Journal r c!1r.1ca1 •Jnc·:•logy
`, :1 ro 1 1 Jan.1 201~ ,
`Ge1arnl C 'Jilect,011
`\/·1; J05894rl
`2012-01-22 1 3.44 49
`
`'° 2013 VOLUME 31 ISSUE 1
`
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`SANDOZ INC.
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`

`

`Rilotw umab ,n
`MET posit ve gastric cancer
`
`RILOMET-1
`
`RILOMET-1: A Phase 3, Multicenter, Randomized,
`Double-Blind, Placebo- Controlled Study
`of Rilotumumab (AMG 102) with Epirubicin,
`Cisplatin, and Capecitabine (ECX) as First-Line
`Therapy in Advanced MET-Positive Gastric or
`Gastroesophageal Junction Adenocarcinoma
`
`Primary Endpoint:
`• Overall survival (OS)
`
`Secondary Endpoints:
`• Progression-free survival (PFS)
`• Time to progression (TTP)
`• Overall response rate (ORR), disease c ontrol
`rate (OCR), and time to response (TTR)
`• Safety and immunogenicity
`
`Rilotumumab is an investigational agent that has not been approved
`by regulatory agencies for the use under investigation for this trial.
`Key Inclusion Criteria:
`• Pathologically confirmed unresectable locally
`advanced or metastatic gastric or GEJ
`adenocarcinoma
`• Eastern Cooperative Oncology Group (ECOG)
`performance status of O or 1
`• Tumor MET-positive by centralized
`immunohistochemistry (IHC)
`• Tumor Human Epidermal Growth Factor
`Receptor 2 (HER2)-negative
`For Additional Information:
`• Amgen Call Center: (866) 57-AMGEN
`or (866) 572-6436
`• www.ClinicalTrials.gov
`(NCT01697072)
`
`1. Iveson T, et al. EurJ Cancer. 2011;47(Supp/. 1):$443. Oral
`presentation at 2011 European Muttidisclpllnary Cancer Congress:
`Sept 23-27, 2011; Stockholm, Sweden. Abstract i6S04.
`2. Zhu M, et al. J Clin OncoJ. 2012:30(15 SuppJ):2535. Poster
`discussion at 2012 American Society of Clink:al Oncology Annual
`Maeting; Jun 1-5, 2012; Chicago, IL. Abstract #2535.
`3 . OavidenkO I, et al. Ann Oncol. 2012;23(Suppl. 9):ix230. Poster
`presentation at European Society of MedicaJ Onco&ogy 2012
`
`Congress; Sept 28-Qct 2, 2012; Vtenna, Austria. Abstract 687P. AMGEN'
`Oncology
`
`02013Amgen Inc.
`All rightsres..-l.
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`Volume 31, Issue 1
`
`January 1, 2013
`
`Official Journal of the
`American Society of Clinical Oncology
`
`J OURNAL OF
`C LINICAL
`O NCOLOGY
`
`············
`
`CONTENTS
`
`EDITORIALS
`
`Toward Improved Understanding of the Ethical and Clinical Issues Surrounding
`Mandatory Research Biopsies
`Jeffrey Peppercorn (see article on paqe 17)
`Achieving the Best of Both Worlds
`Andrew H. Ko and David Cella (see article on paqe 23)
`Improving T-Cell Therapy for Epstein-Barr Virus Lymphoproliferative Disorders
`Catherine M. Bollard (see article on paqe 39)
`Screening for Familial Ovarian Cancer: A Ray of Hope and a Light to Steer by
`Kara C. Long and Noah D. Kauff (see article on paqe 49)
`On the Merits and Limitations of Whole-Brain Radiation Therapy
`Atif J. Khan and Adam P. Dicker (see article on paqe 65)
`
`COMMENTS AND CONTROVERSIES
`Curability of Advanced Indolent or Low-Grade Follicular Lymphomas: Time for a
`New Paradigm?
`Fernando Cabanillas
`
`3
`
`5
`
`8
`
`11
`
`14
`
`continued on following page
`
`Jou11111/ o(C/111ic.l 011.-olof!J (ISS;\" 0732-183:\) a, publi'1lc<l 36 111ncs a year. three times monthly. by the t\mcri<·an Soc,ct) of Climcal Or>cology, 2318 MiU Koad. Surtc
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`'\;'onmembcN ,houl<l ,en<l change, of address to Jrmn11JI ~(Cli11ia1/ Onrolcw Cu~tomer Scn-icc. 2 l 1R \11II Road, Su1rc 800. <\lexandri.a, \ ':-\. 12314.
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`mu<;:t be ,1<.unn1lJnied h} name of affiliated m'irirution, dJtc of tcnn, and the \ignaturc of program/residency coordinator on lll!>titut.ion letterhead. Orde~ \\ilJ he billed Jt i11dn:1du.:.1I
`r-.itc until pmof of !>talus lS rccci,cd. C11rrcnt prices arc in cAL'Ct for had: ,0Ju1ne5, and b.Jck issu"-"'· B.tc-l L<.SUCS .-.old in conjwlction with a sul.N...-npuon rJtc ;1rc on a pmrnted UJ.\J.'1-.
`Subscription-. are .1ccepred on a 12-momh l'khis. Pnces 3('(' ~uhjcct to change \\irhout notice. S~,lc: i,-,uc..,, both current and bad •• exi,;;t in limited qll.llluties and arc offered for
`sale suhjcct rn J,ailahiln:y. ]CO Lc!(:lcy Archi,e (dectronic l>1ck '"""' from Janual"} 1983 through December 1998) 1> ,lso ,,a,1,blc; plc:isc inquire.
`
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`

`

`Volume 31, Issue 1
`
`January 1, 2013
`
`·····················································································································································································
`
`0
`
`ORIGINAL REPORTS
`Ethics
`
`Use of Research Biopsies in Clinical Trials: Are Risks and Benefits
`Adequately Discussed?
`Michael J. Overman, Janhavi Medak, Scott Kopetz, et al (see editori al on page 1)
`
`Gastrointestinal Cancer
`
`Impact of FOLFIRINOX Compared With Gemcitabine on Quality of Life in Patients
`With Metastatic Pancreatic Cancer: Results From the PRODIGE 4/ACCORD 11
`Randomized Trial
`Sophie Gourgou-Bourgade, Caroline Bascoul-Mollevi, Fran~oise Desseigne, et al (see editor ial on
`page 3)
`Postoperative Adjuvant Chemotherapy Use in Patients With Stage 11/111 Rectal
`Cancer Treated With Neoadjuvant Therapy: A National Comprehensive Cancer
`Network Analysis
`Polina Khrizman, Joyce C. Niland, Anna ter Veer, et al
`
`lmmunotherapy
`Adoptive Transfer of Epstein-Barr Virus (EBV) Nuclear Antigen 1-Specific T Cells As
`Treatment for EBV Reactivation and Lymphoproliferative Disorders After Allogeneic
`Stem-Cell Transplantation
`Vanya lcheva, Simone Kayser, Daniel Wolff, et al (see editorial on page 5)
`
`Gynecologic Cancer
`
`Results of Annual Screening in Phase I of the United Kingdom Familial Ovarian
`Cancer Screening Study Highlight the Need for Strict Adherence to
`Screening Schedule
`Adam N. Rosenthal, Lindsay Fraser, Ranjit Manchanda, et al (see editorial on page 8)
`
`AIDS-Related Cancer
`
`Pegylated Liposomal Doxorubicin, Rituxlmab, Cyclophosphamide, Vlncristlne, and
`Prednisone In AIDS-Related Lymphoma: AIDS Malignancy Consortium Study 047
`Alexandra M. Levine, Ariela Noy, Jeannette Y. Lee, et al (listen to the podcast by Dr Smith at
`www.jco.org/podcasts)
`
`Neurooncology
`O 8 A European Organisation for Research and Treatment of Cancer Phase Ill Trial of
`Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With One to
`Three Brain Metastases From Solid Tumors After Surgical Resection or
`Radiosurgery: Quality-of-Life Results
`Riccardo Soffietti, Martin Kocher, Ufuk M. Abacioglu, et al (see editorial on page 11; listen to the
`podcast by Dr Osoba at www.j co.orq/podcasts)
`
`Prognostic Impact of Pregnancy After Breast Cancer According to Estrogen
`Receptor Status: A Multicenter Retrospective Study
`Hatem A. Azim Jr, Niels Kroman, Marianne Paesmans, et al
`
`Breast Cancer
`
`17
`
`23
`
`30
`
`39
`
`49
`
`58
`
`65
`
`73
`
`continued on followin9 page
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`

`

`Volume 31, Issue 1
`
`January 1, 2013
`
`····················································································································································································
`
`Use of Radiation Therapy in the Last 30 Days of Life Among a Large
`Population-Based Cohort of Elderly Patients in the United States
`8. Ashleigh Guadagnolo, Kai-Ping Liao, Linda Elting, et al
`
`Radiation Oncology
`
`Hematologic Malignancies
`
`Bruton Tyrosine Kinase Inhibitor lbrutinib (PCl-32765) Has Significant Activity in
`Patients With Relapsed/Refractory B·Cell Malignancies
`Ranjana H. Advani, Joseph J. Buggy, Jeff P. Sharman, et al (see article on page 128)
`Deregulated Expression of £Vl1 Defines a Poor Prognostic Subset of MLL·Rearranged
`Acute Myelold Leukemias: A Study of the German-Austrian Acute Myeloid Leukemia
`Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group
`Stefan Griischel, Richard F. Schlenk, Jan Engelmann, et al
`Results From a Prospective, Open-Label, Phase II Trial of Bendamustine in
`Refractory or Relapsed T·Cell Lymphomas: The BENTLY Trial
`Gandhi Damaj, Remy Gressin, Krimo Bouabdallah, et al
`
`Palliative and Supportive Care
`
`Parenteral Hydration in Patients With Advanced Cancer: A Multicenter, Double-Blind,
`Placebo-Controlled Randomized Trial
`Eduardo Bruera, David Hui, Shalini Dalal, et al
`
`Pediatric Oncology
`
`Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors
`of Childhood Cancer
`Stephanie A. Kovalchik, Cecile M. Ronckers, Lene H.S. Veiga, et al
`
`UNDERSTANDING THE PATHWAY
`
`Targeting B·Cell Receptor Signaling for Anticancer Therapy: The Bruton's Tyrosine
`Kinase Inhibitor lbrutinib Induces Impressive Responses in B·Cell Malignancies
`Adrian Wiestner (see article on page 88)
`
`ASCO SPECIAL ARTICLE
`
`Clinical Cancer Advances 2012: Annual Report on Progress Against Cancer From the
`American Society of Clinical Oncology
`Bruce J. Roth, Lada Krilov, Sylvia Adams, et al
`
`0
`
`0
`
`ART OF ONCOLOGY
`
`How They Do This
`Abby R. Rosenberg
`
`CORRESPONDENCE
`
`Capturing Data on Colostomy Formation in Anal Cancer
`Rob Glynne-Jones, Sandy Beare, Rubina Begum, et al
`Reply to R. Glynne-Jones et al
`Didier Peiffert, Laetitia Tournier-Rangeard, Jean-Pierre Gerard, et al
`
`80
`
`88
`
`95
`
`104
`
`111
`
`119
`
`128
`
`131
`
`162
`
`164
`
`165
`
`continued on following page
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`

`

`Volume 31, Issue 1
`
`January 1, 2013
`
`····················································································································································································
`
`Improvement in Progression-Free Survival in OCEANS Bevacizumab Arm: A Critical
`Point of View
`Federica Tomao, Silverio Tomao, and Pierluigi Benedetti Panici
`
`166
`
`DIAGNOSIS IN ONCOLOGY
`(a rt icles avai l able online)
`Multimodal Magnetic Resonance Imaging and 18F-L-Dihydroxyphenylalanine
`Positron Emission Tomography in Early Characterization of Pseudoresponse
`and Nonenhancing Tumor Progression in a Pediatric Patient With Malignant
`Transformation of Ganglioglioma Treated With Bevacizumab
`Giovanni Merana, Arnoldo Piccardo, Marla Luisa Garre, et al
`
`lll"'.;,.~rn Gastric Perforation Secondary to Regression of Lung Adenocarcinoma
`
`J After Gefitinib Treatment
`•
`~ ..... ~ . Wei-Pang Chung, Hsiang-Lin Song, Chung-Liang Ho, et al
`l!l"""
`
`Diagnosis of Primary CNS Melanoma With Neuroimaging
`• Kathryn E. Somers, Jeevak Almast, Rachel A. Biemiller, et al
`
`Radiation Therapy and Adjuvant Chemotherapy in a Patient With a
`Malignant Glloneuronal Tumor and Underlying Ataxia Telangiectasia:
`A Case Report and Review of the Literature
`Mariko D. DeWire, Chris Beltran, Frederick A. Boop, et al
`
`Severe Acute Interstitial Lung Disease After Crizotinib Therapy in a Patient
`With f'ML4-ALK-Positive Non-Small-Cell Lung Cancer
`Akihiro Tamiya, lsamu Okamoto, Masaki Miyazaki, et al
`
`el
`
`e6
`
`e9
`
`e12
`
`e15
`
`. ' l!l
`II
`
`.-
`. ii'.
`"A°JJ....
`l!l
`
`.
`
`,;
`
`••
`.
`. .
`
`Also in This Issue
`Information for Subscribers
`Information for Contributors
`Manuscript Submission Checklist
`Current Abstracts
`Forthcoming Reports
`
`0
`@
`
`www .jco.orq
`
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`

`

`VOLUME 31
`
`• NUMBER 1
`
`· JANUARY 1 2013
`
`JOURNAL OF CLINICAL O NCOLOGY
`
`ORIG I NAL REPORT I
`
`RanIana H. Advani. Stanford Un.vers1ty
`Medical Center, Stanford, Joseph J.
`Buggy, Sara Rodnguez. Betty Y Chang,
`Juthamas Sukbuntherng, Raquel Izumi,
`Ahmed Hamdy, and Eric Hedrick. Phar(cid:173)
`macychcs. Sunnyvale, CA Jeff P. Shar(cid:173)
`man. US Oncology, Willamette Valley
`Cancer Center, Spnngf,eld. OR. Sonah
`M Smith. Universrtv of Ch,cago,
`Chicago. IL, Thomas E Boyd, US
`Oncology, Yakima Valley Memorial
`Hospital. Yakima; Kathryn S. Kohbaba,
`US Oncology, Northwest Cancer
`Spec1ahsts. Vancouver. WA. Barbara
`Grant, University of Vermont. Burhng(cid:173)
`ton. VT Richard R Furman. Weill
`Cornell Med cal College, New York. NY,
`and Nathan H. Fowler. MD Anderson
`Cancer Center, Houston, TX
`
`Published online ahead of print at
`www Ico.org on October 8, 2012
`
`Supported by Pharmacychcs
`
`R.HA and N.H F. contributed equally
`to this work
`
`Authors' disclosures of potential con
`fhcts of mterest and author conmbu(cid:173)
`uons are found at the end of this
`article.
`
`Clinical trial 1nformat1on: NCT00849654.
`
`Correspcnd1ng author: Ran1ana H
`Advani, MD. Stanford University Medi(cid:173)
`cal Center, 875 Blake Wilbur Dr. Suite
`CC-2338. Stanford, CA 94305-58? 1,
`Ermail: radvan1@stanford edu.
`
`C> 2012 by American Society of Chnica
`Oncology
`
`0732-183X/13/3101-88/$20.00
`
`DOI: 10.1200/JC0.2012 42.7906
`
`Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765)
`Has Significant Activity in Patients With
`Relapsed/Refractory B-Cell Malignancies
`
`Ranjana H. Adva11i, Joseph f. Buggy, Jeff P. Sl1arman, So11ali M. Smith, T/10mas E. Boyd, Barbara Grant,
`Kathryn S. Kolibaba, Richard R. forman, Sara Rodrig11ez, Betty Y. Chang, Juthamas S11kb1mthemg,
`Raquel lwmi, Ahmed Hamdy, Eric Hedrick, and Nathan H. Fowler
`
`See accompanying article on page 128
`
`A B S T R A C T
`
`Purpose
`Survival and progression of mature B-cell malignancies depend on signals from the 8-cell antigen
`receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We
`evaluated ibrutinib (PCl-32765). a small-molecule irreversible inhibitor of BTK, in patients with
`B-cell malignancies.
`Patients and Methods
`Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received
`escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and
`two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was
`monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum(cid:173)
`tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full
`BTK occupancy by ibrutinib. Response w as evaluated every two cycles.
`Results
`Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most
`adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not
`observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg
`per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmaco(cid:173)
`kinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at
`least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50
`evaluable patients was 60%, including complete response of 16%. Median progression-free
`survival in all patients was 13.6 months.
`Conclusion
`lbrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across
`B-cell histologies.
`
`J Clin Oncol 31 :88-94. © 2012 bv American Societv of Clinical Oncologv
`
`INTRODUCTION
`
`Signaling from the B-cell antigen receptor (BCR)
`regulates multiple cellular processes, including pro(cid:173)
`liferation, differentiation, apoptosis, and cell migra(cid:173)
`tion, and is essential for normal B-cell development
`and survivalY The BCR pathway is in1plicated in
`the pathogenesis of several B-cell malignancies, in(cid:173)
`cluding diffuse large B-cell lymphoma (DLBCL),
`follicular l)rmphoma, mantle-cell lymphoma, and
`10
`B-cell chronic lymphocytic leukemia (CLL).3
`"
`Bruton tyrosine kinase (BTK), a member of the Tee
`kinase family, is a signaling molecule positioned
`early within the BCR signali ng cascade, in close
`
`proximity to Syk a11d phosphoinositide 3-kinase
`delta.11 14 Functional null mutations of BTK in hu(cid:173)
`mans lead to the inherited disease X-1.inked agam(cid:173)
`maglobul.inemia (XLA), which is characterized by a
`complete lack of mature peripheral B cells and low
`levels of serum im m unoglobulin (Ig). 15 Because the
`phenotype of human XLA is largely restricted to B
`lymphocytes, .BTK is a uniquely attractive target for
`selective B-cell inhibition.
`lbrutinib (PCl-32765) is a selective and irre(cid:173)
`versible small-molecule BTK inhibitor (half maxi·
`ma! inhibitory concentration, 0.5 nmol/L) that
`inh ibits BCR signaling in human B cells via spe·
`cilic active-site occupancy. I6 In vitro, ibrutinib is
`
`88
`
`0 2012 by American Society of Cl,n,cal Oncology
`
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`

`

`BTK Inhibitor lbrutinib for B-Cell Malignancies
`
`selectively cytotoxic to DLBC L cell lines driven by chronic active BCR
`signaling.17 Orally administered ibrutinib resulted in objective clinical
`responses in d ogs that spontaneously developed non -Hodgkin lym(cid:173)
`ph oma ( NHL).16 In this study, an active site-directed affinity probe
`assay was used to demonstrate that efficacy correlated well with th e
`degree of active-site occu pancy of BTK by ibrutinib.
`Because o f the central role of BCR sign alin g, the restricted
`expression of BTK, and promising preclinical activity with this
`n ovel agent, we evaluated ibrutinib in a p h ase I o p en-lab el, dose(cid:173)
`escalation trial to d etermine the d ose, safety profile, pharmacoki(cid:173)
`netics (PKs), pharmaco dynamics, a nd tumo r response in patients
`with relapsed or refractory B-cell N H L a nd B-cell C LL.
`
`Eligibility
`Patients with relapsed or refractory, histologically confirmed NHL, CLL, or
`Waldenstrom macroglobulinemia (WM) who had failed at least one previous
`therapy were eligible. lnclusion criteria included: Eastern Cooperative Oncology
`Group performance status s I, age 2'. 18 years, measureable disease (NHL: at least
`one lymph node 2 cm in any axis; CLL: 2'. 5,000 leukemia cells/ µL; WM: lgM
`level 2'.: 1,000 mg/dL with bone marrow infiltration), absolute neutrophil cotmt 2'.
`1,500/µ,L, platelet count 2'. 75,000/µ,L (unless CLL with cytopenia secondary to
`marrow uwolvement), ru,d adequate renal ru,d hepatic function.
`Major exclusion criteria included: more than four previous system ic
`therapies; previous allogeneic stem-cell transplantation; immunotherapy,
`chemotherapy, radiotherapy, or experimental therapy within 4 weeks of study;
`major surgery within 4 weeks of study; active infection within 4 weeks of cycle
`one, day l; CNS involvement by lymphoma; history of previous cancer < 2
`years before study (except skin basal or squamous cell carcinom as, cervical
`cancer in situ, or other in situ carcinomas); and significant comorbidities.
`
`Study Design
`This phase I study was conducted at eight centers in the United States in
`accordance with Good Clinical Practice guidelines, as provided by the Inter(cid:173)
`national Conference on Harm onisation and principles of the Declaration of
`Helsinki. The institutional review board at each participatin g site approved the
`study, and all patients provided written informed consent before enrollment.
`Patients received ibrutinib capsules orally once daily at l.25, 2.5, 5, 8.3, or
`12.5 mg/kg per day on a 28 days on, 7 days off, schedule (35-day cycle), or
`received continuous daily dosing of8.3 mg/kg or 560 m g until disease progr es(cid:173)
`sion (PD), unacceptable toxicity, or patient or investigator decision to e nd
`therapy. To better evaluate BTK occupancy, at least six patients were enrolled
`in each cohort. Dose escalation continued until MTD was achieved based on
`protocol-defined dose-lin,iting toxicities (DLTs), defined as the occurrence in
`cycle one of any o f the following: grade 2'. 3 nonhematologic adverse event
`(AE), grade 2'. 3 prolongation of the QTc interval, grade 2'. 3 neutropcnia,
`feb rile neutropenia, grade 4 thrombocytopenia, or dosing delay because o f
`toxicity for m ore than 7 days. Dose escalation to next level proceeded after
`DL T assessment of patients at the end o f cycle on e. T he MTD was defined
`as the highest dose level at which 2'. 33% of patients in the cohort experi(cid:173)
`enced a DLT or, in the absence of a DLT, until three dose levels above the
`dose level in which full BTK occupancy could be demonstrated. Patien ts
`with complete respo nse (CR), partial response ( PR), or stable disease (SD)
`who had received therapy for 6 months were allowed to continue therapy at
`a fixed dose of 560 or 420 mg per day on an extension trial until confirma(cid:173)
`tion of PD or at physician's discretion.
`
`Study Assessments
`AEs were monitored throughout treatm ent, and toxicities were assessed
`by the National Cancer Institute Common Toxicity Criteria for AEs (version
`3.0). Physical examination, blood samples for hematology and clinical chem(cid:173)
`istry, urinalysis, T/ B/ natural killer cell counts, and serum lg were assessed on
`day l of each cycle. Disease response assessments included computed tomog-
`
`raphy scans and physical examination. Review of clinical laboratory results
`assessments were conducted eve1y two cycles w1til PD or use of alternative
`antineoplastic therapy. Computed tomography or positron emission tomog(cid:173)
`raphy and bone marrow biopsy/aspirate were required to confirm CR. Best
`clinical response (CR, PR, SD, PD) was determined by investigators based on
`criteria defined by the International Working Group revised response criteria
`for malignant lymphoma,18 and the International Workshop on CLL guide(cid:173)
`lines for diagnosis and treatment of CLL. 19 Patients discontinuing therapy for
`reasons other than prngression were observed every2 to 3 months until PD for
`a m aximun1 of 6 months after the last study dose.
`Blood sam p les for PKs or BTK occupancy were collected during cycle
`one on day I (predose ru1d up to 6 hours after dosing), day 2 (predose), day 8
`(predose and up to 4 hours after dosing), and 24 hours after day-28 dosing.
`Plasma was analyzed for ibrut.in ib concentrations by high-performance liquid
`chromatography with tandem mass spectrom etric detection. PK assessments
`were performed on the plasma concentration-time data obtained on day I
`using noncompartmental analysis (WinNonlin Pro, version 5.3; Pharsight,
`Cambridge, MAJ. BTK occupancy in peripheral blood mononuclear cells
`(PBMCs) was measured using a fluorescent. affinity probe (hereafter probe)
`assay, as described previously. 16 Fluorescent probe protein bands were quan(cid:173)
`tified using Molecular Dynamics lmageQuant 5.2 software (GE H ealthcare,
`Waukesha, Wl). The relative density of each band was quantified using vol(cid:173)
`ume integration and local average background correction. The background
`for each quantified band was defined byvolw11e integration of a nearby region
`within the same lane that did not contain a visible band. All background
`regions on the gel were also used to define a lower limit of quantitation equal to
`the average volume ofbackgrou11d regions plus 3X the standard deviation of
`the volumes of the background regions. BTK occupancy was compared using
`Graph Pad Prism version 4.0 (GraphPad, San Diego, CA). Statistically signifi(cid:173)
`cant differences were determined using one-way ru1alysis of variance with
`Bonferroni's post hoc comparison.
`
`Statistical Methods
`This was a dose-escalation trial designed to determine the MTD of
`ibrutinib and characterize the most frequent AEs ru,d DLTs. The intent-to(cid:173)
`treat (ITT) population included all patients receiving any amount of the study
`drug. The evaluable population included all patients who received at least two
`cycles of therapy. The best response recorded was used for response analyses.
`Overall response rate (CR plus PR) was calculated for the entire study popu(cid:173)
`lation as well as for each treatment cohort and histology. Progression-free
`Slllvival was measured fro m the first day of dosing until PD or relapse and
`detern,ined using the Kaplan-Meier method. 20
`
`RESULTS
`
`.
`
`Patient Characteristics
`From March 2009 through September 2010, 56 patients wer e en(cid:173)
`rolled and received one or more doses o fibrutinib. Baseline disease char(cid:173)
`acteristics and previous therapies are listed in Table l . M edian age of the
`patients was 65 years (range, 4 1 to 82 years). Median number of previous
`therapies was three ( range, one to 10), and all but four patients had
`previously received rituximab. Five cohorts were treated with the 28 days
`on, 7 days off, schedule at doses escalating from 1.25 to 12.5 mg/kg
`( cohorts I to V), and two cohorts were treated on the continuous dosing
`schedule at 8.3 mg/kg once daily or a fixed dose of 560 m g once daily
`(Table 2). Median number of cycles received was five.
`
`Safety Profile and Patient Disposition
`The MTD ofibrutinib was not reached. Only two DL Ts occurred:
`one grad e 3 aller gic h ypersensitivity (coh ort lV) in a patient with a
`history of drug hypersensitivity, a nd one dose interruption for more
`than 7 days because of transient grade 2 neutropenia (coh o 1t II ). Table
`2 s ummarizes the most frequently (2: 10% of patients) reported AEs
`
`WWw.jco.org
`
`© 2012 by American Society of Clin,cal Oncology
`
`89
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1009, p. 8 of 13
`
`

`

`Advani et al
`
`Table 1. Baseline Patient Characteristics (N = 56)
`No.
`Characteristic
`
`Age, years
`Median
`Range
`Sex
`Male
`Female
`Histolog1c subtype
`Follicular lymphoma
`CLUSLL
`Mantle-cell lymphoma
`DLBCL
`Marginal zone/mucosal-assoc1ated
`lymphoid tissue lymphoma
`Waldenst r6m macroglobulinem1a
`Pnor therapy
`Median No
`Range
`R1tuximab
`Alkylator based
`Anthracychne based
`Radiotherapy
`Autologous stem-cell transplantation
`
`65
`41-82
`
`3
`1-10
`
`38
`18
`
`16
`16
`9
`7
`4
`
`4
`
`52
`47
`25
`15
`3
`
`%
`
`68
`32
`
`29
`29
`16
`13
`7
`
`7
`
`93
`B4
`45
`27
`5
`
`Abbreviations: CLL. chronic lymphocytic leukemia; DLBCL. diffuse large
`B-cell lymphoma; SLL. small lymphocytic lymphoma.
`
`by dose cohort. The most common AEs observed in the study were
`typically grade I or 2 in severity; grade 3 or 4 events were infrequent
`and independent of dose. Grade 3 to 4 hematologic toxicities incl uded
`neutropenia ( 12.5%), thrombocytopenia (7.2%), and anemia (7.1%).
`Additionally, no evidence of cumuJative hematologic or nonh emato(cid:173)
`logic toxicity was observed in patients with prolonged dosing. No
`consistent relationship between dose level and AEs was apparent. At
`the ti.me of this writing, 20 patients remain on treatment in an exten(cid:173)
`sion trial. Thirty-six patien ts discontinued study treatment: PD
`(n = 20), patient or physician decision (n = 8),AEs (n = 6), and DLTs
`(n = 2). The latter AEs included pain (grade 4), cerebrovascular
`accident (grade 4), small bowel obstruction (grade 3), flare of chronic
`obstructive pulmonary disease (grade 3), low hemoglobin and th rom(cid:173)
`bocytopenia (grade 2), and hypersensitivity pneumonitis (grade 1).
`
`CLL cells, as determined by flow cytometry. At baseline, the probe
`labeled a robust band corresponding to BTK, and this band decreased
`significantly within 4 hours of treatment and throughout the entire
`treatment cycle, suggesting durable and complete inhibition of BTK.
`Figure 1£ shows the dose dependency and durability of BTK occu(cid:173)
`pancy in PBMCs across all patients dosed in the study. BTK occu.
`pancy 2:: 95% was ach ieved 4 hours postdose in all patients in cohort I[
`(2.5 mg/kg per day). Figure lf plots the average BTK active-site occu(cid:173)
`pancy in PBMCs as a function of ibrutinib exposure (day l AUC).
`Complete or nearly complete BTK occupancy was observed in pa(cid:173)
`tients with AU Cs exceeding 160 ng X h/ mL. No decrease was observed
`in the level of serum lg in patients treated over 12 cycles (Appendix Fig
`Al , online only). A decrease in anti- IgE-stimulated basophil degran(cid:173)
`ulation was observed, consistent with the role of BTK downstream of
`the high-affinity lg£ receptor (Appendix Fig A2, online only).
`
`Tumor Response
`Of 50 patients evaluable for tumor response, 60% achieved an
`objective response ( CR or PR), with an overall response rate of 54% in
`the ITT population. Table 3 indicates the best response according to
`dose and schedule. Nine of 56 patients had PD at first assessment, of
`whom three were treated in cohort I, a dose tl1at did not lead to full
`BTK occupancy. Additionally, responses were observed across all his(cid:173)
`tologies, including seven of nine patients with man tle-cell lymphoma
`(three CRs), 11 of l 6 patients with CLUsmall lymphocyticlymphoma
`(two CRs), six of 16 patients with follicular lym phoma (three CRs),
`two of seven patients with DLBCL, three of four patients with WM,
`and one of four patients with marginal zone lymphoma (Appendix
`Table AI, online only). Of 11 patients with CLL, all experienced rapid
`reductions in lyrnphadenopathy during the fir st cycle of treatment
`accompanied byan increase in ab olute lymphocyte count, suggesting
`an egress of malignant cells fro m lymph nodes into peripheral blood.
`Only one of these patients with CLL d id not have an even tual reduc(cid:173)
`tion in lymphocytosis sufficient to be categorized as PR. Responses
`were durable, with median progression-free survival of 13.6 months at
`the ti.me of data cutoff. Twenty patients remain on study at the time of
`data cutoff because of conti nued clinical benefit (Fig 2). Change in
`aggregate tumor size ( data available for 48 patients) and lime on study
`(for all patients) are shown in Figures 2A and 28, respectively.
`
`PKs
`lbrutinib is rapidly absorbed and eliminated after oral adminis(cid:173)
`tration (Fig l A). Mean peak plasma concen trations were observed
`between l and 2 hours after dosing, and drug exposure ( derived from
`area under the concentration-time curve [AUC]) increased in a nearly
`dose-proportional manner (Fig lB). Plasma concentrations declined
`biphasically, with an initial mean half-life (determined after time to
`maximum plasma concentration to 6 hours postdose) of approxi(cid:173)
`mately2 to 3 hours. Mean apparent terminal half-life ranged from 4 to
`8 hours. There was no evidence of accumulation ofibrutinib exposure
`after repeated daily oral dosing.
`
`BTK Occupancy and Pharmacodynamics
`Figures l C and ID show representative probe assay data from a
`patient with CLL in dose-level cohort IV (8.3 mg/kg per day). The
`PBMC sample collected fro m this patient consisted of95.7% CD20+
`
`This study demonstrates that orally administered ibrutinib is well
`tolerated and induces significant objective responses in patients with
`B-cell NHL or CLL who have relapsed or were refractory to standard
`therapy. A majority of AEs were m i.Id (grade I or 2) in severity and
`easily managed or reversible. No significant myelosuppressions or
`renal or hepatic toxicities were observed. Additionally, no cumulative
`toxicity was noted with treatment duration over 6 months.
`Thirty patients achieved objective responses, with responses seen
`at each dose level and across all histologies. Responses were durable,
`with a majority maintaining their responses fo r at least 10 mon ths;
`several patients had remained on study for more than 20 months at the
`time of data cutoff. The highest response rate was observed in patients
`with mantle-cell lymphoma (78%) and CLU small lymphocytic lym(cid:173)
`phom