1. SANOFI Taxynergy Study Protocol L06056
TAXYNERGY: A Phase II Trial to Evaluate Benefit of Early Switch from first-Line Docetaxel/Prednisone to Cabazitaxel/Prednisone and the opposite sequence, exploring molecular markers and mechanisms of taxane resistance in men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) who have not received prior chemotherapy

2. Agenda Protocol Review Safety Reporting and Guidelines
Investigator Responsibilities
Monitoring Expectations
Medidata RAVE review and demo
Cornell Labs/Covance Labs

3. Protocol Review

4. Introduction: Prostate cancer and chemotherapy
TAXYNERGY study
Rationale and objectives
Study design
Objectives and endpoints
Inclusion and exclusion criteria
Collected data
Dose delay and modification
Duration of the study
Study procedures

5. Prostate Cancer
The most commonly diagnosed malignancy and the second leading cause of cancer death in men. In the USA, 241,740 new Prostate Cancer Cases were expected in 2012.
Radical prostatectomy and radiation therapy are the established definitive treatments for clinically localized PC
Over 50,000 men each year progress with a biochemical relapse while others develop metastatic disease resulting in over 30,000 deaths annually.
While chemical castration (hormonotherapy: ADT), is temporarily effective in many patients, most men eventually progress to castrate-resistant prostate cancer (CRPC) and are then treated with docetaxel-based chemotherapy in first line.
Cancer Facts and Figures, American Cancer Society

6. Study design
Phase II, randomized (2:1), open-label, multi-center, evaluating the benefit of an early switch from docetaxel /prednisone (Treatment A) to cabazitaxel/prednisone (Treatment B) or the opposite sequence cabazitaxel/prednisone (Treatment B) to docetaxel/prednisone (Treatment A) if PSA levels are not reduced by at least 30% from baseline after 4 cycles of treatment in men with mCRPC.
If the patients PSA levels are reduced by at least 30% from baseline during the first 4 cycles of treatment, then these patients will continue to receive the initial chemotherapy regimen until disease progression, death, unacceptable toxicity or patient’s refusal of further study treatment.
In addition, a molecular marker of DTE in circulating tumor cells will be performed in all patients throughout this trial to attempt to correlate with clinical response/resistance to taxane therapy. This translational research has the prospect to better differentiate taxanes and inform future development.
~16 sites in the US and Canada
100 patients: 67 patients in treatment A: Docetaxel
33 patients in treatment B: Cabazitaxel

7. Study Design

8. TAXYNERGY: Study Objectives
Primary
To explore the benefit of an early switch from Docetaxel/prednisone to Cabazitaxel/ prednisone in men with metastatic castration resistant prostate cancer (mCRPC) who do not achieve ≥30% PSA decline from baseline by cycle 4 with the initial docetaxel treatment (in comparison with historical control of patients who were treated with Docetaxel and did not switch).
Co-primary objective:
To evaluate the association of the following biomarker with clinical response/resistance to docetaxel or cabazitaxel treatment: Molecular DTE in CTCs
Secondary
-To assess efficacy and safety of the two treatment strategies, switch from cabazitaxel/prednisone to docetaxel/prednisone and docetaxel/prednisone to cabazitaxel/prednisone.
To evaluate efficacy in patients receiving initial taxane treatment before the switch and efficacy under the alternate taxane after the switch within each initial treatment group.
To explore: RNA sequencing on CTCs to assess for tubulin mutations and AR isoforms

9. TAXYNERGY: Endpoints Primary Endpoints
PSA response rate: The proportion of patients in each treatment arm who achieve ≥ 50% PSA reduction from baseline during the whole treatment continuum, before treatment switch and after treatment switch, if applicable
To evaluate the association of Drug Target Engagement (DTE) in circulating tumor cells (CTCs) with clinical response/resistance to docetaxel or cabazitaxel treatment
Secondary Endpoints
PFS – Progression-free Survival
PSA progression-free survival rates
OS – Overall Survival
Objective response rates
Radiographic progression-free survival (rPFS) rates
Clinical progression-free survival (cPFS) rates
Safety

10. Chemotherapy in PCa Management of mCRPC: Chemotherapy in first line
The standard of care for CRPC changed from mitoxantrone/prednisone to docetaxel/prednisone based on TAX-327 and SWOG studies[1,2TAX-327:
Docetaxel improved survival and rates of response in terms of pain, PSA level, and quality of life vs mitoxantrone/prednisone[1SWOG 99-16:
Docetaxel/estramustine improved median survival by 2 mos vs mitoxantrone/prednisone[2]
Management of mCRPC: Chemotherapy in second line
The standard of care for CRPC changed from mitoxantrone/prednisone to cabazitaxel/prednisone based on EFC6193 TROPIC study

11. Inclusion criteria
Histologically- or cytologically-confirmed prostate adenocarcinoma with documented distant metastases (M1 disease)
Progressive disease while receiving hormonal therapy or after surgical castration documented by at least one of the following:
Increase in measurable disease (response evaluation criteria in solid tumors (RECIST)
Appearance of new lesions, including those on bone scan, and/or
Rising PSA defined as 2 sequential increases above a previous lowest reference value (obtained at least 1 week apart). PSA value of at least 2.0 ng/mL is required at study entry.

12. Inclusion criteria- cont’d
Effective castration (serum testosterone levels ≤50 ng/dL (2 nmol/L)) by orchiectomy and/or LHRH agonists or antagonist with or without anti-androgens.
a) If the patient has been treated with luteinizing hormone releasing hormone (LHRH) agonists or antagonist (ie, without orchiectomy), then this therapy should be continued.
b) If patients were either started on complete androgen blockade, or had a PSA response (defined by any reduction in PSA sustained for at least 3 months) after adding an antiandrogen, prior anti-androgen therapy should be stopped before random allocation: at least 6 weeks for bicalutamide and nilutamide, and at least 4 weeks for flutamide, megestrol acetate and any other hormonal therapy (eg, ketoconazole, abiraterone, aminoglutethimide, estrogens) 5α-reductase inhibitors (eg, finasteride, dutasteride) must be discontinued ≥4 weeks prior to initiation of chemotherapy.

13. Exclusion Criteria
Related to methodology:
Prior chemotherapy for prostate cancer, except estramustine and adjuvant/neoadjuvant treatment completed >3 years ago.
Less than 28 days elapsed from prior treatment with estramustine, radiotherapy or surgery to the time of random allocation.
Prior beta isotope therapy, whole pelvic radiotherapy, or radiotherapy to >30% of bone marrow
Adverse events (excluding alopecia and those listed in the specific exclusion criteria) from any prior anticancer therapy of grade >1at the time of random allocation.
Less than 18 years of age.
Performance status >2.
Life expectancy ≤3 months
History of brain metastases, Prior malignancy.
Participation in another clinical trial and any concurrent treatment with any investigational drug within 30 days prior to random allocation.

14. Exclusion Criteria Related to methodology:
Any of the following within 6 months prior to study enrollment: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Associaton (NYHA) class III or IV congestive heart failure, stroke or transient ischemic attack,
Any of the following within 3 months prior to random allocation: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event.
Acquired immunodeficiency syndrome (AIDS)
Any severe acute or chronic medical condition which could impair the ability of the patient to participate in to the study or interfere with interpretation of study results, or patient unable to comply with the study procedures.
Concomitant treatment with biphosphonates or denosumab except if the dose has been stable for 12 weeks prior to enrollment
Absence of signed and dated Institutional Review Board (IRB) approved patient informed consent prior to enrollment into the study.
Patients with reproductive potential who do not agree to use an accepted and effective method of contraception

15. Exclusion Criteria Related to chemotherapy:
History of hypersensitivity to docetaxel or polysorbate 80.
Inadequate organ and bone marrow function as evidenced by:
1) Hemoglobin <9.0 g/dL
2) Absolute neutrophil count <1.5 x 109/L,
3) Platelet count <100 x 109/L,
4) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN),Total bilirubin >1.0 x ULN,
5) Serum creatinine >1.5 x ULN.
Contraindications to the use of corticosteroid treatment.
Symptomatic peripheral neuropathy grade >2 (NCI CTCAE v.4.03).
Treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a two-week wash-out period is necessary for patients who are already on these treatments)

16. Collected data
Clinical, and lab: at baseline, every 3 weeks and at relapse
Clinical examinations (including weight, ECOG PS), laboratory tests (including complete blood counts, serum chemistry) and adverse events
Serum Testosterone only at baseline
Prostate-specific Androgen (PSA)
Pain assessment, completion of analgesic diary and Skeletal Related Event (SRE) assessment
Radiological evaluation of tumor load by computerized tomography (CT) or (MRI) of the whole body (chest, abdomen, and pelvis) at baseline, end of C3, end of C6 (only for patients that switch) and every 12 weeks until progression.
Translational
CTCs (Cornell)
at baseline
at Day 1 and Day 8 of cycle 1, at Day 1 and Day 8 of cycle 5 and at relapse

17. Treatment duration Study drugs Docetaxel 75 mg/m2 q3wk, I.V.
Cabazitaxel 25 mg/m2 q3wk, I.V.
Non-investigational medicinal product commercially available: prednisone or prednisolone (10 mg PO daily)
Treatment duration and follow-up
Part 1: 4 cycles (3 weeks per cycle)
Part 2:
Patients who achieve ≥30% PSA decline from baseline, by cycle 4, will continue their initial taxane treatment. Treatment until progression, death or cut-off
Patients who do not achieve ≥30% PSA decline from baseline, by cycle 4, will switch from docetaxel to cabazitaxel or from cabazitaxel to docetaxel.

18. Duration of the study
Patients will be treated until progressive disease, unacceptable toxicity, death or patient’s refusal of further study treatment. All patients will be followed until death or the study cutoff date, whichever comes first.
Study cut-off will be 6 months after the last patient last treatment.
Patients alive at the cut-off date will be followed for overall survival.
Collection of survival data after the cut-off date will be done every year for a maximum of 3 years.

19. Dose delay & Dose Modification
Dose reduction
Dose can be reduced for cabazitaxel and for docetaxel when necessary. The dose, which has been reduced for toxicity, must not be re-escalated. Up to a maximum of 2 dose reductions will be allowed per patient. If a third dose reduction is required per the modifications below, the patient should discontinue study treatment.
The dose, which has been reduced for toxicity, must not be re-escalated.
Drug
Initial dose (mg/m2)
Dose Reduction 1
Dose Reduction 2
Docetaxel 75 60 50
Cabazitaxel 25 20 15
Dose delay
Treatment may be delayed no more than 2 weeks to allow recovery from acute toxicity
In case of treatment delay greater than 2 weeks, the patient should be withdrawn from treatment study

20. Dose delay & Dose Modification
Liver toxicity
- Docetaxel and Cabazitaxel are extensively metabolized in the liver
Hepatic impairment is likely to increase cabazitaxel or docetaxel concentrations
No data in patients with hepatic impairment for cabazitaxel
- In case of ALT and/or AST increase >1,5 ULN or bilirubin > 1 ULN
delay cabazitaxel for up to 2 weeks until ALT and/or AST returned to ≤ 1,5 x ULN
then retreat patient at reduced dose

21. Dose delay & Dose Modification
Hematological toxicity

22. Information for the Investigator
Cabazitaxel/Docetaxel cannot be given if neutrophil counts are <1,500 cells/mm3
The Investigator needs to monitor blood counts frequently to determine if dosage reduction is needed
Information of the Investigator about the adverse events that may occur during cabazitaxel or docetaxel treatment is key
The combination of neutropenia and diarrhea can become life-threatening
The Investigator needs to inform & follow the patient

23. Screening/Baseline Visit
Inclusion/Exclusion criteria within 8 days prior to randomization.
Demographic characteristics (including ethnicity and race).
Clinical / Physical examination within 8 days prior randomization including major body systems exam, height and weight, ECOG PS, and vital signs (blood pressure, heart rate)
Medical, surgical and oncological history including significant prior and concurrent illnesses, primary diagnosis and prior antitumor therapy.
Concomitant medications will be recorded from 21 days prior to randomization.
Skeletal Related Event (SRE) : within 8 days before randomization: pathological fractures and / or spinal cord compression, need for bone irradiation, including radioisotopes or bone surgery, change of antineoplastic therapy (including introduction of biphosphonates or denosumab in the face of increase in pain) to treat bone pain

24. Screening/Baseline Visit- Pain and Analgesic Diary information.
Pain assessment and analgesic diary for cancer pain :
diary information should be collected for 7 consecutive days prior to first cycle, the last day should be within 3 days prior to first cycle. In case of 1st cycle administration delay, patient should continue to complete the daily pain diary until cycle 1 administration.
Pain intensity score as reported by the subject-see categories below:
0 - No Pain
1 - Mild
2 - Discomforting
3 - Distressing
4 - Horrible
5 – Excruciating
Analgesic use will be recorded in the patient’s diary and on the appropriate eCRF page. The sponsor or sponsor’s designee will convert the analgesic dose to the analgesic score utilizing the table with doses on the next slide.
Each analgesic is designated a score
Non narcotic is awarded 1 point for any route of administration
Narcotic is awarded 4 points for the following routes:
Oral or rectal route Intravenous, intramuscular, or
subcutaneous routes

25. Screening and Baseline-Pain and Analgesic Diary information
Diary and Pain Guidelines will be distributed to guide the process.
The collection will be done at each visit before study treatment administration, at the end of treatment visit and should be administered by a consistently by the same staff member.
No changes should be made to the diary entries as this is retrospective data.
Do not either make any changes (to the diary) without subject permission or lead the subject to make changes you feel are correct.

26. Pain and Analgesic Diary (continued)
The header on patient diary paper should be completed at least with subject ID and date of visit.
The aim is to be able to know for which patient and visit it was completed.
Enter Diary information in eCRF at the visit for the “prior Cycle”
Example) pain information collected for Cycle 1 entered into Cycle 1 when subject returns for Cycle 2 administration.
Questionnaires must be dated (with the date of the diary return), initialed and signed by the patient on the cover page.
In case of corrections, the site staff corrects or makes additions or completes the diary in agreement with the subject.
The patient must sign and date any changes to indicate his agreement.

27. Pain and Analgesic Diary-continued
At Baseline: the last day should be within 3 days prior to first infusion);
In case of delay: diary to be continued daily until the start of the next cycle.
End of Treatment visit: The collection will be done at each visit before study treatment administration.
Follow-up: pain assessment and completion of analgesic will be done every 3 months at each follow-up until death, or study cut-off whichever comes first.

28. Analgesic Score
Clinical / Physical examination within 8 days prior randomization including major body systems exam, height and weight, ECOG PS, and vital signs (blood pressure, heart rate)
Use the Analgesic calculator in Appendix C of the Taxynergy protocol (page 90) by dose or by unit to calculate analgesic score.
According to the protocol appendix C “analgesic scores”: narcotics = 4 points & non-narcotics = 1 point.
For Combination medications: points for the individual active drugs should be added in order to determine the point value for the combination medication.
For the data entry in the eCRF:
Enter the daily analgesic score as calculated according to medications and dosages reported on the patient diary.
If a drug is not listed please contact your CRA for more direction

29. Analgesic Scores- pg 90, Appendix C 6 Sep 12 Protocol Amendment 1

30. Screening/Baseline Visit continued
Hematology within 8 days prior D1 cycle 1 (time between hematological work-up and day 1 cycle 1 should not exceed 8 days; if time exceed 8 days, hematological work-up should be repeated): WBC with differential count, hemoglobin, platelet count
Blood Chemistry and Coagulation tests within 8 days prior D1 cycle 1: sodium, potassium, calcium, phosphorus, BUN, magnesium, creatinine and if creatinine between 1.0 and 1.5 x UNL creatinine, clearance should be calculated with CKD-EPI formula, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin, glucose, lactate dehydrogenase (LDH), and International Normalized Ratio (INR) for patients receiving vitamin K antagonist therapy
Urinalysis: electrolytes, urea, creatinine, WBC with eosinophil count, RBC and proteinuria/creatininuria ratio (UPCR), within 8 days prior to randomization
PSA (last PSA if progression is defined by rising PSA) within 8 days prior to randomization:
Serum testosterone measurement within 21 days prior to randomization

31. Screening/Baseline Visit continued
Tumor assessment within 21 days prior to randomization (6 weeks for bone scan): whole body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as clinically indicated (eg, brain CT-Scan or MRI in case of clinical suspicion of central nervous system involvement) to assess all TARGET or NON TARGET lesions
Biomarkers: CTCs at baseline within 21 days prior to randomization.
Medical History
detailed renal medical history will be documented in the eCRF.
prior Medical/Surgical & Oncologic at Baseline
Physical Examination
Physical examination within 8 days prior randomization including major body systems exam, height and weight, ECOG PS, and vital signs (blood pressure, heart rate).

32. Randomization
Randomization will take place once the consented patient has completed all the necessary screening procedures and is deemed eligible for study entry by the investigator or designee
All eligible patients must be randomized by via IRVS (the patient number will be allocated by IVRS and then populated in the eCRF)
Treatment should begin within 3 days after randomization

33. During study treatment
Clinical/Physical examination before each cycle including major body systems exam weight, ECOG PS, and vital signs (blood pressure, heart rate).
Adverse events assessment: at each cycle.
Pain assessment and analgesic for cancer pain: diary information should be collected for 7 consecutive days prior each cycle (In case of dose delay, continue until start of next cycle)
Skeletal related events: (SRE) pathological fractures and / or spinal cord compression, need for bone irradiation including radioisotopes or bone surgery, change of antineoplastic therapy (including introduction of biphosphonates or denosumab in the face of increase in pain) to treat bone pain.
Concomitant medications will be recorded at every cycle.
Blood chemistry will be done before each study treatment administration (-3 days window is allowed) :sodium, potassium, calcium, phosphorus, BUN, magnesium, creatinine
Hematology will be done before each study treatment administration (-3 days window is allowed) and in case of fever or infection: WBC with differential count, hemoglobin, platelet count

34. Cycle 4 –Switch from one taxane to another
Treatment A [Docetaxel]: Patients who do not achieve 30% PSA reduction from baseline by cycle 4 will switch chemotherapy to receive cabazitaxel 25 mg/m2 intravenously (Day 1) every 3 weeks, plus prednisone 10 mg orally given daily. Patients who do achieve 30% PSA reduction from baseline by cycle 4, will continue with docetaxel until progression, death or patient's refusal or further study treatment.
Treatment B [Cabazitaxel]: Patients who do not achieve 30% PSA reduction from baseline by cycle 4 will switch chemotherapy to receive docetaxel 75 mg/m2intravenously (Day 1) every 3 weeks, plus prednisone 10 mg orally given daily. Patients who do achieve 30% PSA reduction from baseline by cycle 4, will continue with cabazitaxel until progression death or patient's refusal or further study treatment.

35. During Study Treatment (continued)
Urinalysis in case of creatinine increase by 1.5 fold from baseline or in case of decrease by more than 50% and <60 mL/min in calculated creatinine clearance: electrolytes, urea, creatinine, WBC with eosinophil count, RBC and UPCR.
Nephrology advice/consultation in case of decrease by more than 50% in eGFR
PSA: before each next cycle
Whole body CT-scan or MRI and bone scan
Biomarkers: at Day1 and Day 8 of Cycle 1, at Day 1 and Day 8 of Cycle 5

36. Tumor Assessment -During Study Treatment (continued)
Tumor assessment is mandatory at cycle 3, at cycle 6 (for patients who have switched) then every 12 weeks until progression : whole body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as clinically indicated (eg brain CT-Scan or MRI in case of clinical suspicion of central nervous system involvement) CT-Scan or MRI, bone scan and all other exams as clinically indicated (eg brain CT-Scan or MRI in case of clinical suspicion of central nervous system involvement)
The assessment of all TARGET or NON TARGET lesions assessed to ensure comparability, the imaging should be performed using identical techniques throughout the study period. (ie, scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and preferably the same scanner).

37. End of treatment
All patients must continue to be observed for at least 30 days after the final dose of study treatment. The following procedures should be performed within the days following the final dose of study treatment
Clinical/Physical exam: ECOG PS, weight, examination of major body systems, including vital signs
Adverse events assessments.
Pain assessment and analgesic for cancer pain.
SREs: pathological fractures and / or spinal cord compression, need for bone irradiation,including radioisotopes or bone surgery, change of antineoplastic therapy (including introduction of biphosphonates or denosumab in the face of increase in pain) to treat bone pain.
Hematology: WBC with differential count, hemoglobin, platelet count.
Blood Chemistry: sodium, potassium, calcium, phosphorus, BUN, magnesium, creatinine
Concomitant medications assessments
PSA
Tumor assessments (slide #30 for detail)
Biomarkers
Other investigations if clinically indicated
Cohort B patients never treated or received VGCV, AEs only collected to f/u visit (up to 52 weeks post transplantations)

38. End of treatment
Tumor assessment, if end of treatment visit occurs at the time of a planned tumor assessment: whole body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as clinically indicated (eg, brain CT-Scan or MRI in case of clinical suspicion of central nervous system involvement) to assess all TARGET or NON TARGET lesions (measurable and non measurable).

39. Follow-up period
All patients will be followed every 3 months for the first year and then every 6 months (after end of treatment visit) until death or study cut-off, whichever occurs first:
ECOG PS, weight until death or cut-off date, whichever comes first.
All SAEs and/or related to study treatment AEs ongoing at the end of the study, or new related to study treatment AE which occur during the follow-up period will be recorded until recovery, or stabilization of patient’s condition.
Concomitant medications if correspond to treatment of related AEs.stabilization of patient’s condition.
Pain and analgesic for cancer pain: the diary information should be collected daily for 7 consecutive days prior to each scheduled visit.
PSA: until PSA progression
Further anticancer therapy if any, which is at the discretion of the investigator. (Progression of disease must be documented if d/c treatment for other than disease progression)

40. Follow-up period continued
Tumor assessment until radiological PD, if patient discontinued study treatment without radiological progressive disease: whole body (abdominal/pelvic/chest) CT-Scan or MRI, bone scan and all other exams as clinically indicated (eg brain CT-Scan or MRI in case of clinical suspicion of central nervous system involvement) to assess all TARGET or NON TARGET lesions should be assessed. To ensure comparability, the imaging should be performed using identical techniques throughout the study period (ie, scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast agent, and preferably the same scanner)
Survival status; after the cut-off date, collection of survival status will be done every year for a maximum of 3 years.

41. Safety Reporting and Guidelines

42. Investigator Responsibilities for AEs/SAEs
Provide oversight of AE reporting at site
Confirm clinical event
Determine causality
Determine severity of event
Provide narratives for critical SAEs
Acknowledgement of SUSARs within 2 weeks of receipt

43. Site Coordinator’s Responsibilities for AEs/SAEs
Verify clinical event, severity, relationship with drug and procedure with PI and Sub-Investigators
Make initial reports and notifications to Covance
Redact personal health identifiers from source documents
Ensure timely reporting of SAEs to IRB

44. AE Period of Observation
Adverse Events: The period of safety observation starts from the time the patient gives informed consent. All signs and symptoms observed from the time of signature of informed consent will be only recorded as AE if still present at the time of first study drug administration (and reported in cycle 1 of the electronic case report form [e-CRF]) or if they are serious.
All AEs will be recorded until 30 days after the last administration of study drugs.
During the follow-up period, only ongoing related or new related AEs will be recorded.
Ongoing Serious adverse events and related AEs ongoing at the end of the study treatment will be followed during the follow-up period until resolution or stabilization regardless of relationship with study drugs. Adverse events will be recorded according to NCICTCAE Version 4.03

45. How to report an Adverse Event/Serious Adverse Event
Diagnosis:
Identification of underlying disease process
One or two word entity. Not a sentence!!
Only report on the eCRF if definite
Understand difference between symptom and diagnosis
Event:
A single medical disease or entity
Use term for the medical condition and/or surgical procedure and not the symptom!
Example: Appendectomy should be Appendicitis; drain removal instead of site blockage

46. Serious Adverse Event (SAE) Reporting
Report all SAEs and DEATH within 24 hours of knowledge of the event to Covance Drug Safety Services (DSS)
Receive/process events from sites – SAEs, All Pregnancies in partners of subjects enrolled in the clinical study, and symptomatic overdose.
SAE Fax:
Contact information: Riddhima Engineer, Drug Safety Associate
Phone:

47. Event reporting examples
When available, report the unifying clinical condition or final diagnosis
If final diagnosis is not provided, each symptom should be reported as a separate AE, e.g.:
Angina
If angina and numbness in the left arm were accompanying symptoms of MI, do not report as separate events
Report as MI.
Anemia and Syncope
If syncope and anemia were an accompanying symptoms of the Gastrointestinal bleeding, report as such
If no diagnosis is available, report as individual events

48. How to report an Adverse Event/Serious Adverse Event (continued)
Hypothetical diagnoses and rule/out do not belong on the AE eCRF
Event diagnosis: A single medical concept, which incorporates all signs and symptoms of an event
Hierarchical Reporting - A system of reporting using a single medical concept, which incorporates all signs and symptoms of an event taking into consideration the highest ranking disease entity

49. Safety Reporting Process Flow
Covance Safety Senior Member will QC report and distributes documents in a password protected zip file to Sanofi within 24 hours for cases which met the SAE criteria.. During holidays a Covance DSS person will be available to transmit documents to Sanofi
Upon receipt (Day 0), Covance DSA logs in the initial report, reviews SAE Form & Source Docs for completion, and generates queries. Redaction performed as needed
The site completes an initial or follow up event SAE report (SAER) form within 24 hours of the reported event, or when the site becomes aware of it, and faxes the form to Covance PV&DSS. An e-notification will be sent to Covance DSS when information is added to eDC system.
Step 3
Step 1
Step 2
Covance Hotline DSS is available during closures due to Holidays to transmit SAEs to Sanofi -Global Pharmacovigilance and Epidemiology (GPE) in a maximum of 3 calendar days, in case Covance office is closed for more than 2 consecutive days". *

50. Safety Reporting Process Flow (continued)
The Covance DSA forwards the queries to the site, track queries in Trial Tracker and schedules Due Diligence.
Step 4
Step 5
The Covance DSA forwards the queries to the site, track queries in Trial Tracker and schedules Due Diligence

51. AE and SAE Reporting Adverse Events are recorded in the eCRF
EDC system has a notification process which will report SAEs to Covance DSS when an Adverse Event is marked as ‘Serious’ in real time. SAEs will be reported by Covance within 24 hours to Sanofi GPE.
Covance will maintain the clinical EDC database. A tracker will include and track all SAEs using a tracking system. The tracker will include all reported SAEs which reflects data in both the Covance and Sanofi databases per the Covance Safety Management plan.

52. Investigator Responsibilities

53. Investigator Responsibilities
Conduct the trial appropriately per protocol and regulations
Including FDA Form 1572, GCPs
Qualifications
Provide current documentation with regard to regulatory documents and training
Financial Disclosure
Comply with all applicable state and federal laws and regulations governing financial disclosure
Informed Consent
Inform potential subjects of trial risks and benefits as well as how data will be used
Follow HIPAA regulations

54. Investigator Responsibilities
Liability and Insurance
PI is responsible for negligence, recklessness or willful misconduct
Record Keeping and Reporting
Maintain Trial records in accordance with study
Enter data in eCRF in timely manner
Provide written notice to sponsor with plans to destroy records
Confidentiality
Keep study information confidential
Intellectual Property
All inventions and technologies remain sole property of the sponsor

55. Investigator Responsibilities
Publication
Discuss any publication plans with sponsor
Provide a copy of any publication or presentation to the sponsor for review prior to submission
Inspection Rights
Allow sponsor or representatives onsite for monitoring and/or auditing the trial
Term/Termination of Investigator Agreement
Term of agreement is from date signed to completion of Close Out Visit

56. Informed Consent Form (ICF) Documentation
All patients being considered for study participation must sign the IRB approved informed consent and HIPAA form prior to any study procedures being performed
Site must document the consent was granted and a signed copy was given to the patient
After the ICF has been reviewed with the patient, the investigator or designee should print his/her name, sign and date the ICF
All requested initials, signatures and/or dates must be completed on the form (no blanks)
Patients are to sign and date the last page of the ICF
All patients must receive a completed copy of the signed ICF
For all patients, the original signed consent document should be kept in the patient files, available for review

57. Informed Consent continued
The ICF should be reviewed briefly at each study visit to ensure the subject has no questions
Ensure subjects sign the most recent IRB approved version
If a new ICF is IRB approved during subject participation
Review the new consent with the subject
Document the revised version has been signed

58. Standard Due Diligence Documentation
A minimum of two telephone calls on different days should be recorded in the subjects’ source as required
If these attempts are unsuccessful, a certified letter should be sent to the subject
If the subject misses 2 consecutive contact time points and the certified letter is not addressed, the subject will be considered lost to follow-up

59. Regulatory Expectations
Update regulatory documents as needed (expired, new staff)
Medical Licenses, CVs, Lab Certificates, etc.
IRB Approvals
Ensure on time IRB submissions
All ICF changes should be approved by Covance prior to initial submission
Inform Covance/sponsor if the IRB suspends or terminates the trial

60. Monitoring Expectations

61. Monitoring Visits
The first RMV performed within 3 weeks of the first randomized subject.
During enrollment period-The CRA visits the site every 12 weeks.
Post Enrollment –RMVs performed every 26 weeks until the last-patient-out
On-site closeout visit
Source data verification will be done at each monitoring visit
Hospital and clinic charts should be available to the monitor at each visit
Confirmation and follow-up letters will be provided
Confirmation letters will detail the subjects that will be reviewed during the visit
Follow-up letters will detail issues that need to be addressed
Regulatory Binder review
PI and SC should be available at each monitoring visit
Regulatory binder: Will be reviewed at each monitoring visit; All correspondence should be filed in date order with the most recent date on top
File correspondence on a continual basis

62. Monitor Responsibilities
Review Medidata RAVE (eCRFs) entries for accuracy (remote monitoring)
Ensure complete reporting of all adverse events
Review source documents
Ensure site coordinators redaction of source documents
Ensure Regulatory Binder and correspondence are updated and filed as required
Site Management
Between visits, in-house Covance staff will be reviewing subject data and contacting sites for follow up

63. eCRF Completion Expectations
Patient visit data is to be entered into the eCRF within 5 days after the visit
Sites will be expected to enter Adverse Event data on the eCRF as soon as subject informs the site at the visit.
SAE's, Pregnancies of subject’s partner and symptomatic overdoses to be reported in the EDC within 24 hours of awareness, (in addition an Initial AE/SAE report is be completed and sent within 24 hours of notification to Covance DSS)
Sites will be expected to resolve queries within 5 days of notification

64. Protocol Deviations/Violations/Waivers
Protocol deviations/violations will be recorded in the eCRF by the study monitor
Protocol deviations/violations should be reported to your IRB as applicable
if an event is non-reportable ensure you have documentation from the IRB (and filed in your Regulatory (Site) binder)
Definitions:
Protocol Deviation: out of the control of the investigator site
Example: patient did not show for study visit
Protocol Violation: in the realm of control of the investigator site
Example: site did not check inclusion/exclusion criteria before enrolling the patient
No protocol waivers will be granted for this study

65. Source Requirements
Source Documentation includes (but is not limited) to the following:
Signed Informed Consent Form for all subjects
includes screen failures
Laboratory Reports – official copy of laboratory report
Medication Administration Record (MAR)
Analgesic and pain diaries
ALL medical records for each subject available at the site

66. Medidata RAVE Review and Demo

67. Agenda General Guidelines on data entry (Medidata RAVE) Support
Contacts
Demonstration

68. General Guidelines on Data Entry
Dates
Entered into three fields. The two digit day is entered in numeric format in the first field, the three character month is selected from a drop down list in the second field and the four digit year entered in the third field, e.g. “01 Jul 2007”
Dates should be entered in the format DD/MMM/YYYY, e.g. “11/Nov/2006”
Unknown days should be entered as “un” e.g. un Nov 2007
For unknown months UNK should be selected from the drop down list e.g. un UNK 1980
If the date is completely unknown then the whole date field should be left blank and the response to the query that fires should be “Date Unknown”

69. Data Reference forms (outside labs)
Data Reference forms to be completed by the sites for outside labs.
Forms to be sent to sites to completed in advance of the SIV so that during this visit.
CRA to collect the completed forms at the SIV
Upon completion of the Ref. forms please load the form by site name into TT first and then send me the completed form.

70. General Guidelines on Data Entry (continued)
Time
Always use 24-hour clock time format (not am/pm) with the two digit hour in the first field and two digit minute in the second field. e.g. “20:06” or “08:58”
In text fields always enter a colon (as separator) and leading zeros, e.g. time: “02:10”
Entry for midnight and times between midnight and 1 am, the time should be entered as “00:00“(not "24:00")
If time is partially or completely unknown the time field should be left blank and the response to the query that fires should be “Time Unknown”
Decimal numbers
Should always be entered with a decimal period “.” instead of a comma “,”
Use leading zero before decimal (if number is lower than 1), e.g. “0.19”

71. General Guidelines on Data Entry (continued)
Text
Always use English text
Avoid abbreviations for all terms including medical terms
Avoid the use of special characters like “μ”, "°", "^", "~", etc.
Do not use text entries like “see above” or “see below”, enter the referenced text
Do not use ditto marks in case of entries where one row is below the other, enter the referenced text
If the text is too long, enter as much as possible into the planned field and give additional information in the comments form

72. Data Reference forms (outside labs)
Data Reference forms to be completed by the sites for outside labs.
Forms to be sent to sites to completed in advance of the SIV so that during this visit.
CRA to collect the completed forms at the SIV
Upon completion of the Ref. forms please load the form by site name into TT first and then send me the completed form. 72

73. Log Lines
To add an additional log line on a non pre-populated log form
Click on the “Add a new log line” text in the gray bar at the bottom of the form
Please note that any unsaved information is deleted when clicking “Add a new log line”
To deactivate a log line on a non pre-populated log form
Click on the “Inactive” text in the gray bar at the bottom of the form
Then select the number of log line to be inactivated and the reason for inactivation
Please note that once a line is deactivated it cannot be re-activated and a new log-line would have to be added with all information re-entered

74. Queries There are 3 types of queries:
System Queries –will automatically fire when data is entered/saved and does not meet the requirement of the question.
i.e. Date of visit is entered as 25 Jan A query will fire stating that the date entered is a future date or non conformant.
Site by CRA queries –will be generated manually by the CRA/monitor while on-site doing SDV of the data
i.e. CRA can be at your site and find a discrepancy in the source document for the Date of Birth vs. what is in EDC; therefore, a query would be generated
Site by DM queries –manual queries that Data Management will be generating based on their review of the data
i.e. During SAE Reconciliation, a discrepancy is found between the safety database and EDC; therefore, a query would be generated asking for clarification on which is correct

75. Queries (continued) Will display on the screen as pink lines
All queries that pop up while doing entry should be resolved right away
Any manual queries that come from Covance should be answered within 5 days from date of issue
Remember when answering queries, if data needs to be changed, click the pencil to the right of the data field in order to edit the line
If the data in EDC needs to be changed and is not, a Re-query will be generated

76. Tips on avoiding queries (examples)
Vital Signs
Height will always be entered in cm and Weight in kg
Medical History
detailed renal medical history will be documented in the eCRF.
prior Medical/Surgical & Oncologic at Baseline
Study Drug Administration
If any study drug was interrupted, a reason as to why as well as date interruption started must be provided
Physical Examination- (Physical examination within 8 days prior randomization major body systems exam, height and weight, ECOG PS, and vital signs i.e. blood pressure, heart rate)
If body part is abnormal, list the abnormality on the medical history module at baseline
Record signs and symptoms ongoing at Cycle 1 Day on the AE form
Scheduled PEs -If body parts are noted as abnormal list on the AE form

77. eCRF Completion
How do I enter data on this form? What do these icons mean?

78. Icon Key

79. Creating a patient 1. Click on Add Subject
Once the Save button is pressed, a pop up box in the lower right hand corner will appear saying patient created successfully and the Screening visit will appear on the left hand side of the screen

80. Eligibility for Randomization (note inclusion or exclusion from code list)

81. SAE/Adverse Event In the case of an AE In the case of a SAE
If ‘Yes’, check all definitions of the AE that apply and complete the AE Complementary pages.
Refer to the protocol for a definition of adverse event. The Safety Complementary Page are to be faxed or sent electronically immediately, at the latest, within 24 hours of obtaining knowledge. This includes any change of a non-serious AE into a serious one. Check that the data on AE complementary forms are consistent (e.g., same term).
Relationship? (For Adverse Events, the P.I. can check all that apply)
The information above will be reflected in the eCRF
In the case of a SAE
If ‘Yes’, check all definitions of the SAE that apply and complete the SAE Complementary pages.
Refer to the protocol for a definition of serious adverse event. In the case of an SAE, the P.I must complete BOTH, the AE and Safety Complementary Pages, and both pages are to be faxed, or sent electronically immediately, at the latest within 24 hours of obtaining knowledge. This includes any change of a non-serious AE into a serious one. Check that the data on AE and SAE forms are consistent (e.g., same term).

82. SAE/Adverse Event continued
Relevant Medical/surgical history and – specify
Study Treatment
Concomitant diseases

83. Concomitant Medications
Only enter one condition/diagnosis per line on the Medical History form
Medication, route, start and end date
If more than one condition/diagnosis is needed, click on Add new line and a new line will appear

84. Demographics: visit information, informed consent and demography on each line.

85. Taxynergy will have 2 Medical History Pages
Renal medical history
Other Medical/Surgical history
RAVE: Only enter one condition/diagnosis per line on the Medical History form
If more than one condition/diagnosis is needed, click on Add new line and a new line will appear

86. RAVE Support Technical Support On-Line Support EDC Help Desk
Regional toll free number MEDIDATA ( )
Hours - 24 hours a day, 7 days a week

87. Covance Contacts General study/entry support – Covance CRA
Raj Prasad Senior Clinical Data Coordinator

88. Cornell Weill Medical/Covance Central Laboratories

89. Initial Supplies to Sites
Role of Covance Labs
Initial Supplies to Sites
Covance to provide Lab kits for the study
Organize direct shipments from sites to the Cornell’s lab locations.
Covance CLS Laminated Synopsis provided with correct collection procedure for Pax

90. Biomarkers (CTC) Samples
CCLS/Covance will provide Kits A to one group of sites, and Kits B to another group.
Cornell Lab will perform analysis for CTC (prostate circulating tumor cell)
Co-primary endpoint for prognosis
To target drug engagement
Laminated Synopsis for A and B provide collection and shipment directions 90

91. Samples Timepoints for CTC samples (whole blood)
Baseline (1 tube Na citrate)
Cycle 1 Day 1 (4 tubes, 3 Na citrate, 1 Paxgene)
Cycle 5 Day 1 (4 tubes, 3 Na citrate, 1 Paxgene)
Cycle 1 Day 8 (1 tube Na citrate)
Cycle 5 Day 8 (1 tube Na citrate)
Relapse A (3 tubes, 2 Na citrate, 1 Paxgene)
IMPORTANT NOTE: SAMPLES SHOULD NOT BE RETURNED TO COVANCE BUT SHOULD BE SHIPPED DIRECTLYTO THE REFERRAL LABORATORIES AS INSTRUCTED IN THE SYNOPSIS WITH A COPY OF THE REQUISITION FORM. 91

92. Biomarkers (CTC) Samples
Site to complete Cornell Lab requisition
Ambient temperature for the sample
Blood RNA tube is at room temperature (18-25C) prior to use
You must NOT draw blood directly from the needle into the PAXgene™ Blood RNA tube.
You must NOT use a syringe to draw blood and then add it to the tube.
Caution used as the contents of the PAXgene™ tube are irritating to the eyes, respiratory system and skin
Blood must be drawn before chemotherapy infusion 92

93. CCLS Synopsis A : Baseline or Cycle 1 Day 8 or Cycle 5 Day 8
Collect 2.7ml of whole blood into the Sodium Citrate tube labeled M
Ship ambient day of collection the tube to Cornell Weill Medical College (WCMC):
Paraskevi Giannakakou
Weill Medical College of Cornell University
Division of Hematology & Medical Oncology
1300 York Avenue, Room C660
New York, NY 93

94. CCLS Synopsis A : Cycle 1 Day 1 or Cycle 5 Day 1
Collect 3 x 2.7ml of whole blood into the three Sodium Citrate tubes labeled M, R and X and 1 x 2.5 ml of whole blood into the PAXgene Blood RNA tube
Ship ambient day of collection the 4 tubes to WCMC:
Paraskevi Giannakakou
Weill Medical College of Cornell University
Division of Hematology & Medical Oncology
1300 York Avenue, Room C660
New York, NY

95. CCLS Synopsis A : Relapse
Collect 2 x 2.7ml of whole blood into the two Sodium Citrate tubes labeled M and R and 1 x 2.5 ml of whole blood into the PAXGene Blood RNA tube.
Ship ambient day of collection the 3 tubes to WCMC:
Paraskevi Giannakakou
Weill Medical College of Cornell University
Division of Hematology & Medical Oncology
1300 York Avenue, Room C660
New York, NY

96. CCLS Synopsis B : Baseline or Cycle 1 Day 8 or Cycle 5 Day 8
Collect 2.7ml of whole blood into the Sodium Citrate tube labeled M
Ship ambient day of collection the tube to Cornell Ithaca to:
Professor Brian Kirby
Attn: TAXYNERGY trial,
238 Upson Road
124 Hoy Road
Ithaca, NY

97. CCLS Synopsis B : Cycle 1 Day 1 or Cycle 5 Day 1
Collect 3 x 2.7ml of whole blood into the three Sodium Citrate tubes labeled M, R and X and 1 x 2.5 ml of whole blood into the PAXgene Blood RNA tube
Ship ambient day of collection the tube R and the PAXGene tube to Cornell Weill Medical College (WCMC) :
Paraskevi Giannakakou
Weill Medical College of Cornell University
Division of Hematology & Medical Oncology
1300 York Avenue, Room C660
New York, NY
Ship ambient day of collection the tubes M and X to Cornell Ithaca :
Professor Brian Kirby
Attn: TAXYNERGY trial,
238 Upson Road
124 Hoy Road
Ithaca, NY 97

98. CCLS Synopsis B : Relapse
Collect 2 x 2.7ml of whole blood into the three Sodium Citrate tubes labeled M and R and 1 x 2.5 ml of whole blood into the PAXgene Blood RNA tube
Ship ambient day of collection the tube R and the PAXGene tube to Cornell Weill Medical College (WCMC) :
Paraskevi Giannakakou
Weill Medical College of Cornell University
Division of Hematology & Medical Oncology
1300 York Avenue, Room C660
New York, NY
Ship ambient day of collection the tube M to Cornell Ithaca :
Professor Brian Kirby
Attn: TAXYNERGY trial,
238 Upson Road
124 Hoy Road
Ithaca, NY 98

99. PACKAGING PROCEDURES -
! Notify your courier of your shipment!
Problems/questions concerning packaging procedures? Call us using our toll-free number.
Insert the tube(s) into the Specimen Collection Bag containing an absorbent pack. Place bag on flat surface to minimize
wrinkles, especially at adhesive sealing area. Remove tape liner to expose adhesive. Fold along bag opening so star
is inside of box shape. Press from center to edge to seal.
Fold the white copy of the completed requisition form and place it into the pocket on the reverse side of the Specimen
Collection Bag. The bar code must be visible.
Take a Gel Pak and fill it to the indicator line with cool tap water. Seal the bag.
Lightly press the absorbent pack to expel its contents. Massage the bag until water has been absorbed and a gel
material has formed. Expel the air from the Gel Pak and reseal.
Place the Specimen Collection Bag on top of the Gel Pak. Wrap the Gel Pak around the Specimen Collection Bag,sandwiching the specimens in the middle. Do not insert the specimen containers directly into the Gel Pak!

100. PACKAGING PROCEDURES - continued
Important: Ensure the Hematology sample is placed in the fold of the Gel Pak.
Place the Gel Pak into the white kit box.
Insert the kit into the zip bag.
Place the zip bag into the shipping carton. Fill empty spaces with cushioning material (i.e. paper).
Note: If the kit box is too large to place in the ambient shipping carton, wrap a rubberband around the Gel Pak.
Place the Gel Pak containing the specimen collection bag inside the large zip bag.
Seal the shipping carton securely. Affix the label with your address on the box as indicated on the picture above. Note:
Your shipment may be delayed if the label is not affixed to the box.
US domestic shipments: Complete and affix the airway bill to the designated spot on the box.
Rest of world: Insert the shipping documentation into the transparent pouch ensuring that the airway bill remains
visible. Affix the pouch to the cardboard box on the “Place airway bill here” section.

101. Local Lab Procedures

102. Normal Reference Ranges Form for Local Labs
To be completed by sites with each new lot number used inLab
Outside Source(lab) Company Name:Fax:Location Code:Address:Effective Date:Contact name:End Date:Telephone:when superseded by other ranges
Test NameTest Code[1]Gender(M, F, B[2])Age LowAge HighRange LowRange HighUnitsUnits Code*
OUTSIDE SOURCE STAFF:
I confirm that the above reference ranges are correct at the date of signature. Covance will be informed immediately if any of the above reference ranges change.
______________________________________ ________________
Authorized personnel signature Print name/Title Date
COVANCE STAFF:
___________________________________ ______________________________________ ___________________
Initial data entry Print name/Title Date
___________________________________ _______________________________________ ____________________
Entry Verification by Print name/Title Date
[1] External supplier test code, if applicable
[2] M – Male, F – Female; B - Both

103. Thank you for your time
Questions?