Page 1 f 5 NSABP B-47 - A Randmized Phase III Trial f Adjuvant Therapy Cmparing Chemtherapy Alne (Six Cycles f Dcetaxel Plus Cyclphsphamide r Fur Cycles f Dxrubicin Plus Cyclphsphamide Fllwed by Weekly Paclitaxel) t Chemtherapy Plus Trastuzumab in Wmen with Nde-Psitive r High-Risk Nde- Negative HER2-Lw Invasive Breast Cancer CTC v.4; AJCC 7 th ed. Herceptin prvided Fast Facts Althugh the guidelines belw are nt inclusin/exclusin criteria, investigatrs shuld cnsider each f these factrs when selecting patients fr the trial. Investigatrs shuld als cnsider all ther relevant factrs (medical and nn-medical), as well as the risks and benefits f the study therapy, when deciding if a patient is an apprpriate candidate fr this trial. Patients shuld have a life expectancy f at least 10 years, excluding their diagnsis f breast cancer. (Cmrbid cnditins shuld be taken int cnsideratin, but nt the diagnsis f breast cancer.) Wmen f reprductive ptential must agree t use an effective nn-hrmnal methd f cntraceptin (fr example cndms, sme intrauterine devices, diaphragms, tubal ligatin, vasectmized partner, r abstinence) during therapy and fr at least 6 mnths after the last dse f study therapy (chemtherapy r trastuzumab). Submissin f tumr samples frm the breast surgery is required fr all patients (see Sectin 7.1). Therefre, the lcal pathlgy department plicy regarding release f tumr samples must be cnsidered in the screening prcess. Patients whse tumr samples are lcated in a pathlgy department that by plicy will nt submit any samples fr research purpses shuld nt be apprached fr participatin in the B-47 trial. Patient eligibility 1. The patient must have signed and dated an IRB-apprved cnsent frm that cnfrms t federal and institutinal guidelines. 2. The patient must be female. 3. The patient must be 18 years ld. 4. The patient must have an ECOG perfrmance status f 0 r 1 (see Appendix A). 5. The tumr must be unilateral invasive adencarcinma f the breast n histlgic examinatin. 6. All f the fllwing staging criteria (using 7th editin f the AJCC Cancer Staging Manual) must be met: By pathlgic evaluatin, primary tumr must be pt1-3; By pathlgic evaluatin, ipsilateral ndes must be pn0, pn1 (pn1mi, pn1a, pn1b, pn1c), pn2a, pn2b, pn3a, r pn3b If pn0, ne f the fllwing criteria must be met: pt2 and ER negative and PgR negative; r pt2 and ER psitive (PgR status may be psitive r negative) and either grade 3 histlgy r Onctype DX Recurrence Scre f 25; r pt3 regardless f hrmne receptr status, histlgic grade, and Onctype DX 7. HER2 status f the primary tumr must be evaluated prir t randmizatin; all testing perfrmed must indicate that the tumr is HER2-lw as defined belw. IHC must be perfrmed and the IHC staining results must indicate a scre f 1+ (in situ hybridizatin [ISH] testing is nt required) r 2+ (ISH must als be perfrmed and must indicate that the tumr is HER2-lw as described belw). if ISH testing is perfrmed, test results must be as fllws and IHC must be 1+ r 2+: The rati f HER2 t CEP17 must be < 2.0 r, if a rati was nt perfrmed, the HER2 gene cpy number must be < 4 per nucleus. Nte: If the IHC staining intensity is reprted as a range, e.g., 0 t 1+ r 1+ t 2+, the higher intensity scre in the range shuld be used t determine eligibility.the patient must have undergne either a ttal mastectmy r breast-cnserving surgery (lumpectmy). (Patients wh have had a nipple-sparing mastectmy are eligible.) 8. Fr patients wh underg lumpectmy, the margins f the resected specimen must be histlgically free f invasive tumr and DCIS as determined by the lcal pathlgist. If pathlgic examinatin demnstrates tumr at the line f resectin, additinal perative prcedures may be perfrmed t btain clear margins. If tumr is still present at the resected margin after re-excisin(s), the patient must underg ttal mastectmy t be eligible. (Patients with margins psitive fr LCIS are eligible withut additinal resectin.) 9. Fr patients wh underg mastectmy, margins must be free f grss residual tumr. (Patients with micrscpic psitive margins are eligible as lng as pst-mastectmy RT f the chest wall will be administered.) 10. The patient must have cmpleted ne f the prcedures fr evaluatin f pathlgic ndal status listed belw. Sentinel lymphadenectmy alne: If pathlgic ndal staging based n sentinel lymphadenectmy is pn0 r pn1b; If pathlgic ndal staging based n sentinel lymphadenectmy is pn1mi r pn1a, the primary tumr must be T1 r T2 by pathlgic evaluatin and the ndal invlvement must be limited t 1 r 2 psitive ndes.
Page 2 f 5 Sentinel lymphadenectmy fllwed by remval f additinal nn-sentinel lymph ndes if the sentinel nde (SN) is psitive; r Axillary lymphadenectmy with r withut SN islatin prcedure. 11. The interval between the last surgery fr breast cancer (treatment r staging) and randmizatin must be n mre than 84 days. 12. The patient must have ER analysis perfrmed n the primary tumr prir t randmizatin. If ER analysis is negative, then PgR analysis must als be perfrmed. (Either the cre bipsy r surgical resectin specimen can be used fr ER/PgR testing.) Patients with a primary tumr that is hrmne receptr-psitive r receptr-negative are eligible. 13. The mst recent pstperative bld cunts, perfrmed within 6 weeks prir t randmizatin, must meet the fllwing criteria: ANC must be 1200/mm 3 ; Platelet cunt must be 100,000/mm 3 ; and Hemglbin must be 10 g/dl. 14. The fllwing criteria fr evidence f adequate hepatic functin must be met based n the results f the mst recent pstperative tests perfrmed within 6 weeks prir t randmizatin: ttal bilirubin must be ULN fr the lab unless the patient has a bilirubin elevatin > ULN t 1.5 x ULN due t Gilbert s disease r similar syndrme invlving slw cnjugatin f bilirubin; and alkaline phsphatase must be 2.5 x ULN fr the lab; and AST must be 1.5 x ULN fr the lab. Alkaline phsphatase and AST may nt bth be > the ULN. Fr example, if the alkaline phsphatase is > the ULN but 2.5 x ULN, the AST must be the ULN. If the AST is > the ULN but 1.5 x ULN, the alkaline phsphatase must be ULN. Nte: If ALT is perfrmed instead f AST (per institutin's standard practice), the ALT value must be 1.5 x ULN; if bth were perfrmed, the AST must be 1.5 x ULN. 15. Patients with AST r alkaline phsphatase > ULN are eligible fr inclusin in the study if liver imaging (CT, MRI, PET-CT, r PET scan) perfrmed within 90 days prir t randmizatin des nt demnstrate metastatic disease and the requirements in criterin are met. 16. Patients with alkaline phsphatase that is > ULN but 2.5 x ULN r unexplained bne pain are eligible fr inclusin in the study if a bne scan, PET-CT scan, r PET scan perfrmed within 90 days prir t randmizatin des nt demnstrate metastatic disease. 17. The mst recent pstperative serum creatinine perfrmed within 6 weeks prir t randmizatin must be ULN fr the lab. 18. LVEF assessment must be perfrmed within 90 days prir t randmizatin. LVEF assessment perfrmed by 2-D echcardigram is preferred; hwever, MUGA scan may be substituted based n institutinal preferences. Fr patients wh will receive the TC chemtherapy regimen, the LVEF must be 50% regardless f the cardiac imaging facility's lwer limit f nrmal. Fr patients wh will receive the AC WP chemtherapy regimen, the LVEF must be 55% regardless f the cardiac imaging facility's lwer limit f nrmal. Nte: Since the pre-entry LVEF serves as the baseline fr cmparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment. If the baseline LVEF is > 70%, the investigatr is encuraged t have the accuracy f the initial LVEF result cnfirmed and repeat the test if the accuracy is uncertain. (See Sectins 5.2 and 5.3 fr LVEF instructins.) Patient ineligibility 1. Primary tumr with any f the fllwing HER2 testing results: IHC staining intensity: - 0 n all evaluatins f specimen - 3+ n evaluatins f any specimen ISH with a rati f HER2 f CEP17 2.0 n evaluatin f any specimen ISH result indicating HER2 gene cpy number 4 per nucleus n evaluatin f any specimen 2. T4 tumrs including inflammatry breast cancer. 3. Definitive clinical r radilgic evidence f metastatic disease. (Nte: Chest imaging [mandatry fr all patients] and ther imaging [if required] must have been perfrmed within 90 days prir t randmizatin.) 4. Synchrnus r previus cntralateral invasive breast cancer. (Patients with synchrnus and/r previus cntralateral DCIS r LCIS are eligible.) 5. Any previus histry f ipsilateral invasive breast cancer r ipsilateral DCIS. (Patients with synchrnus r previus ipsilateral LCIS are eligible.) 6. Histry f nn-breast malignancies (except fr in situ cancers treated nly by lcal excisin and basal cell and squamus cell carcinmas f the skin) within 5 years prir t randmizatin. 7. Previus therapy with anthracyclines, taxanes, r trastuzumab fr any malignancy. 8. Chemtherapy r HER2-targeted therapy administered fr the currently diagnsed breast cancer prir t randmizatin.
Page 3 f 5 9. Whle breast RT prir t randmizatin r partial breast RT that cannt be cmpleted n r befre the date f randmizatin (see Sectins 9.8 and 9.10.3). 10. Cntinued endcrine therapy such as ralxifene r tamxifen (r ther SERM) r an armatase inhibitr. Patients are eligible if these medicatins are discntinued prir t randmizatin (see Sectin 9.9). 11. Any cntinued use f sex hrmnal therapy, e.g., birth cntrl pills, varian hrmne replacement therapy. Patients are eligible if these medicatins are discntinued prir t randmizatin (see Sectin 4.1). 12. Cardiac disease (histry f and/r active disease) that wuld preclude the use f the drugs included in the treatment regimens. This includes but is nt cnfined t: Active cardiac disease angina pectris that requires the current use f anti-anginal medicatin; ventricular arrhythmias except fr benign premature ventricular cntractins; supraventricular and ndal arrhythmias requiring a pacemaker r nt cntrlled with medicatin; cnductin abnrmality requiring a pacemaker; valvular disease with dcumented cmprmise in cardiac functin; and symptmatic pericarditis. Histry f cardiac disease mycardial infarctin dcumented by elevated cardiac enzymes r persistent reginal wall abnrmalities n assessment f LV functin; histry f dcumented CHF; and dcumented cardimypathy. 13. Hypertensin defined accrding t the fllwing ineligibility criteria: Fr patients wh will receive TC (regardless f the patient's age): Uncntrlled hypertensin defined as sustained systlic BP > 150 mmhg r diastlic BP > 90 mmhg. (Patients with initial BP elevatins are eligible if initiatin r adjustment f BP medicatin lwers pressure t meet entry criteria.) Fr patients < 50 years ld wh will receive AC WP: Uncntrlled hypertensin defined as sustained systlic BP > 150 mmhg r diastlic BP > 90 mmhg. Patients with initial BP elevatins are eligible if initiatin r adjustment f BP medicatin lwers pressure t meet entry criteria. Fr patients 50 years ld wh will receive AC WP: Uncntrlled hypertensin defined as sustained systlic BP > 150 mmhg r diastlic BP > 90 mmhg. Cntrlled hypertensin (systlic BP 150 mmhg and diastlic BP 90 mmhg), if anti-hypertensive medicatin(s) are needed. Nte: Patients wh are nt eligible based n the AC WP regimen BP criteria but wh meet the TC regimen BP criteria are eligible fr B-47, if the intended chemtherapy regimen is changed t TC. 14. Active hepatitis B r hepatitis C with abnrmal liver functin tests. 15. Intrinsic lung disease resulting in dyspnea. 16. Prly cntrlled diabetes mellitus. 17. Active infectin r chrnic infectin requiring chrnic suppressive antibitics. 18. Nervus system disrder (paresthesia, peripheral mtr neurpathy, r peripheral sensry neurpathy) grade 2, per the CTCAE v4.0. 19. Cnditins that wuld prhibit administratin f crticsterids. 20. Chrnic daily treatment with crticsterids with a dse f 10 mg/day methylprednislne equivalent (excluding inhaled sterids). 21. Knwn hypersensitivity t any f the study drugs r excipients, e.g., plysrbate 80 and Cremphr EL. 22. Pregnancy r lactatin at the time f study entry. (Nte: Pregnancy testing must be perfrmed within 2 weeks prir t randmizatin accrding t institutinal standards fr wmen f childbearing ptential.) 23. Other nn-malignant systemic disease that wuld preclude the patient frm receiving study treatment r wuld prevent required fllw-up. 24. Psychiatric r addictive disrders r ther cnditins that, in the pinin f the investigatr, wuld preclude the patient frm meeting the study requirements. 25. Use f any investigatinal prduct within 30 days prir t randmizatin. Pre-study Parameters 1. Histry and physical including height, weight, perfrmance status, menstrual histry, menpausal status, BP, cncmitant meds assessment including BP meds 2. CBC with differential, AST, Alk Phs, ttal bilirubin, serum creatinine, pregnancy test fr wmen f child-bearing ptential 3. Ech (preferred) r MUGA, ECG 4. Chest imaging (CT r x-ray) (PET r PET/CT may be substituted); Liver imaging if AST > ULN; Bne nuclear imaging if Alk Phs > ULN
Page 4 f 5 5. Bilateral breast imaging (mammgram r MRI)
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