AWARD NUMBER: W81XWH-14-1-0444 TITLE: Culd HER2 Hetergeneity Open New Therapeutic Optins in Patients with HER2- Primary Breast Cancer? PRINCIPAL INVESTIGATOR: Gary Ulaner, MD, PhD CONTRACTING ORGANIZATION: Memrial Slan Kettering Cancer Center New Yrk, NY, 10065 REPORT DATE: Oct 2016 TYPE OF REPORT: Annual Reprt PREPARED FOR: U.S. Army Medical Research and Materiel Cmmand Frt Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Apprved fr Public Release; Distributin Unlimited The views, pinins and/r findings cntained in this reprt are thse f the authr(s) and shuld nt be cnstrued as an fficial Department f the Army psitin, plicy r decisin unless s designated by ther dcumentatin.
REPORT DOCUMENTATION PAGE Frm Apprved OMB N. 0704-0188 Public reprting burden fr this cllectin f infrmatin is estimated t average 1 hur per respnse, including the time fr reviewing instructins, searching existing data surces, gathering and maintaining the data needed, and cmpleting and reviewing this cllectin f infrmatin. Send cmments regarding this burden estimate r any ther aspect f this cllectin f infrmatin, including suggestins fr reducing this burden t Department f Defense, Washingtn Headquarters Services, Directrate fr Infrmatin Operatins and Reprts (0704-0188), 1215 Jeffersn Davis Highway, Suite 1204, Arlingtn, VA 22202-4302. Respndents shuld be aware that ntwithstanding any ther prvisin f law, n persn shall be subject t any penalty fr failing t cmply with a cllectin f infrmatin if it des nt display a currently valid OMB cntrl number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE 3. DATES COVERED Octber 2016 Annual Reprt 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 4 Culd HER2 Hetergeneity Open New Therapeutic Optins in Patients with HER2- Primary Breast Cancer? 30 Sep 2015-29 Sep 2016 5b. GRANT NUMBER W81XWH-14-1-0444 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Gary Ulaner E-Mail: ulanerg@mskcc.rg 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Memrial Slan Kettering Cancer Center 1275 Yrk Avenue New Yrk, NY, 10065 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR S ACRONYM(S) U.S. Army Medical Research and Materiel Cmmand Frt Detrick, Maryland 21702-5012 11. SPONSOR/MONITOR S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Apprved fr Public Release; Distributin Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The purpse f this study is t determine if targeted imaging with a HER2-targeting PET tracer can detect HER2-psitive metastases in patients with HER2-negative primary breast cancer. Twenty-three patients have been accrued t the trial. Nine patients demnstrated suspicius fci n 89 Zr-trastuzumab PET/CT. Tw f nine patients with suspicius fci had bipsy-prven HER2-psitive metastases. Thus, 89 Zr-trastuzumab PET/CT may detect HER2-psitive metastases in patients with presumed HER2-negtive primary breast cancer. This is an initial prf-f-cncept that targeted imaging may help identify patients eligible fr targeted therapies. Hwever, false-psitive results limit the ability f 89 Zr-trastuzumab t be translated int clinical use, and a mre specific raditracer will be needed. 15. SUBJECT TERMS Breast cancer, HER2, tumr hetergeneity, PET/CT, 89 Zr-trastuzumab 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT a. REPORT Unclassified b. ABSTRACT Unclassified c. THIS PAGE Unclassified 18. NUMBER OF PAGES Unclassified 10 19a. NAME OF RESPONSIBLE PERSON USAMRMC 19b. TELEPHONE NUMBER (include area cde) Standard Frm 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18
Table f Cntents Page 1. Intrductin. 1 2. Keywrds. 1 3. Accmplishments. 1 4. Impact... 4 5. Changes/Prblems.... 4 6. Prducts.... 5 7. Participants & Other Cllabrating Organizatins. 6 8. Special Reprting Requirements 7 9. Appendices Federal Financial Reprt
Ulaner, Gary PROGRESS REPORT: Octber 2016 DD W81XWH-14-1-0444 Culd HER2 hetergeneity pen new therapeutic ptins in patients with HER2- primary breast cancer? 1. INTRODUCTION: Human epidermal grwth factr receptr 2 (HER2) is a highly valuable bimarker in breast cancer, and its expressin directly influences treatment. Grwing evidence suggests that HER2 expressin may change between the primary breast malignancy and metastases. This is an example f tumr hetergeneity. Inaccurate knwledge f receptr status in metastases due t tumr hetergeneity may lead t subptimal treatment f metastatic breast cancer. Our central hypthesis is that imaging with a targeted HER2 raditracer will allw us t identify patients with HER2-negative primary breast cancers wh develp HER2-psitive metastases, and wh may benefit frm the additin f HER2 therapy. 2. KEYWORDS: Breast cancer Human epidermal grwth factr receptr 2 (HER2) Tumr hetergeneity PET/CT Targeted imaging 89 Zr-trastuzumab 3. ACCOMPLISHMENTS: What were the majr gals f the prject? Task 1. Submissin and apprval f regulatry dcuments 1a. IND fr 89 Zr-trastuzumab 1b. IRB Prtcl Task 2. Determine the prprtin f patients with HER2- primary breast cancer wh develp imagable HER2+ metastases using a targeted HER2 raditracer (Specific Aim #1) 2a. Accrue 50 patients at a rate f 1-2 per mnth 2b. Cnfirm HER2- status f archived pathlgy tissue samples 2c. 89 Zr-trastuzumab PET/CT t identify patients suspicius fr HER2+ metastases 2d. Bipsies t cnfirm HER2+ malignancy 2e. Interim statistical analyses as predefined accrual numbers are met Task 3. Amng patients with HER2+ metastases discvered in Specific Aim #1, determine if HER2-targeted therapy results in a measurable treatment respnse (Specific Aim #2) 3a. Pre-treatment baseline disease assessments with FDG PET and CT 3b. HER2-targeted systemic therapy 3c. Pst-treatment disease assessments with FDG PET and CT 3d. Final statistical analyses 1
Ulaner, Gary PROGRESS REPORT: Octber 2016 DD W81XWH-14-1-0444 Culd HER2 hetergeneity pen new therapeutic ptins in patients with HER2- primary breast cancer? What was accmplished under these gals? Task 1. Submissin and apprval f regulatry dcuments 1a. IND fr 89 Zr-trastuzumab IND fr 89 Zr was cmpleted and maintained 1b. IRB Prtcl IRB fr study prtcl was cmpleted and maintained. Task 2. Determine the prprtin f patients with HER2- primary breast cancer wh develp imagable HER2+ metastases using a targeted HER2 raditracer 2a. Accrue 50 patients at a rate f 1-2 per mnth 23 patients were accrued t the prtcl as f 30-Sep-2016. 2b. Cnfirm HER2- status f archived pathlgy tissue samples HER2- status f archived pathlgy samples was cnfirmed fr all patients. 2c. 89 Zr-trastuzumab PET/CT t identify patients suspicius fr HER2+ metastases 89 Zr-trastuzumab PET/CT was perfrmed in all patients. Nine patients had 89 Zrtrastuzumab fci suspicius fr HER2+ disease. 2d. Bipsies t cnfirm HER2+ malignancy Bipsies were perfrmed in all nine patients with 89 Zr-trastuzumab fci suspicius fr HER2+ disease. Tw f nine were psitive fr HER2+ disease n pathlgy (true psitives) Seven f nine were nt psitive fr HER2+ disease n pathlgy (false psitives) 2e. Interim statistical analyses as predefined accrual numbers are met Interim statistical analyses were perfrmed. Task 3. Amng patients with HER2+ metastases discvered in Specific Aim #1, determine if HER2-targeted therapy results in a measurable treatment respnse 3a. Pre-treatment baseline disease assessments with FDG PET and CT Pre-treatment baseline disease assessments were perfrmed in the tw patients with bipsy-prven, HER2+ metastases. 3b. HER2-targeted systemic therapy HER2-targeted systemic therapy was perfrmed in the tw patients with bipsy-prven, HER2+ metastases. 3c. Pst-treatment disease assessments with FDG PET and CT 2
Ulaner, Gary PROGRESS REPORT: Octber 2016 DD W81XWH-14-1-0444 Culd HER2 hetergeneity pen new therapeutic ptins in patients with HER2- primary breast cancer? Pst-treatment disease assessments were perfrmed in the tw patients with bipsyprven, HER2+ metastases. Bth patients demnstrated respnse t HER2-targeted therapy (ne cmplete, ne partial). 3d. Final statistical analyses Final statistical analyses are pending. What pprtunities fr training and prfessinal develpment has the prject prvided? Nthing t reprt Hw were the results disseminated t cmmunities f interest? The first manuscript fr this prject has been published: Detectin f HER2-psitive metastases in patients with HER2-negative primary breast cancer using the 89 Zr-DFO-trastuzumab PET/CT. Ulaner et al, Jurnal f Nuclear Medicine 2016, e-published ahead f print, PMID: 27151988 The first presentatin fr the prject has been made: Detectin f HER2-psitive metastases in patients with HER2-negative primary breast cancer using 89 Zr-DFO-trastuzumab, Ulaner et al, Annual Meeting f the Sciety f Nuclear Medicine and Mlecular Imaging, San Dieg, Califrnia, June 2016. 3 What d yu plan t d during the next reprting perid t accmplish the gals? The bjective f the study (detectin f HER2+ metastases in patients with presumed HER2- disease) has been accmplished. This is a prf-fcncept that targeted imaging may help identify patients eligible fr targeted therapies. Hwever, the high rate f false psitives limits the usefulness f 89 Zr-trastuzumab t be translated t the clinic. A mre specific raditracer will be needed. We have spken with ur DD Science fficer, Julia M. Huiberts, and have cme up with a plan t btain an Investigatinal New Drug (IND) applicatin frm the Fd and Drug Administratin (FDA) fr a ptentially mre specific HER2-targeting PET raditracer, 89 Zr-pertuzumab, and perfrm the remainder f this trial with 89 Zr-pertuzumab. This will delay the cmpletin f the study by the time it takes t btain the 89 Zr-pertuzumab IND frm the FDA (estimated t be ne year); hwever, this change may increase the specificity f ur HER2- targeted imaging.
Ulaner, Gary PROGRESS REPORT: Octber 2016 DD W81XWH-14-1-0444 Culd HER2 hetergeneity pen new therapeutic ptins in patients with HER2- primary breast cancer? 4. IMPACT: What was the impact n the develpment f the principal discipline(s) f the prject? The results already demnstrate the prf-f-cncept that targeted imaging can be used t help identify patients eligible fr targeted therapies. What was the impact n ther disciplines? The initial results cnfirm that there may be hetergeneity f HER2 expressin between the primary malignancy and distant metastases. This adds t the grwing knwledge f tumr hetergeneity. What was the impact n technlgy transfer? Nthing t reprt. What was the impact n sciety beynd science and technlgy? Nthing t reprt. 5. CHANGES/PROBLEMS: The detectin f 89 Zr-trastuzumab fci that represent HER2- (rather than HER2+) metastatic breast cancer is cnsidered a prblem. As previusly mentined, we have spken with ur DD Science fficer, Julia M. Huiberts, and have cme up with a plan t btain an IND applicatin frm the FDA fr a ptentially mre specific HER2-targeting PET raditracer, 89 Zr-pertuzumab, and perfrm the remainder f this trial with 89 Zrpertuzumab. This will delay the cmpletin f the study by the time it takes t btain the 89 Zr-pertuzumab IND frm the FDA (estimated t be ne year); hwever, this change may increase the specificity f ur HER2-targeted imaging. Changes in apprach and reasns fr change We will change frm 89 Zr-trastuzumab t 89 Zr-pertuzumab imaging, a ptentially mre specific antibdy cnjugate, t attempt t increase specificity f HER2-targeted imaging. Actual r anticipated prblems r delays and actins r plans t reslve them Use f 89 Zr-pertuzumab will require an IND applicatin t the FDA. This will delay the cmpletin f the study by the time it takes t btain the 89 Zr-pertuzumab IND frm the FDA (estimated t be ne year). Changes that had a significant impact n expenditures Nthing t reprt. Significant changes in use r care f human subjects, vertebrate animals, bihazards, and/r select agents Nthing t reprt. 4
Ulaner, Gary PROGRESS REPORT: Octber 2016 DD W81XWH-14-1-0444 Culd HER2 hetergeneity pen new therapeutic ptins in patients with HER2- primary breast cancer? Significant changes in use r care f human subjects Nthing t reprt. Significant changes in use r care f vertebrate animals. Nthing t reprt. Significant changes in use f bihazards and/r select agents Nthing t reprt. 6. PRODUCTS: Publicatins, cnference papers, and presentatins Jurnal publicatins. Ulaner et al, Jurnal f Nuclear Medicine 2016, e-published ahead f print, PMID: 27151988 Bks r ther nn-peridical, ne-time publicatins. Nthing t reprt. Other publicatins, cnference papers, and presentatins. Detectin f HER2-psitive metastases in patients with HER2-negative primary breast cancer using 89 Zr-DFO-trastuzumab, Ulaner et al., Annual Meeting f the Sciety f Nuclear Medicine and Mlecular Imaging, San Dieg, Califrnia, June 2016 Website(s) r ther Internet site(s) Nthing t reprt. Technlgies r techniques Nthing t reprt. Inventins, patent applicatins, and/r licenses Nthing t reprt. Other Prducts Nthing t reprt. PARTICIPANTS & OTHER COLLABORATING ORGANIZATIONS What individuals have wrked n the prject? Prvide the fllwing infrmatin fr: (1) PDs/PIs; and (2) each persn wh has wrked at least ne persn mnth per year n the prject during the reprting perid, regardless f the surce f cmpensatin (a persn mnth equals apprximately 160 hurs f effrt). If infrmatin is 5
Ulaner, Gary PROGRESS REPORT: Octber 2016 DD W81XWH-14-1-0444 Culd HER2 hetergeneity pen new therapeutic ptins in patients with HER2- primary breast cancer? unchanged frm a previus submissin, prvide the name nly and indicate "n change." Name: Gary Ulaner (PI): N change Name: Hanh Pham (Research Assistant): N change Has there been a change in the active ther supprt f the PD/PI(s) r senir/key persnnel since the last reprting perid? Nthing t reprt What ther rganizatins were invlved as partners? Nthing t reprt 7. SPECIAL REPORTING REQUIREMENTS COLLABORATIVE AWARDS: Nt applicable QUAD CHARTS: Nt applicable. 8. APPENDICES: Nne. ****************************************************************************** ********** ADDITIONAL NOTES: n/a 6