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15\0.1\Draft\VersionedOn:03-Aug-2018On:23-Jul-2018 11:0810:11 (GMT)CLINICAL STUDY PROTOCOLStudy Title:A Phase 3, Open-Label, Randomized, Parallel, 2-Arm, Multi-CenterStudy of Talazoparib (BMN 673) versus Physician’s Choice inGermline BRCA Mutation Subjects with Locally Advanced and/orMetastatic Breast Cancer, Who Have Received Prior ChemotherapyRegimens for Metastatic DiseaseProtocol Number:673-301Active InvestigationalProduct:Talazoparib (also known as MDV3800, BMN 673)IND and EudraCTNumbers:Indication:108708 and 2013-002716-28Sponsor:Medivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105Locally advanced and/or metastatic breast cancer with germlineBRCA1 or BRCA2 mutationsPPDDevelopment Phase:Phase 3Sponsor's ResponsibleMedical Monitor:PPDStudy Design:Open-Label, Randomized, Parallel, 2-ArmComparison:Active comparator – physician’s choiceUntil deathDuration of SubjectParticipation:Telephone:Email:, MDPPDPPDDose:1.0 mg/dayStudy Population:Locally advanced and/or metastatic breast cancer subjects withgermline BRCA1 or BRCA2 mutationsOriginal Protocol:v1.0 – 17 July 2013Amendment 1v2.0 – 14 December 2015This study will be conducted according to the principles of Good Clinical Practice as described inInternational Conference on Harmonisation guidelines, including the archiving of essential documents.FINAL 14Dec2015
Medivation, Inc.2673-301 – Amendment 1Page 2SYNOPSISNAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105SUMMARY TABLEReferring to Part of theDossier:FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED PRODUCT:TalazoparibNAME OF ACTIVE INGREDIENT:Talazoparib tosylateTITLE OF STUDY:Page:Reference:A Phase 3, Open-Label, Randomized, Parallel, 2-Arm, Multi-Center Study of Talazoparib (BMN 673)versus Physician’s Choice in Germline BRCA Mutation Subjects with Locally Advanced and/orMetastatic Breast Cancer, Who Have Received Prior Chemotherapy Regimens for Metastatic ul-2018 11:0810:11 (GMT)PROTOCOL NUMBER:673-301STUDY SITES:This study will be conducted at approximately 230 sites internationally in 16 countries (United States,Brazil, Russia, Spain, United Kingdom, Israel, Australia, France, Germany, Italy, Belgium, Ireland,South Korea, Poland, Taiwan, Ukraine). Additional countries and sites may be added.PHASE OF DEVELOPMENT:Phase 3STUDY RATIONALE:The mutation that predisposes breast cancer susceptibility gene (BRCA) mutation carriers to cancerformation selectively renders tumor cells susceptible to poly ADP ribose polymerase (PARP)inhibition while sparing normal cells that, possessing a normal BRCA allele, are relatively resistant toPARP inhibition.The selection of appropriate therapy for metastatic breast cancer is complex because of the manytreatment options and biologic heterogeneity of the disease, including several that have led todevelopment of targeted therapeutics. Among others, the potential treatment options are influenced byestrogen and progesterone receptor and human epidermal growth factor receptor 2 (HER2) status ofthe tumor. Treatment options for subjects presenting with metastatic breast cancer may also beinfluenced by what adjuvant therapy was used, how soon after adjuvant therapy the subject relapses,and by sites of metastasis.No therapies have been approved to date that take advantage of the well-defined vulnerability ofBRCA mutant tumors. It would be a significant advance to provide a therapy which exploits thevulnerability of BRCA-mutant bearing tumors while sparing normal cells carrying one healthy BRCAallele.However, the lack of prospective, controlled studies in BRCA1 and BRCA2-mutant disease, alongFINAL 14Dec2015
Medivation, Inc.NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105673-301 – Amendment 1SUMMARY TABLEReferring to Part of theDossier:Page 3FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED 3-Aug-2018On:23-Jul-2018 11:0810:11 (GMT)Reference:NAME OF ACTIVE INGREDIENT:Talazoparib tosylatewith the mixed data from small retrospective studies, underscores the lack of information for makingtreatment decisions for these subjects. The potential role of BRCA1 in mediation of taxanecytotoxicity is consistent with the observation that the taxanes may be less effective in treatment ofBRCA1-associated metastatic breast cancer than sporadic disease.This coupled with the potential to specifically target the underlying genetic abnormality of the diseasehighlights the unmet need as well as the need for prospective evaluation of a molecularly rational,targeted therapy in comparison to the standard drugs used. While several agents have been shown toprolong progression-free survival (PFS) and some have modestly improved survival in metastaticbreast cancer, the disease is, nevertheless, nearly uniformly fatal. Moreover, standard, non-targetedtherapies are associated with substantial toxicity, which limits the quality of life of subjects while theyare undergoing treatment.Two studies of the PARP inhibitor, olaparib, given as a single agent to breast cancer subjects havebeen published. In one study, subjects with germline BRCA mutations were treated with either 400 mgtwice daily or 100 mg twice daily in a non-randomized fashion. Eleven of 27 subjects (41%) receivingthe higher dose had objective responses while 6 of 27 (22%) of subjects receiving the lower doseresponded. In a second trial, olaparib was evaluated in subjects with germline mutations as well assubjects with triple negative breast cancer in the absence of germline mutations. Ten subjects withgermline mutations were enrolled, including 6 with measurable disease. While there were no objectiveresponders, 5 subjects had stable disease. There were also no responders among 16 triple negativebreast cancer subjects who either did not have germline BRCA mutations or had unknown BRCAstatus.In the Phase 1 study of talazoparib (also known as MDV3800, BMN 673), PRP-001, 18 breast cancersubjects with germline BRCA mutations, who had previously been treated with more than onechemotherapy regimen (range: 1 to 13), were enrolled during dose escalation (n 6) and expansion(n 12) as of 31 Mar 2015. All 18 subjects were treated with talazoparib at dose levels of 900 to 1100μg/day including 12 in the expansion phase at 1000 μg/day (9 of the 12 subjects have been in the studyfor 3 cycles). Eight of 18 subjects have had objective responses, including one confirmed completeresponse (CR) in a subject with a BRCA2 deleterious mutation.FINAL 14Dec2015
Medivation, Inc.673-301 – Amendment 1NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105SUMMARY TABLEReferring to Part of theDossier:Page 4FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED PRODUCT:TalazoparibNAME OF ACTIVE INGREDIENT:Talazoparib tosylateOBJECTIVES:Page:Reference:The primary objective of the study is to compare PFS of subjects treated with talazoparib as amonotherapy relative to those treated with protocol-specific physician’s ul-2018 11:0810:11 (GMT)The secondary objectives of the study are to evaluate the following:!Objective response rate (ORR)!Overall survival (OS)!Safety!Pharmacokinetics of talazoparibThe exploratory objectives are to evaluate the following:!Duration of response (DOR) for objective responders!Quality of life for all enrolled subjects (European Organization for Research and Treatment ofCancer [EORTC] Quality of Life Questionnaire [QLC-C30]/ EORTC Quality of LifeQuestionnaire – Breast Cancer Module [QLQ-BR23])!Research assessments related to blood and tumor sampling that includes characterization oftumor sensitivity and resistance to talazoparibSTUDY DESIGN AND PLAN:The study is an open-label, 2-arm, 2:1 randomized trial of talazoparib versus protocol-specificphysician’s choice. Subjects with germline BRCA mutations who have received no more than 3 priorcytotoxic chemotherapy regimens for locally advanced and/or metastatic breast cancer will beenrolled. Options for protocol-specific physician’s choice include one of the following single-agentchemotherapies:!Capecitabine, eribulin, gemcitabine, vinorelbineoThe protocol-specific physician’s choice must be determined prior to randomizationfor each individual subject.Subjects will be centrally randomized with stratification by the following:!Number of prior cytotoxic chemotherapy regimens for locally advanced and/or metastaticdisease (0 vs. 1, 2, or 3)!Triple negative (estrogen-receptor negative, progesterone-receptor negative, HER2-negative)FINAL 14Dec2015
Medivation, Inc.673-301 – Amendment 1NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105SUMMARY TABLEReferring to Part of theDossier:Page 5FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED PRODUCT:TalazoparibPage:Reference:NAME OF ACTIVE INGREDIENT:Talazoparib tosylatevs. non-triple negative status based on most recent l-2018 11:0810:11 (GMT)!History of central nervous system (CNS) metastases vs. no CNS metastasesSubjects must start treatment 5 days from randomization; starting later will be considered a protocoldeviation. Treatment with talazoparib or protocol-specific physician’s choice will continue untilradiographic disease progression as determined by the central Independent Radiology Facility (IRF),unacceptable toxicity, consent withdrawal, physician’s decision to terminate treatment, or Sponsor’sdecision to terminate the trial. Subjects who discontinue from study medication for any reason otherthan radiographic disease progression as determined by the IRF or initiation of a new antineoplastictherapy must be followed to radiographic progression by imaging assessments (eg, computedtomography [CT] scans). All subjects will be followed for anticancer treatment and survival statusuntil death.NUMBER OF SUBJECTS PLANNED:Up to 429 subjects will be enrolled. Subjects randomized into the study will not be replaced.DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:Individuals eligible to participate in this study must meet all of the following criteria:!Histologically or cytologically confirmed carcinoma of the breast!Locally advanced breast cancer that is not amenable to curative radiation or surgical cureand/or metastatic disease appropriate for systemic single cytotoxic chemotherapy!Documentation of a deleterious, suspected deleterious, or pathogenic germline BRCA1 orBRCA2 mutation from Myriad Genetics or other laboratory approved by the Sponsor; for dataobtained regarding a BRCA1/2 mutation from a non-Myriad laboratory, the pathology reportmust be submitted to and approved by the Sponsor and a blood sample sent to Myriad foranalysis before randomization may occur!No more than 3 prior chemotherapy-inclusive regimens for locally advanced and/or metastaticdisease (no limit on prior hormonal therapies or targeted anticancer therapies such asmechanistic target of rapamycin [mTOR] or CDK4/6 inhibitors, immuno-oncology agents,tyrosine kinase inhibitors, or monoclonal antibodies against CTL4 or VEGF)!Prior treatment with a taxane and/or anthracycline in the neoadjuvant, adjuvant, locallyadvanced, or metastatic setting unless medically contraindicated!18 years of age or olderFINAL 14Dec2015
Medivation, Inc.673-301 – Amendment 1NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105SUMMARY TABLEReferring to Part of theDossier:Page 6FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED 3-Aug-2018On:23-Jul-2018 11:0810:11 (GMT)Reference:NAME OF ACTIVE INGREDIENT:Talazoparib tosylate! Have measurable or non-measurable, evaluable disease by the revised response evaluationcriteria in solid tumors (RECIST) v.1.1!Eastern Cooperative Oncology Group (ECOG) performance status 2!Adequate organ function as defined below:oSerum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 upper limit of normal (ULN); if liver function abnormalities are due to hepaticmetastasis, then AST and ALT 5 ULNooTotal serum bilirubin 1.5 ULN ( 3 ULN for Gilbert’s syndrome)Calculated creatinine clearance 30 mL/min by local laboratory or Cockcroft-GaultformulaooHemoglobin 9.0 g/dL with last transfusion at least 14 days before randomizationAbsolute neutrophil count (ANC) 1500/mm3oPlatelet count 100,000/mm3!Able to take oral medications!Willing and able to provide written, signed informed consent after the nature of the study hasbeen explained, and prior to any research-related procedures!A female of childbearing potential (defined in Section 9.7.4.6) must not be pregnant and mustagree to avoid pregnancy during the study by using a highly effective birth control method(defined in Section 9.7.4.6) from the time of the first dose of study drug through 45 days afterthe last dose of study drug!Male subjects must use a condom when having sex with a pregnant woman and when havingsex with a woman of childbearing potential from the time of the first dose of study drugthrough 105 days after the last dose of study drug. Contraception should be considered fora nonpregnant female partner of childbearing potential!Male and female subjects must agree not to donate sperm or eggs, respectively, from the firstdose of study drug through 105 days and 45 days after the last dose of study drug, respectively!Females of childbearing potential (defined in Section 9.7.4.6) must have a negative serumpregnancy test at Screening and be willing to have additional pregnancy tests during the study!Willing and able to comply with all study proceduresIndividuals who meet any of the following exclusion criteria will not be eligible to participate in theFINAL 14Dec2015
Medivation, Inc.673-301 – Amendment 1NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105SUMMARY TABLEReferring to Part of theDossier:Page 7FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED -2018On:23-Jul-2018 11:0810:11 (GMT)NAME OF ACTIVE INGREDIENT:Talazoparib tosylatestudy:Page:Reference:!First-line locally advanced and/or metastatic breast cancer with no prior adjuvantchemotherapy unless the Investigator determines that one of the 4 cytotoxic chemotherapyagents in the control arm would be otherwise offered to the subject!Prior treatment with a PARP inhibitor (not including iniparib)!Not a candidate for treatment with at least 1 of the treatments of protocol-specific physician’schoice (ie, capecitabine, eribulin, gemcitabine, vinorelbine)!Subjects who had objective disease progression while receiving platinum chemotherapyadministered for locally advanced or metastatic disease; subjects who received low-doseplatinum therapy administered in combination with radiation therapy are not excluded!Subjects who have received platinum in the adjuvant or neoadjuvant setting are eligible;however, subjects may not have relapsed within 6 months of the last dose of prior platinumtherapy!Cytotoxic chemotherapy within 14 days before randomization!Radiation or anti-hormonal therapy or other targeted anticancer therapy within 14 days beforerandomization!Has not recovered from the acute toxicities of previous therapy, except treatment-relatedalopecia or laboratory abnormalities otherwise meeting the inclusion requirements stated in theinclusion criteria!HER2 positive breast cancer!Active inflammatory breast cancer!CNS metastasesoException: Adequately treated brain metastases documented by baseline CT or MRIscan that has not progressed since previous scans and that does not requirecorticosteroids (except prednisone 5 mg/day or equivalent) for management of CNSsymptoms. A repeated CT or MRI following the identification of CNS metastases(obtained at least 2 weeks after definitive therapy) must document adequately treatedbrain metastasesoSubjects with leptomeningeal carcinomatosis are not permittedFINAL 14Dec2015
Medivation, Inc.NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105673-301 – Amendment 1SUMMARY TABLEReferring to Part of theDossier:Page 8FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED 3-Aug-2018On:23-Jul-2018 11:0810:11 (GMT)Reference:NAME OF ACTIVE INGREDIENT:Talazoparib tosylate! Prior malignancy except for any of the following:oPrior BRCA-associated cancer as long as there is no current evidence of the priorcanceroCarcinoma in situ or non-melanoma skin canceroA cancer diagnosed and definitively treated 5 years before randomization with nosubsequent evidence of recurrence!Known to be human immunodeficiency virus positive!Known active hepatitis C virus, or known active hepatitis B virus!Use of any investigational product (IP) or investigational medical device within 14 days beforerandomization!Major surgery within 14 days before randomization!Myocardial infarction within 6 months before randomization, symptomatic congestive heartfailure (New York Heart Association [NYHA] class II), unstable angina, or unstable cardiacarrhythmia requiring medication)!Female subjects who are breastfeeding at Screening or planning to become pregnant at anytime during study participation through 45 days after the last dose of study drug; male subjectswho are planning to impregnate a partner at any time during study participation through105 days after the last dose of study drug!Concurrent disease or condition that would interfere with study participation or safety, such asany of the following:oActive, clinically significant infection either grade 2 by National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 orrequiring the use of parenteral anti-microbial agents within 14 days beforerandomizationoClinically significant bleeding diathesis or coagulopathy, including known plateletfunction disorders!Non-healing wound, ulcer, or bone fracture, not including a pathological bone fracture causedby a pre-existent pathological bone lesion!Known hypersensitivity to any of the components of talazoparibFINAL 14Dec2015
Medivation, Inc.NAME OF COMPANYMedivation, Inc.525 Market Street, 36th FloorSan Francisco, CA 94105673-301 – Amendment 1SUMMARY TABLEReferring to Part of theDossier:Page 9FOR NATIONALAUTHORITY USEONLY:Volume:NAME OF FINISHED PRODUCT:TalazoparibPage:Reference:NAME OF ACTIVE INGREDIENT:Talazoparib tosylateINVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND Jul-2018 11:0810:11 (GMT)Talazoparib will be administered orally once daily (ie, continuous dosing). Talazoparib should betaken at approximately the same time each day, preferably in the morning. Talazoparib will beswallowed whole, and may be taken with or without food. On days of clinic visits when PK samplesare to be drawn, talazoparib should be taken at the clinic after completion of the pre-dose sampling andassessments.The IP is talazoparib tosylate, a white to off-white crystalline powder. The drug substance is a4-methylbenzenesulfonate (tosylate) salt of talazoparib free base, the active moiety. The drug productconsists of the drug substance formulated with a pharmaceutically suitable excipient filled intohydroxymethylpropylcellulose capsules. Capsules will be provided to the sites in dose strengths of0.25 mg and 1.0 mg capsules. The dosage strengths are based o
Medivation, Inc. 673-301 – Amendment 1 Page 2 FINAL 14Dec2015 2 SYNOPSIS NAME OF COMPANY Medivation, Inc. 525 Market Street, 36th Floor San Francisco, CA 94105 . Two studies of the PARP inhibitor, olaparib, given as a single agent to breast cancer subjects have been published. In one stud
