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Study Protocol); AG-013736, PF-02341066 A4061068 Final Protocol Amendment 2, 27 January 2016 CLINICAL PROTOCOL A PHASE 1B, OPEN LABEL, DOSE ESCALATION STUDY TO EVALUATE SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB (AG-013736) IN COMBINATION WITH CRIZOTINIB (PF-02341066) IN PATIENTS WITH ADVANCED SOLID TUMORS Compounds: AG-013736, PF-02341066 Compound Names: axitinib, crizotinib United States (US) Investigational New IND 63,662 Drug (IND) Numbers: IND 73,544 European Clinical Trials Database 2015-001724-31 (EudraCT) Number Protocol Number: A4061068 Phase: 1b Page 1 AG-013736, PF-02341066 A4061068 Final Protocol Amendment 2, 27 January 2016 Document History Document Version Date Summary of Changes and Rationale Amendment 2 26 January 2016 Added EudraCT number. SCHEDULE OF ACTIVITIES: - Contraception check added to align with the Sponsor’s most recent protocol template. - Registration and Study Treatment: updated to clarify which patient subgroup will receive axitinib single agent during a 7-day Lead-In period and which subgroup will start with the combination without the Lead-In period. - Archival Tumor Tissue, De Novo Tumor Biopsy: footnotes updated to align with Patient Selection Section, Inclusion Criterion #1. Section 1. Introduction: literature updated; axitinib and crizotinib safety data updated according to the last version of the Investigator’s Brochure. Section 4. Patient Selection: - Inclusion Criterion #1, Dose Expansion Phase: language updated: 1. to make the selected patient population more in line with the actual 2nd and 3rd line advanced RCC population; 2. to include alternative option for the collection of biopsy in the Dose Expansion Cohort 2 patients. - Exclusion Criterion #8: language updated to align with the current standard language of crizotinib clinical protocols. PK wording: whenever needed, the wording was updated to clarify that PK samples will be collected in at least 8 evaluable patients in the Expansion Phase Cohort 1. The protocol wording (including pregnancy, contraception, AE Reporting, and publication of study results) and Page 2 AG-013736, PF-02341066 A4061068 Final Protocol Amendment 2, 27 January 2016 sections numbering were updated according to the Sponsor’s most recent protocol template. The protocol language (including renal cyst monitoring, overdose instructions, concomitant medications, ophthalmology examinations) was updated according to the current standard language of crizotinib and axitinib clinical protocols. Amendment 1 11 March 2014 SCHEDULE OF ACTIVITIES: - Frequency of hepatic laboratory test monitoring and relevant footnote modified in accordance with the Dear Investigator Letter dated 23Oct2013. - Follow Up for dosing compliance: added recommendation to follow up for dosing compliance also whenever there is a dose change. - Tumor Assessments: footnote updated to be consistent with Section 7.5. Tumor Response Assessments - Home blood pressure monitoring, pulse rate: frequency and relevant footnote updated to clarify it has to be monitored starting from patient registration. - Archived tumor tissue: footnote updated to be consistent with Section 4. Patient Selection. Section 4. Patient Selection: - Inclusion Criteria #1: language updated to clarify the collection of archival tumor tissue in the Dose Escalation Phase. - Inclusion Criteria #10: language about legal representative deleted in accordance with Western Institutional Review Board request. - Inclusion Criteria #8, Exclusion Criteria #2, and Exclusion Criteria #7: language updated to clarify the criteria. Section 5.3.2.2. Dose Modifications in Case of Drug-Related Toxicity – Table 5: - Management of bradycardia modified in accordance with the recently updated crizotinib Core Data Sheet. Page 3 AG-013736, PF-02341066 A4061068 Final Protocol Amendment 2, 27 January 2016 Section 5.3.5. Compliance: added recommendation to perform follow up by telephone whenever there is a dose change. Section 5.5.4. Other Concomitant Medications: - Language on concomitant use of anticoagulants updated. - Language on concomitant use of bradycardia inducing agents updated. Section 6.1.1. Archival Tumor Tissue: language updated to be consistent with Section 4. Patient Selection. Section 7.1.6. Ophthalmologic Examinations and Section 9.6.4. Ophthalmologic Data: language updated to clarify optional tests to be done based on clinical judgement. Section 7.5 Tumor Response Assessments: language updated to be consistent with the Schedule of Activities Section 12.3. Patient Information and Consent: language about legal representative deleted in accordance with Western Institutional Review Board request. Original protocol 10 July 2013 Not Applicable (N/A) This amendment incorporates all revisions to date, including amendments made at the request of country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc. Page 4 AG-013736, PF-02341066 A4061068 Final Protocol Amendment 2, 27 January 2016 TABLE OF CONTENTS LIST OF TABLES.....................................................................................................................9 LIST OF FIGURES .................................................................................................................10 APPENDICES .........................................................................................................................10 1. INTRODUCTION ...............................................................................................................23 1.1. Indication.................................................................................................................23 1.2. Background and Rationale ......................................................................................23 1.2.1. Tumor Angiogenesis and VEGF-Pathway Inhibition.................................23 1.2.2. Renal Cell Cancer.......................................................................................23 1.2.3. Rationale.....................................................................................................24 1.2.3.1. c-MET and Resistance to Antiangiogenic Therapy ..................24 1.2.3.2. Hypothesis to be Tested ............................................................26 1.2.4. Study Drugs ................................................................................................26 1.2.4.1. Crizotinib (XALKORI, PF-02341066) as a c-MET Inhibitor .............................................................................................26 1.2.4.2. Axitinib (INLYTA, AG-013736)............................................27 1.2.5. Rationale for Starting Doses of Axitinib and Crizotinib ............................28 2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................31 2.1. Objectives................................................................................................................31 2.2. Endpoints.................................................................................................................31 3. STUDY DESIGN.................................................................................................................32 3.1. Study Overview.......................................................................................................32 3.1.1. Dose Escalation Phase ................................................................................34 3.1.1.1. Starting Doses for Axitinib and Crizotinib (Dose Level 1) ......34 3.1.1.2. DLT Observation Period ...........................................................34 3.1.1.3. Criteria for Dose Escalation ......................................................35 3.1.2. DLT Definition ...........................................................................................37 3.1.3. Maximum Tolerated Dose Definition.........................................................38 3.1.4. Dose Expansion Phase Test Dose...............................................................38 3.1.5. Dose Expansion Phase................................................................................38 3.2. Recommended Phase 2 Dose ..................................................................................39 4. PATIENT SELECTION ......................................................................................................39 Page 5 AG-013736, PF-02341066 A4061068 Final Protocol Amendment 2, 27 January 2016 4.1. Inclusion Criteria.....................................................................................................39 4.2. Exclusion Criteria....................................................................................................41 4.3. Life Style Guidelines...............................................................................................43 4.3.1. Sunlight Exposure.......................................................................................43 4.3.2. Contraception..............................................................................................43 4.4. Sponsor Qualified Medical Personnel.....................................................................45 5. STUDY TREATMENTS.....................................................................................................45 5.1. Allocation to Treatment ..........................................................................................45 5.2. Investigational Product Supplies.............................................................................46 5.2.1. Dosage Form(s) and Packaging..................................................................46
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