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A Phase I Open-Label Pharmacokinetics and Safety Study MDV3800-01/CCI Protocol Version 2.0 Final 31-Aug-2018 CCI A wholly-owned subsidiary of Pfizer Inc. 525 Market Street, San Francisco, CA 94105 A Phase I Open-Label Pharmacokinetics and Safety Study of Talazoparib (MDV3800) in Patients With Advanced Solid Tumors and Normal or Varying Degrees of Renal Impairment MEDIVATION PROTOCOL: MDV3800-01 PFIZER PROTOCOL: C3441001 CCI Pfizer Medical Monitor PPD MD Protocol Version / Date 2.0 / Final 31-Aug-2018 Phase I Test Compound Talazoparib (PF-06944076; formerly known as MDV3800 or BMN673) Indication Advanced solid tumors Sponsor Medivation, Inc. EUDRACT # 2016-002536-33 IND # CCI Page 1 090177e192741e05\Approved\Approved On: 16-Dec-2019 07:25 (GMT) MDV3800-01/CCI Protocol Version 2.0 Final 31-Aug-2018 MDV3800-01/C3441001/CCI Protocol v. 2.0 – Rationale for Amendment Version 2.0 of the protocol is an amendment applicable to all sites and performed in order to clarify protocol language and to include new pharmacokinetic data for talazoparib. Additionally, some administrative changes have been included regarding the Pfizer and CCI teams. The MDV3800-01/C3441001/CCI protocol was amended as follows: Document Version Date Summary of changes Protocol version 2.0 31 Aug 2018 x INVESTIGATORS: update of the number of sites based on the current active sites. x CCI AND PFIZER TEAM: administrative changes in teams conformation and signature page. x LIST OF ABBREVIATIONS: inclusion of additional abbreviations. x PROTOCOL SYNOPSIS: update of sections Study Duration, Participating Investigational sites, Background andRrationale, definition of Evaluability, Eligibility criteria, PK assessments and Statistical methods. x SECTION 2. BACKGROUND AND RATIONALE: update of language as per the most recent version of Talazoparib IB. x SECTION 4. STUDY DESIGN: revision of language for clarification. x SECTION 5. PATIENT SELECTION: revision of wording to include updated talazoparib wash out period in females and males. x SECTION 6. STUDY TREATMENT: update of language for clarification. x TABLE 6. INSTRUCTIONS FOR USE OF CONCOMITANT THERAPIES: addition of medications previously included in Section 6.2 Potential Interactions between Talazoparib and Concomitant Medications in this table. x TABLE 7. SCHEDULE OF VISITS AND ASSESSMENTS: revision of language for clarification. x SECTION 8. AE REPORTING: update of language for clarification and addition of section “Medication Error”. x TABLE 9. AE REPORTING REQUIREMENTS: update of language for clarification. x TABLE 11. MEDICATION ERROR REPORTING REQUIREMENTS: update of language for clarification. Page 2 090177e192741e05\Approved\Approved On: 16-Dec-2019 07:25 (GMT) MDV3800-01/CCI Protocol Version 2.0 Final 31-Aug-2018 x SECTION 9. STATISTICAL CONSIDERATIONS: revision of Population for Analyses. x SECTION 10. ADMINISTRATIVE, ETHICAL AND REGULATORY STANDARDS: revision of the section eData Protection”. Page 3 090177e192741e05\Approved\Approved On: 16-Dec-2019 07:25 (GMT) MDV3800-01/CCI Protocol Version 2.0 Final 31-Aug-2018 TABLE OF CONTENTS LIST OF ABBREVIATIONS ............................................................................................................................. 11 PROTOCOL SYNOPSIS .................................................................................................................................. 15 1. BACKGROUND AND RATIONALE ......................................................................................................... 27 1.1. Investigational Medicinal Product Overview .............................................................................. 27 1.1.1. Background ......................................................................................................................... 27 1.1.2. Clinical Study Findings with Talazoparib ............................................................................. 27 1.1.3. Pharmacokinetics of Talazoparib ........................................................................................ 28 1.2. Study Rationale ........................................................................................................................... 29 1.2.1. Rationale for Conducting the Study .................................................................................... 29 1.2.2. Rationale for Regimen and Dose Selection ......................................................................... 30 2. OBJECTIVES ......................................................................................................................................... 30 2.1. Primary Objective........................................................................................................................ 30 2.2. Secondary Objective ................................................................................................................... 30 3. STUDY DESIGN..................................................................................................................................... 30 4. PATIENT SELECTION ............................................................................................................................ 33 4.1. Inclusion Criteria ......................................................................................................................... 33 4.2. Exclusion Criteria ......................................................................................................................... 35 5. STUDY TREATMENT ............................................................................................................................. 37 5.1. Study Treatment Identification ................................................................................................... 37 5.2. Investigational Product Information and Management ............................................................. 37 5.2.1. Packaging and Labelling ...................................................................................................... 37 5.2.2. Storage and Dispensation ................................................................................................... 37 5.2.3. Accountability, Return and Destruction.............................................................................. 37 5.3. Study Treatment Administration ................................................................................................ 38 5.3.1. Dosage and Administration ................................................................................................. 38 5.3.2. Treatment Compliance ....................................................................................................... 39 5.3.3. Treatment Duration ............................................................................................................ 39 5.4. Treatment Schedule Adjustment and Adverse Event Management .......................................... 39 5.4.1. General Rules ...................................................................................................................... 39 5.4.2. Dose Modification Due to Adverse Events ......................................................................... 40 5.4.2.1. Assessment of Abnormal Non Liver Tests ................................................................... 40 5.4.2.2. Assessment of Abnormal Liver Tests .......................................................................... 41 5.5. Study Treatment Discontinuation ............................................................................................... 45 Page 4 090177e192741e05\Approved\Approved On: 16-Dec-2019 07:25 (GMT) MDV3800-01/CCI Protocol Version 2.0 Final 31-Aug-2018 6. CONCOMITANT TREATMENT AND PROCEDURES ............................................................................... 45 6.1. Allowed Concomitant Treatments .............................................................................................. 45 6.2. Concomitant Medication for Treatment of Renal Impairment .................................................. 46 6.3. Prohibited Treatments ................................................................................................................ 46 6.4. Palliative Radiotherapy ............................................................................................................... 48 6.5. Contraception/Reproductive Consideration ............................................................................... 48 6.5.1. Females ............................................................................................................................... 48 6.5.2. Males ................................................................................................................................... 49 7. STUDY VISITS AND ASSESSMENTS ....................................................................................................... 49 7.1. Patient Inclusion ......................................................................................................................... 49 7.1.1. Informed Consent ............................................................................................................... 49 7.1.2. Patient Enrollment .............................................................................................................. 50 7.2. Schedule of Visits and Assessments ............................................................................................ 50 7.3. Study Visits .................................................................................................................................
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