Award Wamer: IRMBLT-92 1.6710 corer sromabusis ‘Type 2 (NF2) FaLural Yiskery Covsortium PRIKCLEAL INVESTIGATOR: William Glattery, 1.0. CONTRACTING URGANIZMIIGN: Vouse saz _netirite Tor angeles, cA BCOST REPORT DATE: arvary 2994 TYPE OF RTDORT: Annual PREPAQED FOR; J Fe aumy XeGical Reweaveh rt Jetrics, Warylaxl 21702 Materiel Comrand DISTATEITION STATEMENT: Approved for Public 3e Iietvibution Iulimited Yhe views, opiniocs and/or Findings couleined in chis report are thore of ihe sutho-(s} and should uot be conslrusd as an official Dapustmens. of the arty posit—cu, policy er decision Unuews so dezicnzted by othes documertatica, 20040903 045 ~ v Fon Approved REPORT DOCUMENTATION PAGE CMB No. 079-0182 2 G02) Mauri Wietery consertim | aum7-01-2-0514 wiltisn siattery, #0 1. PCREOR a RESTA TWAGEST FG REDRESSTST 1 FERFSRNRTG ORGANEATIN Tos Arseles, CA 9t057 [AGINEY NAME(S) AND ADDRESSIEI ‘SGCNCY RESORT Waa 3.8. Remy Nodical Rowes2 a: Fore aotrick, Maryland 21722 raveriel commana approved for Peblle Release; Eintribucion unlimited [1S RETRACT paar eS PT Newobromatosls 2 (NF2| Is an autoscral dizer characterized by the development of mulpla tumor within tha train ‘and inal canal. The purnose ofthe study ist define gromlh alas anu cinicalcoures of tumars associate i NFZ, 8” Intemational consonisn of cinal centers and experiaa in NF2 wil be developed. We wl staneardize tne voluatie analyle of Ittaceorialand spinal tums, and apeeas the oatens'eudlclogleal, neurelogcal and ophtha'molagisl functioning over tha course of 3 yeas Currently, 65 subjects are actively envolled. Of tne subjects tha: have hed their exoma, 94% of Yeer 1 audological, 80% of rani Wis, 91% of stl Mls, 90% of neurolgieal, 86% of oprthaimolcle, 89% of SF-36 Neath surveys and 91% af Physica functioning questionnskes have eon roceled. Fiy-fourporcart of Veer 2 audlological, 73% cranial MRIS, 81% of spinal MA, 30% of raurofogial, 79% of ophtnalmelogis, 62% of SF-36 heal surveys ard B9% of physical ‘unctioning quest naires have been received, Two lorelgn cas have experienced eticuty obfsning & Federal wide ‘esvrance nurnver and Army approval ler aubiect enrollment. We have made good progress toward completion ol the ‘SYS goals and antisite ew problems with the colaction of Year 3folow-up data Heuretiavonctorte 2 t2), vestibular sohsenzomad, uelacel tahoe Et real rote, presicrive — Unelaeed fied Toelaceitiea ‘Unelat Table of Contents Cover... SF 298, “Table of Contents. Introduction. peorcnennl Rody. Kay Research Accomplishments. Reportable Outcomes. Conclusions. References. Appendices... INF2Ntural Hslury Gonsorium PLWH Slatin, Intreduetion Neuroffozomatocis 2 (NF2) ls an autosomal dominant cisorder characterized by the development ot rnulipte nervous system tumors. All patients davelop bilateral vestibular schwannomas that load to deafness and desth f untreated. Patients sis tend! develop muliple meningiomas and spinal tumor, which result In signficant motor end sensory defcts i let untested. Inthe past decade, grea" sides have been made in tarms of radogrophic dagnesis, surgical appreaches to thea jumors, and understanding of Ihe molecule bitgy of NF. Unfomunatay,simar advances i the understanding ofthe natura history of these tumors, fundamental to the evaluation of treatments, have not yet been mad. The purpose af tis study isto define the grouth fates ane! inca eoure of tumors associated with NF2. We Seck to accomplish this goal through tho folowing stops: 1. Devalap an Intemational consortium of cies canter with expertise in NF2,kurther expanding the Infrastructure developod in tha Natural History of Westar Sehwannamae in REZ US Army rant. Al patients wil be evalusted at local centers with ful neurological, aphthalmatogical, radlographical, and audlomette evaluations and the data willbe gent to 8 centralized center to analyze the data 2. ‘Develop standardized volumetrio analysis of intracranial and spinal tumors. Currant, we have standardized the volumetric analyse of tumore on the hearing and balance nerves. We wil atiampt to standardize the measurement of he other tors assockated with NF2 8. Form an infestructure for use in future cinical Wiss. All NF2 patents identified at clinical canets wll ba categorizsd as pototalsubjocts fr futuro clllcal lls, 44. Examination of molecular and cinical features which may predic tumor behavlr. ‘THis study wl load to a betor understanding of tre natural history and clinical course of humors associated with NF2. The knowlege wil ow beller recommendations regarding curont treatment options. An understanding ofthe natu history i eloo fundamental fo the determination of efcacy of ‘ture mesial or surgical horapics. Final, the framework of clnical cerers, data menagemert, ard scientific expense established during this projec il form the core for future tusies investigating aher aspects ofthe natural history of NF2 and for therapeutic ireatmant viele NFZ. ram No, DAMNA7-01-1-0740; Anna! Report Page tof 1 Natural Histry of Vestibular Schwannames in NF2 PA WH Slaten, I Body STATEMENT OF WORK Natural History of NF2-Consortum Task 1. ‘Standardize Clinical Date Colection for NF2 Patents @. Finalize proposed case record forms. (month 1) ; Completed Al case record forms were created, finalized, and sent to all participating investigational sites, A Manual of Proceduas, wth the cage record forms, has been sent io all nvastigalonal sites. The Manual of Procedures deta tha excl protocol be followed to obtain the epociiad measurements in tumor size, hearing, eye evaluation, and qual af lle an physical functioning . Creation of Comprehensive Care database and tracking system (months 1-3) : Complated A coordinated systom for collecting and transmiting study data was established, 4s detailed in the Manual of Procedures, House Ear Insttute (HEN serves as the Statistical ‘Analysis and Data Menagement/Coordinating Center for the project. inical Coordinators send aif original data to HEL. A Central Tracking System was established at HEI to hack each subject and assura tha consistent flow of data from each ste Fles for each subject hava been created and kept in locked cablnat. A computerized database has been cested to house the study data. As forms are sent to HEI, the dala are antarad into the database. ©. Assiet in translation of quality of life questionnaire and Comprehensive Care case record forms into Japanese and Gorman (1-4). : In Progress Al the outset ofthe study, Japan was includd as one ofthe investigational shes of the NF2 Consortium. However since that tine, Jepan has withdrawn trom participation ancl a new Investigational ste has been added in France. Questionneires ard case record forms were sant to both tha France and Germany investigational sites. Creation of French forms is in process. 4. Modify previous NF2 natural history consortium methods tor dte transfer ta comply with extra requirements required tor Comprehensive Care database (months 1-2): Completed Siudy methods have been created to ensure wansmittal of data to HEI, Clinical Coordinators fram ‘ch study site are in charge of contacting paliens, setting up appointments or calving ‘scheduling Information trom subjects, assisting with insurance autherleations, communicating facility name and contact information to tha Project Manager st HEI and ta Macra Gupta, WorldCars. The Cinical Coordinator also atonds the subjects exams, eneures completeness of the exams, and fils out tha MF Examination Outcome form and Data Tranemleelon CRS. ‘Tho MRI Faclity pertorms the cranial and spinal MRI exams according to protocol. fils aut the MAL Data Acquisition CRFs and gives ther to the Clirical Coordinator, and Involoes the investigational site forthe stpend for completing tha CRF, WorldCare receives notticatn of subject information, exam date, and faalty fom the Clinical Coordinator. WorldCare ensurcs that test data are gent from the MII facility to WordCara and aa acceptable, Original, completed CRFs are sent to HEL. Queries ragarding incomplete or inconsistent Information on GRFs are answered by the Clinical Coordinator and WorldCare, Grant No, DAMD17-01--0710; Annual Report: Pages 0114 ‘Natural Histry of Vestibular Schwiarmomas in NF2 Pa WH Slaton HEI tacks and monitors data flow, logs, dates and notes facies, notes i data ara racaived by ‘WertdCare, follows up with the statue of data, Task 2, Standardize Valumetic Analysis of riracranial Tumors and Spinas Tumors. a. Davelopment of standard operating procedure for digital analysis of MAls (months 1-2). Completed ‘A Manual of Praceduros is complete for both the Clinical Coordinators and WarldCere, The ‘manual contains information for tre data flor, acquisiton protocct, and deta wanser af images. WorldCare guidelines were merged withthe HE} Manual of Procedures and were distributed tothe Glinical Coordinators and investigators at each invastigational st. bb. Proparation of faciitias at WorldCare, Ine. (month 1). Completed A private sulte for the NF2 Natural Mistory Consortium has been prepared at WorldCare, Ine. At this time, all equipment and methods of sending and receiving deta have been used for the ‘olection and analysis of pationt data. Also, tha fling eystam, logbooks, and petient databace are established to accept and track the workliow of patient data. An adaitional worksite has baen set ‘up nei to tha intial workele to facltete the radiclogiat reading tho eoans, The additonal worksite has resulted in saving considerable time when transferring betwsen Images, ¢. Perform testretest data of other cranial tumors and spinal tumors to datormine amount of change raquired to be caneidered a statistically significant difference (monthe 1-3). : In Progress ‘estates dala has been collected for other oranial lumors, spectically meningiomas. Acquistlon and analysis of testiretest data for spinal tumors Is In process, ‘Perform qualltative and quantitative analysis of MAls {months 4-33).- In Progress “The radlologlt in charge of reading the MFils incioates whether the MFI scans and corrospending deta are acceptable to include in data analysis. Case record forms ata checked to ensure securacy of the data. Data cleaning is an ongoing process as dala is received at HEI, antallng the checking of regular data values, data edting, comactione and undeting, 2. Collection of yoarly MRI data (months 1-35}. : In Progress Of the 65 active patients enrolled in the study, 61 (84%) hava had thelr Yaar 1 Granlal MA exame ‘and 5 (48%) have had thelr Year 2 exams, Spinal Ml exams have been performed on 58 (79%) patlonis at Year 1 and on 34 (47%) patients at Year 2. WC has scanned, analyzed, and sent HEI 53 (87%) ofthe Year 4 Cranlal MAl CRF, 8 (23°) of the Year 2 Cranial MP CAFS, 49 (84%) af the Year 1 Spinal MRI GRFs and 8 (2434) of these Spinal MAI CRFs. Task 2 ‘Prepare intynatonal Consortium of Clie! NF2 Centers 6. Modity previous NFB netural history database for addtional requiramants ofthis study. Campioted “The NF2 Natural History Datahase hes boon modiiad to fnlude cata for visual tests, qualty of Me andi physical functioning questionaires as well as modifications to GAFS fr pation medial history, MA, audiology, necrlogial, and mecleculat biology exams. Obtain focal IAB approval (months 1-2).: Compisted All nine study sites hava received local IRB approval. However, one domestic site (Mt. Sina) has since withdrawn as a stuoy sila due toa lack of pinelpal investigator and ciricat coordina. & Obtain Army IRB approval and single project essurance approval (months 2-18).: In Progress ‘Grant No, DAMD#7-01-140710; Annual Rapon, Pagesot 11 Naural History of Vestibular Sohwannomas in NE2 Pa WH Slaton, 'f the eight ses that are participating in the tun, 2 of the foreign sites have received Army IRB approval for enretiment of subjects, _______ sie Tarra] House Ear ineiute VOT University of Texas raresr2 | “Massachusaite Ganaral Hosplal \ aresioa. Royal Vicioran Eye and Ear Hoeplal | 10/1002 Talvershy of OFFo. OV2OVO2, linkur Nord OcheenzaT Tv ‘Sk Many’s Hospital Hopital Beaujon _ ‘The two sites that are in the process of recciving appraval are St. Mary's Hospital in England and Hopital Besujon in France, 1. Tialn centers on study protocol (opine, qualty of fe, comprehensive sare} (months 5-6). Completed ‘Ammpatig was held forall ileal Coordinators and Prnepal Investigator 0 eviw the ctudy protocol. Study prctooc and marusl of proedures were dskibite to each Co-Princhal Invosigata and Cniesl Coordinator al soch ste, Hel maiaine ongelng ekephone dncussions vith the Gina! Coordinators to fecitate the tidy ar the melycalacon of dat. 4. Train centers in data transfer to Data Mantagemnont Centor {months 3-6}. : Completed Al Clinical Gonters have been glven a manual of proved res informing them ofthe protocol for data transfer to the Data Btanagement Contor at HE! Clinical Coordhnatars are rasponsibte for soncing al orginal, completed CRFs tor auslotogy, neurological, and ophthalmology exams and medical history, SF-36 quality of fe and physical functioning ntervigw tothe Project Manager at HEL. Original, completed MFl CRs are eent to HE! by WorldCare. Tash Subject Racruttmem and Dete Collection (months 3-30). a. Enroll previous Natural History of Vestibular Schwannoma in NF2 palfents In currant study. ‘Completed Some patients elected not to enrol inthe new study and soma pationts wars dropped by the lacal ceanters as they were non-compliant with the Frat atudy. ‘The folowing patients have been enrolled Grant Mo, DAMDI7-01-1-0710; Anrual Repo Page7 114 (Natural History of Vestinular Sehwannomas in NF2. PLL WH Steer. Table 1: Patient Enrollment Patient Collection Genter | Location Patients New | detal Enrolled From | Pationte | Patients Provious Study | Enrolled | Enrotlad | ‘Housa Ear aa Tas Angaleg, CA 2r ol at assachuse:ts Geral Hespial | Boston, MA. @ r 7a] ‘St Marys Hospital Maries UC TA. TA NA ‘akon Nord Oshsansol Hamburg, Germany a @ 1 University of Texas, Hausian | Houston, Tx 1 1 z Royal Vclovan Eye and Ear | Melbourne, Alsvall ry 1 ol Hospi ! ‘Ohin State Ualvershy Respltal | Coumtus, OF T a 7 Hopial Seaujon Pati, Franco RANE Wa Total Patlores Enfolled 47 25 iz NA ~ Sites thal have not yet revetved IRB approval. Currently, 7a patients were enrolled, but 66 are active in the study. Eight palients had been enrolled but have since bean wlindeawn for various reasons: 1 patient clad, 4 patlante vere non- ‘compliant, 2 were nol covered by medical insuranee fer requited exams and 1 patient was withdraumt for teatment pupeses. bb. Individual centers Identify potential patients to replace patlents who dropped out. : In Progress CCinieal Coordinators at each investigational se seen their patient population and idontty potential subjects for the Natural History of NF2 Consortium study. This ls an ongoing process at each site, NeW patients will complote baseline audlometric, MA, neurological, ophthalmologic exams, ‘SF-36 and physical functioning questionnalres and provide biood and tumor samples. : In Progress CCnleal Coordinators ate responsible for ensuring patients complete yearly exams. Although a subject may have completed an exam, its nat considered completa Untl the original copy fs received at HEI and entered inta the database, The falwwing CRFs have been reosived TOTAL PATIENTS= 65 q Your? Year? > Exama CAFE Exar ORFS Completed | Received | Completes __| Received ‘usloogy s6(66%) ——[srsi9 | 28 a85H) 15 64%) [Cranial Mi 59 (91%) /55(95%) [so Gam) 122 ar) Salnal MRL same) | si rm) “127 (eae 2 61%) Naurology. 68 (89%) | 82 (00%) | 2a (oT44) 2? (9906) OphthelmaTog 40 (75%) | aa om) [9 (6850) 16 73%) SF38 56 (96%) [so 1a0%) | 28 ee 23 (2%) Physical Functioning | s6 (86%) [51 (91%) [er (ea) (BSC) Blood Tumor Analysis [3 (5%) OY), NA twa 4d. All enrolied patlents will be seen tor yearly exarninations. HE is in contact wih the Cinical Coordinator from each sile, providing information on upcoming follow-up axame to he scheduled Grant No, DAMDI7-01-1-0710; Annual Report Page 8 of 11 [Nistural History of Vestibular Schwarniomas in NE2 Pil WH Slater, Il Task 5. Interim Anaiyate (months 12-18). 2. Interim statistical analysis and data obtained from initial audiometric, MRI studies, and clinical evaluations will be petforined. : In Progress ‘Alldata from CAFS received up tc date are entered into the database. Preliminary data anaiysis has begun. Currenlly, we are in the process of fearing the date. Data is examined to ensure all ‘values are within possible ranges. Each tumor (elther spinel, vestibular schvrarwioma (V8) oF meningioma) isthe unit of analyela with the start polnt being the data of each Yaar 1 exam and the ‘endpoint being elhar the date of the fist VS treatment or date of fast follow-up itn beatment was performed. Each pationtis reviewed individually to clearly identi the start point and endpoint of their data for each analysis. Task 6. Final Analysis and Report Witing (months 30-36) a. Final analysis of data will ba performed. : Pending Final analysis of the data willbe performed when ell CRF have been recetvad and all data heva bboon ontared into the database b. Final report anc lll be prepared. : Pending ‘Alor oll data has been artarad into the databace and al CARs logged inta out tracking systorn, a {inal repo wil be prepared, detailing the compictian of al goals established atthe outset ot the study. Manuscripts on data obtained front the study wil cover MRI exam methodology, vestibular schwannoma growth, growth of ether NF2 tumors, audiological changes aver time, neurological changes over ime, qually of fein NFZ patients and vieual characteristics of patents, Grant No, DAMD17-01-1-0710; Annual Reports Page @of 1 Niaal Het of Vest Schunomas a NFB om wn sete Key Research Accomplishments ‘= Development of an international consarium of clinical centers with expertise in NF2. ‘+ _Estabienment of landeseized study protoca for mui-nstiutonal, mu-naional natural history study, Development of NF2 spectic database which incudes alnical, rackogrephical,auciornerical, ‘ophthaknalogle, qualty of fe, and molecular bologyganate norton. » Development of standard operating procedure for gia! analysis of MRIs fing information from «a vatisty of MAT machines from diferent manufacturers, Reportable Outcomes, = Staating Committes Meeting, June 4, 2002: Interim data on the progress of this aludy were reported, The data collection process and diraction of fue data analyses ware discussed by all Co-Prncpal Investigators. ~ American Academy of Otolaryngology Head & Neck Surgery Meeting, September 22-25, 2002: ‘Valumatfa Analysis of Vastular Sehwannamnas Ir NE2, subtitid January 2003, + Shork-term Hearing Changes Alte Diagnosis in Neurofibromatosis (NF2Y, March, 2004, “AMAL Scannor Retahlly for Measuring Changes in Vestibular Schwannome Sze’, Otology & Neuratology, 2008; 24666671. ~Paclologles Seclety of North Ameria Annual Meoting, November'30-December 5, 200%: Inbamedullary ‘Spinal Tumors in Neurafioromaiosis Type I: Incidence and Imaging Charactoists. ‘Grant No, DAMD17-05-1-0716; Annual Reports Page 10 of 1