Figure 1 Study Flw Chart ICF fr patients with unknwn BRCA status t underg central BRCA testing during, r prir t, neadjuvant/adjuvant chemtherapy Neadjuvant chemtherapy Minimum 6 cycles (cntaining anthracyclines, taxanes r the cmbinatin f bth) Surgery Surgery Fr TNBC: Axillary nde psitive ( pn1, any tumur size) If axillary nde negative (pn0) T >2 cm ( pt2) Fr ER and/r PgR+ HER2-: 4 psitive lymph ndes Path CR Fr TNBC: Nn-Path CR Fr ER and/r PgR+ HER2-; Nn-Path CR Nt eligible AND CPS&EG scre 3 Adjuvant raditherapy as required Adjuvant Chemtherapy Minimum 6 cycles (cntaining anthracyclines, taxanes r the cmbinatin f bth) Raditherapy/additinal surgery as required Infrmed cnsent fr participatin in the study fr patients with knwn gbrca mutatin status Randmisatin (ideally within 8 weeks after last treatment (surgery, chemtherapy r raditherapy), but in n case lnger than 12 weeks) Olaparib 300 mg rally twice daily, cntinuus fr 12 mnths OR Placeb rally twice daily, cntinuus fr 12 mnths Mammgram and/r breast MRI 6 mnths frm day 1 Fllw up fr lcal and distant recurrence and survival status Patients will cntinue t be fllwed clinically n a 3 mnthly basis during the first 2 years, fllwed by 6 mnthly assessments fr the 3rd, 4th and 5th year, and annually thereafter Yearly breast imaging (mammgram and/r MRI) fr 10 years* *The study will end 10 years after the last patient has been randmised NCI Versin Date: 10-19-15 42(194) NSABP B-55/BIG 6-13
4. PATIENT SELECTION CRITERIA Investigatr(s) shuld keep a patient screening lg f patients wh entered pre-study screening. Each patient shuld meet all f the inclusin criteria and nne f the exclusin criteria fr this study. Under n circumstances can there be exceptins t this rule. Criteria relevant t Part 1 BRCA screening (Table 1) are marked with (**) duble asterisk 4.1 Inclusin criteria Fr inclusin in the study patients shuld fulfil the fllwing criteria: 1. **Prvisin f infrmed cnsent prir t any study specific prcedures 2. **Female r male patients must be 18 years f age 3. a) Fr patients wh underwent initial surgery and received adjuvant chemtherapy TNBC patients must have been axillary nde-psitive ( pn1, any tumur size) r axillary nde negative (pn0) with invasive primary tumur pathlgical size > 2 cm ( pt2). ER and/r PgR psitive/her 2 negative patients must have had 4 pathlgically cnfirmed psitive lymph ndes. b) Fr patients wh underwent neadjuvant chemtherapy fllwed by surgery TNBC patients must have residual invasive breast cancer in the breast and/r resected lymph ndes (nn-pcr) ER and/r PgR psitive/her2 negative patients must have residual invasive cancer in the breast and/r the resected lymph ndes (nn-pcr) AND a CPS&EG scre 3. Instructins n hw t calculate the CPS&EG scre (Mittendrf et al 2011; Jeruss et al 2008) are prvided in Appendix J. 4. **Histlgically cnfirmed nn-metastatic primary invasive adencarcinma f the breast that is ne f the tw fllwing phentypes: a) TNBC defined as: ER and PgR negative defined as IHC nuclear staining <1%. All ER and PgR assessments that are lcally available must be negative. AND NCI Versin Date: 10-19-15 55(194) NSABP B-55/BIG 6-13
HER2 negative (nt eligible fr anti-her2 therapy) defined as: IHC 0, 1+ withut ISH OR IHC 2+ and ISH nn-amplified with rati less than 2.0 and if reprted, average HER2 cpy number < 4 signals/cells OR ISH nn-amplified with rati less than 2.0 and if reprted, average HER2 cpy number < 4 signals/cells (withut IHC) b) ER and/r PgR psitive, HER2 negative breast cancer defined as: ER and/r PgR psitive defined as IHC nuclear staining 1%. Any tumur that has been lcally assessed as ER and/r PgR psitive in either the cre bipsy r the surgical specimen is cnsidered t be ER and/r PgR psitive. AND HER2 negative (nt eligible fr anti-her2 therapy) defined as: IHC 0, 1+ withut ISH OR IHC 2+ and ISH nn-amplified with rati less than 2.0 and if reprted, average HER2 cpy number < 4 signals/cells OR ISH nn-amplified with rati less than 2.0 and if reprted, average HER2 cpy number < 4 signals/cells (withut IHC) Patients with multifcal r multicentric invasive disease are eligible as lng as all the lesins fr which HER2 characterizatin is available are HER2 negative. Patients with synchrnus bilateral invasive disease are eligible as lng as all the lesins assessed fr HER2 n bth sides are negative. In bth cases, the lesin cnsidered at highest risk fr recurrence based n the investigatr's discretin will be used fr eligibility determinatin. 5. Dcumented germline mutatin in BRCA1 r BRCA2 that is predicted t be deleterius r suspected deleterius (knwn r predicted t be detrimental/lead t lss f functin). Lcal gbrca testing results, if available, will be used fr establishing eligibility. If lcal gbrca testing results are nt available, central testing will be prvided fr thse patients wh therwise appear t be eligible (see Sectin 6.2.1). 6. a) Cmpleted adequate breast surgery defined as: The inked margins f breast cnservatin surgery r mastectmy must be histlgically free f invasive breast cancer and ductal carcinma in situ with the exceptin f the psterir margin if this margin is the pectralis NCI Versin Date: 10-19-15 56(194) NSABP B-55/BIG 6-13
majr fascia r the anterir margin if this is the dermis. Patients with resectin margins psitive fr lbular carcinma in situ are eligible. Patients with breast cnservatin must have adjuvant raditherapy. Patients having mastectmy may have adjuvant raditherapy accrding t lcal plicy and/r internatinal guidelines. b) Cmpleted adequate axilla surgery defined as: Adjuvant Chemtherapy Patients: Sentinel lymph nde bipsy alne if negative r if lymph nde(s) nly cntain micrmetastases ( 2.0 mm) OR Psitive sentinel lymph nde bipsy fllwed by axillary ndal dissectin r raditherapy as per lcal guidelines OR Axillary dissectin Neadjuvant Chemtherapy Patients: Sentinel lymph nde bipsy perfrmed befre neadjuvant chemtherapy: If negative r if lymph nde(s) nly cntain micrmetastases ( 2.0 mm), additinal axillary surgery is nt required If psitive, axillary nde dissectin r axillary ndal raditherapy shuld fllw cmpletin f neadjuvant chemtherapy Sentinel lymph nde bipsy perfrmed after neadjuvant chemtherapy: If negative, additinal axillary surgery nt mandated If psitive (micrmetastases are regarded as psitive), additinal axillary surgery is required unless the patient is enrlled in an Executive Cmmittee apprved, Phase III multicentre clinical trials prpsing raditherapy as alternative treatment f the axilla Axillary dissectin 7. Cmpleted at least 6 cycles f neadjuvant r adjuvant chemtherapy cntaining anthracyclines, taxanes r the cmbinatin f bth. Prir platinum as ptentially curative treatment fr prir cancer (e.g. varian) r as adjuvant r neadjuvant treatment fr breast cancer is allwed. (Fr neadjuvant patients all chemtherapy shuld be delivered prir t surgery. N further cycles f chemtherapy pst-surgery are allwed.) NCI Versin Date: 10-19-15 57(194) NSABP B-55/BIG 6-13
8. Patients must have adequate rgan and bne marrw functin measured within 28 days prir t randmisatin with n bld transfusins (packed red bld cells and/r platelet transfusins) in the past 28 days prir t testing fr rgan and bne marrw functin as defined belw: Haemglbin 10.0 g/dl Abslute neutrphil cunt (ANC) 1.5 x 10 9 /L Platelet cunt 100 x 10 9 /L Ttal Bilirubin ULN (institutinal upper limit f nrmal) except elevated ttal bilirubin <1.5 x ULN due t Gilbert s disease r similar syndrme invlving slw cnjugatin f bilirubin AST (SGOT)/ALT (SGPT) 2.5 x ULN ALP 2.5 x ULN T rule ut metastatic breast cancer, patients with screening ALT/AST r ALP abve institutinal upper limit f nrmal shuld have liver ultrasund, CT r MRI at any time pint between diagnsis f current breast cancer and randmisatin. Screening bne scan is required if ALP and/r crrected calcium level are abve the institutinal upper limit. (Nte PET/CT scan may be used as an alternative imaging techniques). 9. Serum r plasma creatinine 1.5 x ULN 10. ECOG perfrmance status 0-1 11. a) Wmen wh are nt pstmenpausal r have nt undergne a hysterectmy must have dcumented negative pregnancy test within 28 days prir t randmisatin. Pstmenpausal is defined as ne r mre f the fllwing: Age 60 yrs Age < 60 and amenrrheic fr 1 year r mre in the absence f chemtherapy and/r hrmnal treatment Fllicle stimulating hrmne (FSH) and plasma estradil levels in the pstmenpausal range fr wmen under 60 Radiatin-induced phrectmy with last menses >1 year ag Bilateral phrectmy b) **Female patients f childbearing ptential wh are sexually active must agree, with their partners, t the use f tw highly effective frms f cntraceptin in NCI Versin Date: 10-19-15 58(194) NSABP B-55/BIG 6-13
cmbinatin thrughut the perid f taking study treatment and fr at least 1 mnth after the last dse f study drug, r they must ttally/truly abstain frm any frm f sexual intercurse. Male patients must agree, with their partners wh are sexually active and f childbearing ptential, t the use f tw highly effective frms f cntraceptin in cmbinatin thrughut the perid f taking study treatment and fr 3 mnths after last dse f study drug, r they must ttally/truly abstain frm any frm f sexual intercurse (Fr details please refer t Appendix F Acceptable Birth Cntrl Methds). 12. **Patient is willing and able t cmply with the prtcl fr the duratin f the study including underging treatment and scheduled visits and examinatins 13. Frmalin fixed, paraffin embedded (FFPE) tumur sample frm the primary tumur, mandatry*. *NOTE: Fr adjuvant patients this refers t the surgical specimen; fr neadjuvant patients, bth the pre-treatment bipsy and the surgical specimen with residual disease specimen are requested, but nly ne is mandatry. If the surgery tumur blcks are available, but cannt be submitted, sites may submit a prtin f invasive tumur frm the riginal blck, either by taking at least ne cre f at least 3 mm in diameter, r by splitting the riginal blck in tw parts, and re-embedding ne in a new blck fr central submissin. If blcks cntaining pre-neadjuvant treatment cre bipsies are available but cannt be submitted, sectins munted n glass slides prepared frm the blck can be prvided. If tumur sample can't be prvided as requested abve r if it's nt available, apprval by Study Team fr patient's entry int the trial is required. 14. Patient shuld be randmised in the trial ideally within a maximum f 8 weeks f cmpletin f their last treatment (surgery, chemtherapy r raditherapy), but in n case lnger than 12 weeks. 4.2 Exclusin criteria Patients shuld nt enter the study if any f the fllwing exclusin criteria are fulfilled: 1. **Invlvement in the planning and/r cnduct f the study. 2. Patients wh d nt have deleterius r suspected deleterius gbrca1 and/r 2 mutatins but nly have BRCA1 and/r BRCA2 mutatins that are cnsidered t be nn detrimental (e.g., Variants f uncertain clinical significance r Variant f unknwn significance r Variant, favur plymrphism r benign plymrphism etc.). 3. **Previus randmisatin in the present study. 4. **Evidence f metastatic breast cancer. Patient cnsidered at high risk f having disseminated disease (i.e. thse with lcally advanced disease, clinical N2-3 r pathlgical N1-3 with the exceptin f pn1a in adjuvant patients) shuld have a CT/MRI scan f the Thrax/Abdmen/Pelvis r any ther area as clinically indicated NCI Versin Date: 10-19-15 59(194) NSABP B-55/BIG 6-13
and a bne scan r a CT scan with bne windws at any pint between diagnsis f the current breast cancer and randmisatin t rule ut metastatic breast cancer. (Nte PET/CT scan may be used as an alternative imaging technique and precludes the need fr bne scan). Patients with screening ALT/AST r ALP abve institutinal upper limit f nrmal shuld have liver ultrasund, CT r MRI at any time pint between diagnsis f current breast cancer and randmisatin. Screening bne scan is required if ALP and/r crrected calcium level are abve the institutinal upper limit. (Nte PET CT scan may be used as an alternative imaging technique). 5. **Expsure t an investigatinal prduct within 30 days r five half lives (whichever is the lnger) prir t randmisatin. 6. **Any previus treatment with a PARP inhibitr, including laparib and/r knwn hypersensitivity t any f the excipients f study treatment. 7. **Patients with secnd primary malignancy, EXCEPTIONS: adequately treated nn-melanma skin cancer, curatively treated in situ cancer f the cervix, Ductal Carcinma in situ (DCIS) f the breast, stage 1 grade 1 endmetrial carcinma ther slid tumurs and lymphmas (withut bne marrw invlvement) diagnsed 5 years prir t randmisatin and treated with n evidence f disease recurrence and fr whm n mre than ne line f chemtherapy was applied. 8. Resting ECG with QTc > 470 msec detected n 2 r mre time pints within a 24 hur perid r family histry f lng QT syndrme. If ECG demnstrates QTc >470 msec, patient will be eligible nly if repeat ECG demnstrates QTc 470 msec. 9. Patients receiving systemic chemtherapy within 3 weeks prir t randmisatin. 10. Patients receiving adjuvant raditherapy within 2 weeks prir t randmisatin. 11. Cncmitant use f knwn ptent CYP3A4 inhibitrs such as ketcnazle, itracnazle, ritnavir, indinavir, saquinavir, telithrmycin, clarithrmycin and nelfinavir. Fr further details and the minimum washut perid prir t starting laparib, refer t Appendix I. 12. Persistent txicities ( CTCAE grade 2) caused by previus cancer therapy, excluding alpecia and CTCAE grade 2 peripheral neurpathy. 13. **Patients with myeldysplastic syndrme (MDS)/acute myelid leukemia (AML) r with features suggestive f MDS/AML. 14. Majr surgery within 2 weeks prir t randmisatin: patients must have recvered frm any effects f any majr surgery. NCI Versin Date: 10-19-15 60(194) NSABP B-55/BIG 6-13
15. Patients cnsidered at pr medical risk due t a serius, uncntrlled medical disrder, nn-malignant systemic disease r active, uncntrlled infectin. Examples include, but are nt limited t, uncntrlled ventricular arrhythmia, recent (within 3 mnths) mycardial infarctin, uncntrlled majr seizure disrder, extensive bilateral lung disease n High Reslutin Cmputed Tmgraphy scan r any psychiatric disrder that prhibits btaining infrmed cnsent. 16. **Patients unable t swallw rally administered medicatin and patients with gastrintestinal disrders likely t interfere with absrptin f the study medicatin. 17. Pregnant r breastfeeding wmen. 18. **Patients with knwn active Hepatitis B r C 19. **Patients knwn t be HIV psitive with ne r mre f the fllwing: a. Baseline CD4 cunt f < 250 cells/mm3 b. Histry f AIDS indicatr cnditins c. Anti-retrviral therapy with any ptent CYP3A4 inhibitr (see Sectin 5.6.2) 20. **Previus allgeneic bne marrw transplant. 21. **Whle bld transfusins in the last 120 days prir t entry t the study which may interfere with gbrca testing (packed red bld cells and platelet transfusins are acceptable, fr timing refer t inclusin criteria n. 8) Fr prcedures fr withdrawal f incrrectly enrlled patients see Sectin 5.3. NCI Versin Date: 10-19-15 61(194) NSABP B-55/BIG 6-13