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Phase Ii Study of Oral Pha-848125Ac in Patients with Thymic Carcinoma Previously Treated with Chemotherapy

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Phase Ii Study of Oral Pha-848125Ac in Patients with Thymic Carcinoma Previously Treated with Chemotherapy Milciclib maleate (PHA-848125AC) CDKO-125a-006-P4 Protocol for Study CDKO-125a-006 09 March 2017 PHASE II STUDY OF ORAL PHA-848125AC IN PATIENTS WITH THYMIC CARCINOMA PREVIOUSLY TREATED WITH CHEMOTHERAPY Sponsor: Tiziana Life Sciences, PLC Therapeutic Area: Oncology Substance Identifier: Milciclib maleate (PHA-848125AC) Protocol Number: CDKO-125a-006 EudraCT Number: 2009-014338-79 IND Number: 73,819 Status: Final Protocol Version Number: 4 Including Amended Information as per: Amendment No. 4 Date Country(ies) Site(s) 09 March 2017 All All Amendment No. 3 Date Countries Sites 27 June 2014 All All Amendment No. 2 Date Countries Sites 13 December 2011 All All Amendment No. 1 Date Countries Sites 21 January 2011 All All This document contains confidential information belonging tothe Sponsor. Except as may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in confidence and not to disclose it to others (except where required by applicable law), nor to use it for unauthorized purposes. In the event of actual or suspected breach of this obligation, the Sponsor and CLIOSS S.r.l. should be promptly notified. Tiziana Life Sciences, PLC - Confidential Page 1 of 101 Milciclib maleate (PHA-848125AC) CDKO-125a-006-P4 Protocol for Study CDKO-125a-006 09 March 2017 SIGNATURES Yaron Ilan, MD - Chief Medical Officer Date Tiziana Life Sciences, PLC & Director of the Department of Medicine Hebrew University Hadassah Medical Center 91120 Jerusalem, Israel Patrizia Crivori, Chem. Pharm. D, PhD Date Head of Statistics CLInical Organization for Strategies and Solutions (CLIOSS) S.r.l. Viale Pasteur, 10 Nerviano, Milan, Italy <First name Last name, Academic Title> , Principal Investigator Date <Department> , <Division (or corresponding)> <Company (legal name)> , <Place, Country> Tiziana Life Sciences, PLC - Confidential Page 2 of 101 Milciclib maleate (PHA-848125AC) CDKO-125a-006-P4 Protocol for Study CDKO-125a-006 09 March 2017 TABLE OF CONTENTS 1. SUMMARY ...........................................................................................................................8 2. ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................20 3. BACKGROUND INFORMATION AND STUDY RATIONALE .....................................23 3.1. Thymic Carcinoma .........................................................................................................23 3.2. PHA-848125AC .............................................................................................................25 3.2.1. Description ...............................................................................................................25 3.2.2. Pharmacology ..........................................................................................................25 3.2.3. Safety Pharmacology ...............................................................................................26 3.2.4. Nonclinical Pharmacokinetics .................................................................................27 3.2.5. Toxicology ...............................................................................................................28 3.2.6. Drug-Drug Interactions ............................................................................................30 3.2.7. Phase I clinical trials ................................................................................................30 3.2.8. Pharmacokinetics in Humans ...................................................................................31 3.3. Rationale for the use of PHA-848125AC in Thymic Carcinoma ..................................34 4. TRIAL OBJECTIVES AND ENDPOINTS .........................................................................35 4.1. Objectives ......................................................................................................................35 4.1.1. Primary Objective ....................................................................................................35 4.1.2. Secondary Objectives ..............................................................................................35 4.1.3. Exploratory Objective ..............................................................................................35 4.2. Endpoints .......................................................................................................................35 4.2.1. Primary Endpoint .....................................................................................................35 4.2.2. Secondary Endpoints ...............................................................................................36 4.2.3. Exploratory Endpoint ...............................................................................................36 5. TRIAL DESIGN AND DESIGN RATIONALE .................................................................36 5.1. Confirmation of histological diagnosis ..........................................................................38 6. SUBJECT SELECTION ......................................................................................................38 6.1. Subject Inclusion Criteria ..............................................................................................38 6.2. Subject Exclusion Criteria .............................................................................................40 7. SCHEDULE OF EVENTS ...................................................................................................41 Tiziana Life Sciences, PLC - Confidential Page 3 of 101 Milciclib maleate (PHA-848125AC) CDKO-125a-006-P4 Protocol for Study CDKO-125a-006 09 March 2017 8. ENROLLMENT PROCEDURES ........................................................................................44 9. TREATMENT ......................................................................................................................44 9.1. Trial Products .................................................................................................................44 9.1.1. Description ...............................................................................................................44 9.1.2. Drug Preparation/Administration/Dispensing .........................................................45 9.1.3. Patient Education & Information .............................................................................46 9.2. Procedure for Handling Drug Spills ..............................................................................47 9.3. Storage and Stability ......................................................................................................47 9.3.1. Source of Drug .........................................................................................................47 9.3.2. Drug Accountability ................................................................................................47 9.4. Treatment Administration ..............................................................................................48 9.4.1. Treatment Dose and Schedule .................................................................................48 9.4.2. Duration of Treatment..............................................................................................48 9.4.3. Dose Modifications ..................................................................................................49 9.4.4. Retreatment and Dose Delay ...................................................................................52 9.4.5. Overdose Instructions ..............................................................................................52 9.4.6. Unblinding ...............................................................................................................52 9.4.7. Assessment and Management of Potential CNS Toxicity .......................................52 9.4.8. Assessment of Potential Ocular Toxicity .................................................................53 9.4.9. Assessment of Potential, Thrombotic Microangiopathy/Hemolytic Uremic Syndrome ...........................................................................................................................54 9.4.10. Concomitant Medications and Other Therapy .......................................................55 9.4.10.1. Antiemetics ......................................................................................................55 9.4.10.2. Antidiarrheals ..................................................................................................56 9.4.10.3. Antiacids ..........................................................................................................56 9.4.10.4. Hematopoietic Growth Factors ........................................................................56 9.4.10.5. Anticoagulants .................................................................................................56 9.4.10.6. Inhibitors or Inducers of CYP3A4...................................................................56 9.4.10.7. Steroids ............................................................................................................56 9.4.10.8. Other Permitted Concomitant Medications .....................................................57 9.4.10.9. Concomitant Radiotherapy ..............................................................................57 Tiziana Life Sciences, PLC - Confidential Page 4 of 101 Milciclib maleate (PHA-848125AC) CDKO-125a-006-P4
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