: $975 US, $1,215 lnt'l; Tier 4: $1,075 US, $1,315 lnt'l; Tier 5: contact ]CO for a quote. Stt IIIIJ"--I•"""'·ico,.of1!Vsultlscriptit)n$/'tier•roJ!ricitlg.sl~tml for descriptions of each tier. Student and resident: United Stat~s and possessions: $21 0; all other countries, $293. To receive ltadentlraid~nt rate, orde!'l must nam~ of affiliated institution, date of term, and the signature of program/residency coordinator on institution letterhead. Onlen wiU be billed at individual of status is received. Current prices ar~ in ~ffw for back volumes and back issu~s. Back issues sold in conjunction with a lllbecription rate ar~ on a prorated basii. ISubsc;riptions are accepted on a 12-monlh basis. Prices are subject to change without notic~. Singl~ issues, both current and back, ~xis! ill limited quantili~s and are offered subj~ct 10 availability.

003 CELLTRION EX. 1028

Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy Eugene H. Huang, Susan L. Tucker, Eric A. Strom, Marsha D. McNeese, Henry M. Kuerer, Aman U. Buzdar, Vicente Valero, George H. Perkins, Naomi R. Schechter, Kelly K. Hunt, Aysegul A. Sahin, Gabriel N. Hortobagyi, and Thomas A. Buchholz ................................................................................................................................................ 4691

GYNECOLOGIC CANCER !! Gene Expression Signature With Independent Prognosti1: Significance in Epithelial Ovarian Cancer Dimitrios Spentzos, Douglas A. Levine, Marco F. Ramoni, Marie Joseph, Xuesong Gu, Jeff Boyd, Towia. A. Libermann. and Stephen A. Cannistra (see editorial on page 4663) ·········---·-·-···-··-·-···-·--····-··-··-·-···- 4700

HEMATOLOGIC MALIGNANCIES

!! Prolonged Clinical and Molecular Remission in Patients: With Low-Grade or Follicular Non-Hodgkin's Lymphoma Treated With Rituximab Plus CttOP Chemotherapy: 9-Year Follow-Up Myron S. Czuczman, Robin Weaver, Baha Alkuzweny, Judy Berlfein, and Antonio J. Grillo-L6pez ........................... 4711

!! Clinical Outcome of Lymphoma Patients After ldiotype V'accination Is Correlated With Humoral Immune Response and Immunoglobulin G Fe Recutptor Genotype Wen-Kai Weng, Debra Czerwinski, John Timmerman, Frank J. Hsu, and Ronald Levy ····-···························-·················-·· 4717

GENITOURINARY CANCER

Racial Disparity of Epidermal Growth Factor Receptor Expression in Prostate Cancer Brian Shuch, Maryann Mikhail, Jaya Satagopan, Peng Lee, Herman Yoe, Caroline Chang, Carlos Cordon-Cardo, Samir S. Taneja, and I man Osman ............................................................................................................................. 4725

CLINICAL TRIALS

Recruitment of Patients Into an Internet-Based Clinical Trials Database: The Experience of OncoLink and the National Colorectal Cancer Research Alliance S.J. Wei, J.M. Metz, C. Coyle, M. Hampshire, H.A. Jones, S. Markowitz, and A.K. Rustgi .................................................. 4730

GASTROINTESTINAL CANCER Copy Number of Chromosome 17 but Not HER2 Amplification Predicts Clinical Outcome of Patients With Pancreatic Ductal Adenocarcinoma Nikolas H. Stoecklein, Andreas M. Luebke, Andreas Erbersdobler, Wolfram T. Knoefel, Winfried Schraut, Pablo E. Verde, Franziska Stern, Peter Scheunemann, Matthias Peiper, Claus F. Eisenberger, Jakob R. lzbicki, Christoph A. Klein, and Stefan B. Hosch ............................................................................................................................. 4737

Allele 2 of the lnterleukin-1 Receptor Antagonist Gene Is J'ssociated With Early Gastric Cancer Jiirgen Glas, Helga-Paula Torok, Agnes Schneider, Gunter Briinnler, Reinhard Kopp, Ekkehard D. Albert,

Manfred Stolte, and Christian Folwaczny -······-······- ·- ··-··········-·-·····················-··········-·······-··-··········- ··-···-···-············-·······················-· ... 4746

Randomized Multicenter Phase II Trial of Bolus Plus lnfusGonal Fluorouracil/Leucovorin Compared With Fluorouracil/Leucovorin Plus Oxaliplatin As Third-line Treatment of Patients With Advanced Colorectal Cancer Nancy Kemeny, Carlos A. Garay, Jayne Gurtler, Howard Hochster, Peter Kennedy, AI Benson, Debra Schwab Brandt, Jonathan Polikoff, Michael Wertheim, Grace Shumaker, Doreen Hallman, Brent Burger, and Sunil Gupta ................................................................................................ ............................................................................................ 4753

Fluorouracil, Doxorubicin, and Streptozocin in the Treatment of Patients With Locally Advanced and Metastatic Pancreatic Endocrine Carcinoma:1s Maria A. Kouvaraki, Jaffer A. Ajani, Paulo Hoff, Robert Wolff, Douglas B. Evans, Richard Lozano, and James C. Yao ............................................................................................................................................................... - ........................................................ 4762

(continued on following page)

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Epidermal Growth Factor Receptor (EGFR) Status in Primary Colorectal Tumors Does Not Correlate With EGFR Expression in Related Metastatic Sites: Implications for Treatment With EGFR-Targeted Monoclonal Antibodies Mario Scartozzi, ltalo Bearzi, Rossana Berardi, Alessandra Mandolesi, Guidalberto Fabris, and Stefano Cascinu .................................... - ....................................................................................................................................................................... 4m

NEUROONCOLOGY

Second-Line Chemotherapy With lrinotecan Plus Carmustine in Glioblastoma Recurrent or Progressive After First-Line Temozolomide Chemotherapy: A Phase II Study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO) Alba A. Brandes, Alicia Tosoni, Umberto Basso, Michele Reni, Francesco Valduga, Silvio Monfardini, Pietro Amista, Linda Nicolardi, Guido Sotti, and Mario Ermani ............................................................................................................... 4779

PEDIATRIC ONCOLOGY

European Intergroup Studies (MMT4-89 and MMT4-91) on Childhood Metastatic Rhabdomyosarcoma: Final Results and Analysis of Prognostic Factors

I

M. Carli, R. Colombatti, 0. Oberlin, G. Bisogno, J. Treuner, E. Koscielniak, G. Tridello, A. Garaventa, 1 R. Pinkerton, and M. Stevens ..................................................................................................................................................................................... ,........ 4787

Short-Term Efficacy of Methylphenidate: A Randomized, Double-Blind, Placebo-Controlted Trial Among Survivors of Childhood Cancer Raymond K. Mulhern, Raja B. Khan, Stuart Kaplan, Susan Helton, Robbin Christensen, Melanie Bonner, Ronald Brown, Xiaoping Xiong, Sengjie Wu, Sridharan Gururangan, and Wilburn E. Reddick ..................................... 4795

Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015) Susan M. Blaney, Mark Bernstein, Kathleen Neville, Jill Ginsberg, Brenda Kitchen, Terzah Horton, Stacey L. Berg, Mark Krailo, and Peter C. Adamson .......................................................................................................................................... 4804

PHASE I AND CLINICAL PHARMACOLOGY

Complementary and Alternative Medicine Use by Patients Enrolled Onto Phase I Clinical Trials Grace K. Oy, Lishan Bekele, Lorelei J. Hanson, Alfred Furth, Sumithra Mandrekar, Jeff A. Sloan, and Alex A. Adjei ............................................................................................................................................................................................................................ 4810

Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies Todd M. Zimmerman, Helena Harlin, Olatoyosi M. Odenike, Seth Berk, Evie Sprague, Theodore Karrison, Wendy Stock, Richard A. Larson, Mark J. Ratain, and Thomas F. Gajewski .................................................................................. 4816

SUPPORTIVE CARE AND QUALITY OF LIFE

Diagnostic Accuracy of the Palliative Prognostic Score in Hospitalized Patients With Advanced Cancer Paul A. Glare, Steffen Eychmueller, and Patrick McMahon ......................................................................................................................... 4823

Quality of Life in Patients With Colorectal Cancer 1 Year After Diagnosis Compared With the General Population: A Population-Based Study Volker Arndt, Henrike Merx, Christa Stegmaier, Hartwig Ziegler, and Hermann Brenner ................................................... 4829

Review Article Systematic Review Evaluating the Timing of Thoracic Radiation Therapy in Combined Modality Therapy for Limited-Stage Small-Cell lung Cancer Daniel B. Fried, David E. Morris, Charles Poole, Julian G. Rosenman, Jan S. Halle, Frank C. Detterbeck, Thomas A. Hensing, and Mark A. Socinski ............................................................................................................................................................... 4837

(continued on following page)

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Jl

Special Article Tissue Collection for Correla1tive Studies in Childhood Cancer Clinical Trials: Ethical Considerations and Special !Imperatives , Barry D. Anderson, Peter C. Adam:son, Susan L. Weiner, Mary S. McCabe, and Malcolm A. Smith .................. ~.... . .. 4846

Diagnosis m Oncology UNCOMMON PRESENTATIONS OF CANCER PATIENTS

Case 1. Metastatic Breast Cnncer Presenting With Panhypopituitarism Hasnain M. Khandwala, Deepu Mirchandani, Rajni Chibbar, and Vance Chow ........................................................................... 4851

Case 2. Colon Cancer Prese111ting With Intestinal Intussusception Oeri Lewis, Todd M. McCarty, Josetph A. Kuhn, and Jeffrey P. Lamont ............................................................................................ 4853 '

Case 3. Positron Emission T«11mography-Computed Tomgraphy Diagnosis of Metastatic Melanoma With lntussuscep·tion Seza A. Gulec, Mark Beller, Keith Edwards, Paul Lizotte, and Steven O'Day ................................................................................. 4854

Art of Oncology Addressing Spiritual Care: C;alling for Help C. John Steer and Chris Lee ···········································-··········-································--···-···-·-··-··--································-··-··················-····················· 4856

Correspondence Get the Facts Straight Daniel B. Kopans ............................................................................................................................................................................................................................ 4859

Delayed Benefit of Mammog1raphy Screening in Premenopausal Women Ismail Jatoi, Peter W. Soballe, and William F. Anderson ............................................................................................................................... 4860

In Reply Romano Demicheli, Gianni Bonado nna, Pinuccia Valagussa, William J.M. Hrushesky, and Michael W. Retsky ................................................................................................................................................................................................................ 4860

Errata ·······························-··-·············-·······································································································-······················································································· 4863

Also m This Issue Announcements Information for Contributors Current Abstracts Calendar of Oncology Events

l!!J Article was published online ahead of print at www.jco.org

www.jco.org www.asco.org

006 CELLTRION EX. 1028

VOLUME 22 · NUMBER 23 · DECEMBER 1 2004

JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT

From the Roswell Park Cancer Institute, Buffalo, NY; Biogen Idee, Cambr1dge, MA; and Neoplastic and Autoimmune D1seases Research Institute. Rancho Santll Fe. CA.

Submitted .Apnl 5. 2004; accepted

September 2. 2004

Supponed by d1nocal grants from 810gen Idee (fO«TTerty known as IOEC

Pharmaceutocals CO<J)Of8toonl. Cambndge. MA.

Plesented "' part at the 45th Annual

Meenng of the Ameocan Soctety of Hematology, San Diego. CA. December 6-9. 2003

Authors' disclosures of potem~al ~ ftJcts of 1nterest are found at the end of thiS arude.

Address repnnt requests to AntoniO J . Gnllo-L6pez. MO. NeoplaStiC and Auto­rnmune Diseases Research Institute, PO Box 3797, Rancho Santa Fe, CA 92067; EHT1a1l: agrillot Oaol.com.

0 2004 by Amencan Society of Clinical Oncology

0732·193X/04/2223-4711/$20.00

001; 10.1200/JC0.2004.04.020

Prolonged Clinical and Molecular Remission in Patients With Low-Grade or Follicular Non-Hodgkin's Lymphoma Treated With Rituximab Plus CHOP Chemotherapy: 9-Year Follow-Up Myron S. Czuczman, Robin Weaver, Baha Alkuzweny, judy Berlfein, and Antonio f. Grillo-L6pez

A 8 S T R A C T

Purpose Long-term follow-up with updated time to disease progression (TIP) and duration of response (OR) data are presented from a multicenter, phase II trial of rituximab/cyclophos­phamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination therapy in 40 patients with CD20+, 8-cell, non-Hodgkin's lymphoma (NHL). Revised response rates based on International Workshop Response Criteria are also provided.

Patients and Methods Enrollment began in April 1994 and consisted of patients w ith histologically confirmed, low-grade, 8-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies. Patients received six cycles of CHOP and six infusions of rituximab.

Results Eight (21 o/ol of the 38 treated patients were classified as International Working Formulation (IWF) A. 16 (42o/ol were IWF B. 13 (34%) were IWF C. and one (3o/o) was IWF D. Nine (24o/o) of 38 patients had received prior chemotherapy. Nine (24o/o) of 38 were considered poor risk according to the Follicular Lymphoma International Prognostic Index. Overall response rate was 100%; 87% of patients achieved a complete response or unconfirmed complete response. The median TIP and DR were 82.3 months and 83.5 months, respectively. Seven of eight patients who were bcl-2 positive at baseline converted to negative, and three of the seven patients have sustained the molecular remission.

Conclusion Although a cure has not been found yet for follicular NHL, the R-CHOP combination provides a lengthy response duration in patients with relapsed or newly diagnosed indolent NHL.

J Clin Oncol22:4711-4716. © 2004 by American Society of Clinical Oncology

INTRODUCTION

In the 1980s and 1990s, the gold standard for treatment of aggressive lymphoma was cyclo­phosphamide, doxorubicin, vincristine, and prednisone (CHOP). CHOP was considered curative in this population in approximately 50% ofpatients. 1

•2 On the basis of the hypoth­

esis that the cure rate could be increased by combining CHOP with the monoclonal anti­body, rituximab (Rituxan; Biogen Idee, Cam-

bridge, MA; and Genentech, San Francisco, CA), the first study of this combination ther­apy was initiated in 1994. Because CHOP alone is curative in a subset of patients with aggressive lymphoma, the decision was made to test the novel combination therapy in pa­tients with indolent disease, as no cure exists for this population. Thus the first trial evalu­ated safety and efficacy of combination therapy in low-grade and follicular non­Hodgkin's lymphoma (NHL).3

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Czuczman at al

After encouraging preliminary results of this study were published,4 three subsequen t trials evaluating the rit­ux:imab/CHOP (R-CHOP) combination in patients with aggressive NH L were performed. The first was a phase II trial in patients with intermediate-grade disease.5 The over­all response rate (ORR) in 33 front-line patients with ad­vanced, aggressive B-cell NHL was 94% (31 o£33 patients), with a complete response (CR) in 20 patients and partial response (PR) in 11 patients. This was followed by a large, randomized trial in 399 previously untreated, older patients with diffuse large B-celllympho ma by the Groupe d' Etude des Lymphomes de I'Adulte.6 Patients received either R-CHOP or CHOP alone. Combination treatment pro­duced significantly better results compared with CHOP alone as follows: better CR rate (76% v 63%, P = .005), improved event-free survival (P < .00 I), and prolonged overall survival (P = .007). In the initial study in low-grade patients and in the first two trials in aggressive patients, no significant additional toxicities occurred beyond those ob­served with CHOP alone.

The third trial conducted in the aggressive population was a phase Ill randomized study using a different ritux­imab schedule from the Groupe d'Etude des Lymphomes de l'Adulte study. Patients were assigned to R-CHOP or CHOP alone. Those achieving a CR o r PR were then ran­domly assigned to maintenance with rituximab or observa­tion. Although the results from this study are still preliminary, patients derived benefit from the addition of rituximab to their therapy.7

This article presents updated time to progression (TIP) and duration of response (DR) data based o n a 9-year follow-up of the original phase II trial ofR-CHOP in low-grade and follicular NHL. In addition, response rates have been updated based on the International Workshop Response Criteria (IWRC) developed for NHL.4 The origi­nal publication presented response rates based on criteria outlined in the study protocol,8 as the IWRC had not been established yet.

PATIENTS AND METHODS

A complete description of the design of this phase II, open-label, single-arm, multicenter study has been reported previously.4

Enrollment for the trial began in April 1994, and the last patient was treated in March 1996. Patients with histologically con­firmed, low-grade or follicular, 8-cell lymphoma who had re­ceived no prior chemotherapy or who had no more than four prior standard therapies were eligible for enrollment. All patients were required to have acceptable hematologic status (hemoglobin ~ 8 gm/dL, absolute neutrophil count ~ I ,500/ JJ.L, and platelets ~ I 00,000/ JJ.L). Patients received six cycles of CHOP and six infusions of rituximab. Two infusions of rituximab were admin­istered before the first cycle, single infusions before the third and fifth cycle, and two infusions after the sixth cycle. The study was approved by the institutional review board at each study site, and

4712

written informed consent was obtained from all patients. The primary efficacy end point of this study was ORR, PR rate, and CR rate; secondary efficacy end points were TIP for responders and DR. TIP was defined as the interval from the date of first dose to the date of progressive disease or date of last contact. DR was defined as the interval from the date of the first observation of objective response to the date of progressive disease or date of last contact. Response categories based on the IWRC have been described previously. 8 Restaging evaluation to determine re­sponse was performed no later than 2 months after treatment was completed.

--. -.-._......-___ =-~ .RESULTS

- a.__;-.J!f:.. -------

Forty patients were enrolled onto this phase II study, and two of the 40 patients were never treated. Thirty-eight pa­tients completed all treatments; 35 patients completed at least one cycle of treatment. Median age was 49 years, with nine patients (24o/o) older than 60 years of age. According to the International Working Formulation (IWF) classifica­tion, eight (21%) of the 38 treated patients had IWF A disease, 16 (42%) had lWF B, 13 (34o/o) had TWF C, and one (3%) had lWF D. Nine (24%) of 38 patients had received prior chemotherapy. Nine (24%) of 38 were considered poor risk according to the Follicular Lymphoma Interna­tional Prognostic Index (FLIPI), and 10 (27%) of 38 pa­tients were in the intermediate/high or high international Prognostic Index risk group. Nearly two thirds ( 64o/o) of the patients had Ann Arbor stage IV disease at diagnosis, and 26o/o had stage Ill disease. Five (13o/o) patients had ~ five nodal sites, and 26 patients (68%) had extranodal disease. This included 18 patients with bone marrow involvement, eight patients with splenomegaly, and seven patients with either pleural effusion, orbital mass, gastric wall, or medi­astinal invo lvement. Eleven patients (29%) had high lactate dehydrogenase levels, and six patients (16%) entered the study with hemoglobin values s 12 gldL (Table 1 ).

ORR evaluated by the IWRC was I OOo/o, with 87o/o (33 of38 patients) CR/unconfirmed complete response (CRu) and 13o/o (five of38 patients) PR (Table 2) . ORR as reported previously, using the protocol-defined response criteria, was lOOo/o, with a 58o/o CR rate (22 of 38 patients). Median TTP in all patients is 82.3 months (range, 4.5 + to 105.6+ months); median DR is 83.5 months (range, 3.1 + to l05.1 + months). As shown in Figure I, TTP for CR/CRu patients was significantly longer than TTP for PR patients (P = .0001 ). The 16 (42%) of38 patients in continuous long­term remission (77.3+ to 105.6+ months) all achieved a CR. Three of these 16 patients had received prior treatment. Figure 2 presents a Kaplan-Meier graph ofTTP in previously treated versus previously untreated patients.

Five (63%) of eight patients with IWF A histology and 28 (93%) of 30 patients with TWF B, C, o r D histology achieved a CR/CRu. The median TTP for the IWF A

JOURNAL OF CLINICAL ONOOL.OOY

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Rituximab Plus CHOP Chemotherapy

Table 1. Summary of Demographic Data and Table 1. Summary of Demographic Data and Patient Characteristics (continued} Patient Characteristics

No. of Patients (N = 38)

Age, years

M edian

M inimum

Maximum

Age group s 60 years 29 > 60 years 9

Sex

Female 19

Male 19

Histologic type

A 8

B 16

c 13

D Bulky disease

< 5cm 24

5-7 em 10

> 7 cm 4

Ann Arbor stage

II 4

Ill 10

IV 24

Baseline W HO

0 30 1 7

2 I PI risk group

Low 12 Low/intermediate 16

Intermediate/high 9 High

FLIP I

Good 17

Intermediate 12

Poor 9 Previous therapy

0 29

1 3

2 3

3 1

2: 4 2

Prior ABMT, 0 38 Prior fludarabine therapy

Yes 1

No 37

Last chemotherapy

Single agents 4

COP or CP combination 3 Aggressive combinations 2

None 29 No. of nodal sites

2:5 5 S4 33

Lactate dehydrogenase group

High 11 Normal 26 Low

www.jro.org

o/o

48.5

29.0

77.0

76 24

50

50

21

42

34

3

63 26

11

11

26

63

79

18

3

32 42

24

3

45

32

24

76

8

8

3

5 100

3 97

11

8

5 76

13

87

29

68

3

No. of Patients

Albumin group

Normal 36 95 Low 2 5

Baseline CD3 .. cells

s 411 cellsiJ,tL 19 50 > 411 cells/1-<L 19 50

Baseline hemoglobin s 12 g/dL 6 16

> 12 g/dL 32 84 Baseline platelets

< 150,000/,_.L 12 32

c: 150.000/,..L 26 68 Baseline lymphocyte count

< 1000/J.LL 9 24

c: 1000/J.LL 29 76

Abbreviations: I PI, International Prognostic Index: FLIPI. Follicular Lym­phoma International Prognostic Index; ABMT, autologous bone marrow transplantation; COP, cyclophosphamide, vincristine. and prednisone; CP, chlorambucil and prednisone.

patients (75.6 months) was not significantly different from the TTP in IWF B, C, or D patients (84.9+ months).

As shown in Table 1, more than half the patients were in the intermediate or poor risk group for FLIPI. Median TTP was longest for the good-risk group and decreased with increasing number of risk factors (Table 3).

Eight patients were bcl-2 positive (t[14;18] chromo­some translocation) at baseline, as tested by sensitive poly­merase chain reaction assay. All of these eight patients achieved a CR. One patient remained bcl-2 positive and experienced disease progression at 76 months; the remain­ing seven patients converted to bcl-2- negative after treat­ment. Three of these seven patients remain negative and are in ongoing remission at 85, 98, and 99 months. The other four patients converted to negative and then reverted to positive. Two of these patients are in ongoing remission at 100 and 101 months; two patients experienced disease pro­gression at 31 and 85 months.

The safety of rituximab in combination with CHOP chemotherapy has been previously described.4 In general, the most frequent and severe adverse events were related to CHOP and included hematologic effects, nausea, vomiting, and alopecia. The most frequent rituximab events occurred during the infusion. These included grade 1 and 2 chills, fever, pruritis, and headache. No quantifiable immune re­sponse to the rituximab antibody was detected.

DISCUSSION

In this phase II trial, 38 patients were treated with R-CHOP combination therapy. All patients achieved a response, with

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Czuczman et al

Table 2. Time to Progression and Duration of Response in Months

No. of Prev1ously Patients Patients Untreated

All 38 29 Complete responderS/unconfirmed 33 26

complete responders

Pan1al responders 5 3

Abbreviations: DR. duratiOn of response; TTP. ttme to progress1on. •Median has not been reached.

an 87% CR/CRu rate. Sixteen patients are still in remission 6 to 9 years after treatment; three of these 16 patients had received prior treatment. In this article, response rate was reanalyzed using the IWRC. These criteria prove to be pre­dictive of response duration. All 16 ongoing responders achieved a CR, whereas the five patients with PRs experi­enced relapse within 2.5 years. In addition, molecular re­missions were noted in seven of eight patients tested for bcl-2 translocation and have been sustained for several years in three of the seven patients.

This was the first trial to evaluate rituximab in combi­nation with CHOP. Therefore, it was essential to closely monitor adverse events occurring with the two therapies and determine whether additive toxicities occurred. To limit the possibility of additive toxicities, rituximab and the CHOP regimen were administered on different days. Sev­eral studies have since demonstrated the safety of the CHOP/rituximab combination. Therefore, to improve convenience for the patient, currently treatments are ad­ministered together. However, the optimal schedule for administering rituximab and chemotherapy concurrently has not yet been determined.

100

90

eo

70

~ u. 60

i so ~ Q. 40 ~

30

PreviOusly Treated DR Range TTP Range

9 83.5+ 31-105.1+ 82.3+ 4 5-105 6• 7 4.1·105.1+ 8.6-105.6+

2 8.7 3.1·28.3 12 4.5-30.2 -=

The value of the addition of rituximab to standard combination therapy in both aggressive and indolent B-cell lymphoma patients with a range of good and poor prognos­tic factors has now been demonstrated in several clinical trials.4 "6•9•10 Specifically, in our study, many patients had adverse prognostic factors as determined by the FLIPL 11

Twenty-four percent of patients were in the poor cate­gory with three or more FLIPI risk factors, and 32% were in the intermediate category with two risk factors. These included age greater than 60 years in 24% of patients, more than five nodal sites in l3o/o of patients, increased serum lactate dehydrogenase level in 29% of patients, hemoglobin :5 12 gldL in 16% of patients, and Ann Arbor stage III/IV in 89% of patients. Despite these poor prognostic factors, response rates and response duration were extremely favorable.

Significant advances have been made in the treatment of indolent B-celllymphoma since this study was initiated; however, the disease still remains incurable. Several trials evaluating rituximab in combination with various chemo· therapeutic agents and with other new therapeutic agents have produced promising results.9

•12

•13

Fig 1. Kaplan-Meier analysis of time to progressiOn by response (N - 38). C. cen­sored; Cr, complete response; Cru, uncon­firmed complete response.

20 • x • Complete Responders/Unconfirmed Complete Responders ( n • 33) • o • Panlal Responders (n • 5)

10 • v · Overall Responders (N • 38)

P ~ .0001 (Cr/Cru vs. PR)

0 4 8 12 16 20 24 28 32 38 40 44 48 52 58 60 84 68 72 76 60 64 88 92 96100 104108 112

lime From Treatment to Progression (months)

4714 JOURNAL OF CWIICAL ONCOLOGY

010 CELLTRION EX. 1028

Rituximab Plus CHOP Chemotherapy

20 • x • Previously Untreated Patients (n = 29)

1 o · o • Previously Treated Patients (n = 9)

Fig 2. Kaplan-Meier analysis o f time to progression: previously untreated (n = 29) versus previously treated [n = 9). C. censored.

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110

Time From Treatment to Progression (months)

Cytokine upregulation of effector cells by interferon alfa-2a/4 interleukin-2, or granulocyte colony-stimulating factor 15

•16 potentially improve rituximab-associated antibody­

dependent cellular cytotoxicity without significantly increas­ing treatment-associated toxicity. Overall response rates in the range of 50% or greater and TTP exceeding the 13 months seen in the initial pivotal tria1 17 of rituximab alone have been demonstrated in trials evaluating com­bination rituximab-cytokine therapy.3•

15•18

Non-anti-CD20 monoclonal antibodies evaluated in B-celllymphoma include epratuzumab (anti-CD22), apoli­zumab (anti-HLA-DR/3), alemtuzumab (anti-CD52), and galiximab (anti-CD80). Early clinical studies demonstrated safe toxicity profiles but limited antitumor activity.18

'20

However, use in combination with rituximab may augment antitumor activity.2 1

Two US Food and Drug Administration- approved anti­CD20 radioimmunoconjugates are currently in use for the treatment of relapsed indolent B-celllymphoma: yttrium-90 ibritumomab tiuxetan (Zevalin; Biogen Inc, Cambridge, MA) and 13 1Iodine-tositumomab (Bexxar; Corixa, Seattle, WA). Long-term follow-up of indolent lymphoma patients treated

Tabla 3. Time to Progression by FLIPI Risk Group

No. of No. of Median TTP FLIPI Factors Patients o/o (months)

Good 1 17 45 83.5·

Intermediate 2 12 32 51 .95.

Poor 3 9 24 30.05t

Abbreviations: FLIPI, Follicular Lymphoma International Prognostic In­dex; TTP. time to progression. ·observed median; Kaplan-Meier estimate could not be made because

of large number of patients still in remission. tKaplan-Meier estimate.

www.jCO.O'S

with either of these radioimmunoconjugates demonstrated high ORR (ie, range of 65% to 73%, with CRs de mon­strated in 35% to 51% of patients) and median response durations in the range of 12.6 to 19.3 months.22

'25 Long­

term remissions of 5 + years have been demonstrated in a minority of patients.

Although more new options have become available for patients with indolent disease over the last several years, this study, with the longest observation tim.e, has still produced the best response rate and response .dura­tion in low-grade or follicular NHL. A decade has passed since the study' s inception, and 42% of patients are still in remission; median TTP is nearly 7 years. These long­term remissions are occurring in previously untreated patients, as well as in those who have had prior treat­ment. Although a cure has not been found yet for follic­ular lymphoma, the R-CHOP combination providoes the possibility of prolonged response duration in patients with B-celllymphoma.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family !mem­bers have indicated a financial interest. No conflict exi:sts for drugs or devices used in a study if they are not being evalluated as part of the investigation. Employment: Robin Weaver, Biogen Idee; Baha Alkuzweny, Biogen Idee. ConsultantJ'Advi­sory Role: Myron S. Czuczman, Biogen Idee; Judy Berlfein, Biogen Idee; Antonio J. Grillo-L6pez, Genentech, Idee, Roche. Stock Ownership: Baha Alkuzweny, Biogen Idee; Judy Berlfein, Biogen Idee; Antonio J. Grillo-L6pez, Genentech. Honoraria: Antonio]. Grillo-L6pez, Genentech, Idee, Roche. Research Funding: Myron S. Czuczman, Biogen Idee. Expert Testimony: Antonio]. Grillo-L6pez, Idee.

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