`
`PhaseII Study
`Strategies Compared
`Page 5950
`
`La
`
`Clinical
`. Cancer
`~
`» Research
`October 1, 2009 « Volume 15 « Number 19 * Pages 5945-6308
`
`The TrkB Signaling
`Pathway Impacts
`Cancer
`Page 5962
`
`,
`
`.
`
`ruee
`
`‘S
`
`CD30 Antibody in
`Lymphoproliferative
`Disorders
`
`0oa
`
`Systemic Nonviral Sodium lodide
`Symporter Gene Transfer
`‘*%*
`Page 6079
`
`-Po
`
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`
`
`ARAmericunAssociationfor CancerResearch
`
`UTR ea) ey OFaore
`Translational Research
`
`Fd
`
`Genome & Co. v. Univ. of Chicago
`PGR2019-00002
`UNIV. CHICAGO EX. 2013
`
`www.aacrjournals.org
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`

`

`Clinical
`Cancer
`
`Research Contents
`
`October 1, 2009
`VoI1S, No 19
`
`CCRTranslations
`Inhibiting the Hypoxia Response for Cancer Therapy: The New Kid on the Block.
`Mel VeeKoh, Taly R. Spivak-Kroizrnan,
`and Ganh Powis
`.
`DO Commentary on Narita et al., p. 6128
`
`.
`
`.
`
`.
`
`.
`
`by Sorafenlb: Toxicity or Target?
`Rapid Development of Hypertension
`Benjamin D. Humphreys and Michael B. Atkins
`et al., p. 6250
`DO Commentary all Maitlalld
`Statistics
`in Clinical Cancer Research
`A Comparison of Phase II Study Strategies. Sally Hunsberger Yingdong Zhao
`and Richard Simon
`:
`Molecular Pathways
`Disrupting Polyamine Homeostasis as a Therapeutic Strategy for Neuroblastoma.
`Nicholas F. Evageliou and Michael D. Hogarty
`On Trk- The TrkB Signal Transduction Pathway Is an Increasingly Important Target in
`Cancer Biology, Carol I. Thiele, Zhijie Li, and Amy E. McKee
`
`:
`
`.
`
`..
`
`5945
`
`5947
`
`........5950
`
`.........5956
`
`..
`
`5962
`
`.
`
`5968
`
`..5974
`
`..
`
`5985
`
`Human Cancer Biology
`CXCL13and CXCL12 In Central Nervous System Lymphoma Patients. Lars Fischer,
`Agnieszka Korfel, Sebastian Pfeiffer, Philipp Kiewe. Hans-Dieter Yolk, Husniye Cakiroglu,
`Thomas Widmann, and Eckhard Thiel.
`····..··................................
`
`at Serine 276 by Protein Kinase A Contributes
`Nuclear NF-KBp65 Phosphorylation
`to the Malignant Phenotype of Head and Neck Cancer. Pattatheyil Arun, Matthew S. Brown,
`Reza Ehsanian, Zhong Chen, and Carter Van Waes .
`
`Loss of Heterozygosity at 2q37 In Sporadic Wilms' Tumor: Putative Role for miR-562.
`Kylie M. Drake, E. Cristy Ruteshouser, Rachael Natrajan, Phyllis Harbor, Jenny wegen.
`Manfred Gessler, Kathy Pntchard-Iones. Paul Grundy, Jeffrey Dome, Vicki Huff, Chris Jones,
`and Micheala A. Aldred.
`.
`
`Down-regulation of ZIP4 by RNAInterference Inhibits Pancreatic Cancer Growth and
`Increases the Survival of Nude Mice with Pancreatic Cancer Xenografts. Min Li, Yuqing Zhang,
`Uddalak Bharadwaj, Qihui (Jim) Zhai, Charlotte H. Ahern, William E. Fisher, F. Charles Brunicardi.
`Craig D. Logsdon, Changyi Chen, and Qizhi Yao....
`
`IDHI Mutations as Molecular Signature and Predictive Factor of Secondary GUoblastomas.
`Sumihito Nobusawa, Takuya Watanabe, Paul Kleihues, and Hiroko Ohgaki.
`
`..5993
`
`..6002
`
`3-Kinase Pathway Gene Alterations in Bladder Cancer.
`Spectrum of Phosphatldyllnosltol
`Fiona M. Platt, Carolyn D. Hurst Claire E Taylor, Walter M. Gregory, Patricia Harnden,
`and Margaret A. Knowles
`ProlnOammatory Mediators Upregulate Snail in Head and Neck Squamous Cell Carcinoma.
`Maie A. S1.John, Mariam Dohadwala.
`fie Luo, Cuanyu Wang, Gina Lee, Hubert Shih, Eileen Heinrich,
`Kostanryn Krysan, Tonya Walser, Saswati Hazra. Li Zhu, Chi Lai, Elliot Abemayor, Michael Fishbein,
`David A. Elashoff, Sherven Sharma, and Steven M. Dubinett
`.
`
`. 6008
`
`....6018
`
`Local Biosynthesis of Estrogen in Human Endometrial Cardnoma through Tumor-Stromal
`CeJ] Interactions. Naomi Takahashi-Shiga, Hiraki Utsunomiya, Yasuhiro Miki, Satoru Nagase,
`Rika Kobayashi, Mitsuyo Matsumoto, Hiroshi Niikura, Kiyoshi Ito, and Nobuo Yaegashi.. .
`
`..6028
`
`WNW.
`
`als.org
`
`

`

`Cancer Therapy: Preclinical
`
`in Waldenstrom Macroglobulinemia.
`Src Tyrosine Kinase Regulates Adhesion and Chemotaxis
`Hai T Ngo, Abdel Kareem Azab, Mena Farag. Xiaoying Iia, Molly M. Melhem, Judith Runnels,
`Aida M. Roccaro, Feda Azab, Antonio Sacco, Xavier Leleu. Kenneth C. Anderson,
`and Irene M. Ghobrial...............................
`
`..
`
`6035
`
`Invasion and
`of Cathepsin S Blocks Colorectal Tumor
`Inhibition
`Antibody-Mediated
`Angiogenesis. Roberta E. Burden, Julie A. Gormley, Thomas J. Iaquin, Donna M. Small,
`Derek J. Quinn, Shauna M. Hegarty, Claire Ward, Brian Walker, lames A. Johnston, Shane A. Olwill,
`and Christopher 1.Scott
`.
`
`CEACAM5-Targeted Tberapy of Human Colonic and Pancreatic Cancer Xenografts with
`Potent Labetuzumab-SN-38
`ImmunoconJugates.
`Serengularn V. Covindan. Thomas M. Cardillo,
`Sung-Iu Moon, Hans I. Hansen, and David M. Goldenberg
`..
`
`...6042
`
`6052
`
`and Sunitlnib with Soiute Carriers
`Sorafenib
`Inhibitors
`of the Multlklnase
`Interaction
`Shuiying Hu, Zhaoyuan Chen, Ryan Franke,
`and ATP-Binding Cassette Transporters.
`Shelley Orwick, Ming Zhao, Michelle A. Rudek, Alex Sparreboorn, and Sharyn D. Baker
`
`.
`
`6062
`
`Higb- Tbroughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small
`Molecules
`Identifies Disulfiram as an Inblbitor
`of Prostate Cancer Cell Growth.
`Kristiina lljin, Kirsi Ketola, Paula Vainio, Pasi Halonen. Pekka Kohcnen, Vidal Fey,
`Roland Crefstrom, Merja Perala, and alii Kallioniemi
`
`following Systemic Nonviral
`Tumors
`Targeted Radioiodine Tberapy of Neuroblastoma
`Delivery of the Sodium Iodide Symporter Gene. Kathrin Klutz, Verena Russ,
`Michael J. Willhauck, Nathalie Wunderlich, Christian Zach, Franz Josef Gildehaus,
`Burkhard Coke, Ernst Wagner, Manfred Ogris. and Christine Spitzweg
`
`of Pancreatic
`by 06 Benzyl Guanine Leads to Inbibitlon
`Blockade of MGMT Expression
`of Apoptosis. Santhi D. Konduri, Jonathan Ticku,
`Cancer Growth and Induction
`George C. Bobustuc, Robert M. Sutphin, Jimmie Colon, Beth Isley, Kishor K. Bhakat,
`Srivenugopal S. Kalkunte, and Cheryl H. Baker
`
`.
`
`6070
`
`6079
`
`6087
`
`Leads to Enbanced
`Inhibition
`Combined Bd-2/Mammallan Target of Rapamydn
`Radlosensitlzatlon
`via Induction
`of Apoptosis
`and Autophagy in Non-Small Cell Lung
`Tumor Xenograft Model. Kwang Woon Kim, Luigi Moretti, Lauren Rhea Mitchell,
`Dae Kwang Jung. and Bo Lu
`
`..
`
`6096
`
`of Poly(ADP-ribose)
`Vasoactivity of AGOI4699, a Clinically ActIve Small Molecule Inhibitor
`Polymerase: a Contributory factor to Chemopotentfation
`In vivo? Majid Ali, Brian A. Telfer,
`Ciao McCrudden, Martin O'Rourke, Huw D. Thomas, Marzieh Kamjoo, Suzanne Kyle
`Tracy Robson, Chris Shaw, David G. Hirst, Nicola 1. Curtin, and Kaye). Williams
`
`..
`
`6106
`
`Antiglloma lnuuunologJc Memory In Response to Conditional Cy!otoxic/lnuuune-Stimulatory
`Gene Tberapy: Humoral and Celluiar
`Immunity Lead to Tumor Regression.
`A.K.M. Ghulam Muhammad, Marianela Candolfi, Gwendalyn D. King, Kader Yagiz, David Foulad,
`Yohei Mineharu, Kurt M. Kroeger, Katherine A. Treuer, W. Stephen Nichols, Nicholas S. Sanderson,
`Iieping Yang, Maksim Khayznikov, Nico Van Rooijen, Pedro R. Lowenstein, and Maria G. Castro..
`Idenllflcatlon
`of a Novel Small Molecule HIF-la Translation
`Inbibltor. Takuhito Narita,
`Shaoman Yin, Christine F. Celin, Carlos S. Moreno, Manuel Yepes, K.G. Nicolaou,
`and Erwin G. Van Meir
`.
`
`,...........
`
`..
`
`Recognizing
`Bispedflc Targeted TolCin Simultaneously
`A Novel Reduced Immunogenidty
`Human Epidermal Growth Factor and Interleuldn-4
`Receptors
`in a Mouse Model of
`Seunguk Oh. Brad J. Stish, Deepali Sachdev, Hua Chen,
`Metastatic Breast Cardnoma.
`Arkadiusz Z. Dudek, and Daniel A. Vallera
`
`....6113
`
`6U8
`
`.. 6137
`
`in a Model of Triple-Negative Breast
`Inbibits Brain Metastatic Colonization
`Vorinostat
`Cancer and Induces DNA Double-Strand
`Breaks. Diane Palmieri, Paul R. Lockman,
`Fancy C. Thomas, Emily Hua, leanne Herring. Elizabeth Hargrave, Matthew Johnson, Natasha Flores,
`Yongzhen Qian, Eleazar Vega-Valle, Kunal S. Taskar, Vinay Rudraraju, Rajendar K. Mittapalli,
`Julie A. Caasch, KaciA. Bohn, Helen R.Thorsheim, David J. Liewehr, Sean Davis, John F. Reilly,
`Robert Walker, Julie L Bronder, Lionel Feigenbaum, Seth M. Steinberg. Kevin Camphausen,
`Paul S. Meltzer, Victoria M. Richon, Quentin R. Smith, and Patricia S. Steeg
`
`..
`
`6148
`
`

`

`Synergistic Effects of Oncolytic Reovirus and Clsplatin Chemotherapy in Murine Malignant
`~elano~a.
`Hardev S. Pandha, Lucy Heinemann. Guy R. Simpson, Alan Melcher, Robin Prestwich,
`Fiona Errington, Matt Coffey, Kevin J. Harrington, and Richard Morgan
`Lymph Node-Targeted Immunotherapy Mediates Potent
`Immunity Resulting In Regression
`of Isolated o:rMelasta~c Human Papillomavirus-Transformed
`Tumors. Kent A. Smith,
`B~enna L. Meisenburg, VI~tor L. Tam, Robb R. P~garigan, Raymond Wong. Diljeet K. Ioea.
`Ll~Lantzy,MayraA. Carrillo. Todd M. Gross, UneJ M. Malyankar, Chih-Sheng Chiang,
`Diane M. Da Silva, Thomas M. Kundtg. W. Martin Kast, Zhiyong Qiu, and Adrian BOL.......
`
`.
`
`. 6158
`
`6167
`
`Translocator Receptor Blockade Reduces Prostate Tumor Growth. Arlee Fafalios,
`Ardavan Akhavan, Ani! V. Parwani, Robert R. Bies, Kevin I. McHugh,
`and Beth R. Pflug
`
`............6177
`
`Imaging, Diagnosis, Prognosis
`Aberrant Methylation of APe, MGMT, RASSF2A, and Wif-1 Genes in Plasma as a Biomarker
`for EarlyDetection of Colorectal Cancer. Bo Bin Lee, Eun Iu Lee, Eun Hyun lung,
`Ho-KyungChun, Dong Kyoung Chang, SangYong Song, Ioobae Park,and Duk-Hwan Kim..
`MicroRNA Expression in Squamous Cell Carcinoma and Adenocardnoma
`of the Esophagus:
`Assodations with Survival. Ewy A. Mathe, Giang Huang Nguyen, Elise D. Bowman, Yiqiang Zhao,
`Anuradha Budhu, Aaron J. Schetter, Rosemary Braun, Mark Reimers, Kensuke Kumamoto,
`Duncan Hughes, Nasser K. Altorki, Alan G. Casson, Chang-Gong Liu, Xin Wei Wang,
`Nozomu Yanaihara, Nobutoshi Hagiwara, Andrew'. Dannenberg, Masao Miyashita,
`Carlo M. Croce, and Curtis C. Harris..........................
`
`.
`
`Interstitial Fluid Pressure as a Prognostic Factor in Cervical Cancer Following Radiation
`Therapy. Seung-Gu Yeo, Iun-Sang Kim, Moon-Iun Cho, Ki-Hwan Kim, and Iae-Sung Kim
`
`.
`
`of a Polymorphism in the Ornithine Decarboxylase Gene with Coloreetal
`Associations
`Cancer Survival. jason A. Zeit Argyrios Ziogas, Natalia Ignatenko. Jane Honda, Ning Qu,
`Alexander S. Bobbs, Susan L. Neuhausen. Eugene W. Gerner, and Hoda Anton-Culver.
`
`Cancer Therapy: Clinical
`A Phase Ii Study of SGN-30 in Cutaneous Anaplastic Large Cell Lymphoma and Related
`Lympboproliferative Disorders. Madeleine Duvic, Sunil A. Reddy, Lauren Pinter-Brown,
`Neil J. Korman, John Zic, Dana A. Kennedy, Jennie Lorenz, Eric L. Sievers, and Voun H. Kim....
`and Biological Correlative Study of IMP321, a Novel MIlC
`A Phase I Pharmacoklnetlc
`Class Ii Agonist, in Patients with Advanced Renal Cell Cardnoma. Chrystelle Brignone.
`Bernard Escudier, Caroline Crygar, Manon Marcu, and Frederic Triebel
`
`6185
`
`..6192
`
`6201
`
`....6208
`
`..6217
`
`. 6225
`
`....6232
`
`.6241
`
`.
`
`....6250
`
`and Pharmacokinetic Study of Dasatinib in Patients with Advanced
`Phase I Dose-Escalation
`Solid Tumors. George O. Dernerri, Patricia La Russo, lain R.J. MacPherson, Ding Wang,
`Jeffrey A. Morgan, Valerie G. Brunton, Prashni Paliwal, Shruti Agrawal, Maurizio VoL
`and T.R.Ieffry Evans
`.
`.
`A Phase I Dose-Finding Study of 5-Azacytidlne In Combination with Sodium Phenylbutyrate
`In Patients with Refractory Solid Tumors. Iianqing Lin, Jill Gilbert, Michelle A. Rudek,
`James A. Zwiebel, Steve Gore, Anchalee Iiemjit, Ming Zhao, Sharyn D. Baker,
`Richard F. Ambinder, James G. Herman, Ross C. Donehower, and Michael A. Carducci..
`Ambulatory Monitoring Detects Sorafenib-Induced Blood Pressure Ele.vatio~s on
`the First Day of Treatment. Michael L. Maitland, Kristen E. Kasza,Theodore Kan:IS?",
`.
`Kristin Moshier, Laura Sit, Henry R. Black, Samir D. Undevia, Walter M. Stadler, WIlham J. Elliott,
`.
`.
`and Mark j. Ratain .
`in Glioblastoma: Evaluation of Clinical
`Phase Ii Study of Neoadjuvantlmatinlb
`and Molecular Effects of the Treatment. Evangelia Razis, Panayotis Selviaridis,
`Stephanos Labropoulos, Jeremy L. Norris, Mei-lun Zhu, David D. Song, Thea Kalebic,
`Michael Torrens, Anna Kalogera-Pountzila, George Karkavelas, Sofia Karanastasi,
`. .
`..
`Jonathan A. Fletcher, and George Fountzitas.............
`
`.
`
`.
`
`.......6258
`
`

`

`In Patients with Metastatic
`Dendritic Cell Vaccination Combined with CfLA4 Blockade
`Melanoma. Antoni Ribas, Begona Comin-Anduix, Bartosz Chmielewski, Jason jalil,
`Pilar de la Rocha, Tara A. McCanneL Maria Teresa Ochoa, Elizabeth Seja, Arturo Villanueva,
`Denise K. Oseguera, Bradley R. Straatsrna, Alistair J. Cochran, John A. Glaspy, Liu Hui,
`Francesco M. Marincola, Ena Wang, James S. Economou, and Jesus Gomez-Navarro
`
`A Phase I Study of Sunltlnlb plus Bevaclzumab In Advanced Solid Tumors, Brian I. Rini,
`Jorge A. Garda, Matthew M. Cooney, Paul Elson, Allison Tyler, Kristi Beatty, Joseph Bokar,
`Tarek Mekhail, R.M. Bukowski, G. Thomas Budd, Pierre Triozzi, Ernest Borden, Percy Ivy,
`Helen X. Chen, Afshin Dolwati, and Robert Dreicer.c....
`
`..
`
`Susceptibility and Prevention
`the
`Predicts
`.1Np63 Overexpresslon, Alone and In Combination with Other Biomarkers,
`Development
`of Oral Cancer
`in Patients with leukoplakia,
`Pierre Saintigny, Adel K. EI-Naggar,
`Vali Papadimitrakopoulou, Hening Ren, You-Hong Fan, Lei Feng, I. Jack Lee, Edward S. Kim,
`..
`Waun Ki Hong. Scott M. Lippman, and Li Mao...
`
`6267
`
`6277
`
`6284
`
`Region
`Site Single· Nucleotide Polymorphism in the 3'·Untranslated
`An mlR·502-Blndlng
`of the SETB Gene Is Associated with Early Age of Breast Cancer Onset. Fengju Song.
`Hong Zheng, Ben Liu, Sheng Wei, Hongji Dai, Lina Zhang. George A. Calin, Xishan Hac,
`Qingyi Wei, Wei Zhang, and Kexin Chen
`
`..
`
`6292
`
`In a Regulatory Subunit of Protein
`a Genetic Variant
`Recent Natural Selection Identifies
`Phosphatase
`2A that Associates with Altered Cancer Risk and Survival. Lukasz F. Grochola,
`Alexei Vazquez, Elisabeth E. Bond, Peter wurl, Helge Taubert, Thomas H. Muller, Arnold J. Levine,
`and Gareth L. Bond
`..
`_...
`..
`
`6301
`
`About
`
`the Cover
`
`In this first preclinical study, synthetic polymeric vectors based on
`pseudodendrinc
`oligoamines were used for tumor-specific delivery of
`the sodium iodide symponer
`(NIS) gene after systemic delivery,
`resulting in a significant therapeutic effect of radioiodine in a
`neuroblastoma mouse model. The figure shows immunofluorescence
`analysis using a Ki67-specific antibody (green) and an antibody
`against CD31 [red, labeling blood vessels) revealing high proliferation
`and blood vessel density in control
`tumors in contrast
`to
`NIS-transduced tumors after radioiodine treatment. For further
`details, please see Klutz and coworkers on page 6079 in this issue.
`
`

`

`Cancer Therapy: Clinical
`
`A Phase I Pharmacokinetic and Biological Correlative Study of
`IMP321, a Novel MHC Class II Agonist,
`in Patients with
`Advanced Renal Cell Carcinoma
`Chrystelle Brignone,'
`Bernard Escudier,2 Caroline Grygar,' Manon Marcu,'
`
`and Frederic Triebel'
`
`Abstract
`
`Purpose: To evalu.atatha safety, tolerability, pharmacokinetics, and pharmacodynamics of
`IMP321, a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class Il-driven
`dendritic cell activation.
`Experimental Design: Patients with advanced renal cell carcinoma were traated with
`escalating ~os~s of
`IMP321 s.c, Blood samples were assayed to datermine plasma
`pharmacoklnetlc parameters, detect human anti-IMP321 antibody formation and deter-
`mine long-lived CDS T cell responses.
`'
`Results: Twenty-one advancad renal cell carcinoma patients received 119 injections
`of IMP321 at dosas ranging from 0.050 to 30 mg/injection s.c, biweekly for 6 injections.
`No clinically significant adverse events were observed. Good systemic exposure to the
`product was obtained following s,c. injections of doses above 6 mg. IMP321 induced
`both sustained CDS T-cell activation and an increase in the percentage of long-lived
`effector-memory CDS T cells in all patients at doses above 6 mg. Tumor growth was
`reduced and progreasion-free survival was better in those patients receiving higher
`doses (>6 mg) of IMP321: 7 of S evaluable patients treated at the higher doses expe-
`rienced stable disease at 3 months compared with only 3 of 11 in the lower dose group
`(p= 0.015).
`Conclusion: The absence of toxicity and the demonstration of activity at doses above
`6 mg warrant
`further disease-directed studies of IMP321 in combined regimens (e.g.,
`chemoimmunotherapy).
`(Clin Cancer Res 2009;15(19):622S-31)
`
`An alternative to the use of toll-like receptors as irnmunopo-
`tentiators is to condition the macrophage/dendritic
`cell network
`by repeated s.c, injections of natural
`[i.e., human protein)
`li-
`gandsthat activate/mature human dendritic cells and induce bet-
`cell (APe) activity in vitro. Two human
`ter antigen-presenting
`proteins, both expressed on activated human T cells and target-
`ingAPCs, have been shown to properly condition dendritic cell
`without inflammation: CD40L and LAG-3 (1-3). CD40L has
`been tested in phase I trials (4) but clinical development has
`been stopped due to secondary effects such as thrombosis
`in-
`duction (its receptor, CD40,
`is also expressed on platelets and
`endothelial cells). Thus. the soluble LAG-3Igfusion protein (or
`
`'Immutep S.A. Orsay, France and 21nstitut Gustave
`Authors' Affiliations:
`RoussyVillejuif, France
`Received 1/12109;
`revised 516109; accepted 5/19/09; published OnlineFirst
`9115109.
`The costs of publication of this article were defrayed in part by the payment
`ofpagecharges. This article must therefore be hereby marked advertisement
`in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
`Note: Supplementary
`data for this article are available at Clinical Cancer
`ResearchOnline (http://clincancerres.aacrjournals.org/).
`Requests for reprints: Frederic Friebel,
`Immutep S.A.• Pare Club Orsay, 2.
`rue Jean Rostand, 91893 Orsay cedex. France. Phone: 33-146835792;
`Fax: 33-146835835; E-mail:
`ftriebel@immutep.com.
`C 2009 American Association for Cancer Research.
`doi:10.1158/1078-0432.CCR-09-OO68
`
`IMP321) is the only protein that is presently available for this
`therapeutic approach (5-B).
`to
`The LAG-3Ig protein is efficacious as a vaccine adjuvant
`inhibit
`tumor growth in mice grafted S.c. with different
`tumor
`carcinogenesis in Her2/neu
`cell lines (9, 10) and spontaneous
`transgenic mice (11).
`In particular,
`the mere s.c. presence of
`LAG-3 leads to RCC tumor
`(RENCA) rejection in mice, due to
`boosted tumor-specific cytotoxic COBTvcellresponses (9). Inter-
`estingly, the expression ofLAG~3on a tumor efficiently promotes
`intratumoral
`recruitment, activation. and type-I commitment of
`APCs, and leads to a wide intratumoral
`influx of nonspecific and
`specific reactive cells, and the release of lrnmunoregulatory and
`cytotoxic mediators (12).
`In this report, data are presented demonstrating that in pre-
`viously treated advanced RCC patients who are immunosup-
`pressed(13-16),
`IMP321 induced an increasein the percentage
`of circulating activated COB T cells and of long-lived effector-
`memory (EM) COB Tcells in all patientstreatedby repeatedinjec-
`tions of doses above 6 mg. Importantly, this immunosumulatory
`effect was obtained without any detectable toxicity of this first-
`in-class lrnrnunopotentiator
`targeting MHC class 11"" APCs.
`Materials and Methoda
`Eligiblepatients were at least ages 18 y; had histologic
`Patients.
`documented metastaticrenal clearcelladenocarcinoma:an EasternCo-
`operative Oncology Group performancestatus of 0 or I; measurable
`
`www.aacrjoumals.org
`
`6225
`
`elin Cancer Res 2009;15(19) October 1,2009
`
`

`

`CIIncer Therapy: Clinlca'
`
`Transilltional Relevance
`
`In this article, we describe a first-in-man dose-
`escalation phase I trial of IMP321 (LAG-3Ig) given to
`patients with advanced cancers. The data reported
`here strongly support the future development of this
`agentforclinical use.IMP321 was safe,well-tolerated,
`and induced long-lived effector-memory COBT-cell
`responses in all patients treated at doses above
`6 mg. The recommended phase IIdose for further study
`was 6 mg s.c, biweekly for 6 months. Phase 1111 studies
`of this first-in-class immunopotentiator plus cytotoxic
`chemotherapy are currently open to recruitment.
`
`liver, and renaJ function. and life ex-
`disease; adequate bone marrow,
`pectancy of at least 3 mo. Prior nephrectomy was not required. Patients
`were included in this study only if an efficacious treatment could not
`be proposed. Most of them had received previous courses of sunitinib
`and/or sorafenib.
`Patients were excluded if they had known clinically active auto-
`immune disease, known active hepatitis B or C, known HIV positivity,
`known cerebral metastases, or had received anticancer chemotherapy or
`immunotherapy within 4 wk of study entry or mitomycin C or nitro-
`soureas within 6 wk of study entry. The use of concomitant
`investiga-
`tional drugs was prohibited during or within 4 wk of study entry.
`Pregnant or nursing women were excluded. Women of childbearing
`potential were required to have a negative pregnancy test within 7 d of
`treatment
`initiation and to use adequate birth control measures during
`the study. Patients were excluded if they had severe allergy, had any con-
`dition that was unstable or could jeopardize their safety or ability to com-
`ply with study procedures, or could interfere with evaluation of the
`results. All patients gave written informed consent to participate in the
`study, which was conducted in accordance with the Declaration of Hel-
`sinki, the Good Clinical Practice guidelines, and all applicable local laws
`and regulations. The study protocol and amendments were approved by
`an institutional review board and an independent ethics committee.
`Study design and treatments.
`In this single-center, open-label, non-
`randomized,
`fixed dose-escalation trial done in an ambulatory and day-
`hospital setting, patients received IMP321 S.c. biweekly for six injections.
`Three to six patients were enrolled in successive cohorts with the fol-
`lowing IMP321 dosing: 0.05, 0.25, 1.25,6.25, and 30 mg per injection.
`To be evaluable for the dose escalation decision-making process, a pa-
`tiem must have received at least 6 wk of treatment with IMP321. Toxi-
`cities were assessed using the National Cancer
`Institute Common
`Toxicity Criteria version 3.0. Dose-limiting toxicity was defined as any
`grade 3 to 4 toxicity. If one patient had developed a dose-limiting tox-
`icity, dose escalation would have been stopped and the prior dose level
`was considered the maximum tolerated dose. No intra patient dose es-
`calation was permitted. Also, because of the fixed dose study design, no
`dose reduction for a patient was allowed.
`Study assessments. Before initiating treatment,
`each patient was
`tumor measure-
`evaluated for medical history, physical examination,
`ment using computer-assisted tomography, Eastern Cooperative Oncol-
`ogy Group performance status, complete differential blood count. serum
`chemistries, urinalysis, and electrocardiogram. These assessments were
`also done before each subsequent
`injection. All observations were re-
`corded,
`including results of physical examinations, vital signs, adverse
`events, concomitant medications,
`and laboratory tests. Patients were
`monitored every 2 wk and as needed for adverse events. Tumor response
`and progression were assessed using Response Evaluation Criteria in Sol-
`id Tumors with imaging studies done 2 wk after the third and the sixth
`injections. Blood samples were collected in EDTA-conta.ining tubes for
`analysis of plasma concentrations of IMP321 after the first S.c. injection,
`in dry tubes on baseline and 2 wk after the third (day 57) and the sixth
`
`(day 85) injection for detection of serum anti-IMP321 antibodies, and in
`lithium heparin-containing tubes for monitoring the coa T-cellimmune
`response.
`ll-lP-l, a human acute monocytic leukemia
`IMP321 potency assay.
`cell line that expresses MHC class II molecules, was used to measure
`IMP321 potency in inducing the secretion ofCCIA (MIP-'I [!.). The cells
`were incubated for 4 h at 37°C with IMP321 in complete RPMI, 10%
`FCS (Invitrogen). The concentration of CCLA in supernatants was deter-
`mined with so Cytometric Beads Array following manufacturer's in-
`structions using a FACSCanto cytometer
`and FCAP Array Software
`(BD Biosciences). The difference between the blank values and the
`read-out observed with low concentrations
`of IMP321 was considered
`statistically relevant for a P value below 0.001 (parametric two-tailed
`Student'S t test; Xl.STATsoftware).
`Preclinical pharmacokinetics studies had
`Pharrnarokinetics
`analysis,
`been done on two groups of four cynomolgus monkeys treated with a
`single LAG-3Igdose of 5 mg/kg injected by either the S.c. or i.v.route of
`administration. Clinical pharmacokinetics
`studies were done for a total
`of 14 patients treated at dose levels 2, 3, 4, and 5. Venous blood samples
`were collected before treatment and at 0.5, 1,2,4, and 24 h posttreatment
`on day 1 in tubes containing EDTA,and plasma was obtained by centri-
`fugation and stored at -BO°C until
`further analysis. The measurement
`of sLAC-3 in the plasma was done by EUSA plates coated with an anti-
`LAC-3 monoclonal
`antibody (mAb; clone I 1E3). The diluted plasma
`(1:20 and 1:40) and IMP321 standard (ranged from 500-7.8 pgfmL)
`were incubated overnight. Soluble LAG-3 was revealed using a biotiny-
`lated anti-lAG-3 mAb (clone 17B4, labeled using Pierce Biotechnology's
`kit) followed by an incubation with peroxidase-conjugated streptavidin
`(GE Healthcare] and by the addition of 3,3',5,5'-tetramethylbenzidine
`(BD Biosciences}, The reaction was stopped by acidification, and absor-
`bance were determined at the 450 and 600 nm wavelengths. 00450 nm
`minus OD600 nmvalues were plotted as a function of standard concentra-
`tion and the standard curve was generated with a quadratic polynomial-
`2 model.
`plasma samples
`in undiluted
`The levels of cytoldnes/chemokines
`were assessed using the human Prolnflammatcry
`4-plex ultrasensltive
`kit (allowing the quamitation of IFN-')', ILr1~, IL-6, and tumor necrosis
`factor-c) and the human Chemokine 9-plex ultrasensitive kit (allowing
`the quantitation
`of Botaxine, Botaxine-S, IL-B, IP410, MCP-l, MCP-4,
`MDC, MIP-l~,
`and TARe) developed
`by Meso Scale Discovery
`(MSD). The MSD platform is a solid phase immunoassay methodology
`that uses electrochemilumlnescence
`to detect protein bound to micro-
`titer plates with electrodes. The plates were read using the MSDSECTOR
`Imager Model 1250.
`Serum samples obtained at
`antibodies.
`Detection
`of anti-IMP321
`baseline and a and 12 wk after the initial dosing were tested for anti-
`drug antibodies using ELlSA.lhe serum was diluted 1:100 to avoid any
`matrix effect, loaded (at least two determinations/sample]
`on microtiter
`plates (Maxisorb, NUNC) precoated with IMP321 (I ~g/well) and re-
`vealed by a mix of horseradish peroxidase-conjugated
`goat anti-human
`II" and goat anti-human ~ (Serotec]. As controls, various concentrations
`of a recombinant
`human mAb fragment Fab4dHLX-MH directed to
`IMP321 produced from human Ig library in Escherichia coli (MorphoSys)
`were added to each plate and the assay sensitivity was 3 ng/mL Fabequiv-
`alent. Absorbance were determined at the wavelengths of 450 and 600 nm.
`The sera from most of the patients were also assessed in the bridg-
`ing immunogenidty
`assay on the MSO platform. Streptavidin-coated
`plates were used to capture IMP321 that had been biotinylated using
`a kit purchased
`from Pierce Biotechnology.
`IMP32J binds to any
`drug-specific antibody present in serum samples. The drug-specificanti-
`body then binds to another drug molecule,
`this time labeled by the
`MSDSULFO-Tag.Only this specific br