AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 2016CLINICAL PROTOCOLA PHASE 1B, OPEN LABEL, DOSE ESCALATION STUDY TO EVALUATESAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF AXITINIB(AG-013736) IN COMBINATION WITH CRIZOTINIB (PF-02341066) IN PATIENTSWITH ADVANCED SOLID TUMORSCompounds:AG-013736, PF-02341066Compound Names:axitinib, crizotinibUnited States (US) Investigational NewDrug (IND) Numbers:IND 63,662IND 73,544European Clinical Trials Database(EudraCT) Number2015-001724-31Protocol Number:A4061068Phase:1bPage 1
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 2016Document HistoryDocumentVersion DateSummary of Changes andRationaleAmendment 226 January 2016Added EudraCT number.SCHEDULE OF ACTIVITIES:- Contraception check added to alignwith the Sponsor’s most recent protocoltemplate.- Registration and Study Treatment:updated to clarify which patientsubgroup will receive axitinib singleagent during a 7-day Lead-In period andwhich subgroup will start with thecombination without the Lead-In period.- Archival Tumor Tissue, De NovoTumor Biopsy: footnotes updated toalign with Patient Selection Section,Inclusion Criterion #1.Section 1. Introduction: literatureupdated; axitinib and crizotinib safetydata updated according to the last versionof the Investigator’s Brochure.Section 4. Patient Selection:- Inclusion Criterion #1, Dose ExpansionPhase: language updated: 1. to make theselected patient population more in linewith the actual 2nd and 3rd line advancedRCC population; 2. to includealternative option for the collection ofbiopsy in the Dose Expansion Cohort 2patients.- Exclusion Criterion #8: languageupdated to align with the currentstandard language of crizotinib clinicalprotocols.PK wording: whenever needed, thewording was updated to clarify that PKsamples will be collected in at least 8evaluable patients in the ExpansionPhase Cohort 1.The protocol wording (includingpregnancy, contraception, AE Reporting,and publication of study results) andPage 2
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 2016sections numbering were updatedaccording to the Sponsor’s most recentprotocol template.The protocol language (including renalcyst monitoring, overdose instructions,concomitant medications, ophthalmologyexaminations) was updated according tothe current standard language ofcrizotinib and axitinib clinical protocols.Amendment 111 March 2014SCHEDULE OF ACTIVITIES:- Frequency of hepatic laboratory testmonitoring and relevant footnotemodified in accordance with the DearInvestigator Letter dated 23Oct2013.- Follow Up for dosing compliance:added recommendation to follow up fordosing compliance also whenever thereis a dose change.- Tumor Assessments: footnote updatedto be consistent with Section 7.5. TumorResponse Assessments- Home blood pressure monitoring,pulse rate: frequency and relevantfootnote updated to clarify it has to bemonitored starting from patientregistration.- Archived tumor tissue: footnoteupdated to be consistent with Section 4.Patient Selection.Section 4. Patient Selection:- Inclusion Criteria #1: language updatedto clarify the collection of archival tumortissue in the Dose Escalation Phase.- Inclusion Criteria #10: language aboutlegal representative deleted inaccordance with Western InstitutionalReview Board request.- Inclusion Criteria #8, ExclusionCriteria #2, and Exclusion Criteria #7:language updated to clarify the criteria.Section 184.108.40.206. Dose Modifications inCase of Drug-Related Toxicity –Table 5:- Management of bradycardia modifiedin accordance with the recently updatedcrizotinib Core Data Sheet.Page 3
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 2016Section 5.3.5. Compliance: addedrecommendation to perform follow up bytelephone whenever there is a dosechange.Section 5.5.4. Other ConcomitantMedications:- Language on concomitant use ofanticoagulants updated.- Language on concomitant use ofbradycardia inducing agents updated.Section 6.1.1. Archival Tumor Tissue:language updated to be consistent withSection 4. Patient Selection.Section 7.1.6. OphthalmologicExaminations and Section 9.6.4.Ophthalmologic Data: language updatedto clarify optional tests to be done basedon clinical judgement.Section 7.5 Tumor ResponseAssessments: language updated to beconsistent with the Schedule ofActivitiesSection 12.3. Patient Information andConsent: language about legalrepresentative deleted in accordance withWestern Institutional Review Boardrequest.Original protocol10 July 2013Not Applicable (N/A)This amendment incorporates all revisions to date, including amendments made at therequest of country health authorities, institutional review boards/ethics committees(IRBs/ECs), etc.Page 4
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 2016TABLE OF CONTENTSLIST OF TABLES.9LIST OF FIGURES .10APPENDICES .101. INTRODUCTION .231.1. Indication.231.2. Background and Rationale .231.2.1. Tumor Angiogenesis and VEGF-Pathway Inhibition.231.2.2. Renal Cell Cancer .231.2.3. Rationale .241.2.3.1. c-MET and Resistance to Antiangiogenic Therapy .241.2.3.2. Hypothesis to be Tested .261.2.4. Study Drugs .2220.127.116.11. Crizotinib (XALKORI , PF-02341066) as a c-METInhibitor .218.104.22.168. Axitinib (INLYTA , AG-013736).271.2.5. Rationale for Starting Doses of Axitinib and Crizotinib .282. STUDY OBJECTIVES AND ENDPOINTS.312.1. Objectives.312.2. Endpoints.313. STUDY DESIGN.323.1. Study Overview.323.1.1. Dose Escalation Phase .322.214.171.124. Starting Doses for Axitinib and Crizotinib (Dose Level 1) .3126.96.36.199. DLT Observation Period .3188.8.131.52. Criteria for Dose Escalation .353.1.2. DLT Definition .373.1.3. Maximum Tolerated Dose Definition.383.1.4. Dose Expansion Phase Test Dose.383.1.5. Dose Expansion Phase.383.2. Recommended Phase 2 Dose .394. PATIENT SELECTION .39Page 5
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 20164.1. Inclusion Criteria.394.2. Exclusion Criteria.414.3. Life Style Guidelines.434.3.1. Sunlight Exposure.434.3.2. Contraception.434.4. Sponsor Qualified Medical Personnel.455. STUDY TREATMENTS.455.1. Allocation to Treatment .455.2. Investigational Product Supplies .465.2.1. Dosage Form(s) and Packaging .4184.108.40.206. Axitinib.4220.127.116.11. Crizotinib.465.2.2. Preparation and Dispensing .465.3. Administration.475.3.1. Food Requirements.475.3.2. Recommended Dose Modifications.418.104.22.168. Axitinib Intra-Patient Dose Escalation.422.214.171.124. Dose Modifications in Case of Drug-Related Toxicity.4126.96.36.199. Management of Axitinib-Related Hypertension .595.3.3. Crizotinib-Related Adverse Events Safety Monitoring.5188.8.131.52. Pneumonitis.5184.108.40.206. Renal Cyst .605.3.4. Overdose Instructions .605.3.5. Compliance .605.4. Investigational Product Storage and Accountability.615.5. Concomitant Medication(s).625.5.1. Inhibitors and Inducers of CYP Enzymes .625.5.2. Hematopoietic Growth Factors.635.5.3. Anti Diarrhea, Anti Emetic Therapy .635.5.4. Other Concomitant Medications.635.5.5. Concomitant Surgery .645.5.6. Concomitant Radiotherapy .64Page 6
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 20166. STUDY PROCEDURES .646.1. Screening.646.1.1. Archival Tumor Tissue .656.1.2. De Novo Tumor Biopsy.656.2. Study Period .656.3. Follow-up Visit .656.4. Patient Withdrawal .667. ASSESSMENTS.677.1. Safety Assessment.677.1.1. Pregnancy Testing .677.1.2. Adverse Events .687.1.3. Laboratory Safety Assessment .687.1.4. Vital Signs and Physical Examination.687.1.5. ECG Measurements .697.1.6. Ophthalmology Examinations .697.2. Pharmacokinetics Assessments .707.2.1. Blood Sample Collection for Pharmacokinetic Analysis .717.2.2. Collection of Crizotinib PK Samples .717.2.3. Collection of Axitinib PK Samples .727.2.4. Processing, Storage and Shipment of Crizotinib and Axitinib PKSamples .727.3. Pharmacodynamic Assessments.727.3.1. Archived Tumor Tissue and De Novo Tumor Biopsies .737.3.2. Peripheral Blood .737.4. Banked Biospecimens .737.4.1. Markers of Drug Response .737.4.2. Additional Research.747.5. Tumor Response Assessments .758. ADVERSE EVENT REPORTING.758.1. Adverse Events.758.2. Reporting Period .768.3. Definition of an Adverse Event.76Page 7
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 20168.4. Medication Errors.778.5. Abnormal Test Findings.788.6. Serious Adverse Events.788.6.1. Protocol-Specified Serious Adverse Events .798.6.2. Potential Cases of Drug-Induced Liver Injury.798.7. Hospitalization .808.8. Severity Assessment.818.9. Causality Assessment .818.10. Exposure During Pregnancy.828.11. Occupational Exposure .838.12. Withdrawal Due to Adverse Events (See Also the Section on PatientWithdrawal).838.13. Eliciting Adverse Event Information .838.14. Reporting Requirements.848.14.1. Serious Adverse Event Reporting Requirements .848.14.2. Non-Serious Adverse Event Reporting Requirements .848.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities .849. DATA ANALYSIS/STATISTICAL METHODS.849.1. Analysis sets .859.2. Statistical Methods and Properties .859.2.1. Statistical Methods for Dose Escalation/De-Escalation: mTPI .859.2.2. Statistical Method for Estimating the MTD .869.3. Sample Size Determination.879.4. Efficacy Analysis .879.4.1. Analysis of Efficacy Endpoints (Dose Expansion Phase Cohorts) .889.5. Analysis of Other Endpoints .889.5.1. Analysis of Pharmacokinetics.8220.127.116.11. Pharmacokinetic Analysis of Crizotinib and Axitinib .818.104.22.168. Effect of Crizotinib on Axitinib Pharmacokinetics.822.214.171.124. Population Pharmacokinetic Analysis or PK/PD Modeling .8126.96.36.199. Statistical Analysis of Biomarker Endpoints .899.6. Safety Analysis.90Page 8
AG-013736, PF-02341066A4061068Final Protocol Amendment 2, 27 January 20169.6.1. Analysis of Primary Safety Endpoint .909.6.2. Analysis of Secondary Safety Endpoints.909.6.2.1. Adverse Events.909.6.2.2. Laboratory Tests Abnormalities.909.6.2.3. ECG.909.6.3. Concomitant Medications/Follow-up Systemic Therapy .919.6.4. Ophthalmologic Data.919.7. Data Monitoring Committee .9110. QUALITY CONTROL AND QUALITY ASSURANCE.9211. DATA HANDLING AND RECORD KEEPING .9211.1. Case Report Forms/Electro
concomitant medications, ophthalmology examinations) was updated according to the current standard language of crizotinib and axitinib clinical protocols. Amendment 1 11March2014 SCHEDULE OF ACTIVITIES: - Frequency of hepaticlaboratory test monitoring and relevant footnote modified in accordance withthe Dear Investigator Letter dated 23Oct2013.
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PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING (PART I) (CHAPTER 1, 7) NAITEE TING, BOEHRINGER-INGELHEIM 2 DRUG DEVELOPMENT PROCESS Drug Discovery Non-clinical Development Clinical Development Phase I Clinical pharmacology (PK/PD, MTD) Phase II Drug efficacy/safety, dose ranging Phase III Long-term, large scale, confirmatory
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The Precede-Proceed model for health promotion planning and evaluation Phase 1 Social diagnosis Phase 2 Epidemiological diagnosis Phase 3 Behavioral and Environmental diagnosis Phase 4 Educational and Organizational diagnosis Phase 5 Administrative and Policy diagnosis Phase 6 Implementation Phase 7 Process Phase 8 Impact Phase 9 Outcome Health .
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P90X CLASSIC Phase 1 23 Phase 2 24 Phase 3 25 P90X DOUBLES Phase 1 26 Phase 2 26 Phase 3 27 P90X LEAN Phase 1 28 Phase 2 29 Phase 3 30 TABLE OF CONTENTS Warning: Due to the physical nature of this program, Beachbody recommends that you get a complete physical examination from your physician before getting started. .
A static phase converter is one that externally changes a three phase motor to a capacitor-start, capacitor-run single phase motor; running at approximately the same amperage as a single phase motor of the same horse-power. The single phase amp draw of a three phase motor on our Phase Splitter is 1 1/2 times the three phase name-plate amps.