Clinical trial NCT01011439
Conditions: Thymic Carcinoma
Keywords: B3 and C malignant thymoma
Sponsor: Tiziana Life Sciences LTD
Start date: 2010-02-22; Completion date: 2018-12-17
Enrollment: 72 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The intent of the study is to assess the antitumor activity of PHA-848125AC as second-line treatment in patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy.

Detailed description:
The Simon's optimal 2 stage design is adopted for this single-arm, open-label, multicenter phase II clinical trial of PHA-848125AC administered to patients with recurrent or metastatic, unresectable thymic carcinoma previously treated with chemotherapy (only one prior systemic therapy allowed). The intent of the study is to assess the antitumor activity of PHA-848125AC and ultimately to improve the outcome of patients with thymic carcinoma who have already exploited one chemotherapy option. The primary end point for this study is a progression free survival rate of 3 months.

Arms: arm 1: 100 and 50 mg Capsule 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle
Interventions: intervention 1: Milciclib Maleate
Intervention descriptions: intervention 1: 150 mg/day once daily, for 7 consecutive days (days 1 to 7) followed by 7 days of rest (days 8 to 14) in a 2-week cycle.

Number of cycles: until disease progression or unacceptable toxicity.

Protocol documents:
SAP_002.pdf: 
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ANALYSIS DISPLAY PLAN 
TABLE and LISTING MOCK-UPs 
 
 
 
Compound: 
PHA-848125AC 
Protocol No.: 
CDKO-125a-006 
Protocol title: 
Phase II Study of Oral PHA-848125AC in Patients with Thymic Carcinoma Previously Treated with Chemotherapy 
Clinical phase: 
Phase II 
Authors: 
Miriam Fossati and Anna Petroccione 
 
 
 
 
 


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GENERAL ISSUES .................................................................................................................................................................................................... 8 
APPENDIX 1: STUDY INFORMATION .......................................................................................................................................................................... 9 
Appendix 1 – Section 9 – Statistical and Analytical Issues ....................................................................................................................................... 10 
Appendix 1.9.1.<x> – Treatment Efficacy - Kaplan Meier Estimates for Progression Free Survival – Treated / Evaluable Patients – ................... 10 
Appendix 1.9.2.<x > – Treatment Efficacy - Kaplan Meier Estimates for Overall Survival  – Treated / Evaluable Patients – ................................ 11 
APPENDIX 2: SUMMARY TABLES ............................................................................................................................................................................... 12 
Appendix 2 - Section 1 - Patient Disposition .............................................................................................................................................................. 13 
Appendix 2.1.1 - Patient Disposition: Patient Screening - Screened Patients – ......................................................................................................... 13 
Appendix 2.1.2 - Patient Disposition: Patient Disposition by Investigational Site - Enrolled Patients – .................................................................. 14 
Appendix 2.1.3 - Patient Disposition: Study Period Completion and Primary Off Study Reason - Enrolled Patients – ........................................... 15 
Appendix 2.1.4 - Patient Disposition: Treatment Period Completion and Primary Off Treatment Reason - Treated Patients – .............................. 16 
Appendix 2.1.5 – Patient Disposition: Frequency of Patients according to Time on Treatment - Treated Patients – ............................................... 17 
Appendix 2 – Section 2 – Demography and Pretreatment Characteristics ............................................................................................................. 18 
Appendix 2.2.1 – Demography and Pretreatment: Demography Characteristics - Treated Patients - ....................................................................... 18 
Appendix 2.2.2 – Demography and Pretreatment: Summary Statistics of Age, Weight and Height - Treated Patients - ......................................... 19 
Appendix 2.2.3 – Demography and Pretreatment: Tumor History - Primary Diagnosis and Diagnosis at Study Entry - Treated Patients – ........... 20 
Appendix 2.2.4 – Demography and Pretreatment: Tumor History – Time from Primary Diagnosis and Diagnosis at Study Entry to Treatment 
Start - Treated Patients – ............................................................................................................................................................................................. 21 
Appendix 2.2.5 – Demography and Pretreatment: History of Other Cancers - Treated Patients - ............................................................................ 22 
Appendix 2.2.6 - Demography and Pretreatment: Tumor History - Prior Antitumor Treatments / Procedures: Type and Setting - Treated Patients –
 .................................................................................................................................................................................................................................... 23 
Appendix 2.2.7 – Treatment Efficacy: Oncologic Assessment at Study Entry - Treated Patients – .......................................................................... 24 
Appendix 2.2.8 – Demography and Pretreatment: Signs and Symptoms - Treated Patients - ................................................................................... 25 
Appendix 2 – Section 3 – Treatment Exposure .......................................................................................................................................................... 26 
Appendix 2.3.1 – Treatment Exposure: Summary Statistics of the Number of Cycles / Weeks of Treatment - Treated Patients - .......................... 26 
Appendix 2.3.2 - Treatment Exposure: Frequency Distribution of Cycles according to the Percentage of Scheduled Dose Administered - Treated 
Patients - ..................................................................................................................................................................................................................... 27 
Appendix 2.3.3 – Treatment Exposure: Summary Statistics of Dose Intensity, Relative Dose Intensity and Cumulative Dose - Whole Treatment 
Period - - Treated Patients - ........................................................................................................................................................................................ 28 


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Appendix 2.3.4 - Treatment Exposure: Frequency Distribution of Cycles according to their Duration - Treated Patients – ................................... 29 
Appendix 2.3.5 – Treatment Exposure: Frequency Distributions of Patients and Cycles with Treatment Modifications - Treated Patients - ......... 30 
Appendix 2.3.6 –Treatment Exposure: Frequency Distributions of Patients by Reasons for Treatment Modifications - Treated Patients – ........... 31 
Appendix 2 – Section 4 – Treatment Efficacy ............................................................................................................................................................ 32 
Appendix 2.4.1.<x> – Treatment Efficacy: Progression Free Survival Rate at 3 Months - Evaluable /Treated Patients – ....................................... 32 
Figure 2.4.1.<x> – Treatment Efficacy: Kaplan-Meier Curve for Progression Free Survival - Evaluable /Treated Patients – ................................. 33 
Appendix 2.4.2.<x> – Treatment Efficacy: Best Confirmed Tumor Response - Evaluable/Treated Patients - ......................................................... 34 
Appendix 2.4.3.<x> – Treatment Efficacy: Best Unconfirmed Tumor Response - Evaluable/Treated Patients - ..................................................... 35 
Appendix 2.4.4.<x> – Treatment Efficacy: Statistical Analysis of  Time-To-Event Endpoints - Treated / Evaluable - ........................................... 36 
Appendix 2.4.4.<x> – Treatment Efficacy: Statistical Analysis of  Time-To-Event Endpoints - Treated / Evaluable - ........................................... 36 
Figure 2.4.2..<x> – Treatment Efficacy: Kaplan-Meier Curve for Overall Survival - Treated / Evaluable Patients– ............................................... 37 
Appendix 2.4.5 – Treatment Efficacy: ECOG Performance Status: On Treatment Worst Assessment vs. Pretreatment - Treated Patients with at 
Least One Assessment On Treatment - ...................................................................................................................................................................... 38 
Appendix 2 – Section 5 – Adverse Events ................................................................................................................................................................... 39 
Appendix 2.5.1 – Adverse Events: Patients with on Treatment AEs by System Organ Class and Maximum CTC Grade - Treated Patients – ...... 39 
Appendix 2.5.2 – Adverse Events: Patients with on Treatment AEs by AE MedDRA Preferred Term and Maximum CTC Grade - Treated 
Patients – ..................................................................................................................................................................................................................... 40 
Appendix 2.5.3 – Adverse Events: Patients with on Treatment AEs by SOC, AE MedDRA Preferred Term and Maximum CTC Grade - Treated 
Patients - ..................................................................................................................................................................................................................... 41 
Appendix 2.5.4 – Adverse Events: Patients with AEs with Possible to Definite Relationship to Study Treatment by SOC and Maximum CTC 
Grade  - Treated Patients – ......................................................................................................................................................................................... 42 
Appendix 2.5.5 – Adverse Events: Patients with AEs with Possible to Definite Relationship to Study Treatment by AE MedDRA Preferred Term 
and Maximum CTC Grade  - Treated Patients – ........................................................................................................................................................ 43 
Appendix 2.5.6 – Adverse Events: Patients with AEs with Possible to Definite Relationship to Study Treatment by SOC, AE MedDRA Preferred 
Term and Maximum CTC Grade - Treated Patients – ............................................................................................................................................... 44 
Appendix 2.5.7 – Adverse Events: Patients with on Treatment Serious AEs by SOC, AE MedDRA Preferred Term and Maximum CTC Grade - 
Treated Patients – ....................................................................................................................................................................................................... 45 
Appendix 2.5.8 – Adverse Events: Patients with Serious AEs with Possible to Definite Relationship to Study Treatment by SOC, AE MedDRA 
Preferred Term and Maximum CTC Grade - Treated Patients – ................................................................................................................................ 46 
Appendix 2.5.9 – Adverse Events: Patients with on Treatment AEs Leading to Withdrawal from Study Treatment by SOC, AE MedDRA 
Preferred Term and Maximum CTC Grade - Treated Patients – ................................................................................................................................ 47 
Appendix 2.5.10 – Deaths: Frequency of Death according to Most Probable Cause and Time of Occurence - Treated Patients – .......................... 48 


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Appendix 2 - Section 6 – Laboratory Assessments .................................................................................................................................................... 49 
Appendix 2.6.1 – Hematology: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment - Treated 
Patients with at Least One Assessment On Treatment - - All Cycles, Cycle 1, Cycles > 1- ...................................................................................... 49 
Appendix 2.6.2 – Hematology: Frequency Distribution of Treatment Cycles based on Maximum CTC Grade On Treatment versus Pretreatment - 
Cycles with at Least One Assessment - - All Cycles, Cycle 1, Cycles > 1 - .............................................................................................................. 50 
Appendix 2.6.3 – Blood Chemistry: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment (Part 
I) - Treated Patients with at Least One Assessment On Treatment - - All Cycles, Cycle 1, Cycles > 1- .................................................................. 51 
Appendix 2.6.4 – Blood Chemistry: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment (Part 
II) - Treated Patients with at Least One Assessment On Treatment - - All Cycles – ................................................................................................. 52 
Appendix 2.6.5 – Blood Chemistry: Frequency Distribution of Treatment Cycles based on Maximum CTC Grade On Treatment versus 
Pretreatment (Part I) - Cycles with at Least One Assessment - - All Cycles, Cycle 1, Cycles > 1 - .......................................................................... 53 
Appendix 2.6.6 – Blood Chemistry: Frequency Distribution of Treatment Cycles based on Maximum CTC Grade On Treatment versus 
Pretreatment (Part II) - Cycles with at Least One Assessment - - All Cycles- ........................................................................................................... 54 
Appendix 2.6.7 – Coagulation: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment - Treated 
Patients with at Least One Assessment On Treatment - - All Cycles, Cycle 1, Cycles > 1 – .................................................................................... 55 
Appendix 2.6.8 – Laboratory Tests without a NCI-CTC Grade: Frequency Distribution of Patients Based on On Treatment Worst Assessment 
versus Pretreatment - Treated Patients with at Least One Assessment On Treatment - - All Cycles, Cycle 1, Cycles > 1 – .................................... 56 
Appendix 2.7 – Other Safety Assessments .................................................................................................................................................................. 57 
Appendix 2.7.1 – Other Safety Assessments: Blood Pressure - On Treatment Worst Assessment versus Pretreatment - Treated Patients with at 
Least One Assessment On Treatment - ...................................................................................................................................................................... 57 
Appendix 2.7.2 – Other Safety Assessments: ECG - On Treatment Assessment versus Pretreatment Condition - Treated Patients with at Least 
One Assessments On Treatment - ............................................................................................................................................................................... 58 
Appendix 2.7.3 – Other Safety Assessments: ECG - On Treatment Abnormality Findings - Treated Patients with at Least One Assessment On 
Treatment – ................................................................................................................................................................................................................. 59 
Appendix 2.7.4 – Other Safety Assessments: Funduscopic Examination - On Treatment Worst Assessment versus Pretreatment - Treated Patients 
with at Least One Assessment On Treatment - .......................................................................................................................................................... 60 
APPENDIX 3: INDIVIDUAL DATA LISTINGS ............................................................................................................................................................ 61 
Appendix 3 - Section 1 - Patient Disposition .............................................................................................................................................................. 62 
Appendix 3.1.1 – Patient Disposition: Patient Registration – Registered Patients – ................................................................................................. 62 
Appendix 3.1.2 – Patient Disposition: Registered but Not Enrolled Patients - Screening Failures - ......................................................................... 63 
Appendix 3.1.3 – Patient Disposition: Summary of Patient Information - Enrolled Patients- ................................................................................... 64 
Appendix 3.1.4 – Patient’s Survival Status during Follow Up - Treated Patients- .................................................................................................... 65 


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Appendix 3 - Section 2 - Protocol Deviations ............................................................................................................................................................. 66 
Appendix 3.2.1 - Protocol Deviations: Violations of Inclusion / Exclusion Criteria - Enrolled Patients – ............................................................... 66 
Appendix 3 – Section 3 – Patients Evaluability for Efficacy Analysis ..................................................................................................................... 67 
Appendix  3.3.1- Patients Evaluability for Efficacy Analysis: Listing of Evaluability Criteria and Individual Evaluability Status                                                  
-Treated Patients- ........................................................................................................................................................................................................ 67 
Appendix 3 – Section 4 – Demography and Pretreatment ........................................................................................................................................ 68 
Appendix 3.4.1 - Demography and Pretreatment: Tumor History - Primary Diagnosis - Treated Patients - ............................................................ 68 
Appendix 3.4.2 - Demography and Pretreatment: Tumor History – Diagnosis at Study Entry - Treated Patients – ................................................. 69 
Appendix 3.4.3 - Demography and Pretreatment: Tumor History – Independent Review Committee Confirmation of Diagnosis - Treated Patients 
– .................................................................................................................................................................................................................................. 70 
Appendix 3.4.4 - Demography and Pretreatment: History of Other Cancers - Treated Patients– ............................................................................. 71 
Appendix 3.4.5 - Demography and Pretreatment: Tumor History - Prior Antitumor Treatments/Procedures - Treated Patients – .......................... 72 
Appendix 3.4.6 - Demography and Pretreatment: Tumor History - Prior Systemic Therapies - Treated Patients – ................................................. 73 
Appendix 3.4.7 – Demography and Pretreatment: Tumor History - Prior Surgeries - Treated Patients – ................................................................. 74 
Appendix 3.4.8 – Demography and Pretreatment: Tumor History - Prior Radiotherapies - Treated Patients – ........................................................ 75 
Appendix 3.4.9 - Demography and Pretreatment: General Medical History and Physical Examination Findings - Treated Patients – ................... 76 
Appendix 3 – Section 5 – Treatment Exposure .......................................................................................................................................................... 77 
Appendix 3.5.1 – Treatment Exposure: Treatment Administration Details - Treated Patients – ............................................................................... 77 
Appendix 3.5.2 – Treatment Exposure: Reasons for Treatment Delay, Dose Reduction - Treated Patients - ........................................................... 78 
Appendix 3.5.3 – Treatment Exposure: Dose Intensity and Cumulative Dose - Treated Patients – .......................................................................... 79 
Appendix 3.5.4 – Treatment Exposure: Pharmacokinetics Blood Sampling Time - Treated Patients – .................................................................... 80 
Appendix 3 – Section 6 – Treatment Efficacy ............................................................................................................................................................ 81 
Appendix 3.6.1 - Treatment Efficacy - Target and Non Target Lesions by Assessment Visit  - Treated Patients – ................................................. 81 
Appendix 3.6.2 - Treatment Efficacy - Response Status by Assessment Visit - Treated Patients - ........................................................................... 82 
Appendix 3.6.3 - Treatment Efficacy – Best Overall Response and Time to Progression, Progression Free Survival, Overall Survival, Response 
Duration and Stable Disease Duration - Treated Patients - ........................................................................................................................................ 83 
Appendix 3.6.4 – Treatment Efficacy: ECOG Performance Status - Treated Patients - ............................................................................................ 84 
Appendix 3 – Section 7 – Adverse Events ................................................................................................................................................................... 85 
Appendix 3.7.1 – Adverse Events: All Reported Adverse Events by Assessment Visit and AE MedDRA Preferred Term - Treated Patients - ..... 85 
Appendix 3.7.2 - Adverse Events: Adverse Events Related to Study Procedure at Pretreatment - Treated Patients – ............................................. 86 
Appendix 3.7.3 – Adverse Events: Serious Adverse Events - Treated Patients - ...................................................................................................... 87 


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Appendix 3.7.4 – Adverse Events: Adverse Events with CTC Grade 3 to 5 - Treated Patients - .............................................................................. 88 
Appendix 3.7.5 – Adverse Events: Patients with Adverse Events Leading to Withdrawal from Study Treatment - Treated Patients - ................... 89 
Appendix 3.7.6 – Adverse Events: End of AE Reporting Period and Follow-Up - Treated Patients – ..................................................................... 90 
Appendix 3.7.7 – Adverse Events: All Reported Adverse Events by System Organ Class, AE MedDRA Preferred Term and Investigator’s Term - 
Treated Patients - ........................................................................................................................................................................................................ 91 
Appendix 3.7.8 – Adverse Events: Hospitalization - Treated Patients - .................................................................................................................... 92 
Appendix 3.7.9 – Deaths - Treated Patients - ............................................................................................................................................................. 93 
Appendix 3.7.10 – Deaths: Autopsy Result - Treated Patients – ............................................................................................................................... 94 
Appendix 3 - Section 8 – Laboratory Assessments .................................................................................................................................................... 95 
Appendix 3.8.1 – Laboratory Assessments: Hematology by Laboratory Test, Patient and Study Period - Treated Patients - .................................. 95 
Appendix 3.8.2 – Laboratory Assessments: Blood Chemistry by Laboratory Test, Patient and Study Period - Treated Patients - .......................... 96 
Appendix 3.8.3 – Laboratory Assessments: Coagulation by Patient, Study Period and Laboratory Test - Treated Patients – ................................. 97 
Appendix 3.8.4 – Laboratory Assessments: Urinalysis - Treated Patients – .............................................................................................................. 98 
Appendix 3.8.5 – Laboratory Assessments: Laboratory Normal Ranges of Hematological Tests ............................................................................ 99 
Appendix 3.8.6 – Laboratory Assessments: Laboratory Normal Ranges of Non-Hematological Tests - Treated Patients - .................................. 100 
Appendix 3 - Section 9 – Other Safety Assessments ................................................................................................................................................ 101 
Appendix 3.9.1 – Other Safety Assessments: Vital Signs  - Treated Patients – ....................................................................................................... 101 
Appendix 3.9.2 – Other Safety Assessments: ECG - Treated Patients – ................................................................................................................. 102 
Appendix 3.9.3 – Other Safety Assessments: Visual Acuity and Funduscopic Examination - Treated Patients – ................................................. 103 
Appendix 3.9.4 – Other Safety Assessments: Chest X-Ray - Treated Patients – ..................................................................................................... 104 
Appendix 3.9.5 – Other Safety Assessments: Pregnancy Test - Treated Patients – ................................................................................................. 105 
Appendix 3.9.6 – Other Safety Assessments: Physical Examination - Treated Patients - ....................................................................................... 106 
Appendix 3 – Section 10 – Other Information ......................................................................................................................................................... 107 
Appendix 3.10.1 - Other Information: Concomitant Medications - Treated Patients – ........................................................................................... 107 
Appendix 3.10.2 – Other Information: Concomitant Radiotherapies - Treated Patients – ...................................................................................... 108 
Appendix 3.10.3 – Other Information: Blood Derivatives - Treated Patients - ....................................................................................................... 109 
Appendix 3.10.4 - Other Information: Other Anti-Tumor Therapies at Follow-up - Treated Patients – ................................................................. 110 
Appendix 3.10.5 - Other Information: Physician’s Comments - Treated Patients - ................................................................................................. 111 
ADDITIONAL DISPLAYS .............................................................................................................................................................................................. 112 
Listing 3.3.1 – Patients Evaluability for Efficacy Analysis: Patients not Included in the Efficacy Analysis of Evaluable Patients - Enrolled 
Patients - ................................................................................................................................................................................................................... 113 
Listing 3.4.1 – Demography and Pretreatment: Tumor History - Summary of Prior Antitumor Treatment Procedure - Treated Patients – .......... 114 


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Listing 3.7.1 - Adverse Events: All Reported Adverse Events by AE MedDRA Preferred Term and Assessment Visit - Treated Patients – ....... 115 
Listing 3.7.2 – Adverse Events: AEs with Possible/Probable/Definite Relationship to Study Treatment - Treated Patients - ............................... 116 
Listing 3.7.3 – Adverse Events: AEs Leading to Dose Delay or Change - Treated Patients - ................................................................................. 117 
Listing 3.8.1 - Laboratory Assessments: Hematology by Patient, Study Period and Laboratory Test - Treated Patients – .................................... 118 
Lisring 3.8.2 – Laboratory Assessments: Hematology by Laboratory Test, Patient and Study Periods with More than One Assessment - Treated 
Patients - ................................................................................................................................................................................................................... 119 
Listing 3.8.3 – Laboratory Assessments: Hematology – Maximum CTC Grade by Laboratory Test, Patient and Time Window - Treated Patients –
 .................................................................................................................................................................................................................................. 120 
Listing 3.8.4 - Laboratory Assessments: Blood Chemistry by Patient, Study Period and Laboratory Test - Treated Patients – ............................ 121 
Listing 3.8.5 – Laboratory Assessments: Blood Chemistry by Laboratory Test, Patient and Study Periods with More than One Assessment - 
Treated Patients - ...................................................................................................................................................................................................... 122 
Listing 3.8.6 – Laboratory Assessments: Blood Chemistry - Maximum CTC Grade by Laboratory Test, Patient and Time Window (Part I) - 
Treated Patients - ...................................................................................................................................................................................................... 123 
Listing 3.8.7 – Laboratory Assessments: Blood Chemistry - Maximum CTC Grade by Laboratory Test, Patient and Time Window (Part II) - 
Treated Patients - ...................................................................................................................................................................................................... 124 
REVISION HISTORY ............................................................................................................................................................................................... 125 
 


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GENERAL ISSUES 
 
“Page by Regimen” for outputs, in this study one regimen only: 150 mg/day x 7 days q 2 wks. 
 
The outputs will have names starting with “Appendix 1.9.n.<X>  ” or “Appendix 2.4.n.<X>  ”or “Figure 2.4.n.<X>  ”, where X  will be set to different 
values according to the subset population described: <x > = 1 for evaluable patients,  2 for treated patients.  
 
 


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APPENDIX 1: STUDY INFORMATION 
 
 
 
 


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Appendix 1 – Section 9 – Statistical and Analytical Issues  
Appendix 1.9.1.<x> – Treatment Efficacy - Kaplan Meier Estimates for Progression Free Survival 
– Treated / Evaluable Patients – 
 
Page by Regimen 
 
Progression Free 
Survival 
(days) 
 
Patient No 
Number of Patients 
Failed 
Number of Patients 
Left 
Probability 
Standard Error 
95% CI – LL (**) 
95% CI – UL (**) 
0 
 
xx 
xx 
1 
0.xxx 
0.xx 
0.xx 
   1 * 
008 
xx 
xx 
0.xx 
0.xxx 
0.xx 
0.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Censored Observation 
** Confidence Intervals around Kaplan Meier estimates  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Descriptive statistics are obtained with SAS PROC LIFETEST considering the Kaplan-Meier method.  For Pat-No use ID statement in PROC LIFETEST   
 
 


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Appendix 1.9.2.<x > – Treatment Efficacy - Kaplan Meier Estimates for Overall Survival  
– Treated / Evaluable Patients – 
 
Page by Regimen 
 
Overall Survival 
(months) 
 
Patient No 
Number of Patients 
Failed 
Number of Patients 
Left 
Probability 
Standard Error 
95% CI – LL (**) 
95% CI – UL (**) 
0 
 
xx 
xx 
1 
0.xxx 
0.xx 
0.xx 
   1 * 
 
xx 
xx 
0.xx 
0.xxx 
0.xx 
0.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Censored Observation 
** Confidence Intervals around Kaplan Meier estimates  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Descriptive statistics are obtained with SAS PROC LIFETEST considering the Kaplan-Meier method.  For Pat-No use ID statement in PROC LIFETEST   
 
 
 
 
 
 
 


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APPENDIX 2: SUMMARY TABLES 
 
 
 


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Appendix 2 - Section 1 - Patient Disposition 
Appendix 2.1.1 - Patient Disposition: Patient Screening 
- Screened Patients – 
 
n 
% 
Total Patients Screened 
xxx 
100.0 
Patients Screened  and not Enrolled 
xxx 
xxx.x 
Patients Enrolled 
xxx 
xxx.x 
 
%=(n/Total patients screened)*100 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 
 
 


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Appendix 2.1.2 - Patient Disposition: Patient Disposition by Investigational Site 
- Enrolled Patients – 
 
Page by Regimen  
 
 
 
Enrolled Patients 
 
 
All Enrolled 
(N=xx) 
Treated 
(N=xx) 
Not Treated 
(N=xx) 
 
 
n 
n 
n 
Investigational Site 
All Centers 
xx 
xx 
xx 
<Center_1> 
xx 
xx 
xx 
< Center_j>  
xx 
xx 
xx 
 
Treated / Not Treated: patients who received / did not receive at least one treatment dose  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
N=xx: xx is the total number of patients for each distinct patient group (treated, not treated, all enrolled) 
 


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 Appendix 2.1.3 - Patient Disposition: Study Period Completion and Primary Off Study Reason 
- Enrolled Patients – 
 
Page by Regimen  
 
Enrolled Patients 
All Enrolled 
(N=xx) 
Treated 
(N=xx) 
Not Treated 
(N=xx) 
n 
% 
n 
% 
n 
% 
Off Study Patients 
Total Off Study   
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Death 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Lost to follow-up 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
… 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Reason Not Provided 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
On Study Patients 
Total On Study 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Off Treatment 
xx 
xxx.x 
xx 
xxx.x 
 
 
 
%=(n/N)*100 
On Study Patients: patients whose Off Study Reason form has not been received and no death is reported. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
N=xx: xx is the total number of patients for each analyzed group (treated, not treated, all enrolled) 


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Appendix 2.1.4 - Patient Disposition: Treatment Period Completion and Primary Off Treatment Reason 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients 
(N=xx) 
n 
% 
Off Treatment Patients 
Total Off Treatment 
xxx 
xxx.x 
Adverse Event 
xxx 
xxx.x 
Lack of Compliance 
xxx 
xxx.x 
… 
xxx 
xxx.x 
Reason Not Provided 
xxx 
xxx.x 
On Treatment Patients 
Still on Treatment 
xxx 
xxx.x 
 
 
 
%=(n/N)*100 
On Treatment Patients: patients whose last available information refers to the study treatment period.  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.1.5 – Patient Disposition: Frequency of Patients according to Time on Treatment 
- Treated Patients – 
 
Page by Regimen  
 
Time on Treatment 
Treated Patients 
 (N=xx) 
n 
% 
Less or equal to 2 weeks 
xx 
xx.x 
 2 - < 6 weeks 
xx 
xx.x 
 6 - < 12 weeks 
xx 
xx.x 
 12 - <18 weeks 
xx 
xx.x 
 18 weeks 
xx 
xx.x 
 
 
%=(n/N)*100 
Time on Treatment: from first dose date to last dose date. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2 – Section 2 – Demography and Pretreatment Characteristics 
Appendix 2.2.1 – Demography and Pretreatment: Demography Characteristics 
- Treated Patients - 
 
Page by Regimen  
 
 
Treated Patients 
(N=xx) 
n 
% 
Gender 
Male 
xx 
xx.x 
 
Female 
xx 
xx.x 
 
Total Reported  
xx 
xx.x 
Race 
White  
xx 
xx.x 
 
… 
xx 
xx.x 
 
Total Reported  
xx 
xx.x 
Age (years) 
<40 yrs 
xx 
xx.x 
 
40 – 54 yrs 
xx 
xx.x 
 
55 – 65 yrs 
xx 
xx.x 
 
> 65 yrs 
xx 
xx.x 
 
Total Reported  
xx 
xx.x 
 
 
%=(n/N)*100 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.2.2 – Demography and Pretreatment: Summary Statistics of Age, Weight and Height 
- Treated Patients - 
 
Page by Regimen  
 
 
Treated Patients 
(N=xx) 
Age (years) 
No. of Pts 
xx 
 
Mean 
xx.x 
 
SD  
xx.x 
 
Median 
xx 
 
Min 
xx 
 
Max  
xx 
Weight (Kg) 
No. of Pts 
xx 
 
Mean 
xx.x 
 
SD  
xx.x 
 
Median 
xx 
 
Min 
xx 
 
Max  
xx 
Height (cm) 
No. of Pts 
xx 
 
Mean 
xx.x 
 
SD  
xx.x 
 
Median 
xx 
 
Min 
xx 
 
Max  
xx 
 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.2.3 – Demography and Pretreatment: Tumor History - Primary Diagnosis and Diagnosis at Study Entry 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
 
 
n 
% 
Primary Diagnosis made by:  
Histological 
xx 
xxx.x 
 
Cytological 
xx 
xxx.x 
 
Total Reported  
xx 
xxx.x 
WHO Classification  
B3 – Well Differenciated Thymic Carcinoma 
xx 
xxx.x 
 
C – Thymic Carcinoma  
xx 
xxx.x 
 
Total Reported 
xx 
xxx.x 
Tumor Extent at Study Entry 
Locally Advanced 
xx 
xxx.x 
 
Metastatic 
xx 
xxx.x 
 
Total Reported 
xx 
xxx.x 
Metastatic Disease Sites 
Liver 
xx 
xxx.x 
 
…  
… 
… 
 
Other 
xx 
xxx.x 
 
Total Reported 
xx 
xxx.x 
Total No. of Recurrence(s)/Progression(s) 
1 
xx 
xxx.x 
 
2 
xx 
xxx.x 
 
>2 
xx 
xxx.x 
 
Total Reported 
xx 
xxx.x 
Masaoka Clinical Staging at Study Entry 
I 
xx 
xx 
 
IIA 
xx 
xx 
 
IIB 
xx 
xx 
 
IIIA 
xx 
xx 
 
IIIB 
xx 
xx 
 
IVA 
xx 
xx 
 
IVB 
xx 
xx 
 
Total Reported 
xx 
xxx.x 
 
%=(n/N)*100  
Metastatic Disease Site: pts with more than 1 metastatic site are counted for each reported site. Total reported: no. of pts. independently of the sites involved 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 


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Appendix 2.2.4 – Demography and Pretreatment: Tumor History – Time from Primary Diagnosis and Diagnosis at Study Entry to Treatment Start 
- Treated Patients – 
 
Page by Regimen  
 
 
Treated Patients (N=xx) 
 
No. of 
Pts. 
Min 
Median 
Max 
Primary Diagnosis (Months) 
xx 
xxx.x 
xxx.x 
xxx.x 
Current Diagnosis of locally advanced or metastatic disease (Weeks) 
xx 
xxx.x 
xxx.x 
xxx.x 
 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.2.5 – Demography and Pretreatment: History of Other Cancers 
- Treated Patients - 
 
Page by Regimen  
 
Previous History of Other Cancers 
Treated Patients 
(N=xx) 
n 
% 
Yes 
xx 
xxx.x 
No 
xx 
xxx.x 
Total Reported 
xx 
xxx.x 
 
 
%=(n/N)*100 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 
 


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Appendix 2.2.6 - Demography and Pretreatment: Tumor History - Prior Antitumor Treatments / Procedures: Type and Setting 
- Treated Patients – 
 
Page by Regimen  
 
 
 
Treated Patients 
(N=xx) 
 
 
n 
% 
Prior Antitumor Treatments / Procedures No prior treatments / procedures 
xx 
xxx.x 
At least one prior treatment / procedure 
xx 
xxx.x 
Total Reported 
xx 
xxx.x 
Type 
Surgery only 
xx 
xxx.x 
 
Systemic only 
xx 
xxx.x 
 
Radiotherapy  only 
xx 
xxx.x 
 
Surgery + Systemic 
xx 
xxx.x 
 
………… 
xx 
xxx.x 
Setting  
Neo-Adjuvant 
xx 
xxx.x 
 
Adjuvant 
xx 
xxx.x 
 
Primary Tumor 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
 
%=(n/N)*100  
 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Type: Count each pt for each tr. / procedure type (e.g. surgery,…) reported, regardless of how many times the same type of tr. is reported for him.  Ex.: A pt with systemic reported 
3 times and surgery reported 2 times, will be counted once for “systemic + surgery” in the table. 
Setting: Count each pt for each reported setting (e.g. neo-adjuvant,…) regardless of how many times the same setting is reported for him. Ex.: A pt with primary tumor reported 
once and metastatic reported 3 times, will be counted once for primary tumor and once for metastatic.  


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Appendix 2.2.7 – Treatment Efficacy: Oncologic Assessment at Study Entry 
- Treated Patients – 
 
Page by Regimen 
 
Tumor Lesions  
Treated Patients 
(N= xx) 
n 
% 
Total Reported 
xx 
xxx.x 
Patients with Both Target and Non-Target Lesions  
xx 
xxx.x 
Target Lesions only 
xx 
xxx.x 
Non-Target Lesions only 
xx 
xxx.x 
 
%=(n/N)*100 
Tumor Lesions include Lymph Nodes 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 


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Appendix 2.2.8 – Demography and Pretreatment: Signs and Symptoms 
- Treated Patients - 
 
Page by Regimen  
 
Treated Patients  (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event 1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event i 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC i] 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
... 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
%=(n/N)*100 
N = no. of treated patients 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each by group, SOC and AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event and sort SOCs by descending 
frequency of “Any Term” at “Any Grade”.  
 


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Appendix 2 – Section 3 – Treatment Exposure 
Appendix 2.3.1 – Treatment Exposure: Summary Statistics of the Number of Cycles / Weeks of Treatment 
- Treated Patients - 
 
Page by Regimen  
 
 
No. of 
Patients 
Sum.of 
Cycles/Weeks 
of Treatment 
Min 
Median 
Max 
Treatment Duration 
Cycles 
xx 
xx.x 
xx.x 
xx 
xx.x 
Weeks 
xx 
xx.x 
xx.x 
xx 
xx.x 
 
Treatment Duration: from the first dose date to end of treatment. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.3.2 - Treatment Exposure: Frequency Distribution of Cycles according to the Percentage of Scheduled Dose Administered 
- Treated Patients - 
 
Page by Regimen  
 
 
 
Dose Administered (as Percentage of the Scheduled Dose) 
No. of 
Patients 
Total No. 
of Cycles 
Full Dose  
80% - < Full Dose 
50% - < 80% 
<50% 
No. of 
Cycles 
% 
No. of 
Cycles 
% 
No. of 
Cycles 
% 
No. of 
Cycles 
% 
xx 
xxx 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
 
Scheduled Dose: assigned dose level (mg/day)*7, where 7 is the per protocol no. of drug administrations per cycle. 
Full Dose: greater or equal 95% of Scheduled Dose  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.3.3 – Treatment Exposure: Summary Statistics of Dose Intensity, Relative Dose Intensity and Cumulative Dose 
- Whole Treatment Period - 
- Treated Patients - 
 
Page by Regimen  
 
No. 
of Pts 
Dose Intensity  
(mg/wk) 
Relative Dose Intensity 
(%) 
Cumulative Dose 
(mg)  
 
Min 
Median 
Max 
Min 
Median 
Max 
Min 
Median 
Max 
 
 
 
xx 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
 
 
 
xx 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
 
 
 
xx 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
 
 
 
xx 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
 
 
 
 
 
Relative Dose Intensity: the ratio between dose intensity and intended dose intensity  x 100. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
The whole stydy period is to be considered for the analysis. 
 


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Appendix 2.3.4 - Treatment Exposure: Frequency Distribution of Cycles according to their Duration 
- Treated Patients – 
 
Page by Regimen  
 
No. of 
Total No. 
Cycle Duration 
< 13 Days 
13-15 Days 
16-28 Days 
> 28 Days 
Patients 
of Cycles 
No. of Cycles 
No. of Cycles 
No. of Cycles 
No. of Cycles 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 
 


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Appendix 2.3.5 – Treatment Exposure: Frequency Distributions of Patients and Cycles with Treatment Modifications 
- Treated Patients - 
 
Page by Regimen   
 
Treated  Patients (N=xx) 
No. of Patients 
No. of Cycles 
Treatment Modifications 
n 
% 
n 
Any Modification 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
Intra Cycle Modification 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
Treatment Delay 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
Dose Reduction   
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
 
xx 
xxx.x 
xx 
 
%=(n/N)*100 
Dose Reduction : at cycle start  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract]. 
 
 
Programming Notes: 
 
Patients are to be counted just once per tr. modification category. Cycles at which multiple occurrences of the same tr. modification category were reported are to be counted just 
once per tr. modification category.  


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Appendix 2.3.6 –Treatment Exposure: Frequency Distributions of Patients by Reasons for Treatment Modifications 
- Treated Patients – 
 
Page by Regimen   
 
Treated  Patients (N=xx) 
No. of Patients 
Reasons for Treatment Modification 
n 
% 
Any Reason 
xx 
xxx.x 
 
xx 
xxx.x 
 
xx 
xxx.x 
Hematological toxicity 
xx 
xxx.x 
 
xx 
xxx.x 
 
xx 
xxx.x 
Non-hematological toxicity 
xx 
xxx.x 
 
xx 
xxx.x 
 
xx 
xxx.x 
Other 
xx 
xxx.x 
 
xx 
xxx.x 
 
xx 
xxx.x 
Unknown Reason 
xx 
xxx.x 
 
xx 
xxx.x 
 
xx 
xxx.x 
 
%=(n/N)*100  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
n: count patients for each toxicity class (i.e. hematological/non-hematological/other),  regardless of what kind of treatment modification is performed; if multiple occurrences of the 
same toxicity class are reported within a cycle or throughout different cycles patients are to be counted just once per class. 
 


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Appendix 2 – Section 4 – Treatment Efficacy 
Appendix 2.4.1.<x> – Treatment Efficacy: Progression Free Survival Rate at 3 Months 
- Evaluable /Treated Patients – 
 
Page by Regimen 
 
Progression Free Survival at 3 Months  
Evaluable Patients/ Treated  
(N=xx) 
n 
% 
95 % CI - LL 
95 % CI - UL 
Success 
xx 
xxx.x 
xx.xx  
xx.xx 
Failure 
xx 
xxx.x 
 
 
Total 
xx 
xxx.x 
 
 
 
 
%=(n/N)*100. N=no. of treated/evaluable patients 
Success: Patients who were progression free for longer than 91 days (i.e. 3 months) and with an overall response at the 3rd month assessment equal to SD or better. Valid 
assessments were to be within day 134; the outcome of assessments performed outside this time window was considered as failure regardless of the outcome recorded.  
Failure: All patients who were not success. 
95% CI: Exact Binomial Confidence Limits  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 


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Figure 2.4.1.<x> – Treatment Efficacy: Kaplan-Meier Curve for Progression Free Survival 
- Evaluable /Treated Patients – 
 
 
Page by Regimen 
 
 
 
 
 
 
 
 
 
 
 
Progression Free Survival (months): from the treatment start date to the date of death from any cause 
Median Progression Free Survival (95% CI):  xx.xx (xx.xx - xx.xx) 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Create three versions of the graph: the graph automatically created by the SAS proc lifetest - Kaplan-Meier method ( .gif format) as control, and two other graphs obtained by 
plotting the relevant variables with SAS proc gplot (same procedure, two different output file formats: .gif and .pdf )  
 “General Footnotes” not to be printed for  .gif graphs. 


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Appendix 2.4.2.<x> – Treatment Efficacy: Best Confirmed Tumor Response 
- Evaluable/Treated Patients - 
 
Page by Regimen 
 
Best Confirmed Tumor Response 
Treated / Evaluable Patients  
(N=xx) 
n 
% 
95 % CI - LL 
95 % CI - UL 
Objective Response (CR + PR) 
xx 
xxx.x 
xxx.xx  
xxx.xx 
Disease Control (CR+PR+ SD) 
xx 
xxx.x 
xxx.xx  
xxx.xx 
Complete Response (CR) 
xx 
xxx.x 
 
 
Partial Response (PR) 
xx 
xxx.x 
 
 
Stable disease (SD) 
xx 
xxx.x 
 
 
Progression of Disease (PD) 
xx 
xxx.x 
 
 
Not Evaluable  
xx 
xxx.x 
 
 
 
%=(n/N)*100. N=no. of treated (evaluable) patients. 
95% CI: Exact Binomial Confidence Limits  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
95% CI: 95% Exact Confidence Limits for tumor response rate.  
Valid Response values CR, PR, SD,PD, NE  


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Appendix 2.4.3.<x> – Treatment Efficacy: Best Unconfirmed Tumor Response 
- Evaluable/Treated Patients - 
 
Page by Regimen 
 
Best Unconfirmed Tumor Response 
Treated / Evaluable 
Patients  
(N=xx) 
n 
% 
Overall Response (CR + PR) 
xx 
xxx.x 
Complete Response (CR) 
xx 
xxx.x 
Partial Response (PR) 
xx 
xxx.x 
Stable Disease (SD) 
xx 
xxx.x 
Progression of  Disease (PD) 
xx 
xxx.x 
Not Evaluable (NE) 
xx 
xxx.x 
 
 
 
Unconfirmed Tumor Response: for each patient it’s the best response reported throughout the study period as overall response, regardless of the confirmation. 
 
%=(n/N)*100. N=no. of treated patients. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Valid Response values CR, PR, SD,PD, NE  
 


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 Appendix 2.4.4.<x> – Treatment Efficacy: Statistical Analysis of  Time-To-Event Endpoints 
- Treated / Evaluable - 
 
Page by Regimen 
 
Treated / Evaluable Patients  (N=xx) 
No. of  
Pts. 
No. of 
Events 
Min 
Max 
Median 
Median 95% CI - 
LL 
Median 95% CI - UL 
Progression Free Survival (months) 
xx 
xx 
xxx.xx   xxx.xx  + 
xxx.xx 
xxx.xx 
xxx.xx 
Overall Survival (months) 
xx 
xx 
xxx.xx   
xxx.xx   
xxx.xx 
xxx.xx 
xxx.xx 
Duration of response (months) 
xx 
xx 
xxx.xx   xxx.xx  + 
xxx.xx 
xxx.xx 
xxx.xx 
 
 
N=:  no. of treated (evaluable) patients. 
No. of Events: the no. of failure patients.for the given endpoint. 
Median: estimated by the Kaplan-Meier method. 
+: Censored observation 
Overall survival: from the treatment start date to the date of death from any cause 
Progression free survival: from the treatment start date to the date of objective progression or death from any cause 
Duration  of response : from the date when response was first assessed to the date of progression or date of censoring,whichever comes first 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Summary statistics are to be calculated by SAS PROC LIFETEST using the Kaplan-Meier method. 


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Figure 2.4.2..<x> – Treatment Efficacy: Kaplan-Meier Curve for Overall Survival 
- Treated / Evaluable Patients– 
 
 
Page by Regimen 
 
 
 
 
 
 
 
 
 
 
 
Median Progression Free Survival (95% CI):  xx.xx (xx.xx - xx.xx) 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Create three versions of the graph: the graph automatically created by the SAS proc lifetest - Kaplan-Meier method ( .gif format) as control, and two other graphs obtained by 
plotting the relevant variables with SAS proc gplot (same procedure, two different output file formats: .gif and .pdf )  
 “General Footnotes” not to be printed for  .gif graphs. 
 
 


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Appendix 2.4.5 – Treatment Efficacy: ECOG Performance Status: On Treatment Worst Assessment vs. Pretreatment 
- Treated Patients with at Least One Assessment On Treatment - 
 
Page by Regimen 
 
Treated  Patients (N=xx) 
On-Treatment Worst Assessment 
 
0  
1 
… 
Total 
Pretreatment Assessment 
n 
% 
n 
% 
n 
% 
n 
% 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
2   
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
>2   
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
%=(n/N)*100.  
N = treated patients with at least one Performance Status assessment after treatment start date. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 


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 Appendix 2 – Section 5 – Adverse Events 
Appendix 2.5.1 – Adverse Events: Patients with on Treatment AEs by System Organ Class and Maximum CTC Grade 
- Treated Patients – 
 
Page by Regimen  
 
Treated  Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC n] 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
%=(n/N)*100 
N = no. of treated patients 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, sort SOCs by descending frequency of  “Any Grade”  
For each SOC (System Organ Class), count patients according to the maximum CTC grade reported for that SOC.  


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Appendix 2.5.2 – Adverse Events: Patients with on Treatment AEs by AE MedDRA Preferred Term and Maximum CTC Grade 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x xx 
xxx.x 
[Term 1] 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x xx 
xxx.x 
[Term i] 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x xx 
xxx.x 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, sort AEs by descending frequency of “Any Grade”.  
For each AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event.  
 


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Appendix 2.5.3 – Adverse Events: Patients with on Treatment AEs by SOC, AE MedDRA Preferred Term and Maximum CTC Grade 
- Treated Patients - 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event 1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event i 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC i] 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
... 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each by group, SOC and AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event and sort SOCs by descending 
frequency of “Any Term” at “Any Grade”.  
 


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Appendix 2.5.4 – Adverse Events: Patients with AEs with Possible to Definite Relationship to Study Treatment by SOC 
and Maximum CTC Grade  
- Treated Patients – 
 
Page by Regimen  
 
Treated  Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x xx 
xxx.x xx 
xxx.x 
[SOC 1] 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x xx 
xxx.x xx 
xxx.x 
[SOC n] 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x xx 
xxx.x xx 
xxx.x 
 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, sort SOCs by descending frequency of  “Any Grade”.  
For each  SOC (System Organ Class), count patients according to the maximum CTC grade reported for that SOC. 
 


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Appendix 2.5.5 – Adverse Events: Patients with AEs with Possible to Definite Relationship to Study Treatment by AE MedDRA Preferred Term 
and Maximum CTC Grade  
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[Term 1] 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[Term i] 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, sort AEs by descending frequency of  “Any Grade”  
For each AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event.  
 


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Appendix 2.5.6 – Adverse Events: Patients with AEs with Possible to Definite Relationship to Study Treatment by SOC, AE MedDRA Preferred Term 
and Maximum CTC Grade 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event 1 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event i 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC i] 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
... 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, SOC and AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event and  sort SOCs by descending 
frequency of “Any Term” at “Any Grade”.  
 


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Appendix 2.5.7 – Adverse Events: Patients with on Treatment Serious AEs by SOC, AE MedDRA Preferred Term and Maximum CTC Grade 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event 1 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event i 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC i] 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
... 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, SOC and AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event and sort SOCs by descending 
frequency of “Any Term” at “Any Grade”.  
 


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Appendix 2.5.8 – Adverse Events: Patients with Serious AEs with Possible to Definite Relationship to Study Treatment by SOC, 
AE MedDRA Preferred Term and Maximum CTC Grade 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event 1 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event i 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC i] 
Any Term 
xx 
xxx.x xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
... 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Within each “by group”, SOC and AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event and  sort SOCs by descending 
frequency of “Any Term” at “Any Grade”. 
 
 


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Appendix 2.5.9 – Adverse Events: Patients with on Treatment AEs Leading to Withdrawal from Study Treatment by SOC, 
AE MedDRA Preferred Term and Maximum CTC Grade 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Maximum CTC Grade 
Any Grade 
3-4 
1 
… 
Unk 
System Organ Class 
Preferred Term 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any System 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC 1] 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event 1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Event i 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
… 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
[SOC i] 
Any Term 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
... 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
Only AEs whose Action Taken was “Drug Permanently Withdrawn” are displayed. 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Select AE with action taken=drug permanently withdrawn. 
Within each by group, SOC and AE (i.e. for each Preferred Term), count patients according to the maximum CTC grade reported for that event and sort SOCs by descending 
frequency of “Any Term” at “Any Grade” 


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Appendix 2.5.10 – Deaths: Frequency of Death according to Most Probable Cause and Time of Occurence 
- Treated Patients – 
 
Page by Regimen  
 
Treated Patients (N=xx) 
Total 
=<28 Days since 
Treatment Last 
Dose 
>28 Days since 
Treatment Last 
Dose 
Most Probable Cause 
n 
% 
n 
% 
n 
% 
Any cause 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
        Progressive Disease 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
        Adverse Event 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
         ……. 
… 
… 
… 
… 
… 
… 
       Unknown 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
%=(n/N)*100 
N = no. of treated patients  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
See ADP for classification of causes of death vs source of info. 
 


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Appendix 2 - Section 6 – Laboratory Assessments 
Appendix 2.6.1 – Hematology: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment 
- Treated Patients with at Least One Assessment On Treatment - 
- All Cycles, Cycle 1, Cycles > 1- 
 
Page by Regimen  /  Laboratory Test: < WBC >  
 
 
 
Maximum CTC Grade on Treatment 
 
0 
… 
4 
Total 
Study Period  
Pretreatment CTC Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
 (N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle    1 
 (N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle >1 
 (N=xx) 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
N = treated patients with at least one assessment after treatment start date. 
%=(n/N)*100.  
Only lab. tests included in the NCI CTCAE v3.0 document. Maximum CTC Grade: the Maximum CTC grade reported for each treated patient and each lab test during the treatment 
period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0. 
 


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Appendix 2.6.2 – Hematology: Frequency Distribution of Treatment Cycles based on Maximum CTC Grade On Treatment versus Pretreatment 
- Cycles with at Least One Assessment - 
- All Cycles, Cycle 1, Cycles > 1 - 
 
Page by Regimen  /  Laboratory Test: < WBC >  
 
 
 
Maximum CTC Grade on Treatment 
 
0 
… 
4 
Total 
Study Period  
Pretreatment CTC 
Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle    1 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle >1 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
N = cycles with at least one assessment  
%=(n/N)*100.  
Only lab. tests included in the NCI CTCAE v3.0 document. Maximum CTC Grade: the Maximum CTC grade reported for each cycle and each lab test during the treatment period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0. 
 


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Appendix 2.6.3 – Blood Chemistry: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment (Part I) 
- Treated Patients with at Least One Assessment On Treatment - 
- All Cycles, Cycle 1, Cycles > 1- 
 
Page by Regimen  /  Laboratory Test: < AST >  
 
 
 
Maximum CTC Grade on Treatment 
 
0 
… 
4 
Total 
Study Period  
Pretreatment CTC 
Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
(N=xx) Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle    1 
(N=xx) Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle >1 
(N=xx)
 
 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
N = treated patients with at least one assessment after treatment start date. 
%=(n/N)*100.  
(Part I): Only lab. tests included in the NCI CTCAE v3.0 document and whose abnormality is determined by one-way modifications only. 
Maximum CTC Grade: the Maximum CTC grade reported for each treated patient and each lab test during the treatment period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0. 
 


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Appendix 2.6.4 – Blood Chemistry: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment (Part II) 
- Treated Patients with at Least One Assessment On Treatment - 
- All Cycles – 
Page by Regimen  /  Laboratory Test: < Sodium >  
 
 
<Hyper/ Hypo>  - Maximum CTC Grade on Treatment 
 
 
1  
…. 
5 
Total 
Study Period 
Pretreatment CTC Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
(N=xx) 
Total 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
4 (H) 
 
 
 
 
 
 
 
 
 
3 (H) 
  
  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
2 (H) 
… 
… 
… 
… 
… 
… 
… 
… 
 
1 (H) 
… 
… 
… 
… 
… 
… 
… 
… 
 
 0 
… 
… 
… 
… 
… 
… 
… 
... 
 
1 (L) 
 
 
 
 
 
 
 
 
 
2 (L) 
… 
… 
… 
… 
… 
… 
… 
… 
 
3 (L) 
… 
… 
… 
… 
… 
… 
… 
… 
 
4 (L) 
… 
… 
… 
… 
… 
… 
… 
… 
 
Not Assessed 
… 
… 
… 
… 
… 
… 
… 
… 
 
N = treated patients with at least one assessment after treatment start date. 
%=(n/N)*100.  
(Part II): Only lab. tests included in the NCI CTCAE v3.0 document and whose abnormality is determined by two-way modifications.  
Maximum CTC Grade: the Maximum treatment emergent CTC grade reported for each treated patient during the treatment period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0 for which both ‘hyper’ and ‘hypo’ grading is provided. For this study: Magnesium, Potassium, Sodium. 


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Appendix 2.6.5 – Blood Chemistry: Frequency Distribution of Treatment Cycles based on Maximum CTC Grade On Treatment versus Pretreatment (Part I) 
- Cycles with at Least One Assessment - 
- All Cycles, Cycle 1, Cycles > 1 - 
 
Page by Regimen  /  Laboratory Test: < AST >  
 
 
 
Maximum CTC Grade on Treatment 
 
0 
… 
4 
Total 
Study Period  
Pretreatment CTC 
Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
(N=xx) Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle    1 
(N=xx) Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle >1 
(N=xx) Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
N = cycles with at least one assessment. 
%=(n/N)*100. 
(Part I): Only lab. tests included in the NCI CTCAE v3.0 document and whose abnormality is determined by one-way modifications only. 
Maximum CTC Grade: the Maximum CTC grade reported for each cycle and each lab test during the treatment period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0. 


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Appendix 2.6.6 – Blood Chemistry: Frequency Distribution of Treatment Cycles based on Maximum CTC Grade On Treatment versus Pretreatment (Part II) 
- Cycles with at Least One Assessment - 
- All Cycles- 
 
Page by Regimen  /  Laboratory Test: < Sodium >  
 
 
<Hyper/ Hypo>  - Maximum CTC Grade on Treatment 
 
 
1  
…. 
5 
Total 
Study Period 
Pretreatment CTC Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
(N=xx) 
Total 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
4 (H) 
 
 
 
 
 
 
 
 
 
3 (H) 
  
  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
2 (H) 
… 
… 
… 
… 
… 
… 
… 
… 
 
1 (H) 
… 
… 
… 
… 
… 
… 
… 
… 
 
 0 
… 
… 
… 
… 
… 
… 
… 
... 
 
1 (L) 
 
 
 
 
 
 
 
 
 
2 (L) 
… 
… 
… 
… 
… 
… 
… 
… 
 
3 (L) 
… 
… 
… 
… 
… 
… 
… 
… 
 
4 (L) 
… 
… 
… 
… 
… 
… 
… 
… 
 
Not Assessed 
… 
… 
… 
… 
… 
… 
… 
… 
N = cycles with at least one assessment. 
%=(n/N)*100.  
(Part II): Only lab. tests included in the NCI CTCAE v3.0 document and whose abnormality is determined by two-way modifications. 
Maximum CTC Grade: the Maximum treatment emergent CTC grade reported for each cycle and each lab test during the treatment period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0 for which both ‘hyper’ and ‘hypo’ grading is provided. For this study: Magnesium, Potassium, Sodium 


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 Appendix 2.6.7 – Coagulation: Frequency Distribution of Patients based on Maximum CTC Grade On Treatment versus Pretreatment 
- Treated Patients with at Least One Assessment On Treatment - 
- All Cycles, Cycle 1, Cycles > 1 – 
 
Page by Regimen  /  Laboratory Test: < INR >  
 
Study Period 
 
Maximum CTC Grade on Treatment 
 
0 
… 
4 
Total 
 
Pretreatment CTC 
Grade 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle    1 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle >1 
(N=xx) 
0 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
1 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
N = treated patients with at least one assessment after treatment start date 
%=(n/N)*100.  
Only lab. tests included in the NCI CTCAE v3.0 document. Maximum CTC Grade: the Maximum CTC grade reported for each treated patient and each lab test during the treatment 
period. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
 
Sort by “page by variables”. 
Select collected lab tests listed in NCI CTCAE v3.0. 
 


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Appendix 2.6.8 – Laboratory Tests without a NCI-CTC Grade: Frequency Distribution of Patients Based on On Treatment Worst Assessment versus Pretreatment 
- Treated Patients with at Least One Assessment On Treatment - 
- All Cycles, Cycle 1, Cycles > 1 – 
 
- <Panel>: e.g. Hematology    Laboratory Test: < Eosinophils >  
 
Study Period  
 
On Treatment Worst Assessment 
 
Above UNL 
Within NLs 
Below LNL  
Total 
Pretreatment Value 
n 
% 
n 
% 
n 
% 
n 
% 
All Cycles (N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Above ULN 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Within NLs 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Below LLN 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
Not Assessed 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Cycle 1 (N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Above ULN 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
Within NLs 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
Below LLN 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
Not Assessed 
… 
… 
… 
… 
… 
… 
 
 
Cycle >1 (N=xx) 
….. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
……. 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
 
 
N = treated patients with at least one assessment after treatment start date 
%=(n/N)*100.  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by “page by variables”. 
< Panel >: 
Hematology 
 
- 
< Lab Test >: Erythrocytes (RBC), Eosinophils, Basophils, Monocyctes. 
 
 
Blood Chemistry 
 
- 
< Lab Test >: Blood Urea Nitrogen (BUN), Urea (Carbamide) Blood, Phosporus, IgG, IgM, IgA,GGT, LDH, Creatinine, Total proteins. 
 
 
 


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Appendix 2.7 – Other Safety Assessments 
Appendix 2.7.1 – Other Safety Assessments: Blood Pressure - On Treatment Worst Assessment versus Pretreatment 
- Treated Patients with at Least One Assessment On Treatment - 
 
Page by Regimen 
 
Treated Patients (N=xx) 
On-Treatment Worst Assessment 
Normal 
Abnormal 
Total 
Pretreatment Assessment 
n 
% 
n 
% 
n 
% 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Normal  
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Abnormal 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
Normal: systolic blood pressure < 140 and diastolic blood pressure < 90 
Abnormal: systolic blood pressure  140 or diastolic blood pressure 90. 
%=(n/N) * 100. N = treated patients with at least one blood pressure measurement after treatment start date. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 
 


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Appendix 2.7.2 – Other Safety Assessments: ECG - On Treatment Assessment versus Pretreatment Condition 
- Treated Patients with at Least One Assessments On Treatment - 
 
Page by Regimen 
 
Treated Patients (N=xx) 
On-Treatment ECG Abnormality  
No 
At least One 
Total 
Pretreatment ECG Abnormality 
n 
% 
n 
% 
n 
% 
Total 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
No 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
Yes  
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
Unknown 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
 
%=(n/N)*100.  
N = treated patients with at least one EGC assesment after treatment start date. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
 


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Appendix 2.7.3 – Other Safety Assessments: ECG - On Treatment Abnormality Findings 
- Treated Patients with at Least One Assessment On Treatment – 
 
Page by Regimen 
 
Abnormality Category 
Treated Patients (N=xx) 
n 
% 
Rhythm 
xx 
xxx.x 
P-Wave Morphology 
xx 
xxx.x 
Conduction 
xx 
xxx.x 
QRS  
xx 
xxx.x 
ST-T Wave 
xx 
xxx.x 
---- 
xx 
xxx.x 
 
%=(n/N)*100.  
N = treated patients with at least one EGC assessment after treatment start date. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Abnormality categories: count patients within each category. If multiple occurrences of the same abnormality (e.g. conduction) are reported, the patient should be counted only 
once. 


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Appendix 2.7.4 – Other Safety Assessments: Funduscopic Examination - On Treatment Worst Assessment versus Pretreatment 
- Treated Patients with at Least One Assessment On Treatment - 
 
Page by Regimen 
 
Fundus 
Pretreatment Assessment 
On-Treatment Worst Assessment  
Normal 
Abnormal, not clinically relevant 
Abnormal, clinically relevant 
Total 
n 
% 
n 
% 
n 
% 
n 
% 
Right Eye 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Normal  
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Abnormal, not clinically relevant 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Abnormal, clinically relevant 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Leftt Eye 
(N=xx) 
Total 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Normal  
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Abnormal, not clinically relevant  
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Abnormal, clinically relevant 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
Unknown 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
xx 
xxx.x 
 
%=(n/N)*100.  
N = treated patients with at least one assessment after treatment start date. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 


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APPENDIX 3: INDIVIDUAL DATA LISTINGS 
 
 
 
 


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Appendix 3 - Section 1 - Patient Disposition  
Appendix 3.1.1 – Patient Disposition: Patient Registration 
– Registered Patients – 
 
Enrolled 
Pt 
Treated 
Pt 
Pt. 
No. 
Pt. 
Screening 
No. 
Center No. 
Age 
/Sex 
/Race 
Date of Birth 
Date of Informed 
Consent 
Date of 
Enrollment 
 
N 
N 
Sxxx 
 
xxxxx 
35/M/W ddmmmyyyy 
ddmmmyyyy 
 
N 
N 
Sxxx 
 
xxxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
 
Y 
N 
xxxx 
Sxxx 
xxxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
Y 
Y 
xxxx 
Sxxx 
xxxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
Y 
Y 
xxxx 
Sxxx 
xxxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
Y 
Y 
xxxx 
Sxxx 
xxxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by enrolled patients (N, Y), treated patients (N, Y),  patient no. 
Pt. Screening No.: for enrolled patients it is reported on the patient enrollment page of CRF. 
Date of informed consent: it is reported on the demography page of CRF.  


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Appendix 3.1.2 – Patient Disposition: Registered but Not Enrolled Patients 
- Screening Failures - 
 
 
Pt. No. 
Center 
No. 
Date of Informed 
Consent 
Reason for Screening Failure 
Other Reason, specify 
Comments 
Sxxx 
xxxxx 
ddmmmyy 
Inclusion/Exclusion Criteria not fulfilled  
 
 
Sxxx 
xxxxx 
ddmmmyy 
Other: … 
 
 
Sxxxx 
xxxxx 
ddmmmyy 
 
 
 
Sxxxx 
xxxxx 
ddmmmyy 
 
 
 
Sxxxx 
xxxxx 
ddmmmyy 
 
 
 
 
 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by patient no. 
Reason for Screening Failure: it is reported on the screening failure page of CRF 


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Appendix 3.1.3 – Patient Disposition: Summary of Patient Information 
- Enrolled Patients- 
Page by Regimen  
 
 
 
 
Time on Treatment: time from the first dose date to last dose date 
Time on Study: time from the informed consent  date to the last recorded date  
(§) Last Recorded Date is different from Investigator’s Decision date or Consent Withdrawn date in the Off Study form 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by patient no. 
 
Cumulative dose: from start to end of treatment. 
Usually Time Unit of Time on Study is the same as for Duration of Treatment, but it is not mandatory, i.e. could be weeks and months respectively.  
 
Pt. No 
First Dose 
Date 
Last Dose 
Date 
Cum. Dose 
(mg 
 
Total 
No. of 
Cycles 
Tr. 
Status 
Time on 
Treat. 
(weeks) 
Primary  
Off Tr. 
Reason 
End of AE 
Reporting  
Period 
  FU 
Status 
Study 
Status 
Last 
Recorded 
Date 
 
Time on 
Study 
( weeks ) 
Primary Off Study 
Reason 
xxxx 
ddmmmyy 
ddmmmyy 
xxx.x 
1 
Off. 
xxx.x 
AE 
ddmmmy 
On  FU 
On 
ddmmmyy 
 
xx 
xxxxxxxxx 
xxxx 
ddmmmyy 
ddmmmyy 
xxx.x 
4 
 
xxx.x 
Pt’s refusal 
 
No FU 
Off 
ddmmmyy 
§ 
xx 
xxxxxxxx 
xxxx 
ddmmmyy 
ddmmmyy 
xxx.x 
2 
Off 
xxx.x 
Progression 
ddmmmy 
- 
Off 
ddmmmyy 
 
xx 
xxx xxxxx 


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Appendix 3.1.4 – Patient’s Survival Status during Follow Up 
- Treated Patients- 
 
Page by Regimen  
 
Pt. No 
Visit 
Status 
Alive as of:  
Date 
Last Known 
Alive Date 
Date of  
Death 
Most  
Probable 
Cause 
Details 
xxxx 
FU-1 
Alive 
ddmmmyyyy 
 
 
 
 
 
… 
…. 
 
 
 
 
 
 
FU-2 
Expired 
… 
… 
ddmmmyyyy 
Progressive 
Disease  
xxxxxxxxxxxxx 
xxxx 
FU-1 
Lost to FU 
… 
ddmmmyyyy 
… 
 
 
 
 
… 
… 
… 
… 
 
 
 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by patient no., visit 
By regimen: in this study one regimen only: 150 mg/day x 7 days q 2 wks 


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Appendix 3 - Section 2 - Protocol Deviations  
Appendix 3.2.1 - Protocol Deviations: Violations of Inclusion / Exclusion Criteria 
- Enrolled Patients – 
 
Page by Regimen  
 
Treated 
Pt. 
Pt. 
No. 
Center 
No. 
Criterion 
Number 
Criterion 
Y/N 
 
N 
xxxx 
xxxx 
IC01 
……….. 
Y 
 
 
 
 
IC02 
……….. 
N 
* 
 
 
 
… 
…….. 
.. 
 
 
 
 
EC01 
……….. 
Y 
* 
 
 
 
EC02 
… 
N 
 
 
 
 
…. 
….. 
… 
 
Y 
xxxx 
xxxx 
IC01 
…. 
N 
* 
 
Only  patients with at least one protocol deviation. The * identified the protocol deviation. 
IC: Inclusion Criterion;  EC: Exclusion Criterion 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by treated patients (N, Y), patient no, Criterion no. (incl., excl.). 
Only  patients with at least one protocol deviation or missing evaluation and/or waiver granted are to be displayed 


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 Appendix 3 – Section 3 – Patients Evaluability for Efficacy Analysis 
 
                      Appendix  3.3.1- Patients Evaluability for Efficacy Analysis: Listing of Evaluability Criteria and Individual Evaluability Status                                                        
-Treated Patients- 
 
 
 
 
Dose Cy1+Cy2 
 
Tumor Assessment 
 
 
 
Pt. 
No 
Hystological 
Confirmation  
>/= 80%  
Cum. Intended Dose 
 
At Pretreat. On  Treat.  
Death 
Before 1st 
Tumor 
Assessment 
Eval.Pt.   
Reasons for 
Non-
Evaluability 
xxxx 
Y 
 
Y 
 
Y 
Y 
 
N 
Y 
 
 
xxxx 
Y 
 
Y 
 
Y 
Y 
 
N 
Y 
 
 
xxxx 
N 
 
Y 
 
Y 
Y 
 
 
N 
 
R1 
xxxx 
Y 
 
Y 
 
N 
Y 
 
N 
N 
 
R3 
xxxx 
Y 
 
Y 
 
Y 
N 
 
N 
N 
 
R4 
xxxx 
Y 
 
N 
 
Y 
Y 
 
N 
N 
 
R2 
xxxx 
Y 
 
Y 
 
Y 
N 
 
Y 
Y 
 
 
xxxx 
Y 
 
Y 
 
Y 
Y 
 
N 
N 
 
R3 
 
Reasons for Non-Evaluability:  
R1:  the patient did not receive diagnosis confirmation by an Independent Review Committee 
R2:  the patient didn’t receive at least 80% of the intended dose for the first two treatment cycles 
R3:  the pretreatment oncologic assessment was not performed 
R4:  no on treatment oncologic assessment was performed and the patient didn’t die before the first scheduled (re)assessment  
 
[Protocol No. (Study Description)] 
[program path; date/time produced; date data extract] 
 
Programming notes: 
Sort by patient no.  
 


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Appendix 3 – Section 4 – Demography and Pretreatment  
Appendix 3.4.1 - Demography and Pretreatment: Tumor History - Primary Diagnosis 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No 
Age 
/Sex 
/Race 
Primary Diagnosis 
Type of 
Diagnosis 
Date of 
Diagnosis 
Months to 
Tr. Start 
 
WHO 
Classification 
Masaoka 
Stage 
xxxx 
38/M/W 
xxxxxxxxxxxxxxxxxx 
Cytological 
ddmmmyyyy 
xxx.x 
 
B3 
II 
xxxx 
xx/x/x 
xxxxxxxxxxxxxxxxxx 
Histological 
mmmyyyy 
xxx.x 
* 
C 
IIB 
xxxx 
… 
……………………… 
… 
… 
… 
 
… 
… 
xxxx 
… 
……………………… 
… 
… 
… 
 
… 
… 
xxxx 
… 
……………………… 
… 
… 
… 
 
… 
… 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
B3=  Well-differentiated thymic carcinoma, C= Tymic Carcinoma 
Months to Tr. Start: From date of primary diagnosis to treatment start date. 
*: Estimated time when incomplete date was reported. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt no. 
 


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Appendix 3.4.2 - Demography and Pretreatment: Tumor History – Diagnosis at Study Entry 
- Treated Patients – 
 
Page by Regimen    
 
Pt. 
No 
Age/Sex 
/Race 
Extent at 
Study Entry 
Date of 
Current 
Diagnosis 
Weeks to 
Tr. Start 
Masaoka 
Stage 
Total No. of 
Recurrences 
/Progression 
Sites of 
Metastatic 
Disease 
Specify 
Months from  
Primary 
Diagnosis 
xxxx 
38/M/W 
Locally 
Advanced 
ddmmmyyyy 
xxx.x 
II 
1 
 
 
    xxx.x  * 
xxxx 
xx/x/xx 
Metastatic 
yyyy 
    xxx.x  * 
IIB 
3 
Lung 
 
    xxx.x  * 
 
 
 
 
 
… 
 
Bone 
 
 
 
 
 
 
 
… 
 
Brain 
 
 
xxxx 
xx/x/xx 
Metastatic 
ddmmmyyyy 
xxx.x    
… 
x 
Lymph nodes 
 
xxx.x 
 
 
 
 
 
 
 
Other 
xxxxxxxxxxxxx 
 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
Weeks to Tr. Start: From date of diagnosis to treatment start date.  
Total No. of Recurrences /Progression : including current one. 
Months from Primary Diagnosis: From initial diagnosis date to current diagnosis date. 
*: Estimated time when incomplete date was reported. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt no. 
 
 


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Appendix 3.4.3 - Demography and Pretreatment: Tumor History – Independent Review Committee Confirmation of Diagnosis 
- Treated Patients – 
 
Page by Regimen  
 
 
 
 
B3= Well-differentiated thymic carcinoma, C= Tymic Carcinoma 
Tumor Type at Diagnosis by Independent Reviewer: * if Other  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt no. , date of diagnosis by independent reviewer. 
Pt. 
No. 
WHO 
Classification 
by Investigator 
Date of 
Diagnosis by 
Independent 
reviewer 
Reviewer’s Name 
 
Tumor 
Type at 
Diagnosis 
according 
to 
Reviewer 
Thymic  
Carcinoma 
Type 
Confirmed by 
Reviewer? 
 
Details of  
Thymic  
Carcinoma (C) 
Details of  
Thymic  
Carcinoma (C), 
Specify 
Other Tumor 
Type, Specify 
Comments 
xxxx 
B3 
ddmmmyyyy 
xxxxxxxx 
B3 
Y 
 
Squamous cell 
thymic carcinoma 
 
 
 
xxxx 
C 
ddmmmyyyy 
xxxxxxxx 
Other 
N 
* 
 
 
xxxxxxxxx 
 
xxxx 
C 
ddmmmyyyy 
xxxxxxxx 
C 
Y 
 
Other 
xxxxxxxx 
 
 
xxxx 
C 
ddmmmyyyy 
xxxxxxxx 
Other 
N 
* 
 
 
xxxxxxxxx 
xxxxxxxxx 


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Appendix 3.4.4 - Demography and Pretreatment: History of Other Cancers 
- Treated Patients– 
 
Page by Regimen  
Pt. No 
Age/Sex/Race 
Site of 
Tumor 
Histological 
Type 
Date of 
Diagnosis 
Months to 
Tr. Start 
xxxx 
38/M/W 
xxxxxxxx 
xxxxxxxx 
ddmmmyyyy 
xxx.x 
xxxx 
xx/x/xx 
xxxxxxxx 
xxxxxxxx 
yyyy 
xxx.x  * 
xxxx 
xx/x/xx 
xxxxxxxx 
xxxxxxxx 
ddmmmyyyy 
xxx.x    
 
 
 
 
 
 
 
 
 
 
 
 
 
Only patients with at least one other cancer are displayed. 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
Months to Tr. Start: From date of diagnosis of other cancer to treatment start date.  
*: Estimated time when incomplete date was reported. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by pt no., line no. (no print). 
Select only patients with Other Cancer = ‘yes’ or derived ‘yes’. 
 


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Appendix 3.4.5 - Demography and Pretreatment: Tumor History - Prior Antitumor Treatments/Procedures 
- Treated Patients – 
 
Page by Regimen  
 
Pt. No 
Primary 
Diagnosis 
Chron. 
Seq. No. 
Start Date 
Stop Date 
Weeks to 
Tr. Start 
Duration of 
Antitumor 
Treatment 
(months) 
Time since 
Previous 
Antitumor 
Treatment 
(months) 
Setting 
Type 
xxxx 
xxxx 
1 
ddmmmyyyy 
NA 
xx.x 
xx.x 
 
Primary Tumor 
Surgery 
 
 
2 
ddmmmyyyy 
mmmyyyy 
xx.x * 
xx.x  * 
xx.x  * 
Adjuvant  
Chemotherapy   
 
 
 
 
 
 
 
 
 
Radiation Therapy 
xxxx 
xxxx 
1 
 
 
 
 
 
.... 
…. 
 
 
… 
 
 
 
 
 
…. 
….. 
 
 
 
 
 
 
 
 
 
 
 
Only patients with at least one therapy are displayed. 
NA= Not Applicable  
Weeks to Tr. Start: from antitumor treatment/procedure stop date to treatment start date. 
Duration  of Antitumor Treatment (weeks): from start date to stop date.  
Time since previous Antitumor Treatment (weeks): from stop date of previous line (chron. seq.) to start date of current line. 
*: Estimated time when incomplete date was reported 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt no., chron. seq. number. 
Select only patients with prior antitumor treatments/procedures = ‘yes’ or derived ‘yes’ . 
 
 


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Appendix 3.4.6 - Demography and Pretreatment: Tumor History - Prior Systemic Therapies 
- Treated Patients – 
 
Page by Regimen  
 
Pt.  
No. 
Chron Seq. 
No. 
Setting 
Drug 
Name 
Dose /  
Unit / 
Schedule 
Start Date 
Stop Date 
Duration of 
treatment 
(months) 
Best 
Response 
Response Date Relapse / Progression 
Date 
xxxx 
2 
 Primary Tumor 
xxxxxxxx 
 
ddmmmyyyy 
ddmmmyyyy 
xxx.x 
CR 
ddmmmyyyy 
ddmmmyyyy 
 
3 
 Metastatic 
xxxxxxxx 
… 
ddmmmyyyy 
ddmmmyyyy 
xxx.x 
 
NA 
NA 
xxxx 
1 
 Primary Tumor 
xxxxxxxx 
xxxxxxx 
ddmmmyyyy 
mmyyyy 
xxx.x* 
PR 
ddmmmyyyy 
mmyyyy 
 
2 
 
xxxxxxxx 
xxxxxxx 
 
 
 
 
 
 
 
n 
 
… 
… 
 
 
 
 
 
 
xxxx 
1 
 
xxxxxxxx 
 
ddmmmyyyy 
ddmmmyyyy 
xxx.x 
 
 
 
 
Only patients with at least one therapy are displayed. 
Best Response: CR= Complete Response, PR= Partial Response, SD= Stable Disease, PD = Progressive Disease, NE=Not Evaluable, NAS= Not Assessed, NA= Not Applicable. 
*: Estimated time when incomplete date was reported 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes:  
Sort by pt no., chron. seq. number. 
Select only patients with systemic therapy =‘yes’ or derived ‘yes’. 
Start/Stop Date: correspond to start/stop date in the header page when for the given Chron. Seq No. the variable Type can be linked to “Systemic Therapy” (see ALG document for 
derivation) 
 


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Appendix 3.4.7 – Demography and Pretreatment: Tumor History - Prior Surgeries 
- Treated Patients – 
 
Page by Regimen  
 
Pt. No. 
Primary diagnosis 
Chron.  
Seq. No. 
Setting 
Date 
Surgical 
Procedure 
xxxx 
xxxx 
1 
Primary Tumor 
ddmmmyyyy 
xxxxxxxxxxxxxxxxxxxxxxx 
 
 
2 
Locally Advanced 
ddmmmyyyy 
xxxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xxxx 
 
 
 
 
… 
 
1 
… 
… 
… 
 
 
… 
…. 
 
 
 
Only patients with at least one surgery are displayed. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt no., chron. seq. number. 
Select only patients with any prior surgery =‘yes’ or derived ‘yes’. 
Date: corresponds to start date in the header page when for the given Chron. Seq No. the variable Type can be linked to “Surgery” (see ALG document for derivation) 
 


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Appendix 3.4.8 – Demography and Pretreatment: Tumor History - Prior Radiotherapies 
- Treated Patients – 
Page by Regimen  
 
Pt. 
No. 
Primary 
Diagnosis 
Chron. 
Seq. 
No. 
Setting 
Irradiated  
BM (%) 
Start Date 
Stop Date 
Irradiation 
Site 
Best 
Response 
Date of  Best 
Response 
Date of  
Progression 
xxxx 
xxxx 
1 
Primary 
Tumor 
xx.x 
ddmmmyyyy 
ddmmmyyyy 
xxxxxxx 
CR 
ddmmmyyyy 
ddmmmyyyy 
 
 
2 
Adjuvant  
 
 
 
xxxxxxx 
 
NA 
ddmmmyyyy 
 
 
 
 
 
 
 
xxxxxxx 
PR 
ddmmmyyyy 
NA 
xxxx 
xxxx 
1 
.... 
xx.x 
mmmyyyy 
mmmyyyy 
xxxxxxx 
… 
 
 
xxxx 
xxxx 
… 
…. 
xx.x 
ddmmmyyyy 
ddmmmyyyy 
xxxxxxx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only patients with at least one radiotherapy are displayed. 
Best Response: CR = Complete Response, PR= Partial Response, SD = Stable Disease, PD = Progressive Disease, NE= Not Evaluable, NAS= Not Assessed, NA = Not Applicable 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt no., chron. seq. number. 
Select only patients with  Prior Radiotherapies =‘yes’ or derived ‘yes’. 
Start/Stop Date: correspond to start/stop date in the header page when for the given Chron. Seq No. the variable Type can be linked to “Radiotherapy” (see ALG document for 
derivation) 
 
 


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Appendix 3.4.9 - Demography and Pretreatment: General Medical History and Physical Examination Findings 
- Treated Patients – 
 
Page by Regimen   
 
Pt. No. 
Age/Sex/Race 
Primary Diagnosis 
Medical Conditions / 
Physical Findings 
Status 
xxxx 
38/M/W 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Active 
 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Controlled 
 
 
 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Past 
xxxx 
xx/x/x 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Past 
xxxx 
xx/x/x 
xxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Active 
 
 
Only patients with at least one finding are displayed. 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes:  
Sort by pt. no, status (Active, Controlled and Past) 
Select only patients with medical history/physical findings = ‘yes’ or derived ‘yes’. 
 


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Appendix 3 – Section 5 – Treatment Exposure  
Appendix 3.5.1 – Treatment Exposure: Treatment Administration Details 
- Treated Patients – 
 
Page by Regimen  
  
Pt. 
No. 
Cycle 
Tr.  
Delay 
Dose 
Reduced 
at Cycle 
Start 
Intra Cycle 
Modification 
Dose 
Level 
(mg/day) 
BSA 
(m2) 
Day 
Taken Dose  
(mg) 
Date of Admin. 
Time of 
Admin. 
xxxx Cy 1 
 
 
Y 
xxx.x 
x.xx 
1 
xxx.x 
ddmmmyyyy 
hh:mm 
 
 
 
 
 
 
 
… 
xxx.x 
 
hh:mm 
 
 
 
 
 
 
 
5 
 
ddmmmyyyy 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
Cy 2 
Y 
Y 
 
xxx.x 
x.xx 
1 
xxx.x 
ddmmmyyyy 
hh:mm 
 
… 
… 
 
 
 
 
 
… 
… 
… 
xxx 
Cy 1 
 
 
 
 
x.xx 
1 
xxx.x 
ddmmmyyyy 
hh:mm 
 
… 
… 
 
 
… 
 
… 
 
… 
… 
 
 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no., study period, day, date of administration. 
 


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Appendix 3.5.2 – Treatment Exposure: Reasons for Treatment Delay, Dose Reduction 
- Treated Patients - 
 
Page by Regimen  
 
Pt 
No. 
Cycle 
Cycle 
Duration 
(weeks) 
Trt. 
Delay 
Reason  Specify 
Dose  
Reduced at 
cycle start 
Reason  Specify 
Intra-cycle 
Modification 
Reason 
Specify 
Dose 
Level 
(mg/day) 
Day 
Taken 
Dose 
(mg) 
xxxx 
Cy 1 
xx.xx 
 
 
 
 
 
 
 
xxxxxxxxx 
 
xxx.x 
1 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
xxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
…. 
 
 
Cy 2 
xx.xx 
 
 
 
Y 
(H) 
xxxxxx 
 
xxxxxxxxx 
 
xxx.x 
1 
xxx.x 
 
 
….. 
 
 
 
… 
 
 
 
 
 
 
. 
… 
 
Cy n 
xx.xx 
(xx.xx) 
 
 
 
… 
 
 
 
 
 
 
. 
… 
xxxx 
Cy 1 
xx.xx 
Yes 
(N-H) 
xxxxxx 
 
 
 
Y 
 
 
… 
1 
xxx.x 
 
… 
… 
 
 
 
… 
 
 
 
 
 
 
… 
…. 
 
Only patients/cycles for whom any treatment modifications are reported. 
Duration of the last cycle of treatment is calculated from last cycle start date to end of treatment date; the per-protocol cycle duration is reported within brackets 
 
Reason for Intra Cycle Modification includes Reason for Dose Omitted and Dose Reduced Intra Cycle. 
Reasons: H=Hematological toxicity, N-H=Non-Hematological toxicity, O=Other, specify. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., study period, day. Select only patients for whom any modification applies, i.e. either treatment delay=Y or Dose reduced at cycle start=Y or intra-cycle 
modification=Y. 
 


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Appendix 3.5.3 – Treatment Exposure: Dose Intensity and Cumulative Dose 
- Treated Patients – 
 
Page by Regimen  
Intended Dose Intensity (mg/wk): xxx.x   
 
    
Pt. 
No. 
Age 
/Sex 
/Race 
Study Period 
No. of 
Days of 
Treatment 
Taken Dose 
 (mg) 
BSA 
(m2) 
% 
Scheduled 
Dose 
Treatment 
Duration 
(weeks) 
Absolute  
D.I.  
(mg/wk) 
Relative  
D.I. 
(%) 
Progressive 
Cum. Dose 
(mg) 
xxx 
38/F/W 
Cy 1 
xx 
xxx.x 
x.xx 
xx.x 
xx.x 
xxx.x 
xx.x 
xxx.x 
 
 
Cy 2 
xx 
xxx.x 
 
xx.x 
xx.x 
xxx.x 
xx.x 
xxx.x 
 
 
Cy x 
xx 
xxx.x 
x.xx 
xx.x 
xx.x (3) 
xxx.x 
xx.x 
xxx.x 
 
 
Whole Period 
 
 
 
 
xx.x  
xxx.x 
xx.x 
xxx.x 
xxxx 
xx/x/x 
Cy 1 
xx 
xxx.x 
x.xx 
xx.x 
xx.x 
xxx.x 
xx.x 
xxx.x 
 
 
Cy 2 
xx 
xxx.x 
 
xx.x 
xx.x 
xxx.x 
xx.x 
xxx.x 
 
 
Cy x 
xx 
xxx.x 
x.xx 
xx.x 
xx.x (3) 
xxx.x 
xx.x 
xxx.x 
 
 
Whole Period 
 
 
 
 
xx.x  
xxx.x 
xx.x 
xxx.x 
 
Race: W= White, B= Black, A= Asian, O= Not listed, N= Not allowed to ask per local regulation. 
% Scheduled Dose: the ratio between dose (mg) and intended dose x 100. 
Treatment Duration for last cycle and whole period: from the last cycle start date or from first dose date respectively, to end of treatment date. Duration reported in brackets is used 
for dose intensity calculation and considers the per protocol cycle duration. 
Relative D.I.: the ratio between absolute dose intensity and intended dose intensity x 100. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no., study period.  
 


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Appendix 3.5.4 – Treatment Exposure: Pharmacokinetics Blood Sampling Time 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study 
Period 
Tr.  
Admin  
Date 
Tr. 
Admin. 
Time 
Study Day 
Study 
Time 
Specimen  
Collection  
Date 
Specimen 
Collection 
Time 
xxxx 
52/F/W 
Cy 1 
ddmmmyyyy 
hh:mm 
1 
1 
ddmmmyyyy 
hh:mm 
 
 
 
 
 
 
2 
ddmmmyyyy 
hh:mm 
 
 
 
 
 
 
3 
ddmmmyyyy 
hh:mm 
 
 
 
ddmmmyyyy 
hh:mm 
x 
… 
… 
… 
 
 
… 
… 
… 
… 
… 
… 
… 
xxxx 
xx/x/x 
Cy 1 
ddmmmyyyy 
hh:mm 
1 
…. 
ddmmmyyyy 
hh:mm 
 
 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no., study period, tr. Admin. date, study day, study time, collection date, collection time.  
Study day is the one indicated on the PK form of the CRF. 
 


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Appendix 3 – Section 6 – Treatment Efficacy  
Appendix 3.6.1 - Treatment Efficacy - Target and Non Target Lesions by Assessment Visit  
- Treated Patients – 
Page by Regimen 
 
Pt. 
No. 
Study 
Period 
Date 
Days 
to/from 
Tr. Start 
Les. 
Type 
Les. 
No. 
Lesion 
Description 
Eval. 
(Y/N) 
Lymph 
Node 
Prior 
Loco-
regionally 
Treated 
Lesion 
New 
Les. 
N. 
A. 
Method 
Target L. 
Measure 
(mm) 
Target L. 
% Change 
from Pretr 
Target
L. 
Nadir 
Target.L.  
% Change 
from Nadir 
Non 
Target 
L. 
Status 
xxx 
Pretr. 
ddmmmyyyy 
xxx 
T 
xx 
xxxxxxxxxx 
 
Y 
Y 
 
 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
xx 
xxxxxxx 
 
 
 
 
 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
 
All Target L. 
 
 
 
 
 
 
xxxx 
 
 
 
 
 
 
 
 
NT 
xx 
xxxxx 
 
 
 
 
 
… 
 
 
 
 
 
 
Onc 1 
ddmmmyyyy 
xxx 
T 
xx 
xxxxxxxxxx 
Y 
Y 
 
 
 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
xx 
xxxxxxx 
Y 
 
 
 
 
xx 
xxxx 
±xxx.x 
 
 
 
 
 
 
 
 
xx 
xxxxxxx 
Y 
 
 
Y 
 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
 
All Target L 
Y 
 
 
 
 
 
xxxx 
±xxx.x 
Y 
 
 
 
 
ddmmmyyyy 
xxx 
NT 
xx 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
A 
 
Onc x 
ddmmmyyyy 
xxx 
T 
… 
… 
 
… 
 
 
 
.. 
…. 
……. 
 
 
 
 
 
 
 
 
 
All Target L 
Y 
 
 
 
 
 
xxxx 
±xxx.x 
 
xxxx 
 
xxx 
Pretr. 
ddmmmyyyy 
xxx 
T 
xx 
xxxxxxxxxx 
 
 
 
 
 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
 
All Target L. 
 
 
 
 
 
 
xxxxx 
 
 
 
 
 
Onc. 1 
ddmmmyyyy 
xxx 
T 
xx 
xxxxxxxxxx 
N 
 
 
 
 
xx* 
xxxx 
 
 
 
 
 
 
 
 
 
 
All Target L 
N 
 
 
 
 
 
xxxx 
 
 
 
 
 
Lesion Type: T=Target Lesion, NT=Non Target Lesion 
Eval (Y/N): a target lesion is not considered as evaluable if missing measure and/or method, or method different from pretreatment assessment; the set of all target lesions is not evaluable if even one 
only target lesion is not evaluable. 
 
N.A.: Not Assessed.  
Method: 1=Physical Exam. (measurement by caliper), 2=X-ray, 3=Echo/Ultrasounds, 4=CT scan, 5=Scintigraphy, 6=MRI/NMR, 7=Linear Tomography, 8=Photography, 10=Bronchoscopy, 13=Spiral 
CT-Scan, 14=PET, 15=MIBG Scan, 16=99tc Scan, 17=MR Spectroscopy, 18=Thallium Spectroscopy, 19=Angiography, 20=Bone Scan, 98=Other, specify in the Physician’s Comments page. 
Methods different from the pretreatment one are marked by ‘’. 
Non Target Lesions: Status: A=Absent (CR); P=Present ( Non-CR/Non-PD); UPD=Unequivocal Progressive Disease.  
Nadir: lowest  value of All Target Lesions throughout the whole study period, baseline included. %Change from Nadir: only for study periods following the period when the nadir is reported. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no., study period, les type (T, NT), les. no..  


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Appendix 3.6.2 - Treatment Efficacy - Response Status by Assessment Visit 
- Treated Patients - 
 
Page by Regimen 
 
 
 
 
 
 
 
 
 
If CR or PR 
Pt. 
No. 
Study 
Period 
Assessment 
Date 
Days 
from 
Tr. 
Start 
Response  
Response 
Status 
Date of 
Documented  
PD 
Weeks to 
PD 
First Response 
Date  
Response 
Confirmation 
Date 
xxx 
Onc 1 
ddmmmyyyy 
xxx 
Target Lesion 
CR 
 
 
 
 
 
 
 
 
Non Target Lesion 
NE 
 
 
 
 
 
 
 
 
Overall  
PR 
 
 
 
 
 
Onc 1 
ddmmmyyyy 
xxx 
… 
… 
… 
… 
… 
… 
 
 
 
 
Overall  
PD 
ddmmmyyyy 
xxx.x 
 
 
 
Best OR 
-- 
 
Best Overall  
PR 
 
 
ddmmmyyyy 
ddmmmyyyy* 
xxx 
Onc 1 
… 
… 
 
xx 
 
 
 
 
 
… 
… 
 
 
… 
 
 
 
 
 
Onc 3 
… 
… 
 
xx 
ddmmmyyyy  
xxx.x 
 
 
 
Best OR 
-- 
 
Best Overall  
CR 
… 
… 
ddmmmyyyy * 
ddmmmyyyy 
 
 
Assessment date: the date of the first tumor lesion assessment in the relevant study period. 
. 
Response Status: CR = Complete Response, PR = Partial Response, SD = Stable Disease, NCR/NPD= Non-CR/Non-PD, UPD= Unequivocal PD, PD = Progressive Disease, NE= 
Not Evaluable, NA = Not Applicable. 
Date of Documented PD was derived as the first tumor lesion assessment date in the relevant study period. Weeks to PD: from the first treatment date to the date of  documented PD.   
First Response Date: when not recorded on CRF, the * indicates that the date was derived as the latest date among all tumor lesion assessment dates at the first visit when a response 
(CR or PR) was reported.  Response Confirmation Date: when not recorded on CRF, the * indicates that the date was derived as the latest date among all tumor lesion assessment 
dates at the second visit when a response (CR or PR) was reported. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
Programming Notes: 
Sort by pt. no., study period, les type (target, non-target, overall).  
 


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Appendix 3.6.3 - Treatment Efficacy – Best Overall Response and Time to Progression, Progression Free Survival, Overall Survival, Response Duration and Stable Disease 
Duration 
- Treated Patients - 
 
Page by Regimen/Assigned Dose Level (mg/m2/day): <xi > 
 
Pt. 
No 
Pt.  
Evaluable  
for 
Efficacy 
(Y/N) 
Tr. Start 
Date 
Total 
No. of  
Cycles 
Dose 
Intensity 
(mg/wk) 
Best 
Overall 
Response
Date of 
First 
Response 
Date of 
PD 
Date of 
Death 
Last Onc. 
Assessment  
Date 
Last 
Recorded 
Date 
TTP  
(days) 
OS 
(days) 
PFS 
(days) 
Response 
Duration 
(days) 
Stable 
Disease 
Duration 
(days) 
xxx 
Y 
ddmmmyyyy 
4 
xxx.x 
CR 
ddmmmyy 
 
ddmmmyyyy ddmmmyyyy 
 
xxx.x + 
 
xxx.x 
xxx.x + 
 
xxx 
Y 
ddmmmyyyy 
3 
xxx.x 
SD 
 
ddmmmyyyy  
 
ddmmmyyyy ddmmmyyyy
xxx.x  
xxx.x + 
xxx.x 
 
xxx.x  
xxx 
Y 
ddmmmyyyy 
x 
xxx.x 
PR 
  ddmmmyy
*    
 
 
ddmmmyyyy ddmmmyyyy
xxx.x + 
xxx.x + 
xxx.x + 
xxx.x + 
 
xxx 
Y 
ddmmmyyyy 
x 
xxx.x 
PD 
 
ddmmmyyyy  
 
ddmmmyyyy ddmmmyyyy
xxx.x 
xxx.x + 
xxx.x 
 
 
xxx 
N 
ddmmmyyyy 
x 
xxx.x 
CR 
ddmmmyy 
 
 
ddmmmyyyy ddmmmyyyy
xxx.x + 
xxx.x + 
xxx.x + 
xxx.x + 
 
xxx 
Y 
ddmmmyyyy 
x 
xxx.x 
SD 
 
 
ddmmmyyyy ddmmmyyyy 
 
xxx.x 
 
xxx.x 
 
xxx.x 
xxx 
Y 
ddmmmyyyy 
x 
xxx.x 
SD 
 
 
ddmmmyyyy ddmmmyyyy 
 
xxx.x + 
 
xxx.x 
 
xxx.x + 
 
Best Overall Response: as reported by the investigator at the completion of treatment; CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive 
Disease, NE= Not Evaluable.  
Date of First Response: when not recorded on CRF, the * indicates that the date was derived as the latest date among all tumor lesion assessment dates at the first visit when a 
response (CR or PR) was reported.  
Last Recorded Date: for patients still alive it is the last available date in CRF.  
(+): indicates censored time. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by pt. no.  
D.I.: the dose intensity to be reported is the one calculated for the whole treatment period. 


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Appendix 3.6.4 – Treatment Efficacy: ECOG Performance Status 
- Treated Patients - 
 
Page by Regimen 
 
Pt.  
No. 
Study 
Period 
Date 
Study 
Day 
ECOG 
PS 
xxxxxx 
Pretr. 
ddmmmyyyy 
 
   3 § 
 
Cy 1 
ddmmmyyyy 
1 
0 
 
 
 
 
 
 
… 
…. 
…. 
…. 
 
 
 
 
 
 
Cy n 
ddmmmyyyy 
1 
 
 
 
 
 
 
 
At pretreatment: Performance Status >1 is identified by § (violation of inclusion criterion 05). 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
 
Sort by pt. no., study period, date. 
 
 


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Appendix 3 – Section 7 – Adverse Events  
Appendix 3.7.1 – Adverse Events: All Reported Adverse Events by Assessment Visit and AE MedDRA Preferred Term 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No. 
Study 
Period 
Cycle Start 
Date 
Adverse 
Event 
CTC 
Grade 
Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. 
to 
Study 
Proc. 
Rel. 
to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Action 
Taken 
Outcome 
xxxx 
Pretr. 
 
xxxxxxxxxx 
1 
N 
ddmmmyyyy 
 
ddmmmyyyy 
 
Y 
 
N 
 
R 
 
 
 
xxxxxxxxxx 
1 
N 
 
Y 
 
Y 
N 
 
N 
 
NR 
 
 
 
xxxxxxxxxx 
2 
… 
 
Y 
ddmmmyyyy 
 
N 
 
Y 
 
R 
 
Cy 1 
ddmmmyyyy 
xxxxxxxxxx 
x 
… 
 
Y 
 
Y 
 
No 
 
No 
NR 
 
 
 
xxxxxxxxxx 
… 
… 
ddmmmyyyy 
 
 
Y 
 
Un 
N 
No 
NR 
 
 
 
xxxxxxxxxx 
3 
Y 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
Po 
Y 
D/C 
R 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Action Taken: No=None; D/C=Dose Delayed/Changed; PW=Drug Permanently Withdrawn. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq no..  
Include also records of End of Adverse Events Reporting Period and of Follow-up. 
 


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Appendix 3.7.2 - Adverse Events: Adverse Events Related to Study Procedure at Pretreatment 
- Treated Patients – 
 
Page by Regimen  
 
Pt. No. 
Adverse Event 
CTC 
Grade Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. to Study 
Procedure 
Rel. to Study 
Disease 
Outcome 
xxxx xxxxxxx 
x 
N 
ddmmmyyyy 
 
ddmmmyyyy 
 
Y 
N 
… 
 
xxxx 
x 
N 
 
 
 
 
 
N 
... 
 
xxxxxxx xxxx xxx 
x 
N 
 
Y 
 
 
 
Y 
R 
 
xxxxxxx 
x 
N 
ddmmmyyyy 
 
 
Y 
 
… 
NR 
xxxx … 
… 
… 
… 
… 
… 
… 
… 
N 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
Y 
… 
 
 
 
 
 
 
 
 
 
… 
 
 
Only AEs reported at pretreatment visit and related to study procedure are displayed. 
AP/SP: Already present/Still present. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)]  
[program path; date/time produced; date data extract] 
 
Programming Notes: 
Sort by pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq. no. 
Select only records at pretreatment and with variable “Related to study procedure” =Y or missing 
 


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Appendix 3.7.3 – Adverse Events: Serious Adverse Events 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No. 
Adverse 
Event 
Study 
Period 
Cycle 
Start Date 
Serious 
CTC 
Grade 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. to 
Study 
Proc. 
Rel. to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Action 
Taken Outcome 
xxxx 
xxxxxxxxxx  Pretr. 
 
 
2 
ddmmmyyyy 
 
ddmmmyyyy 
 
N 
 
N 
 
R 
 
 
Cy 1 
ddmmmyyyy 
 
3 
ddmmmyyyy 
 
 
 
 
De 
Y 
D/C 
NR 
 
 
… 
…. 
Y 
4 
 
Y 
 
Y 
 
Pr 
Y 
D/C 
R 
 
 
Cy x 
ddmmmyyyy 
Y 
… 
… 
Y 
ddmmmyyyy 
 
 
… 
... 
PW 
… 
 
xxxxxxxxxx 
Cy 1 
ddmmmyyyy 
 
1 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
… 
Y 
No 
NR 
 
 
… 
….. 
 
… 
ddmmmyyyy 
 
 
Y 
 
Po 
… 
… 
R 
 
 
Cy x 
ddmmmyyyy 
Y 
… 
 
Y 
ddmmmyyyy 
 
 
… 
… 
… 
NR 
xxxx 
… 
… 
… 
 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
 
 
All occurrences of AEs that were reported as Serious at least once for the patient in the course of the study are displayed. 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Action Taken: No=None; D/C=Dose Delayed/Changed; PW=Drug Permanently Withdrawn. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., AE MedDRA Preferred Term, study period, AE page no., AE seq no..  
Select AE Preferred terms that had the variable ‘Serious’=Y at least once within the patient in the course of the study, including pretreatment, End of Adverse Events Reporting 
Period and of Follow-up. 
 


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Appendix 3.7.4 – Adverse Events: Adverse Events with CTC Grade 3 to 5 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No 
Adverse 
Event 
Study 
Period 
Cycle Start 
Date 
CTC 
Grade 
Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. to 
Study 
Proc 
Rel. to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Action 
Taken 
Outcome 
xxxx 
xxxxxxxx
xx 
Pretr. 
 
3 
N 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
No 
Y 
No 
R 
 
xxxxxxxx
xx 
Cy 1 
ddmmmyyyy 
3 
N 
 
Y 
 
Y 
 
Un 
Y 
D/C 
NR 
 
 
… 
 
… 
Y 
… 
… 
 
… 
 
Pr 
N 
… 
… 
 
 
Cy x 
ddmmmyyyy 
... 
... 
 
Y 
 
Y 
 
Pr 
N 
No 
NR 
 
xxxxxxxx
xx 
Cy 1 
ddmmmyyyy 
… 
... 
ddmmmyyyy 
 
 
Y 
 
Un 
Y 
No 
NR 
 
 
… 
 
4 
Y 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
De 
Y 
D/C 
R 
 
 
Cy x 
ddmmmyyyy 
 
 
 
 
 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only AE occurrences at the time when CTC grade > 2 are displayed. 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Action Taken: No=None; D/C=Dose Delayed/Changed; PW=Drug Permanently Withdrawn. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract 
 
Programming Notes:  
Sort by pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq. no..  
Selct only the occurrences of AEs when CTC grade > 2. Include also occurrences reported with grade > 2 at pretreatment or at End of Adverse Events Reporting Period or at 
Follow-up. 
 


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Appendix 3.7.5 – Adverse Events: Patients with Adverse Events Leading to Withdrawal from Study Treatment 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No. 
Adverse 
Event 
Study 
Period 
Cycle 
Start Date 
CTC 
Grade 
Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. to 
Study 
Proc. 
Rel. to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Action 
taken 
Outcome 
xxxx 
xxxxxxxxxx  
Pretr. 
 
2 
 
ddmmmyyyy 
 
ddmmmyyyy 
 
N 
 
N 
 
R 
 
 
Cy 1 
ddmmmyyyy 
3 
Y 
ddmmmyyyy 
 
 
 
 
De 
Y 
D/C 
NR 
 
 
… 
…. 
4 
Y 
 
Y 
 
Y 
 
Pr 
Y 
D/C 
R 
 
 
Cy x 
ddmmmyyyy 
… 
N 
… 
Y 
ddmmmyyyy 
 
 
… 
... 
PW 
… 
 
xxxxxxxxxx 
Cy 1 
ddmmmyyyy 
1 
… 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
… 
Y 
No 
NR 
 
 
… 
….. 
… 
… 
ddmmmyyyy 
 
 
Y 
 
Po 
… 
 
R 
 
 
Cy x 
ddmmmyyyy 
… 
… 
 
Y 
ddmmmyyyy 
 
 
… 
… 
 
NR 
xxxx 
… 
… 
… 
… 
 
… 
… 
… 
… 
 
… 
… 
 
… 
 
Only patients that had at least one AE whose Action Taken was Drug Permanently Withdrawn are displayed. 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Action Taken: No=None; D/C=Dose Delayed/Changed; PW=Drug Permanently Withdrawn. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by, pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq no..  
Select patients that had at least one AE whose Action Taken was Drug Permanently Withdrawn. Of these patients report all AEs. 
Include also records of  End of Adverse Events Reporting Period and of Follow-up. 


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Appendix 3.7.6 – Adverse Events: End of AE Reporting Period and Follow-Up 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No 
Tr. Last  
Date 
Study 
Period 
Adverse 
Event 
CTC 
Grade Serious Start Date 
A. 
P. 
Stop 
Date 
S.  
P. 
Rel. to 
Study  
Treat. 
Rel. to  
Study 
Disease 
Outcome 
If Ongoing 
xxxx ddmmmyyyy 
AE End 
xxxxxxxxxx 
x 
N 
 
Y 
 
Y 
No 
N 
NR 
Chronic/Stable 
 
 
 
xxxxxxx 
x 
N 
 
Y 
 
Y 
Un 
Y 
NR 
Continue to follow 
 
 
 
xxxxxxxxxx 
x 
... 
ddmmmyyyy 
 
 
Y 
Po 
N 
NR 
New Anticancer 
therapy 
xxxx ddmmmyyyy  AE FU1 
§ xxxxxxx 
x 
… 
 
Y 
 
Y 
De 
N 
NR 
Chronic/Stable 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs not recovered in Follow-up are identified by §. 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract 
 
Programming Notes:  
Sort by  pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq. no.. 
Select AEs with study period = ‘End of AE reporting period’ or ‘Follow-up’. 
 


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Appendix 3.7.7 – Adverse Events: All Reported Adverse Events by System Organ Class, AE MedDRA Preferred Term and Investigator’s Term 
- Treated Patients - 
 
Page by Regimen  
 
Pt. No. 
System  
Organ Class 
Adverse Event  
Investigator’s Term 
Study Period 
Cycle  
Start Date 
CTC  
Grade 
Serious 
Rel. to  
Study  
Proc. 
Rel. to  
Study  
Treat. 
Rel. to 
Study 
Disease 
xxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
Pretr. 
 
x 
N 
N 
De 
… 
 
 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
Cy 1 
ddmmmyyyy 
x 
Y 
 
Pr 
Y 
 
 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
Cy x 
ddmmmyyyy 
x 
N 
 
… 
... 
 
 
 
xxxxxxxxxxxxx 
Cy x 
ddmmmyyyy 
x 
N 
 
… 
Y 
 
 
… 
… 
Cy 1 
ddmmmyyyy 
x 
… 
 
Po 
 
 
 
… 
… 
Cy x 
ddmmmyyyy 
x 
… 
 
… 
 
xxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
… 
 
x 
… 
 
 
 
 
 
xxxxxxxxxxxxx 
xxxxxxxxxxxxx 
… 
 
x 
… 
 
 
 
 
 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., System Organ Class, AE MedDRA Preferred Term, AE Investigator’s Term, study period, AE page no., AE seq no.. 
 
 


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Appendix 3.7.8 – Adverse Events: Hospitalization 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No. 
Age/Race 
/Sex 
Tr. Start 
Date 
Tr. Last  
Date 
Reason 
Description 
Date of  
Admission 
Date of  
Discharge 
Ongoing  Duration  
(days) 
Weeks 
from  
Tr. Start 
xxxx 
35/W/M 
ddmmmyyyy 
ddmmmyyyy 
Adverse 
event 
 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
xxx 
 
 
 
 
Progressive 
Disease 
 
ddmmmyyyy 
 
Y 
 
xxx 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
Instrumental 
procedure 
 
ddmmmyyyy 
 
Y 
 
xxx 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
Other 
xxxxxxxxxxxxxx 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
Duration (days): from date of admission to date of discharge.  
Weeks from Tr. Start: from treatment start date to date of admission. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., admission date, seq. no. 
 
 
 
 


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Appendix 3.7.9 – Deaths 
- Treated Patients - 
 
Page by Regimen    
 
Pt. 
No. 
Age 
/Sex 
/Race 
Tr. Start 
Date 
Tr. Last  
Date 
Total 
No. of 
Cycles 
Cumulative 
Dose 
(mg/m2) 
Date of 
Death 
CRF 
Source 
Days 
from Tr. 
Last Date 
Most 
Probable  
Cause 
Details 
Investigator 
Causality 
Assessment 
xxxx 
38/M/W 
ddmmmyyyy 
ddmmmyyyy 
2 
xxxx.x 
ddmmmyyyy 
FU 
xxx 
PD 
 
Un 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
x 
xxxx.x 
ddmmmyyyy 
Death 
xxx* 
AE 
xxxxxxxxxx 
No 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
x 
xxxx.x 
ddmmmyyyy 
Death 
xxx 
Other 
xxxxxxxxxx 
Po 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
x 
xxxx.x 
ddmmmyyyy 
AE 
xxx 
AE 
xxxxxxxxx 
Pr 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
x 
xxxx.x 
ddmmmyyyy 
AE 
xxx 
AE 
 
… 
xxxx 
xx/x/x 
ddmmmyyyy 
ddmmmyyyy 
x 
xxxx.x 
ddmmmyyyy 
AE 
xxx 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
CRF Source: (Death): Death date reported in Death Form, (FU): Death date reported in Survival Follow-up Form, (AE): Death date reported in AE Form. 
Days from treatment last date: * if <= 28 days. 
Investigator Causality Assessment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no.. 
 
 


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Appendix 3.7.10 – Deaths: Autopsy Result 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Days from 
Tr. Last 
Date to 
Death Date  
Most Probable Cause 
Details 
Investigator 
Causality 
Assessment 
Autopsy 
Performed 
Autopsy 
Date 
Autopsy 
Result 
xxxx 
38/M/W 
xxx 
Progressive Disease 
 
Pr 
Y 
ddmmmyyyy 
xxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxx 
xxxx 
xx/x/x 
xxx* 
Adverse Event 
 
Po 
Y 
ddmmmyyyy 
… 
xxxx 
xx/x/x 
xxx 
Other  
xxxxxxxxxxx 
… 
N 
 
 
xxxx 
xx/x/x 
xxx 
… 
 
… 
N 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Days from treatment last date to death date: * if <= 28 days. 
Investigator Causality Assessment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no.. 
 
 


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Appendix 3 - Section 8 – Laboratory Assessments  
Appendix 3.8.1 – Laboratory Assessments: Hematology by Laboratory Test, Patient and Study Period 
- Treated Patients - 
 
Page by Regimen /Laboratory Test: < e.g. Neutrophils >  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study  
Period 
Cycle  
Start Date 
Date of 
Sampling 
Study 
Day 
Collected 
Value 
Collected 
Unit 
L/H  
Converted  
Value 
Converted  
Unit 
CTC  
Grade      
xxxx 
52/F/W 
Pretr. 
 
ddmmmyyyy 
-xx 
xxx.xx 
xxxx 
L 
xxx.xx 
xxxx 
x 
 
 
Cy x 
ddmmmyyyy 
ddmmmyyyy 
xx 
… 
… 
… 
… 
… 
    3  * 
 
 
 
 
 
xx     
… 
… 
… 
… 
… 
    4  * 
 
 
… 
… 
… 
... 
… 
… 
… 
… 
… 
... 
xxxx 
 
Pretr. 
 
ddmmmyyyy 
xx 
… 
… 
… 
… 
… 
2 
… 
 
… 
… 
… 
 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades= 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by “page by variables”, pt. no, study period, date of sampling, study day. If feasible lab test is to be ordered as per CRF appearance.  
The listing must include all the hematological labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 


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 Appendix 3.8.2 – Laboratory Assessments: Blood Chemistry by Laboratory Test, Patient and Study Period 
- Treated Patients - 
 
Page by Regimen /Laboratory Test: < e.g. ALT >  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study 
Period 
Cycle Start 
Date 
Date of 
Sampling 
Study 
Day 
Collected 
Value 
Collected
Unit  
Collected 
Lower 
Limit  
Collected 
Upper 
Limit 
L/H 
Converted 
Value 
Converted 
Unit 
CTC 
Grade 
xxxx 
52/F/W 
Pretr. 
 
ddmmmyyyy 
- xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
L 
xxx.xx 
xxxx 
N 
 
 
 
 
……. 
 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
 
… 
… 
N 
 
 
Cy x 
ddmmmyyyy 
ddmmmyyyy  
xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
H 
… 
… 
3* 
 
 
 
 
 
 
… 
… 
… 
… 
 
… 
… 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
ddmmmyyyy 
xx 
… 
… 
… 
… 
L 
 
 
4* 
 
 
 
 
 
… 
… 
… 
… 
… 
 
 
 
… 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades= 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by “page by variables”, pt. no, study period, date of sampling, study day.  
If feasible lab test is to be ordered as per CRF appearance. 
The listing must include all the biochemistry labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 
 


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Appendix 3.8.3 – Laboratory Assessments: Coagulation by Patient, Study Period and Laboratory Test 
- Treated Patients – 
 
Page by Regimen 
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study 
Period 
Cycle Start 
Date 
Date of 
Sampling 
Study 
Day 
Laboratory 
Test 
Collected 
Value 
Collected 
Unit  
Collected 
Lower 
Limit  
Collected 
Upper 
Limit 
L/H 
Converted 
Value 
Converted 
Unit 
CTC 
Grade 
xxxx 
52/F/W 
Pretr. 
 
ddmmmyyyy 
- xx 
aPTT 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
L 
xxx.xx 
xxxx 
2 
 
 
 
 
 
 
INR 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
 
… 
… 
1 
 
 
 
 
ddmmmyyyy 
 
aPTT 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
H 
… 
… 
2 
 
 
 
 
 
 
INR 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
H 
… 
… 
2 
 
 
Cy x 
ddmmmyyyy 
ddmmmyyyy 
xx 
… 
… 
… 
… 
… 
 
… 
… 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
ddmmmyyyy 
xx 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
 
 
 
… 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades= 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no, study period, date of sampling, study day, lab test.  
If feasible lab test is to be ordered as per CRF appearance. 
The listing must include all the coagulation labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 


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Appendix 3.8.4 – Laboratory Assessments: Urinalysis 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study 
Period 
Cycle Start 
Date 
Date of 
Sampling 
Study 
Day 
Laboratory 
Test 
Collected  
Value 
xxxx 
52/F/W 
Pretr. 
 
ddmmmyyyy 
- xx 
ph 
xx 
 
 
 
 
 
 
glucose 
negative 
 
 
 
 
 
 
… 
trace 
 
 
Cy. 1 
ddmmmyyyy 
ddmmmyyyy 
xx 
ph 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
protein 
1+ 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no, study period, date of sampling, study day, lab test.  
If feasible lab test is to be ordered as per CRF appearance. 
Each assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 


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Appendix 3.8.5 – Laboratory Assessments: Laboratory Normal Ranges of Hematological Tests 
 
 
Laboratory Test  
Description 
Laboratory Test  
Code 
Sex 
Age Min 
(years) 
Age Max 
(years) 
Lower Limit 
Upper Limit 
Unit 
xxxxx 
 
Both 
 
 
xxx.xx 
xxx.xx 
xxxxx 
xxxxx 
 
… 
 
 
… 
… 
… 
xxxxx 
 
Male 
 
 
… 
… 
… 
xxxxx 
 
Both 
 
 
… 
… 
… 
… 
 
Female 
 
 
… 
… 
… 
… 
 
… 
 
 
… 
… 
… 
… 
 
… 
 
 
… 
… 
… 
… 
 
… 
 
 
… 
… 
… 
 
 
Normal ranges are not collected for hematological tests, Standard Normal Ranges expressed in Conventional Unit are used. 
Age class: age range 0-150 is a conventional range when lab. test normal ranges are valid for all ages 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:   
Sort by lab. Test (description, code), sex. 
For each test belonging to WBC, report the unit expressed both in percentage and absolute count. 


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Appendix 3.8.6 – Laboratory Assessments: Laboratory Normal Ranges of Non-Hematological Tests 
- Treated Patients - 
 
Page by: Laboratory Code: <xxxxx>    Laboratory Name: <xxxxxxxxxx>. 
 
Laboratory 
Class 
Assay 
Initial Set (Y/N) 
Date of Change 
Sex 
Age Min (years) 
Age Max (years) 
Lower Limit 
Upper Limit 
Unit 
Blood 
Chemistry 
xxxxx 
Y 
 
Male 
xx 
xx 
xxx.xx 
xxx.xx 
… 
 
 
 
 
 
… 
… 
… 
… 
… 
 
 
 
 
Female 
xx 
xx 
… 
… 
… 
 
 
 
 
 
… 
… 
… 
… 
… 
xxxxxxxxxxxx 
xxxxx 
N 
ddmmmyyyy 
Both 
xx 
xx 
… 
… 
… 
… 
… 
 
 
… 
… 
… 
… 
… 
… 
 
xxxxx 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
Units are not converted, they are listed according to CRF reported units. 
Age class: age range 0-150 is a conventional range when lab. test normal ranges are valid for all ages.   
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:   
Sort by “page by variables”, laboratory class, assay, date of change, sex, age min. 
Lab test ranges are not to be converted; they are to be listed according to the units reported on CRF.   
 


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Appendix 3 - Section 9 – Other Safety Assessments 
Appendix 3.9.1 – Other Safety Assessments: Vital Signs  
- Treated Patients – 
 
Page by Regimen   
 
Pt.  
No. 
Age 
/Sex 
/Race 
Study 
Period 
Date 
Height 
(cm) 
Weight 
(kg)  
Temperature 
(°C). 
Route 
Syst. B.P.  
(mmHg) 
 
Diast. B.P.  
(mmHg) 
 
Pulse 
(bpm) 
xxxx 
35/M/W 
Pretr. 
ddmmmyyyy 
xxx.x 
xxx.x 
xxx.x 
xxxx 
170  
* 
   100   
* 
xxx 
 
 
Cy 1 
ddmmmyyyy 
 
xxx.x   
xxx.x 
xxxx 
164  
* 
xxx 
 
xxx 
 
 
Cy 2 
ddmmmyyyy 
 
xxx.x   
xxx.x 
xxxx 
xxx 
 
110 
§ 
xxx 
xxxx 
 
….. 
…. 
… 
 
 
 
…. 
 
…. 
 
….. 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
(*) Systolic Blood Pressure 140 mmHg or Diastolic Blood Pressure  90 mmHg.  
(§) Increase from pretreatment: Systolic BP20;  Diastolic BP 10 mmHg. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt. no., study period, date.  
 
 


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Appendix 3.9.2 – Other Safety Assessments: ECG 
- Treated Patients – 
 
Page by Regimen  
 
Pt. No. Age/Sex 
/Race 
Study Period 
ECG Date 
Ventricular 
Rate 
(bpm) 
Tracing 
Abnormalities 
Category 
 
Specific Abnormality 
Further Details 
xxxx 
35/M/W 
Pretr. 
ddmmmyyyy 
xxx 
N 
 
 
 
 
 
 
 
 
 
Y 
Rhythm 
 Sinus Tachicardia 
 
 
 
Cy 1 
ddmmmyyyy 
xxx 
 
QRS 
 xxxxxxxxxxxx 
 
 
 
 
 
 
 
 
  
 
 
 
Cy 2 
ddmmmyyyy 
xxx 
 
 
* xxxxxxx 
 
 
 
 
 
 
 
 
 xxxxxxx 
 
 
 
Cy 3 
ddmmmyyyy 
xxx 
 
 
 xxxxxxx 
 
 
 
 
ddmmmyyyy 
 
 
 
 xxxxxxx 
 
xxxx 
xx/x/x 
Pretr. 
ddmmmyyyy 
xxx 
Y 
ST-T 
Wave 
 Other 
xxxxxxxx 
 
 
Cy 1 
ddmmmyyyy 
… 
N 
… 
 
… 
… 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
(*) Specific Abnormality not present at pretreatment.  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no., study period. 
 
 


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Appendix 3.9.3 – Other Safety Assessments: Visual Acuity and Funduscopic Examination 
- Treated Patients – 
 
Page by Regimen   
 
Pt. No. Study 
Period 
Cumulative 
Dose 
(mg) 
Date of 
Visual acuity  
Assessment 
Snellen 
Equivalent 
Right Eye 
Snellen 
Equivalent 
Left Eye 
Date of 
Funduscopic 
Examination 
Right Eye 
Left Eye 
xxxx 
Pretr. 
 
ddmmmyyyy 
20/xx 
20/xx 
ddmmmyyyy 
Normal 
Normal 
 
Cy 1 
xxxx.x 
ddmmmyyyy 
20/xx 
20/xx 
ddmmmyyyy 
Abnormal, clinically relevant 
Abnormal, clinically relevant 
 
… 
… 
ddmmmyyyy 
20/xx 
20/xx 
ddmmmyyyy 
Abnormal, not clinically relevant 
Abnormal, not clinically relevant 
 
Cy j 
xxxx.x 
ddmmmyyyy 
 
 
ddmmmyyyy 
Normal 
Normal 
 
… 
xxxx.x 
ddmmmyyyy 
20/xx 
20/xx 
ddmmmyyyy 
Abnormal, not clinically relevant 
Abnormal, not clinically relevant 
xxxx 
… 
…. 
…. 
… 
… 
… 
… 
… 
 
Cumulative dose (mg) : from treatment start up to end of relevant treatment cycle  
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt. no., study period. 
 
 


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 Appendix 3.9.4 – Other Safety Assessments: Chest X-Ray 
- Treated Patients – 
 
Page by Regimen  
 
Pt. No 
Age/Sex/Race 
Date 
Days 
to/from 
Tr. Start 
Study 
Period 
Results 
xxxx 
38/M/W 
ddmmmyyyy 
-1 
Pretr. 
Normal 
 
 
ddmmmyyyy 
4 
Cy 1 
Normal 
 
 
ddmmmyyyy 
20 
 
Abnormal; not clinically relevant 
xxxx 
xx/x/x 
… 
… 
Pretr. 
Abnormal; clinically relevant 
… 
… 
… 
 
… 
… 
 
 
 
 
 
 
 
 
Only patients with chest x-ray performed are displayed 
Race: W= White, B= Black, A= Asian, O= Not listed, N= Not allowed to ask per local regulation. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes:  
Sort by pt. no., date, study period. 
 


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Appendix 3.9.5 – Other Safety Assessments: Pregnancy Test 
- Treated Patients – 
 
Page by Regimen  
 
Pt. No 
Age/Sex/Race 
Study  
Period 
Date 
Method 
Result 
Reason for 
Not Performing 
xxxx 
38/F/W 
Pretr. 
 
 
 
Surgically sterile 
xxxx 
41/F/W 
Pretr. 
ddmmmyyyy 
Serum 
Negative 
 
xxxx 
43/F/W 
… 
ddmmmyyyy 
Urine 
Negative 
 
xxxx 
47/F/W 
 
ddmmmyyyy 
Urine 
   Positive  * 
 
xxxx 
57/F/W 
 
 
 
 
Postmenopausal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All female patients are displayed. 
Race: W= White, B= Black, A= Asian, O= Not listed, N= Not allowed to ask per local regulation. 
Result: Positive results are marked by a *. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes:  
Sort by pt. no., study period. 
All female patients are to be displayed in the listing, including those for whom pregnancy test section is not present in the database. 
 


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Appendix 3.9.6 – Other Safety Assessments: Physical Examination 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study 
Period 
Physical Examination 
(including neurological status 
evaluation) Performed? 
Date of Physical 
Examination 
xxxxxx 
35/M/W 
Cy 1 
Y 
ddmmmyyyy 
 
 
Cy 2 
Y 
ddmmmyyyy 
 
 
Cy i 
Y 
ddmmmyyyy 
xxxxxx 
50/M/W 
Cy 1 
Y 
ddmmmyyyy 
 
 
Cy n 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt. no., study period. 
 
 


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Appendix 3 – Section 10 – Other Information   
Appendix 3.10.1 - Other Information: Concomitant Medications 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Tr. Start 
Date 
Tr. Last 
Date 
Trade / Generic 
Name 
Reason for Use 
Start Date 
Stop Date 
Ongoing at 
Final Visit 
(Y/N) 
Duration 
(days) 
Weeks 
from 
Tr. Start 
xxxx 
35/M/W 
ddmmmyyyy 
ddmmmyyyy 
xxxxxxxxxxxx 
xxxxxxxxxxxx 
ddmmmyyyy 
 
Y 
 
xxx.x 
 
 
 
 
xxxxxxxxxxxx 
xxxxxxxxxxxx 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
xxx.x 
 
 
 
 
xxxxxxxxxxxx 
xxxxxxxxxxxx 
ddmmmyyyy 
 
Y 
 
xxx.x 
xxxx 
50/M/W 
ddmmmyyyy 
ddmmmyyyy 
xxxxxxxxxxxx 
xxxxxxxxxxxx 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
xxx.x 
 
 
Only patients with at least one concomitant medication are displayed 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
Duration (days): from start date to stop date. 
Weeks from Tr. Start: from treatment start date to start date of concomitant medication. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt. no., start date. 
Select only patients with concomitant medication=’yes’ or derived ‘yes’ 


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Appendix 3.10.2 – Other Information: Concomitant Radiotherapies 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Tr. Start Date 
Tr. Last 
Date 
Lesion 
Number 
Lesion 
Description 
% Bone 
Marrow 
Irradiated 
Start Date 
Stop Date 
Duration 
(days) 
Weeks 
from 
Tr. Start 
xxxx 
35/M/W 
ddmmmyyyy ddmmmyyyy 
xxxx 
 
xx.xx 
ddmmmyyyy 
 
 
xxx.x 
 
 
 
 
xxxx 
 
…….. 
ddmmmyyyy ddmmmyyyy 
xxx 
xxx.x 
 
 
 
 
 
 
…….. 
ddmmmyyyy 
 
 
xxx.x 
xxxx 
xx/x/x 
ddmmmyyyy ddmmmyyyy 
 
 
…….. 
ddmmmyyyy ddmmmyyyy 
xxx 
xxx.x 
 
 
Only patients with at least one concomitant radiotherapy are displayed. 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Duration (days): from start date to stop date. 
Weeks from Tr. Start: from treatment start date to start date of concomitant radiotherapy. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt no., start date. 
Select only patients with  concomitant radiotherapy = ‘yes’ or derived ‘yes’. 
 


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Appendix 3.10.3 – Other Information: Blood Derivatives 
- Treated Patients - 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Date 
Weeks 
from Tr. 
Start 
Type 
Description 
No. of Units 
xxx 
35/M/W 
ddmmmyyyy 
xx.x 
Whole Blood 
 
xx 
 
 
 
 
Packed RBC 
 
… 
 
 
… 
 
Packed WBC 
 
… 
xxx 
xx/x/x 
ddmmmyyyy 
xx.x 
Platelets 
 
… 
 
 
ddmmmyyyy 
xx.x 
Other 
xxxxxxxxxxxxxxxxxxxxxxx 
… 
 
 
 
 
 
 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation.. 
Weeks from Tr. Start: from treatment start date to date of blood derivatives. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no,  date.  
 
 


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Appendix 3.10.4 - Other Information: Other Anti-Tumor Therapies at Follow-up 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age/Sex/Race 
Visit 
Start Date 
Days from  
Tr. Last Date 
Description 
xxxx 
35/M/W 
FU-1 
ddmmmyyyy 
xxx 
xxxxxxxxxxxxxxxx 
 
 
 
ddmmmyyyy 
xxx 
xxxxxxxxxxxxxxxx 
 
 
 
ddmmmyyyy 
xxx 
xxxxxxxxxxxxxxxx 
xxxx 
xx/x/x 
FU-2 
ddmmmyyyy 
xxx 
xxxxxxxxxxxxxxxx 
 
 
Only patients with at least one therapy are displayed. 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation.. 
Days from Tr. Last: from treatment last date to start date of anti-tumor therapy. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., start date. 
Select only patients with antitumor therapy =‘yes’ or derived ‘yes’. 
 


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Appendix 3.10.5 - Other Information: Physician’s Comments 
- Treated Patients - 
 
Page by Regimen  
 
Pt. No. 
Age/Sex/Race 
Section 
Visit 
Page 
Date 
Comments 
xxxx 
35/M/W 
xxxxx 
xxxxxxx 
xx 
ddmmmmyyyy 
xxx xxxxx xxxxxxx xxxxxxxxxxxxxxxxxxx xxxxx 
 
 
xxxxx 
xxxxxxx 
xx 
ddmmmmyyyy 
xxx xxxxx xxxxxxx xxxxxxxxxxxxxxxxxxx xxxxx 
xxxx 
xx/x/x 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
… 
… 
xxxx 
 
… 
… 
… 
… 
… 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation.. 
  
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., section, visit, page, date.  
 


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Page 112 of 125 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADDITIONAL DISPLAYS 
 
 
 
 


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Listing 3.3.1 – Patients Evaluability for Efficacy Analysis: Patients not Included in the Efficacy Analysis of Evaluable Patients 
- Enrolled Patients - 
 
Page by Regimen  
Pt. 
No 
First Dose 
Date 
Total  
Administered 
Dose in  
Cy1+Cy2 
Date of Last 
Tumor 
Assessment 
Days 
from 
First 
Dose 
Date of 
Death 
Days 
from 
First 
Dose 
Confirmation 
of Diagnosis 
(Y/N) 
Reasons for Non-Evaluability 
xxxx 
 
 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
Patient not treated 
xxxx ddmmmyyyy 
xxx.x 
ddmmmyyyy -xx 
 
 
 
Less than 80% of Intended Dose at Cy1+Cy2) / No tumor assessment at pretreatment 
xxxx ddmmmyyyy 
xxx.x 
 
 
 
 
 
No tumor assessment at pretreatment / No on treatment oncologic assessment nor death 
before (re)assessment 
xxxx ddmmmyyyy 
xxx.x 
ddmmmyyyy 
xx 
ddmmmyyyy xx 
 
No tumor assessment at pretreatment 
xxxx ddmmmyyyy 
xxx.x 
ddmmmyyyy 
xx 
ddmmmyyyy 
xx 
N 
Diagnosis not confirmed 
 
 
 
 
 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by patients no..  Report all reasons for non-evaluability. 


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Listing 3.4.1 – Demography and Pretreatment: Tumor History - Summary of Prior Antitumor Treatment Procedure 
- Treated Patients – 
 
Page by Regimen 
 
Pt. No. 
Age/Sex 
/Race 
Any Surgery ? 
Any Radiotherapy ? 
Any Systemic Therapy ? 
xxxx 
38/M/W 
Y 
 
Y  
xxxx 
xx/x/x 
Y 
 
 
xxxx 
xx/x/x 
 
Y 
 
xxxx 
xx/x/x 
 
 
Y 
xxxx 
xx/x/x 
Y 
 
 
 
Race: W= White, B= Black, A= Asian, O= Not Listed, N= Not Allowed to ask per local regulation. 
   
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming notes: 
Sort by pt. no.  
 
 
 


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Listing 3.7.1 - Adverse Events: All Reported Adverse Events by AE MedDRA Preferred Term and Assessment Visit 
- Treated Patients – 
 
Page by Regimen    
 
Pt. 
No. 
Adverse 
Event 
Study Period 
Cycle 
Start Date 
CTC 
Grade 
Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. 
to 
Study 
Proc. 
Rel. 
to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Action 
Taken Outcome 
xxxx 
xxxxxxxxxx  
Pretr. 
 
2 
 
ddmmmyyyy 
 
ddmmmyyyy 
 
N 
 
N 
 
R 
 
 
Cy 1 
ddmmmyyyy 
3 
 
ddmmmyyyy 
 
 
 
 
De 
Y 
D/C 
NR 
 
 
… 
…. 
4 
Y 
 
Y 
 
Y 
 
Pr 
Y 
D/C 
R 
 
 
Cy x 
ddmmmyyyy 
… 
Y 
… 
Y 
ddmmmyyyy 
 
 
… 
... 
PW 
… 
 
xxxxxxxxxx 
Cy 1 
ddmmmyyyy 
1 
 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
… 
Y 
No 
NR 
 
 
… 
….. 
… 
 
ddmmmyyyy 
 
 
Y 
 
Po 
… 
… 
R 
 
 
Cy x 
ddmmmyyyy 
… 
Y 
 
Y 
ddmmmyyyy 
 
 
… 
… 
… 
NR 
xxxx 
… 
… 
… 
… 
 
… 
… 
… 
… 
 
… 
… 
… 
… 
 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Action Taken: No=None; D/C=Dose Delayed/Changed; PW=Drug Permanently Withdrawn. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by AE MedDRA Preferred Term, AE page no., AE seq no, pt. no., study period  
Include also records of  End of Adverse Events Reporting Period and of Follow-up. 
 
 
 


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Listing 3.7.2 – Adverse Events: AEs with Possible/Probable/Definite Relationship to Study Treatment 
- Treated Patients - 
 
Page by Regimen 
 
Pt. No 
Study 
Period 
Cycle Start 
Date 
Adverse 
Event 
CTC 
Grade 
Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. 
to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Action 
Taken 
Outcome 
xxxx   
Cy 1 
ddmmmyyyy 
xxxxxxxxxx 
1 
N 
ddmmmyyyy 
 
ddmmmyyyy 
 
Po 
N 
… 
R 
 
 
 
xxxxxxxxxx 
1 
N 
 
Y 
 
Y 
Pr 
N 
… 
NR 
 
 
 
xxxxxxxxxx 
2 
… 
 
Y 
ddmmmyyyy 
 
De 
Y 
… 
R 
 
Cy 2 
ddmmmyyyy 
xxxxxxxxxx 
x 
… 
 
Y 
 
Y 
Po 
… 
No 
NR 
 
 
 
xxxxxxxxxx 
… 
… 
ddmmmyyyy 
 
 
Y 
De 
N 
No 
NR 
 
 
 
xxxxxxxxxx 
   3   
Y 
ddmmmyyyy 
 
ddmmmyyyy 
 
De 
Y 
D/C 
R 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
AP/SP: Already present/Still present. 
Related to Study Treatment: Po=Possible, Pr=Probable, De=Definite.  
Action Taken: No=None; D/C=Dose Delayed/Changed; PW=Drug Permanently Withdrawn. 
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq. no. 
Only AEs with possible/probable/definite relationship to study treatment are to be selected. 
 


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Listing 3.7.3 – Adverse Events: AEs Leading to Dose Delay or Change 
- Treated Patients - 
 
Page by Regimen 
 
Pt. No 
Study 
Period 
Cycle Start 
Date 
Adverse 
Event 
CTC 
Grade 
Serious 
Start Date 
A. 
P. 
Stop Date 
S. 
P. 
Rel. 
to 
Study 
Treat. 
Rel. to 
Study 
Disease 
Outcome 
xxxx   
Cy 1 
ddmmmyyyy 
xxxxxxxxxx 
1 
N 
ddmmmyyyy 
 
ddmmmyyyy 
 
Po 
N 
R 
 
 
 
xxxxxxxxxx 
1 
N 
 
Y 
 
Y 
Pr 
N 
NR 
 
 
 
xxxxxxxxxx 
2 
… 
 
Y 
ddmmmyyyy 
 
De 
Y 
R 
 
Cy 2 
ddmmmyyyy 
xxxxxxxxxx 
x 
… 
 
Y 
 
Y 
Po 
… 
NR 
 
 
 
xxxxxxxxxx 
… 
… 
ddmmmyyyy 
 
 
Y 
De 
N 
NR 
 
 
 
xxxxxxxxxx 
   3   
Y 
ddmmmyyyy 
 
ddmmmyyyy 
 
De 
Y 
R 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
Only AE occurrences at the time when Action Taken was Dose Delay or Change are displayed. 
AP/SP: Already present/Still present. 
Related to Study Treatment: No=Unrelated, Un=Unlikely, Po=Possible, Pr=Probable, De=Definite.  
Outcome: R=Recovered; RS=Recovered with sequelae; D=Death; Un=Unknown; NR=Not recovered. 
 
[Protocol No. (Study Description)] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by pt. no., study period, AE MedDRA Preferred Term, AE page no., AE seq. no.. 
Selct only the occurrences of AEs when variable Action Taken= ‘Dose Delayed/Changed’.  
 


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 Listing 3.8.1 - Laboratory Assessments: Hematology by Patient, Study Period and Laboratory Test 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study  
Period 
Cycle  
Start Date 
Date of 
Sampling 
Study 
Day 
Lab. Test 
Collected 
Value 
Collected 
Unit 
L/H 
Converted  
Value 
Converted  
Unit 
CTC  
Grade     
xxxx 
52/F/W 
Pretr. 
ddmmmyyyy 
ddmmmyyyy 
-xx 
Hemoglobin 
xxx.xx 
xxxx 
L 
xxx.xx 
xxxx 
x 
 
 
 
 
 
 
Platelet 
… 
… 
… 
… 
… 
    3  * 
 
 
 
 
 
 
WBC 
… 
… 
… 
… 
… 
    4  * 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
... 
 
 
Cycle x 
ddmmmyyyy 
ddmmmyyyy 
xx 
Hemoglobin 
… 
… 
… 
… 
… 
2 
… 
… 
… 
… 
… 
 
Platelet 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation.  
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades= 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no, study period, date of sampling, study day, lab test. If feasible lab test is to be ordered as per CRF appearance. 
The listing must include all the hematological labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 


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Lisring 3.8.2 – Laboratory Assessments: Hematology by Laboratory Test, Patient and Study Periods with More than One Assessment 
- Treated Patients - 
 
Page by Regimen /Laboratory Test: < Neutrophils >  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study  
Period 
Cycle  
Start Date 
Cycle Total 
Dose   
(mg)  
Date of 
Sampling 
Study 
Day 
Collected 
Value 
Collected 
Unit 
L/H  
Converted  
Value 
Converted  
Unit 
CTC  
Grade    
xxxx 
52/F/W 
Pretr. 
 
 
ddmmmyyyy 
-xx 
xxx.xx 
xxxx 
L 
xxx.xx 
xxxx 
x 
 
 
Cy x 
ddmmmyyyy 
xxxx.xx 
ddmmmyyyy 
xx 
… 
… 
… 
… 
… 
    3  * 
 
 
 
 
 
 
xx     
… 
… 
… 
… 
… 
    4  * 
 
 
… 
… 
 
… 
... 
… 
… 
… 
… 
… 
... 
xxxx 
 
Pretr. 
 
 
ddmmmyyyy 
xx 
… 
… 
… 
… 
… 
2 
… 
 
… 
… 
 
… 
 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only study periods with more than one assessment for the test are displayed 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades= 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by “page by variables”, pt. no, study period, date of sampling, study day. If feasible lab test is to be ordered as per CRF appearance.  
The listing must include all the hematological labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each selected assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 


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Listing 3.8.3 – Laboratory Assessments: Hematology – Maximum CTC Grade by Laboratory Test, Patient and Time Window 
- Treated Patients – 
 
Page by Regimen    
 
 
 
Maximum CTC Grade at 
Laboratory 
Test 
Pt. 
No. 
Pretr. 
Cycle 1 
Cycles >1 
All 
Cycles 
Neutrophils 
xxxx 
3 
2 
    4  * 
   4  * 
 
xxxx 
1 
    2  * 
1 
   2  * 
 
xxxx 
x 
x 
x 
x 
 
xxxx 
x 
x 
x 
x 
… 
xxxx 
x 
x 
x 
x 
… 
… 
… 
… 
… 
 
 
 
Only lab. test included in the NCI CTCAE v3.0 document are displayed. 
Pretreatment Value: the most recent value among the pretreatment assessment(s). 
CTC Grade - NCI CTCAE v3.0: U= Unknown.    The '*' identifies CTC grades higher than Pretreatment grade. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by lab test,  pt. no. If feasible lab test is to be ordered as per CRF appearance. 
Select collected lab tests listed in NCI CTCAE v3.0. 
 


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Listing 3.8.4 - Laboratory Assessments: Blood Chemistry by Patient, Study Period and Laboratory Test 
- Treated Patients – 
 
Page by Regimen  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study  
Period 
Cycle  
Start Date 
Date of 
Sampling 
Study 
Day 
Lab. Test 
Collected 
Value 
Collected 
Unit 
Collected 
Lower Limi
Collected 
Upper 
Limit 
L/H Converted  
Value 
Converted  
Unit 
CTC  
Grade   
xxxx 
52/F/W 
Pretr. 
ddmmmyyyy 
ddmmmyyyy 
-xx 
ALT 
xxx.xx 
xxxx 
xxx.xx 
xxx.xx 
L 
xxx.xx 
xxxx 
x 
 
 
 
 
 
 
AST 
… 
… 
 
 
… 
… 
… 
    3  * 
 
 
 
 
 
 
Albumin 
… 
… 
 
 
… 
… 
… 
    4  * 
 
 
 
 
 
 
… 
… 
… 
 
 
… 
… 
… 
... 
 
… 
Cycle x 
ddmmmyyyy 
ddmmmyyyy 
xx 
ALT 
… 
… 
 
 
… 
… 
… 
2 
… 
 
… 
… 
… 
 
AST 
… 
… 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
… 
… 
… 
… 
 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation.  
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades = 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by pt. no, study period, date of sampling, study day, lab test. If feasible lab test is to be ordered as per CRF appearance. 
The listing must include all the blood chemistry labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 
 


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Listing 3.8.5 – Laboratory Assessments: Blood Chemistry by Laboratory Test, Patient and Study Periods with More than One Assessment 
- Treated Patients - 
 
Page by Regimen /Laboratory Test: < ALT >  
 
Pt. 
No. 
Age 
/Sex 
/Race 
Study 
Period 
Cycle Start 
Date 
Cycle Total 
Dose   
(mg)  
Date of 
Sampling 
Study 
Day 
Collected 
Value 
Collected
Unit  
Collected 
Lower 
Limit  
Collected 
Upper 
Limit 
L/H 
Converted 
Value 
Converted 
Unit 
CTC 
Grade 
xxxx 
52/F/W 
Pretr. 
 
 
ddmmmyyyy 
- xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
L 
xxx.xx 
xxxx 
N 
 
 
 
 
 
……. 
 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
 
… 
… 
N 
 
 
Cy x 
ddmmmyyyy 
xxxx.xx 
ddmmmyyyy  
xx 
xxx.xx 
xxx.xx 
xxx.xx 
xxx 
H 
… 
… 
3* 
 
 
 
 
 
 
 
… 
… 
… 
… 
 
… 
… 
 
 
 
 
 
 
 
 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
ddmmmyyyy 
xx 
… 
… 
… 
… 
L 
 
 
4* 
 
 
 
 
 
 
… 
… 
… 
… 
… 
 
 
 
… 
 
… 
… 
 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
Only study periods with more than one assessment for the test are displayed 
Race: W=White, B=Black, A=Asian, O=Not listed, N=Not allowed to ask per local regulation. 
Converted Unit: either the unit reported in the NCI CTCAE v3.0 or the Conventional Unit, depending on the analyzed lab test. 
CTC Grade - NCI CTCAE v3.0: N= Not Applicable, U= Unknown.      The '*' identifies the occurrence(s) of CTC grades= 3 or 4. 
L/H: Below/Above Normal Limits. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes: 
Sort by “page by variables”, pt. no, study period, date of sampling, study day.  
If feasible lab test is to be ordered as per CRF appearance. 
The listing must include all the biochemistry labs (including also the ones that are not listed in the NCI CTCAE v.3.0). 
Each selected assessment (i.e. record) is to be displayed only if date is not missing or collected value is not missing. 
 


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Listing 3.8.6 – Laboratory Assessments: Blood Chemistry - Maximum CTC Grade by Laboratory Test, Patient and Time Window (Part I) 
- Treated Patients - 
 
Page by Regimen   
 
 
 
Maximum CTC Grade at 
Laboratory 
Test 
Pt. 
No. 
Pretr. 
Cycle 1 
Cycles >1 
All 
Cycles 
ALT 
xxxx 
3 
2 
    4  * 
   4  * 
 
xxxx 
1 
    2  * 
1 
   2  * 
 
xxxx 
x 
x 
x 
x 
 
xxxx 
x 
x 
x 
x 
… 
xxxx 
x 
x 
x 
x 
Albumin 
xxxx 
0 
1* 
2* 
2* 
 
Only lab. tests included in the NCI CTCAE v3.0 document and whose abnormality is determined by one-way modifications only, are displayed. 
Pretreatment Value: the most recent value among the pretreatment assessment(s). 
CTC Grade - NCI CTCAE v3.0: U= Unknown.    The '*' identifies CTC grades higher than Pretreatment grade. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by lab test, pt. no. If feasible lab test is to be ordered as per CRF appearance. 
Select collected lab tests listed in NCI CTCAE v3.0. 
 


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Listing 3.8.7 – Laboratory Assessments: Blood Chemistry - Maximum CTC Grade by Laboratory Test, Patient and Time Window (Part II) 
- Treated Patients - 
 
Page by Regimen  
 
 
 
Maximum CTC Grade at 
Laboratory 
Test 
Pt. 
No. 
Pretreatment 
Cycle 1 
Cycles >1 
All Cycles 
 
 
L 
N 
H 
L 
N 
H 
L 
N 
H 
L 
N 
H 
Calcium 
xxxx 
 
0 
 
2 
 
 
2 
 
1 
2 
 
1 
 
xxxx 
 
0 
 
 
0 
 
 
 
3 
 
 
3 
 
xxxx 
 
0 
 
 
0 
 
 
0 
 
 
0 
 
 
xxxx 
1 
 
 
2 
 
 
3 
 
 
3 
 
 
… 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
Sodium 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only lab. tests included in the NCI CTCAE v3.0 document and whose abnormality is determined by two-way modifications (L = value lower than normal range, H = value higher 
than normal range, N= value within normal range), are displayed. 
Pretreatment Value: the most recent value among the pretreatment assessment(s). 
CTC Grade - NCI CTCAE v3.0: U= Unknown. 
 
[Protocol No.; Study Description] 
[Program Path; Date/Time Produced; Date Data Extract] 
 
Programming Notes:  
Sort by lab test, pt. no. If feasible lab test is to be ordered as per CRF appearance. 
Select collected lab tests listed in NCI CTCAE v3.0 for which both ‘hyper’ and ‘hypo’ grading is provided. For this study: Magnesium, Potassium, Sodium. 
 


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REVISION HISTORY 
 
Version Date 
Reviewed by:  
(Printed name) 
Reason for change 
1.0 
8th  July 2013 
 
Initial version 
 
 
 
 
 
Reviewed and Approved by: 
 
Role 
Printed Name 
Signature 
Date 
Statistician 
Anna Petroccione 
 
 
CL 
 
Marcella Martignoni 
 
 
 
 

Prot_000.pdf: 
Milciclib maleate (PHA-848125AC) 
CDKO-125a-006-P4 
Protocol for Study CDKO-125a-006 
09 March 2017 
 
 
Tiziana Life Sciences, PLC - Confidential 
Page 1 of 101 
 
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 
09 March 2017 
Country(ies) 
All 
Site(s) 
All 
Amendment No. 3 
Date 
27 June 2014 
Countries 
All 
Sites 
All 
Amendment No. 2 
Date 
13 December 2011 
Countries 
All 
Sites 
All 
Amendment No. 1 
Date 
21 January 2011 
Countries 
All 
Sites 
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. 
 


Milciclib maleate (PHA-848125AC) 
CDKO-125a-006-P4 
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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>  
 


Milciclib maleate (PHA-848125AC) 
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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 


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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 


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9.4.10.10. Other Anticancer or Experimental Therapy ..................................................57 
9.5. Management of Patients after Data Cut-Off ..................................................................57 
10. SUBJECT WITHDRAWAL FROM STUDY PARTICIPATION ....................................58 
11. ASSESSMENTS ................................................................................................................58 
11.1. Timing of Assessments ................................................................................................58 
11.2. Efficacy Assessments ...................................................................................................58 
11.2.1. Tumor Imaging ......................................................................................................58 
11.2.1.1. Measurability of Tumor Lesions .....................................................................59 
11.2.1.2. Recording Tumor Measurements ....................................................................60 
11.2.1.3. Target Lesions Tumor Response .....................................................................61 
11.2.1.4. Non Target Lesions Tumor Response .............................................................62 
11.2.1.5. Confirmation of Tumor Response ...................................................................63 
11.2.1.6. Determination of Overall Response by RECIST (version 1.1) .......................63 
11.3. Outcomes Research Assessments ................................................................................65 
11.4. Safety Assessments ......................................................................................................65 
11.4.1. Adverse Event Assessment ....................................................................................65 
11.4.1.1. Definition of Adverse Events ..........................................................................65 
11.4.1.2. Eliciting Adverse Event Information ...............................................................66 
11.4.1.3. Adverse Event Reporting Period .....................................................................67 
11.4.1.4. Reporting Requirements ..................................................................................68 
11.4.1.5. Recording Adverse Events in the Case Report Forms ....................................68 
11.4.1.6. Grading of Adverse Event Severity .................................................................69 
11.4.1.7. Exposure In Utero ............................................................................................70 
11.4.2. Laboratory Safety Assessments .............................................................................71 
11.4.3. Other Safety Assessments ......................................................................................73 
11.5. Other Assessments .......................................................................................................74 
11.5.1. Confirmation of histological diagnosis ..................................................................74 
11.5.2. Pharmacokinetics ...................................................................................................74 
11.5.3. Laboratory Exploratory Studies on Tumor Specimens ..........................................74 
11.5.3.1. Collection of Tumor Specimen(s) ...................................................................74 


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11.5.3.2. Molecular characterization of patient’s tumors ...............................................74 
12. STATISTICAL METHODS ..............................................................................................74 
12.1. Sample Size Calculation ..............................................................................................74 
12.2. Definition of Analyzed Study Populations ..................................................................76 
12.3. Analyses .......................................................................................................................76 
12.3.1. Study Conduct and Subject Disposition ................................................................76 
12.3.2. Baseline Characteristics .........................................................................................76 
12.3.3. Treatment Administration/Compliance .................................................................77 
12.3.4. Efficacy Analyses ..................................................................................................77 
12.3.5. Outcomes Research Analyses ................................................................................78 
12.3.6. Safety Analyses ......................................................................................................78 
12.3.7. Analyses of Other Endpoints .................................................................................79 
12.3.7.1. Baseline Expression of Molecular Markers in Tumor Biopsies ......................79 
12.3.7.2. Pharmacokinetics .............................................................................................79 
12.3.7.3. Concomitant Medications and Post-Treatment Anti-tumor Therapies ...........79 
12.4. Interim Analysis Plan ...................................................................................................80 
12.5. Data Monitoring Committee ........................................................................................80 
13. END OF STUDY ...............................................................................................................80 
14. QUALITY CONTROL AND QUALITY ASSURANCE .................................................80 
15. DATA HANDLING AND RECORD KEEPING ..............................................................80 
15.1. Case Report Forms .......................................................................................................80 
15.2. Record Retention .........................................................................................................81 
16. ETHICS ..............................................................................................................................81 
16.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ...................81 
16.2. Ethical Conduct of the Trial .........................................................................................82 
16.3. Subject Information and Consent ................................................................................82 
17. SPONSOR DISCONTINUATION CRITERIA .................................................................82 
18. DISSEMINATION AND PUBLICATION OF RESULTS ...............................................82 
19. REFERENCES ...................................................................................................................83 
 


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TABLES 
Table 1. PHA-848125AC pharmacokinetic data from CDKO-125a-001 study ....................33 
Table 2. PHA-848125AC pharmacokinetic data from CDKO-125a-002 study ....................33 
Table 3. PHA-848125AC pharmacokinetic data from CDKO-125a-003 study ....................34 
Table 4. Criteria for PHA-848125AC Dose Modifications...................................................50 
Table 5. Drug-induced Tremors and Corresponding Neurologic Signs ................................53 
Table 6. Response Criteria ....................................................................................................63 
Table 7. Best overall response when confirmation of CR and PR required ..........................64 
Table 8. Reporting requirements for adverse events .............................................................68 
Table 9. Grading of Adverse Event Severity for Events not reported in the CTCAE Version 
3.0 .............................................................................................................................69 
 
APPENDICES 
Appendix 1. Recommended Informed Consent Form ..........................................................88 
Appendix 2. The Distribution of Active Bone Marrow in the Adult ....................................99 
 
 


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1. SUMMARY 
Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
Title of Study: PHASE II STUDY OF ORAL PHA-848125AC IN PATIENTS WITH THYMIC 
CARCINOMA PREVIOUSLY TREATED WITH CHEMOTHERAPY 
Protocol Number: CDKO-125a-006 
Therapeutic Area: Oncology 
Background Information 
Thymic carcinomas are a category of heterogeneous thymic tumors, with distinct molecular characteristics 
and with the most aggressive behavior and poorest prognosis among thymomas [1]. Thymomas are rare 
tumors but nevertheless the most common neoplasms of the anterior mediastinal compartment, with an 
overall incidence in US (1973-1998) of 0.15 per 100000 person/years [2]. Patients with locally advanced or 
disseminated thymic malignancies are usually symptomatic, presenting with chest pain, shortness of breath, 
paralysis of the phrenic nerve, pleural effusion and superior vena cava syndrome. Immune disorders have 
also been associated with thymoma, the most common being myasthenia gravis [3]. There is no known cause 
for thymomas, however, in recent years, a few studies on molecular changes in thymomas and thymic 
carcinomas have been published. In particular, the expression of KIT and epidermal growth factor receptor 
(EGFR), targets, respectively, of imatinib and EGFR inhibitors (ie, erlotinib, gefitinib), have been tested by 
immunohistochemistry in a limited number of thymic malignancies: KIT was positive in 73% of thymic 
carcinomas and 5% of thymomas, in contrast, EGFR expression was more often present in thymomas (83%) 
than in thymic carcinomas (50%) [4]. Another study investigated HER2/neu amplification and expression of 
the apoptosis-related markers p53, BCL-2, BAX, BCL-XL, and p21 [5]; p53 and Bcl-2 were definitely more 
expressed in thymic carcinomas than thymomas and correlated with more advanced stages and 
unresectability, whereas no HER2/neu amplification was observed. Other markers, such as expression of 
thymidylate synthase and dihydropyrimidine dehydrogenase, which predict sensitivity to 5-fluorouracil-
based chemotherapy, were not correlated with clinicopathological characteristics in a series of thymic 
malignancies [6].  
The loss of control of cell cycle checkpoints seems a common occurrence in thymomas, supporting the idea 
that functional cooperation between different cell cycle inhibitor proteins regulates cell growth control and 
tumor suppression. Univariate analyses on the expression of p21 and p27 in specimens from 25 encapsulated 
thymomas (using immunohistochemistry) suggest that negative expressions of p21 and p27 (natural 
inhibitors of CDKs) significantly correlates with poor prognosis for disease-free survival [7]. In addition, 
some members of the neurotrophin receptors family seem to play a significant role in this disease: in a study 
investigating the expression of neurotrophin receptors in thymic epithelial tumors on a quite large series of 
patients (N=99) [8], the pattern of TRKA expression was analyzed according to WHO classification for the 
histologic subtypes (A, AB, B1, B2, B3, C). All patients, except one, had immunostaining for TRKA 
expression in the tumors gradually increasing from type A to C. Conversely, none of the tumors showed 
TRKB or TRKC immunoreactivity. In addition, from type A to type C, there was a decreasing percentage of 
tumors with p75 immunostaining. These observations suggest a further elucidation on the specific role of 
TRKA and p75 in this disease. 
Besides the above mentioned WHO histological classification of thymoma, the Masaoka staging system is 
commonly employed to evaluate invasiveness and to determine the therapy, since the optimal treatment for 
this disease depends on its clinical stage [1]. Locally advanced or metastatic thymomas are often treated with 
combined treatment modalities, including surgery, radiation and chemotherapy. There are no drugs officially 
approved for the treatment of thymoma and thymic carcinoma. However, several antineoplastic agents are 
used; cisplatin/doxorubicin-based combination chemotherapy [PAC regimen (cisplatin, doxorubicin, 
cyclophosphamide) or ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide)] seem to 


Milciclib maleate (PHA-848125AC) 
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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
produce the best overall response rate and survival. Other combined and /or single agent chemotherapy with 
cisplatin, etoposide, ifosfamide, epirubicin, maytansine, octreotide and steroids are used as well [9-11]. 
Examining treatments for patients with advanced disease who had received one or more prior lines of 
therapy, published data generally indicates a limited activity. Single agent studies with gefitinib, imatinib or 
a combination study erlotinib+bevacizumab did not produce satisfactory results [12,13,14], although only 
two cases of possible clinical benefit were observed with imatinib and sorafenib, due to the rare incidence of 
KIT mutations in those patients’ tumors [15,16]. An optimal treatment strategy has yet to be determined and 
other drugs are warranted to improve the outcome of patients with advanced invasive tumors [10]. The 
unmet medical need for new agents for the treatment of thymic malignancies is therefore high, as 
demonstrated by the number of studies with experimental agents currently in progress.  
Given the rarity of thymic carcinoma subtype, prospective phase II studies of chemotherapy specifically 
targeting thymic carcinoma patients are rare. Combined therapies such as ADOC or VIP (cisplatin, 
ifosfamide, etoposide) achieved, as a first line treatment for the advanced disease, a median survival time 
around 19-20 months [17,18]. In previously untreated, unresectable thymic carcinoma, first-line combination 
of carboplatin and paclitaxel achieved an overall response rate of 36% with a median survival time of 22.7 
months and a median progression-free survival of 7.9 months [19].   
In a single agent study with pemetrexed, on 23 previously treated evaluable patients with unresectable stage 
IV A and B disease, there were 4 objective responses (2 CRs and 2 PRs) (17% RR). Responses were 
obtained only in stage IVA thymoma patients, with a median duration of time to progression of 45.4 weeks; 
in thymic carcinoma patients the median duration of time to progression was much shorter (5.1 weeks) [20]. 
In other two recent series of previously treated patients with thymic malignancies, objective responses were 
reported in B2 and B2/3 tumors (no type C thymic carcinoma patients were enrolled in the first study) with a 
gemcitabine/ capecitabine combination [21] and with the histone deacetylase inhibitor (HDAC) belinostat 
[22]. Also in this second study, responses were obtained only in thymoma patients and no responses were 
seen in the 8 evaluable patients with thymic carcinoma. Thymic carcinoma is therefore confirmed as a type 
of cancer where prognosis is particularly poor and the course of the disease more aggressive compared to the 
other thymomas.   
Given the current clinical scenario, in thymic carcinoma patients previously treated with chemotherapy, a 
single agent therapy is able to induce a median PFS of approximately 5.1 weeks [20], roughly corresponding 
to an estimated  PFS rate at 3 months of about 17%. Therefore a 33% target PFS-rate at three months could 
be regarded as clinically interesting for a new investigational agent.     
PHA-848125, N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H- 
pyrazolo[4,3-h]quinazoline-3-carboxamide, is a potent inhibitor of the kinase activity of the CDK2/Cyclin A 
complex, some closely related CDKs (i.e. CDK1, CDK4, and CDK5) and TRKA; the block in G1 phase of 
the cell cycle observed in tumor cells exposed to PHA-848125 supports the postulated mechanism of action 
as determined by this biochemical activity: in fact, PHA-848125 is able to modulate both the 
phosphorylation of the Retinoblastoma protein (pRB), a substrate of CDK/Cyclin complex, as well as to 
reduce the phosphorylation status of TRKA and of the proteins of the TRKA signaling pathway [23].  
PHA-848125, formulated for oral administration as maleate salt (PHA-125848AC), is being tested, with 
different schedules of administration, in two ongoing phase I trials in advanced/metastatic solid tumor 
patients, in a phase I/II study in patients with recurrent malignant glioma, in a phase I combination study 
with gemcitabine in advanced/metastatic solid tumor patients and in a phase II study in patients with 
malignant pleural mesothelioma. 
In the first-time in man study CDKO-125a-001, in which PHA-848125AC was administered for 7 
consecutive days every 2 weeks to solid tumor patients, the flat dose identified as recommended phase II 
dose (RP2D) was 150 mg/day; this dose was associated with mild/moderate reversible adverse events, 
represented by maximum grade 2 nausea and/or vomiting and/or diarrhea and maximum grade 2 reversible 
tremors. 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
As for efficacy, notably, one out of three patients with thymic carcinomas, treated in the study CDKO-125a-
001 at the dose 150 mg/day, showed a partial response reached after 11 treatment cycles, and another patient 
showed a stable disease with progressively shrinking tumor lesions after 2, 4 and 6 treatment cycles; the 
third patient was taken off study after two cycles for disease progression. It is of note that lesion regression 
was reported in patients with the most unfavorable histology (thymic carcinoma). 
Study rationale 
Chemotherapy was shown to have significant antitumor activity against unresectable, recurrent or metastatic 
thymomas and thymic carcinomas, but an optimal treatment strategy has not been determined and other 
drugs are needed to improve the outcome of patients with advanced invasive tumors [10]. 
In recent years, a few studies on molecular changes in thymomas and thymic carcinomas point to alterations 
that may be of use in selecting patients for targeted therapies. Unfortunately for some of them, such as KIT 
and EGFR inhibitors, the reported results seem to be discouraging [12-14]. In addition, despite a lack of 
correlation of thymidilate synthase expression with thymoma clinicopathological characteristics, pemetrexed 
obtained interesting responses in stage IVA thymomas, but not in thymic carcinomas [20]. 
The pyrazoloquinazoline PHA-848125 is a compound counteracting the effects of some of the other so far 
identified, but not yet exploited, molecular alterations found in thymoma and thymic carcinoma, e.g. 
underexpressed p21 and p27 and overexpressed TRKA [7,8]. These targets have not yet been investigated in 
therapeutic intent clinical trials. 
In fact, p21 and p27 encode natural potent cyclin-dependent kinase inhibitors and their ablation in the cancer 
cell results in an activation of cyclin E/CDK2 or cyclin D/CDK4 complexes and thus uncontrolled cell cycle 
progression and cell proliferation [24-32], while TRKA activation promotes tumor growth [33], probably 
thorough MAPK pathway activation. PHA-848125 potently inhibits both the CDK/Cyclin complexes and 
TRKA, proposing in this way to be a “selective dual inhibitor” and appearing particularly attractive in this 
disease. 
The preliminary results in early clinical trials on thymic carcinomas patients (2 out of 3 patients with clinical 
benefit) support the hypothesis that PHA-848125 could be of therapeutic value for patients with this tumor 
type. 
An exploratory analysis on the relationship of molecular features of p53 (natural regulator of p21), p21, p27, 
cyclin D1, p75, TRKA and other genes/proteins involved in the PHA-848125AC mechanism of action with 
treatment efficacy variables will be possibly performed in tumor biopsies of consenting patients obtained 
before study entry. 
Trial Objectives 
Primary objective:  
Assessment of the antitumor activity of PHA-848125AC as second-line treatment in patients with recurrent 
or metastatic, unresectable thymic carcinoma previously treated with chemotherapy. Antitumor activity will 
be evaluated on the basis of the progression-free survival status at 3 months. 
Secondary objectives: 
Assessment of additional measures of tumor control to further characterize the efficacy profile of PHA-
848125AC in recurrent or metastatic, unresectable thymic carcinoma patients previously treated with 
chemotherapy. 
Evaluation of the safety profile of repeated administrations of PHA-848125AC in patients with recurrent or 
metastatic, unresectable thymic carcinoma previously treated with chemotherapy. 
Exploratory objective: 
Relationship of baseline molecular features in tumor biopsies of p53, p21, p27, cyclin D1, p75, TRKA and 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
other genes/proteins involved in the PHA-848125AC mechanism of action with treatment efficacy.   
Trial endpoints 
Primary endpoint: 
Progression-free survival rate at 3 months (PFS-3 rate). The PFS-3 rate, will be calculated as the proportion 
of evaluable patients known to be alive and progression-free at ≥ 3 months since study treatment start out of 
the total number of evaluable patients. 
Secondary endpoints: 
- Confirmed Objective Response Rate (CR + PR) according to RECIST guideline (version 1.1). 
- Disease Control Rate (Confirmed Objective Response Rate + > 6 weeks SD rate). 
- Progression-free survival, calculated as the time from the date of treatment start to the date of first 
documentation of objective progression or of death due to any cause, whichever comes first 
- Duration of Response, measured from the time measurement criteria are first met for CR/PR (whichever is 
first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded on study). 
- Overall Survival (OS), i.e. the time from the date of treatment start to the date of death from any cause. 
- Overall safety profile, evaluated on the basis of laboratory and clinical safety parameters (i.e. hematology 
and blood chemistry, urinalysis, vital signs, ophthalmologic examinations and adverse events emerging 
during the trial).  The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Version 3.0 will be used for the severity grading of adverse events and hematological and blood 
chemistry abnormalities. 
Exploratory endpoint: 
Baseline characterization of selected biomarkers (p53, p21, p27, cyclin D1, p75, TRKA and other 
genes/proteins involved in the PHA-848125AC mechanism of action) in tumor tissue of consenting patients. 
Assessments will be done on paraffin embedded blocks, obtained from all patients before study entry, by 
IHC and other possible techniques, such as FISH and PCR. 
Study Design   
In consideration of the exploratory nature of the study, the Simon’s optimal 2 stage design [23] is adopted 
for this single-arm, open-label, multicentre phase II clinical trial.  
Histological confirmation of diagnosis of thymic carcinoma for all patients will be obtained by an 
Independent Review Committee.  
Sample Size Determination and Statistical Methods: 
The total number of evaluable patients for the primary efficacy analysis ranges from 17 (if the trial stops at 
the end of the 1st stage) to 54 (if the trial proceeds up to the completion of the 2nd stage). Accounting for a 
10%-15% proportion of non evaluable patients, up to 20 patients could be required in the 1st stage of the 
study and up to overall 60 patients could be required for completing the trial (1st and 2nd stage). 
The primary endpoint of the study is the progression-free survival status at 3 months and the primary 
efficacy analysis will be performed on the proportion of successes (i.e. patients alive and in a progression-
free status at 3 months since treatment start) out of the total number of evaluable patients (PFS-3 rate).  
Considering a 33% PFS-3 rate as clinically interesting, against a clinically uninteresting hypothesis of a 
PFS-3 rate no higher than 17%, the system of hypotheses to be tested is: 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
H0:  p  p0,   p0 = 0.17      vs.      H1:  p  p1,    p1= 0.33 
The analysis will be performed at the overall level  = 0.05 (1-sided). 
The design below outlined will provide 80% power (1-β) not to reject the treatment as insufficiently 
effective, if the true PFS-3 rate is 33% or higher.  
In the first stage, 17 evaluable patients are to be assessed. If  3 successes are observed, the study treatment 
will be considered as providing insufficient evidence of efficacy and the trial will be terminated.  
If at least 4 successes are observed in the 1st stage, patients’ enrollment will proceed up to an overall 
enrollment of 54 evaluable patients. At the final analysis,  14/54 successes (PFS-3 rate ≥ 25.9%) will be 
required to reject the null hypothesis and suggest that the drug might have an interesting level of efficacy.  
 
H0    vs.    H1 
  
(1-
sided)   
powe
r (1-
) 
1st Stage (*) 
2nd Stage 
Pts 
STOP 
and  
reject 
drug 
Pts 
Reject drug 
Do not reject drug 
p0  0.17  vs.  p1  
0.33 
(PFS-3 rate) 
0.05 
0.80 
17 
evaluable 
pts 
 3  / 17 
successes 
54 
evaluable 
pts 
 13 / 54 succ.   
(PFS-3 rate  
24.1%) 
 14 / 54 succ. 
 (PFS-3 rate  
25.9%) 
(*) Probability of Early Termination: PET=0.675,  if the drug is actually ineffective;   
      Probability to continue the trial > 0.863, if the true PFS-3 rate is at least 33%:  
Expected sample size assuming ineffective drug: 29 
No. of enrolled patients:   20 patients in the 1st stage,   60 patients overall  (if 10%-15% inevaluable patients)  
 
The progression free survival at 3 months will be evaluated based on the antitumor activity evaluated during 
the oncologic assessment at 3 months after first drug administration. The oncologic assessment will be 
performed preferably between 92-98 days from treatment start, but all patients with assessments performed 
up to 134 days will be considered evaluable for the primary end-point. 
Supportive analyses of the primary endpoint will include the estimation of the PFS-3 rate together with its 
exact, two-tail, 95% confidence interval and the estimation of the PFS curve by the Kaplan-Meier method 
[24] in both the evaluable and the treated patient population.  The other efficacy endpoints including the 
confirmed objective response rate, the disease control rate, the duration of response, and the overall survival 
will be descriptively analyzed in both the evaluable and the treated patient populations.  Kaplan-Meier 
estimates will be generated and plotted for the overall survival endpoint.  
Patients’ baseline characteristics, treatment exposure and safety data will be analyzed in the treated patient 
population and, if clinically interesting, in other subsets such as the evaluable patient population.  
Descriptive statistical analyses and individual data listings will be used to report all collected data including 
patient disposition, protocol deviations, baseline characteristics, treatment exposure, efficacy, and safety 
data. 
Patient Populations:  
 
Screened Patients:  This population will include all subjects who are screened about their eligibility for 
the trial, regardless of whether or not they will be enrolled in the study.  This population will be 


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evaluated in the analysis of patients’ disposition. 
 
Enrolled Patients:  This population will include all subjects who are enrolled in the trial, regardless of 
whether subjects receive the study drug or not.  This population will be evaluated in the analysis of 
patients’ disposition. 
 
Treated Patients: The treated patient population consists of all enrolled patients who actually receive at 
least one study drug administration. This population will be evaluated in the analysis of patient 
disposition, baseline characteristics, treatment efficacy and safety and treatment exposure. 
 
Patients Evaluable for Efficacy Analysis:  This is the patient population for the primary efficacy 
analysis of PFS-3 rate and consists of all treated patients who fulfill the following additional conditions:  
 
They have received histological confirmation of thymic carcinoma by an Independent Review 
Committee  
 
They have received at least 80% of drug in the first two cycles overall. 
 
They have baseline and 1 on-treatment tumor/oncologic assessment(s) or die before tumor 
re-assessment. 
If deemed of clinical interest, patient disposition, baseline characteristics, treatment efficacy and 
safety and treatment exposure will be analyzed also in this population. 
Exploratory studies 
Exploratory analyses on the relationship of molecular features of p53, p21, p27, cyclin D1, p75, TRKA and 
other genes/proteins involved in the PHA-848125AC mechanism of action with treatment efficacy variables 
will be performed if sufficient data and samples (tumor biopsies obtained before study entry) are collected. 
Subject Selection 
Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:  
1. Signed and dated IRB/IEC-approved Informed Consent. 
2. Histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic carcinoma 
recurrent or progressing after prior chemotherapy (only one prior systemic therapy allowed). 
3. Presence of measurable disease defined as at least one lesion that can be accurately measured by CT 
scan in at least one dimension, as > 10 mm for non nodal lesions (longest diameter to be recorded) and  
15 mm for lymph nodal lesions (short axis to be recorded). (CT scan is the desirable method for lesion 
measurement. Other measurement techniques [eg MRI] are acceptable [but not for lung lesions] 
provided that the size of the measurable lesion is twice the slice thickness of the MRI). 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are usually not considered measurable unless there has been demonstrated progression in the 
lesion. 
4. Age  18 years. 
5. ECOG performance status 0-1. 
6. Estimated life expectancy of at least 3 months. 
7. Negative pregnancy test (if female in reproductive years). 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
8. Agreement upon the use of effective contraceptive methods (hormonal or barrier method of birth 
control, or abstinence) prior to study entry and for the duration of study participation, if men and 
women of child-producing potential. 
9. Adequate liver function: 
- Total Serum Bilirubin  1.5 x upper limit of normal (ULN) 
- Transaminases (AST/ALT)  2.5 ULN (if liver metastases are present, then  5 ULN is allowed) 
- ALP  2.5 ULN (if liver and/or bone metastases are present, then  5 ULN is allowed). 
10. Adequate renal function: 
- Serum Creatinine  ULN 
or 
- Creatinine Clearance calculated by Cockcroft and Gault’s formula > 60 mL/min.. 
11. Adequate hematologic status: 
- ANC  1,500 cells/mm3  
- Platelet Count  100,000 cells/mm3 
- Hemoglobin  9.0 g/dL.  
12. At the time of start of treatment, at least 2 weeks must have elapsed since completion of prior 
chemotherapy, minor surgery and radiotherapy (provided that no more than 25% of bone marrow 
reserve has been irradiated). 
13. With the exception of alopecia, resolution of all acute toxic effects of any prior chemotherapy, surgery 
or radiotherapy to NCI CTC (Version 3.0) grade  1 and to the baseline laboratory values as defined in 
Inclusion Criteria Number 9, 10, 11. 
14. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests required in this 
protocol. 
15. Capability to swallow capsules intact (without chewing, crushing, or opening). 
Subject Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment: 
1. Any of the following in the past 6 months: myocardial infarction, uncontrolled cardiac arrhythmia, 
unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis. 
2. Grade >1 retinopathy as determined by an ophthalmologist. 
3. Known brain metastases. 
4. Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment. 
5. Active, uncontrolled bacterial, viral, or fungal infections. 
6. Known infection with HIV, active hepatitis B or hepatitis C. 
7. Pregnant or breast feeding women. 
8. Previous (within the last 5 years) or current malignancies at other sites, except for adequately treated 
basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri. 
9. Current enrollment in or participation in another therapeutic clinical trial within 4 weeks preceding 


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treatment start. 
10. Diabetes mellitus uncontrolled. 
11. Gastrointestinal disease (e.g. Crohn’s disease, ulcerative colitis, or short gut syndrome) that would 
impact on drug absorption. 
12. Patients under treatment with anticoagulants or with coagulation disorders or with signs of hemorrhage 
at baseline. 
13. Patients with previous history or current presence of neurological disorders, including epilepsy 
(although controlled by anticonvulsant therapy), Parkinson’s disease and extra-pyramidal syndromes. 
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may 
increase the risk associated with study participation or may interfere with the interpretation of study 
results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this 
study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor. 
Treatment and Test Articles  
On the basis of the results of the first single agent Phase I study in solid tumor patients (CDKO-125a-001 
study), PHA-848125AC will be administered at the flat dose of 150 mg/day once daily for 7 consecutive 
days in each treatment cycle. A treatment cycle will comprise 7 days of PHA-848125AC administration 
(Days 1 to 7) followed by 7 days of rest (Days 8 to 14) for a total of a 14 days period (2-week cycle). 
PHA-848125AC is formulated as 10 mg, 50 mg and 100 mg hard gelatin capsules to be swallowed intact 
(without chewing, crushing or opening). The drug product is to be stored under refrigerated conditions (5  
3°C; 36-46 °F) and in the original packaging, out of the reach of children. 
PHA-848125AC is administered as home-based treatment. After an overnight fasting, with free access to 
water, patients will take the study drug with a large glass of plain water without ice. A light breakfast can be 
served 1.5-2 hours after study drug intake. 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
Schedule of Events 
The following table summarizes information on the timing of study assessments. 
SCHEDULE OF EVENTS 
Protocol Activities 
and Forms to Be Completed 
Pre 
Treatment 
Treatment 
Post 
Treatment 
Cycles 
Last 
Cycle 
 21 
Days 
 7 
Days 
Week 1 
Day 1 (*) 
Week 2 
between Days 
11-14 
AE 
FU 
(§) 
Follow 
up 
Informed Consent 1 
X 
 
 
 
 
 
 
Medical/ Oncologic History & Physical 
Examination 2 
X 
 
 
X 
X 
 
 
Vital Signs 3 
 
X 
X 
 
 
 
 
ECG 4 
X 
 
As medically indicated 
X 
 
 
Chest X-Ray 5 
X 
 
 
 
X 
 
 
Ophthalmologic exam. 6 
X 
 
 
X (even cycles)  
X 
 
 
Laboratory Assessments 
Serum/ Urine Pregnancy Test 7 
 
X 
 
 
 
 
 
Urinalysis 8 
 
X 
X (*)  
X (even cycles)  
X 
 
 
Hematology 9 
 
X 
X (*) 
X 
 
 
 
Blood Chemistry 10 
 
X 
X (*) 
X 
 
 
 
Coagulation 11 
 
X 
X (*) 
X (even cycles)  
X 
 
 
Tumor Assessments 
Tumor Imaging: chest/abdomen/pelvic CT 
scan or MRI 12 
X 
 
 
q6wks 
X 
 
q6wks 
Survival 13 
 
 
 
 
 
 
q6wks 
(+ 
q6mos) 
Other Clinical Assessments 
Adverse Event Assessment  (including 
neurological status evaluation)  14 
 
X 
X 
 
X 
 
Concomitant Medications 15 
 
X 
X 
 
 
 
Special Studies 
Biomarker Status Assessment 16 
X 
Pharmacokinetic Blood Sampling 17 
 
 
As needed 
 
 
Histological confirmation 18 
X 
Study Treatment 
Enrollment 19 
 
X 
 
 
 
 
 
PHA-848125AC Administration 20 
 
 
Once daily 
for 7 cons. 
days 
(D1 to D7) 
 
 
 
 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
Footnotes for Schedule of Events 
1. Informed Consent: Every patient must sign the informed consent to participate in this trial before starting any trial 
related procedures. After signature, a Patient Screening Number is assigned centrally by CLIOSS on behalf of Tiziana 
Life Sciences, PLC. 
2. Medical/Oncology History & Physical Examination: Includes oncologic history, history of other disease processes 
(active, controlled or resolved) and concomitant illnesses (all of them at pretreatment only).  Physical examination will 
be done at pretreatment, and, on treatment, at the end of each cycle (see Section 11.4.3 Other safety assessments). 
For patients remaining on treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, 
the physical examination will be done in concomitance with the visit to the site (once every 3 cycles, 1.5 months). 
Oncologic and non-oncologic medical history, including prior antitumor treatments/procedures, are to be reported in the 
relevant case report form (CRF).  
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
3. Vital signs: Blood pressure/pulse (supine): at baseline and on Day 1 of each treatment cycle, before treatment 
administration. Height (in cm or inches): at baseline only.  Weight (in kilograms or pounds): at baseline and on Day 1 of 
each treatment cycle. ECOG performance status: at baseline and on Day 1 of each treatment cycle. Temperature (in °C 
or in °F): at baseline and on Day 1 of each treatment cycle. For patients remaining on treatment for a period of time 
more than 6 cycles and come back to the site every 3 cycles, vital signs (including blood pressure/pulse, weight, ECOG 
performance status and temperature) will be done in concomitance with the visit to the site (once every 3 cycles, 1.5 
months). 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
4. ECG: 12-lead study. To be done at baseline, at the end of the last cycle and to be repeated during treatment as 
medically indicated. 
5. Chest X-Ray: Mandatory at screening visit and at the end of last cycle as safety assessment.  
6. Ophthalmologic Examination: to be conducted at baseline, at the end of even cycles (between days 11 and 14) 
and at the end of last cycle. For patients remaining on treatment for a period of time more than 6 cycles and come back 
to the site every 3 cycles, opthalmological examination will be done in concomitance with the visit to the site (once every 
3 cycles, 1.5 months). Includes visual acuity test and fundoscopic examination by an ophthalmologist. Additional 
assessments will be performed if clinically indicated. Ophthalmologic evaluations will be possibly done by the same 
ophthalmologist for a given patient. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
7. Pregnancy Test: For women of reproductive potential.  Must be done within 7 days prior to initial study treatment. 
8. Urinalysis: pH, dipstick for glucose, protein and blood. To be done at baseline and at the end of last cycle. During 
treatment, should be performed at the end of even cycles (between days 11 and 14). For patients remaining on 
treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, the urinalysis tests may be 
done locally when the visit to the site is not planned  (one visit planned to the site every three cycles, 1.5 months) and 
must be sent to the site for safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
9. Hematology (local laboratory): Hemoglobin, erythrocytes (RBC), white blood cell (WBC) with differential count 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils, differential other cells), platelets (PLTs). To be done at 
baseline and between Day 11-14 of each cycle. In case of toxicity preventing re-treatment, hematology should be re-
assessed on Day 1 of the next cycle before starting treatment. For patients remaining on treatment for a period of time 
more than 6 cycles and come back to the site every 3 cycles, the hematological tests may be done locally when the visit 
to the site is not planned  (one visit planned to the site every three cycles, 1.5 months) and must be sent to the site for 
safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
10. Blood Chemistry (local laboratory): sodium, potassium, chloride, magnesium, blood urea nitrogen (BUN) or urea, 
creatinine, albumin, AST/SGOT, ALT/SGPT, Alkaline Phosphatase (ALP), total bilirubin, creatinine clearance 
(calculated by Cockroft and Gault’s formula), amylase and lipase.  
To be done at baseline and between Day 11-14 of each cycle. In case of toxicity preventing re-treatment, blood 
chemistry should be re-assessed on Day 1 of the next cycle before starting treatment. For patients remaining on 
treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, the biochemical tests may 
be done locally when the visit to the site is not planned  (one visit planned to the site every three cycles, 1.5 months) 
and must be sent to the site for safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 


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11. Coagulation: INR (International Normalized Ratio), activated partial thromboplastin time (APTT in seconds). To be 
done at baseline, at the end of last cycle and, during treatment, at the end of even cycles (between Days 11 and 14). 
For patients remaining on treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, 
the coagulation tests may be done locally when the visit to the site is not planned (one visit planned to the site every 
three cycles, 1.5 months) and must be sent to the site for safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
12. Tumor imaging: chest/abdomen/pelvic CT scan/ MRI : At baseline, to be done within 21 days before Day 1; 
during the treatment period (irrespectively from cycles duration), the first one to be done 6 weeks (between days 42 and 
48) after first drug administration, the second one to be done 3 months (between days 92 and 98) after first drug 
administration, following ones to be repeated every 6 weeks (between days 42 and 48) after the previous one, and at 
end of last cycle (if not done in the previous 4 weeks). During Follow Up, to be performed every 6 weeks, until PD or 
until a new antitumor therapy starts. Patients with responding tumors (complete or partial response) must have 
response confirmed by CT scan at least 4 weeks after the 1st documentation of response. The same method of 
assessment and the same technique should be used to characterize and follow the same lesion at baseline and during 
treatment. CT scan is the desirable method for lesion measurement. Other measurement techniques (eg MRI) are 
acceptable (but not for lung lesions) provided that the size of the measurable lesion is twice the slice thickness of the 
MRI. After data cut-off of 31 May 2017, the patients should perfom CT scan according to routine clinical practice 
and/or at investigator’s discretion. 
13. Survival: To be assessed during Follow Up every 6 weeks until PD or until a new antitumor therapy starts; every 6 
months thereafter, up to 2 years from the end of treatment. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
14. Adverse Event Assessment (including neurological status evaluation): Events should be assessed and 
documented at each scheduled clinic visit since patient signs the Informed Consent: before treatment administration at 
baseline (baseline signs and symptoms), at the end of each treatment cycle, and 28 days after the last dose of study 
drug administration. For patients remaining on treatment for a period of time more than 6 cycles and come back to the 
site every 3 cycles, the events will be assessed by phone call if the visit to the site is not planned (one visit planned to 
the site every three cycles, 1.5 months). The phone call information will be reported in the medical chart and included in 
the CRF. 
Patients must be followed for adverse events also until every ongoing drug-related toxicities and serious adverse events 
have resolved or the investigator assesses them as “chronic” or “stable”. However, if the patient begins a new 
anticancer therapy before 28 days after the last dose of study drug administration, the adverse event reporting period 
will end at the time the new treatment is started. AEs will be recorded in the relevant CRF pages. 
After cut-off date of 31 May 2017, AE/SAE data will be no longer collected into the CRF, but assessments 
information should continue to be collected into the patient’s medical notes.  
After protocol Amendment 5 approval, only SAEs will continue to be reported to CLIOSS Pharmacovigilance for 
patients still receiving treatment, up to 28 days after milciclib discontinuation, according to Section 9.5. 
15. Concomitant Medications: all concomitant medications should be reported in the relevant CRF, including 
supportive care drugs, and drugs used for treating adverse events or chronic diseases. For patients remaining on 
treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, the concomitant medications 
will be assessed by phone call if the visit to the site is not planned (one visit planned to the site every three cycles, 1.5 
months). The phone call information will be collected in the medical chart and included in the CRF. Following approval 
of Amendment 4, management  of patients should be as per Section 9.5 
16. Biomarker Status Assessment: retrieval of tumor paraffin embedded blocks (slides), obtained from consenting 
patients before study entry (if available) and characterization of baseline molecular features of p53, p21, p27, cyclin D1, 
p75, TRKA and other genes/proteins involved in the PHA-848125AC mechanism of action.   
17. Pharmacokinetics: blood samples may be collected if, in the opinion of the Investigator and of the Sponsor, an 
evaluation of PK parameters is needed for safety reasons. 
18. Histological confirmation: histological confirmation of diagnosis of thymic carcinoma for all patients will be 
obtained by an Independent Review Committee during the course of the study, based on paraffin embedded tumor 
tissue slides retrieved from patients. 
19. Enrollment: The Investigator is requested to sign a Request For Enrollment form. His/her signature is the 
guarantee that all the eligibility criteria are met. Patient Number is assigned by the Sponsor. Treatment must be 
administered within 7 days from patient enrollment. 
20. PHA-848125AC administration: The study drug will be administered at 150 mg (flat dose) once daily for 7 
consecutive days of each treatment cycle (from day 1 to Day 7). After an overnight fasting with free access to water, 
patients will take the study drug with a large glass of plain water without ice. A light breakfast can be served 1.5-2 hours 
later. PHA-848125AC capsules have to be stored under refrigerated conditions (5  3 °C; 36-46 °F) and out of reach of 
children 


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Name of Company: Tiziana Life sciences, PLC 
Name of Finished Product: PHA-848125AC (Milciclib maleate) 
(*) Cycle 1, Day 1 assessments: hematology, blood chemistry, urinalysis and coagulation do not need to be repeated 
before treatment on Cycle 1, Day 1 if they were performed during screening within 1 week before first study drug 
administration. 
Cycle > 1, Day 1 assessments: hematology and blood chemistry do not need to be repeated before treatment on 
Cycles> 1, Day 1 if no toxicity preventing re-treatment resulted from laboratory assessments done within the previous 4 
days. 
(§) AE FU: end of adverse events reporting period (to be done 28 days after last study drug administration) and follow 
up of unresolved drug related/serious AEs.  After data cut-off of 31 May 2017, AE/SAE data and related follow up 
will be no longer collected into the CRF, but assessments information should continue to be collected into the 
patient’s medical notes.  After approval of Amendment 4 to the protocol, only SAEs should be reported to 
CLIOSS Pharmacovigilance for patients still receiving study treatment, up to 28 days after discontinuation of 
milciclib, according to Section 9.5. 
 


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2. ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT/SGPT 
Alanine aminotransferase 
ANC 
Absolute neutrophils count 
APTT 
Activated partial thromboplastin time 
AST/SGOT 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve from time zero to infinity 
BAX 
BCL2-associated X protein 
BCL-2 
B-cell CLL/lymphoma 2 gene (BCL2) 
BCL-XL 
BCL2-like 1 (BCL2L1) 
BID 
Two times daily 
BUN 
Blood Urea Nitrogen 
CDKs 
Cyclin-dependent kinases 
CL 
Total plasma clearance 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
CR 
Complete Response 
CRF 
Case Report Form 
DMBA 
9,10-dimethyl-1,2-benzanthracene 
DPYD 
Dihydropyrimidine dehydrogenase 
ECOG  
Eastern Cooperative Oncology Group  
GCP 
Good clinical practice 
EGFR 
Epidermal growth factor receptor 
FISH 
Fluorescence in Situ Hybridization 
FU 
Follow-up 
GI 
Gastrointestinal 
HER2/neu 
v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived 
oncogene homolog (ERBB2) 
HLP 
Hemolymphopoietic 
IC50 
Concentration resulting in 50% inhibition 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 


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IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
Ki 
Inhibition constant 
KIT 
V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 
LC-MS/MS 
HPLC coupled with tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NMS 
Nerviano Medical Sciences  
NOAEL 
No-observed-adverse-effect-level 
NOEL 
No-observed-effect-level 
NSCLC 
Non Small Cell Lung Cancer 
OS 
Overall Survival 
P21 
Cyclin-dependent kinase inhibitor 1A (CDKN1A) 
P27 
Cyclin-dependent kinase inhibitor 1B (CDKN1B) 
P53 
Tumor protein p53 (TP53) 
P75 
Nerve growth factor receptor (NGFR) 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PFS-3  
Progression-Free Survival at 3 months 
PHA-848125AC 
PHA-848125 maleate salt 
PR 
Partial Response 
pRb 
Retinoblastoma 1 (RB1) 
PS 
Performance Status 
PT 
Prothrombin time 
PXR 
Pregnane-X-Receptor 
RP2D 
Recommended Phase II Dose 
SAE 
Serious adverse event 
SD 
Stable Disease 
SGOT/AST 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT/ALT 
Serum Glutamic Pyruvic Transaminase 
SMRP 
Soluble mesothelin-related proteins 


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t1/2 
Terminal half-life 
TGI 
Tumor Growth Inhibition 
tmax 
Time of occurrence of Cmax 
TRAMP 
Transgenic Adenocarcinoma Mouse Prostate 
TRKA 
Thropomyosin Receptor Kinase A (NTRK1) 
TYMS 
Thymidylate synthase 
ULN 
Upper Limit of Normal 
Vss 
Volume of distribution at steady-state 
WBC 
White Blood Cells 
wks 
Weeks 
WHO 
World Health Organization 
 


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3. BACKGROUND INFORMATION AND STUDY RATIONALE 
3.1. Thymic Carcinoma 
Thymic carcinomas are a category of heterogeneous thymic tumors with distinct molecular 
characteristics, the most aggressive behavior and poorest prognosis among thymomas [1]. 
Although rare, thymomas are nevertheless the most common neoplasms of the anterior 
mediastinal compartment, with an overall incidence in US (1973-1998) of 0.15 per 100000 
person/years [2].  
Patients with locally advanced or disseminated thymic malignancies are usually 
symptomatic, presenting with chest pain, shortness of breath, paralysis of the phrenic nerve, 
pleural effusion and superior vena cava syndrome. Immune disorders have also been 
associated with thymoma, the most common being myasthenia gravis [3]. 
There is no known cause for thymomas, however, in recent years, a few studies on molecular 
changes in thymomas and thymic carcinomas have been published. In particular, the 
expression of KIT and epidermal growth factor receptor (EGFR), targets, respectively, of 
imatinib and EGFR inhibitors (ie, erlotinib, gefitinib), have been tested by 
immunohistochemistry in a limited number of thymic malignancies: KIT was positive in 
73% of thymic carcinomas and 5% of other thymomas, in contrast, EGFR expression was 
more often present in other thymomas (83%) than in thymic carcinomas (50%) [4]. Another 
study investigated HER2/neu amplification and expression of the apoptosis-related markers 
p53, BCL-2, BAX, BCL-XL, and p21 [5]; p53 and Bcl-2 were definitely more expressed in 
thymic carcinomas than thymomas and correlated with more advanced stages and 
unresectability, whereas no HER2/neu amplification was observed. Other markers, such as 
expression of thymidylate synthase and dihydropyrimidine dehydrogenase, which predict 
sensitivity to 5-fluorouracil-based chemotherapy, were not correlated with 
clinicopathological characteristics in a series of thymomas [6].  
The loss of control of cell cycle checkpoints seems a common occurrence in thymomas, 
supporting the idea that functional cooperation between different cell cycle inhibitor proteins 
regulates cell growth control and tumor suppression. Univariate analyses on the expression 
of p21 and p27 in specimens from 25 encapsulated thymomas (using immunohistochemistry) 
suggest that negative expressions of p21 and p27 (natural inhibitors of CDKs) significantly 
correlates with poor prognosis for disease-free survival [7]. In addition, some members of 
the neurotrophin receptors family seem to play a significant role in this disease: in a study 
investigating the expression of neurotrophin receptors in thymic epithelial tumors on a quite 
large series of patients (N=99) [8], the pattern of TRKA expression was analyzed according 
to WHO classification for the histologic subtypes (A, AB, B1, B2, B3, C). All patients, 
except one, had immunostaining for TRKA expression in the tumors gradually increasing 
from type A to C. Conversely, none of the tumors showed TRKB or TRKC 
immunoreactivity. In addition, from type A to type C, there was a decreasing percentage of 
tumors with p75 immunostaining. These observations suggest a further elucidation on the 
specific role of TRKA and p75 in this disease. 


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Besides the above mentioned WHO histological classification of thymoma, the Masaoka 
staging system is commonly employed to evaluate invasiveness and to determine the 
therapy, since the optimal treatment for this disease depends on its clinical stage [1]. Locally 
advanced or metastatic thymomas are often treated with combined treatment modalities, 
including surgery, radiation and chemotherapy. There are no drugs officially approved for 
the treatment of thymoma and thymic carcinoma. However, several antineoplastic agents are 
used. Cisplatin/doxorubicin-based combination chemotherapy [PAC regimen (cisplatin, 
doxorubicin, cyclophosphamide) or ADOC regimen (doxorubicin, cisplatin, vincristine, 
cyclophosphamide)] seem to produce the best overall response rate and survival. Other 
combined and /or single agent chemotherapy with cisplatin, etoposide, ifosfamide, 
epirubicin, maytansine, octreotide and steroids are used as well [9-11]. Examining 
treatments for patients with advanced disease who had received one or more prior lines of 
therapy, published data generally indicates a limited activity, in fact single agent studies with 
gefitinib, imatinib or a combination study erlotinib+bevacizumab did not produce 
satisfactory results [12-14], although only two cases of activity of possible clinical benefit 
were observed with imatinib and sorafenib, due to the rare incidence of KIT mutations in 
those patients’ tumors [15,16]. An optimal treatment strategy has yet to be determined and 
other drugs are warranted to improve the outcome of patients with advanced invasive tumors 
[10]. The unmet medical need for new agents for the treatment of thymic malignancies is 
therefore high, as demonstrated by the number of studies with experimental agents currently 
in progress.  
Given the rarity of the thymic carcinoma subtype, prospective phase II studies of 
chemotherapy specifically targeting thymic carcinoma patients are rare. Combined therapies 
such as ADOC or VIP (cisplatin, ifosfamide, etoposide) achieved, as a first line treatment for 
the advanced disease, a median survival time around 19-20 months [17, 18]. In previously 
untreated, unresectable thymic carcinoma, first-line combination of carboplatin and 
paclitaxel achieved an overall response rate of 36% with a median survival time of 22.7 
months and a median progression-free survival of 7.9 months [19].   
In a single agent study with pemetrexed, on 23 previously treated evaluable patients with 
unresectable stage IV A and B disease, there were 4 objective responses (2 CRs and 2 PRs) 
(17% RR). Responses were obtained only in stage IVA thymoma patients, with a median 
duration of time to progression of 45.4 weeks; in thymic carcinoma patients the median 
duration of time to progression was much shorter (5.1 weeks) [20]. In other two recent series 
of previously treated patients with thymic malignancies, objective responses were reported 
in B2 and B2/3 tumors (no type C thymic carcinoma patients were enrolled in the first study) 
with a gemcitabine/ capecitabine combination [21] and with the histone deacetylase inhibitor 
(HDAC) belinostat [22]. Also in this second study, responses were obtained only in 
thymoma patients and no responses were seen in the 8 evaluable patients with thymic 
carcinoma. Thymic carcinoma is therefore confirmed as a type of cancer where prognosis is 
particularly poor and the course of the disease more aggressive compared to the other 
thymomas.   


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Given the current clinical scenario, in thymic carcinoma patients previously treated with 
chemotherapy, a single agent therapy is able to induce a median PFS of approximately 5.1 
weeks [20], roughly corresponding to an estimated  PFS rate at 3 months of about 17%. 
Therefore a 33% target PFS-rate at three months could be regarded as clinically interesting 
for a new investigational agent.   
3.2. PHA-848125AC 
3.2.1. Description 
PHA-848125, N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-
dihydro-1H- pyrazolo[4,3-h]quinazoline-3-carboxamide, is a potent inhibitor of the kinase 
activity of the CDK2/Cyclin A complex (Ki = 32 nM), showing activity also towards closely 
related CDKs (ie, CDK1, CDK4, and CDK5) and TRKA. 
The compound is formulated for oral administration as maleate salt (PHA-848125AC). 
Throughout this document, “PHA-848125” indicates the active compound as free base, 
which was used under various salt forms in preclinical studies. 
Details regarding the results of the pre-clinical and clinical studies are contained in the PHA-
848125AC Investigator Brochure, Version 7, 2011 [23]. 
3.2.2. Pharmacology 
CDKs are serine/threonine kinases that, in concert with their activators (cyclins) and 
negative regulators, play a crucial role in the cell cycle progression [24,25]. CDK/Cyclin 
complexes regulate the phosphorylation and inhibitory binding of the pRb to members of the 
E2F transcription factors family, that are essential for the transcriptional regulation of a 
number of genes whose products control cell cycle progression. These include genes 
essential for the progression from the G1 into the S phase of the cell cycle and genes that are 
involved in the regulation of DNA replication. 
Deregulation of CDKs activity, alterations of expression and/or genetic mutations of cyclins, 
CDKs, Cyclin Dependent Kinase Inibitors (CDKIs) and other components of the pRb 
pathway have been reported in more than 90% of human neoplasms [26]. For example, 
CDK2 activators, such as Cyclin E2 and A2 are found overexpressed in 50% of breast and 
lung cancer, and decreased levels of their natural inhibitors (ie, p21, p27) predict a poor 
prognosis in breast, prostate, colon, gastric, lung and esophageal cancer. Indeed, alterations 
in the Rb pathway lead to release of E2F transcription factors, high commitment to cell cycle 
progression and, ultimately, in uncontrolled proliferation. These findings strongly support a 
pharmacological inhibition of CDKs as an attractive strategy in the treatment of human 
cancers [27-32]. 
In fact, according to the postulated mechanism of action, as determined in biochemical 
assays, in in vitro experiments PHA-848125 was able to cause a block in G1 phase of the 


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cell cycle in tumor cells: it decreased the phosphorylation level of the Retinoblastoma 
protein (pRB), by inhibiting the CDK/Cyclin complexes, thus preserving the E2F 
transcription factors in an inactive state. 
Additionally, PHA-848125 reduced the phosphorylation status of TRKA and of the proteins 
of the TRKA signaling pathway in cells expressing this receptor tyrosine kinase. 
The antiproliferative effect of PHA-848125 was tested on a panel of 120 tumoral cell lines 
established from different solid tumors (ovary, breast, pancreas, lung, cervix, prostate, skin, 
brain, bone), leukemias and lymphomas. The IC50 values were in the range of 0.1-1 M for 
61 cell lines and in the range of 1-3 M for 42 cell lines, indicating a broad spectrum of 
activity of the compound. Only 17 cell lines were poorly responsive to PHA-848125 with an 
IC50 value > 3 M. 
Significant anti-tumor activity was observed in all tested preclinical animal models with 
different oral treatment schedules of PHA-848125. In various human xenograft models, as 
well as in the TRAMP model, consistent tumor growth inhibition (up to 91%), was reported 
with a repeat daily treatment at tolerated doses (40 mg/kg bid). In the rat DMBA (9,10-
dimethyl-1,2-benzanthracene)-induced mammary carcinoma model, comparable results 
(stasis and partial remission in 58 and 25% of the primary tumors, respectively) were 
obtained with repeat daily treatment at tolerated doses (up to 15 mg/kg bid). In the same 
model, intermittent treatment with a rest period was equally effective. 
Inhibition of pRb phosphorylation status and modulation of the expression of genes 
regulated by E2F transcription factors (ie, cyclins and histones) were measured at mRNA 
and/or protein level, in a dose-dependent manner both in skin and tumors of mice treated 
with PHA-848125. 
A statistically significant increase in survival time was obtained in two disseminated human 
leukemia models (AML and ALL) and in a human glioma model implanted intracranially. 
In combination studies, PHA-848125 exhibited synergistic or more than additive activity 
when administered with docetaxel, topotecan or temozolomide, and additive effect when 
combined with bevacizumab, irinotecan, 5-FU and gemcitabine. Combinations were well 
tolerated. 
3.2.3. Safety Pharmacology 
Safety pharmacology studies were performed to investigate the effects of PHA-848125 on 
central nervous (CNS), respiratory and cardiovascular systems (all doses mentioned are 
expressed as free base). 
Central Nervous System: no effects on general behavior (Irwin’s test) and body temperature 
were observed in rats up to the highest single dose of 160 mg/kg and no alterations in the 
EEG were detected in adult rats given PHA-848125 for 5 consecutive days at 16 or 32 
mg/kg/day. 


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Respiratory System: in a respiratory function study in rats, a dose-related shortening of the 
inspiratory time and an increase in peak inspiratory flow were observed from the dose of 80 
mg/kg with recovery within 4 hours. The dose of 40 mg/kg was considered the NOEL. 
Cardiovascular System: cardiovascular safety pharmacology assessments included in vitro 
evaluation for potential effects on cardiac ion channels (Ikr) and in vivo evaluations for 
effects on cardiovascular parameters and body temperature in conscious beagle dogs. A 
dose-related in vitro inhibition of the Ikr channel occurred from the concentration of 0.1 M 
with a calculated IC50 of 1.32 M (the IC50 for the antiproliferative activity in the A2780 cell 
line was 0.2 M). In a telemetry study in dogs, a temporary moderate decrease in heart rate 
was observed from 0.5 to 3 h after treatment at the dose of 32 mg/kg. QT/QTc interval was 
not affected at any of the tested doses. No effect was seen at 16 mg/kg; this dose was 
considered the NOEL for cardiovascular function. No changes in ECG parameters (including 
QT and QTc) were observed in single and repeat-dose toxicity studies in dogs and monkeys. 
3.2.4. Nonclinical Pharmacokinetics 
Pharmacokinetics of PHA-848125 was investigated in the mouse, rat, dog and monkey after 
single IV and oral administration. Since the compound is intended for oral route 
administration, its pharmacokinetics was further studied after repeated oral administrations. 
Following IV administration, PHA-848125 was characterized by moderate clearance in 
mice, rats and monkeys and high clearance in dogs. The clearance was mainly non renal as 
suggested by the very limited renal excretion of the unchanged drug. The volume of 
distribution was higher than the total body water in all the preclinical species, suggesting an 
extensive tissue distribution of the compound.  
The results of the rat tissue distribution study conducted with [14C]-PHA848125 indicated 
that apart from the GI tract, the highest levels of radioactivity were measured in the liver, 
spleen, skin, kidneys, adrenal glands and lachrymal glands. The blood to plasma ratio was 
between 0.8-1.12 indicating a moderate distribution of the radioactivity into the red blood 
cells. In rats and monkeys PHA-848125 distributed in the brain. Moreover, the study carried 
out in the rat using [14C]-PHA848125, indicated that the distribution of the radioactivity was 
homogeneous in the different brain areas and cerebellum.  
The in vitro plasma protein binding ranged from 78 to 90%, depending on the species. 
The bioavailability of PHA-848125 after oral administration was equal or higher than 30 % 
in all the preclinical species. PHA-848125 plasma levels increased largely in direct 
proportion with the dose. No relevant gender differences were observed in the preclinical 
species. 


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In dogs, the extent and rate of absorption of PHA-848125 was unaffected when the 
compound was administered in hard gelatin capsules or in 5% dextrose solution. No food 
effect was observed. 
The elimination profile of total radioactivity following a single oral administration of [14C]-
PHA-848125AC in rats suggested that the main route of elimination was via faeces, 
accounting for about 70 % of the dose within 96 hours post dose. The urinary excretion of 
the radioactivity represented 16% of the dose. In all preclinical species, after IV and oral 
treatment, the amount of parent compound excreted unchanged in urine was less than 6% of 
the administered dose. In the rat treated by oral route, the excretion of PHA-848125 in bile 
accounted for about 15% of the administered dose. Overall, the excretion data suggested that 
the compound was mainly eliminated via metabolic transformations.  
Metabolism studies (in vitro and in vivo) showed that the major route of metabolism of 
PHA-848125 was the N-oxidation of the N-methyl piperazine moiety to give the metabolite 
M1 (NMS-867734). More than one enzymatic pathway is involved in the metabolism of this 
compound, decreasing the risk for unwanted clinical relevant drug-drug interactions. From a 
qualitative point of view no species differences were observed in the metabolism of PHA-
848125 and no unique metabolite was detected in human microsomes. Given these results, 
both monkeys and dogs represented suitable nonrodent species for the conduct of repeat-
dose toxicological studies. The plasma profile of NMS-867734 was investigated in rats and 
monkeys showing a metabolite/parent AUC ratio of 0.2-0.4 and 0.05, respectively. 
PHA-848125 did not activate human and mouse PXR, suggesting that the compound is 
unlikely to increase the CYP3A mediated enzyme activities by increasing its gene 
transcription. PHA-848125 showed some competitive inhibition on CYP3A4 (Ki = 2.4 M 
and 18.7 M using triazolam and testosterone as substrate, respectively) at concentrations 
much higher than those needed for the pharmacological activity  (Ki = 32 nM for 
CDK2/Cyclin A complex). 
3.2.5. Toxicology 
PHA-848125 was characterized in single and repeat-dose toxicity studies in rats, dogs and 
monkeys. PHA-848125 was also characterized by in vitro genotoxicity and dermal and 
ocular irritation studies. 
Single-dose toxicity studies were carried out administering PHA-848125 by oral route in 
rats, dogs and monkeys. Effects related to the mechanism of action of the compound were 
seen in the hemolymphopoietic (HLP) system, the gastrointestinal (GI) tract and the male 
reproductive organs in all species. Regression was observed at the end of the 2-week 
recovery period for all the changes except for the testes, as expected considering the time of 
maturation of the seminiferous epithelium. Additional toxicities, apparently not related to the 
mechanism of action of the compound, were the vascular effects (congestion and 
hemorrhages in several organs) and the CNS toxicity observed in dogs.  


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In rats, no mortality was observed up to the highest administered single dose of 160 mg/kg. 
The dose of 40 mg/kg (mean AUC = 69 M·h) was the NOAEL in rats after single oral 
administration.  
In dogs, one female given the highest dose of 69.1 mg/kg was sacrificed 9 h after treatment 
due to the severe clinical signs of CNS toxicity (tremors, incoordination, convulsions). In 
this animal, the AUC(0-8h) measured before death was 31.69 M·h. In addition, this dog 
showed hemorrhages in several organs and multifocal edema in the brain. The dose of 34.5 
mg/kg (mean AUC = 17 M·h) was the MTD in dogs after single oral administration.  
In monkeys, no mortality or significant signs of toxicity were observed after the 
administration of single oral doses up to 69.1 mg/kg (mean AUC = 31 M·h). 
Repeat-dose toxicity studies were conducted with PHA-848125 administered by oral route 
daily for 4/7 days, 4 weeks or 3 months period. Noteworthy effects of PHA-848125 in the 
repeat-dose toxicity studies included changes in the HLP system, GI tract and male 
reproductive organs in all species. Effects on female reproductive organs were also seen in 
rats and dogs. The effects on the HLP system were dose-related and were observed at all 
doses tested. In dogs, GI toxicity was seen at all doses with dose-relationship independently 
of the treatment schedule. All the above changes recovered after drug withdrawal, with the 
exception of the effects on the male reproductive system, which were still present at the end 
of the recovery period. 
Additional toxicities, that are considered not related to the mechanism of action of the 
compound, were CNS, ocular and renal toxicities. In addition, hemorrhages in different 
organs were observed in dogs and monkeys 
Clinical signs of CNS toxicity, characterized by tremors, increased reactivity, incoordination 
and convulsions were noted at high doses given as single administration in dogs or repeated 
administrations in rats and monkeys. This effect, observed at daily AUC  30 M·h, 
recovered after drug withdrawal and was not supported by any morphological change in the 
brain. 
Ocular toxicity was observed in rats after prolonged administration ( 1 month) of PHA-
848125. Bilateral retinal atrophy occurred from the dose of 16 mg/kg/day in females (daily 
AUC = 27 M·h) and at 24 mg/kg/day in males (daily AUC = 38 M·h) in the 4-week 
study. The same finding was seen in rats given the dose of 16 mg/kg/day for 3 cycles of 3 
weeks + 1 week rest or 5 cycles of 2 weeks + 1 week rest (mean daily AUC from 25.5 to 
34.5 M·h). This effect did not regress after the 2- or 4-week recovery periods. The dose of 
8 mg/kg/day, given for 4 consecutive weeks or cyclically for 3 months, corresponding to 
mean daily AUC values of  9.8 and 11.7 M·h, respectively, was the NOEL for ocular 
changes. No retinal changes were seen in rats following administration of PHA-848125 for 7 
consecutive days up to the highest dose (51.8 mg/kg/day) or a daily AUC of about 50 M·h. 


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Other effects, observed at lethal doses, involved the kidneys (cortical tubular nephropathy) 
in dogs at the dose of 8 mg/kg/day administered as two 2-week cycles (daily AUC 15 M·h) 
and at 12 mg/kg/day as two 1-week cycles (daily AUC  15 M·h). Some changes were also 
seen in monkeys at the toxic dose of 15.97 mg/kg/day given for 7 days (daily AUC 71 M·h 
in the only surviving animal). Renal changes did not completely regress at the end of the 
recovery period. 
Congestions and hemorrhages in different organs occurred following repeated 
administrations of PHA-848125 at high toxic lethal doses in dogs (34.5 mg/kg/day for 4 
days; daily AUC  27 M·h) and in monkeys (15.97 mg/kg/day for 4 and 7 consecutive 
days; daily AUC > 30 M·h). 
PHA-848125 was not genotoxic in the Ames test and did not induce any structural or 
numerical chromosome aberrations in human peripheral blood lymphocytes in vitro. 
In the dermal and ocular irritation tests, PHA-848125 was not irritating to the skin of rabbits, 
while it induced severe irritant reactions when applied to the eye of rabbits for 1 h. A 
complete recovery occurred within 10-16 days. 
3.2.6. Drug-Drug Interactions 
As detailed in Section 3.2.4, more than one enzymatic pathway is involved in the 
metabolism of PHA-848125AC, decreasing the risk for unwanted clinical relevant drug-drug 
interactions. Also, PHA-848125 did not activate human and mouse PXR, suggesting that the 
compound is unlikely to increase the CYP3A mediated enzyme activities by increasing its 
gene transcription. 
Significant drug-drug-interactions are therefore not expected.   
3.2.7. Phase I clinical trials 
The phase I clinical program of PHA-848125AC as a single agent is ongoing with three 
studies testing four different schedules (daily x 7 every 2 weeks; 4 days on / 3 days off x 3 
weeks every 4 weeks; daily x 21 days every 4 weeks; daily x 14 days every 3 weeks), being 
conducted in US and Europe. Both a flat dose approach and a BSA-based approach have 
been investigated. 
The clinical experience gained so far (July 2009) on overall 90 patients treated for 277 
cycles indicated that the safety profile of the compound is characterized by a dose-limiting 
neurological toxicity and, to a lesser extent, by gastrointestinal toxicity. Nausea and/or 
vomiting and /or diarrhea were mostly of grade 1- 2 in severity and were manageable with 
appropriate therapy, including hydration. Haematological toxicity, mainly represented by 
neutrophils decrease, was reported in some patients only. A prolonged transaminitis was 
occasionally observed with the 7 days on / 7 days off schedule, however, with a treatment 


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schedule encompassing 14 consecutive days every 3 weeks, alterations of liver function tests 
were more frequently reported (starting from the dose of 54 mg/m2/day for 14 days). Ocular 
toxicity was never encountered so far, with the exception of a worsening of ERG during 
treatment compared to baseline in one diabetic patient treated at 24 mg/m2/day for 21 
consecutive days and in a second patient treated at 72 mg/m2/day for 14 consecutive days 
every 3 weeks (dose then reduced to 48 mg/m2/day in the two subsequent cycles). Both 
patients, however, did not show any clinical symptomatology. 
The neurological toxicity consisted in tremors and ataxia. In study CDKO-125a-001, where 
the same schedule of administration proposed in the present study was studied (ie 7 days on 
/7 days off, flat dose) and which therefore represents the best reference study for this 
compound, on 22 patients treated for 112 cycles, mild, short-lasting tremors were observed, 
starting from the dose of 100 mg/day and increasing in frequency and in severity at 200 
mg/day and 300 mg/day. Grade 3 ataxia was repeatedly observed starting from the dose of 
200 mg/day, where a mean Day 7 AUC(0 – 24h) of 29.2 M·h was reported, but occurred also 
in one patient (grade 2) after 7 cycles of treatment at 150 mg/day (in this patient treatment 
was continued at a reduced dose of 100 mg/day, with no further episodes of the event). 
Tremors and ataxia were reversible in all cases in up to 7-8 days, upon drug discontinuation.  
The MTD with the 7 days on /7 days off schedule was attained at the dose of 200 mg/day.  
The Phase II recommended dose (RP2D) with this schedule of administration was identified 
in 150 mg/day. At the RP2D, where a mean Day 7 AUC(0 – 24h) of 25.3 M·h was measured, 
only tremors (up to grade 2) were reported, plus the above mentioned grade 2 ataxia after 7 
treatment cycles. Overall, at this dose level, toxicity consisted mainly of mild/moderate 
nausea, fatigue, diarrhea and tremors, all effects easily manageable and reversible. 
In the same study, for the patients treated under the second schedule (4 days on / 3 days off x 
3 weeks every 4 weeks, flat dose) ataxia was never reported, but grade 1 tremors were 
common findings at doses below 200 mg/day, reaching grade 2-3 in severity and qualifying 
for DLTs at 200 mg/day (mean Day 18 AUC(0 – 24h) of 33.3 M·h). 
As for efficacy, one out of  three thymic carcinoma patients treated at the dose of 150 
mg/day (4 days on /3 days off for 3 weeks every 4 weeks) showed a confirmed partial 
response after 11 treatment cycles (the patient is on study for 22 cycles [22 months] at 150 
mg/day at the time of writing this document), and another patient showed an unconfirmed 
partial response after 7 cycles of treatment (the patient is on study for 7+ cycles [7+ months] 
at 150 mg/day at the time of writing this document). The third patient was taken off study 
after 2 cycles for disease progression. In addition, a stable disease for more than 4 months 
was reported in a NSCLC patient (on study for 12 cycles at 200 mg/day, dose reduced to 100 
mg/day since cycle 10, 7 days on /7 days off schedule) and another stable disease for more 
than 12 months was observed in a colorectal cancer patient (on study for 27 cycles at 150 
mg/day, dose reduced to 100 mg/day since cycle 8, 7 days on /7 days off schedule).   
3.2.8. Pharmacokinetics in Humans 
The pharmacokinetics of PHA-848125AC and its major metabolite, NMS-867734 (M1), has 
been investigated in the three ongoing phase I clinical trials CDKO-125a-001, CDKO-125a-


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002, CDKO-125a-003. Results for PHA-848125AC are summarized in Table 1, Table 2 and 
Table 3, respectively. 
In particular, in the CDKO-125a-001 study, first schedule, which is the same schedule 
adopted in the present study, the pharmacokinetic profile of PHA-848125AC was 
characterized by: 
 achievement of maximal plasma concentration at 2 - 4 hours post dosing, after single and 
repeated administration 
 terminal half-life in the range of 30 and 40 hours 
 good dose proportionality in systemic exposure, in the range of 50-300 mg/day 
 similar exposure to the compound after subsequent cycles of treatment 
 inter-patient variability limited 
 AUC of the major metabolite lower than that of the parent compound, accounting for 
30-50%. Its half-life is comparable to or slightly longer than that of the parent 
compound. 
Of note, at the RP2D of 150 mg/day, which is the dose to be administered to patients in the 
present study: 
 on day 1 in cycle 1, maximal plasma concentration was 0.660.24 M (n=6), attained on 
average at 2.5 h post-dosing. The corresponding daily AUC was 8.862.64 Mh (n=6). 
 after seven days of treatment in cycle 1, maximal plasma concentration was 1.470.51 
M (n=6), attained on average at 2.5 h post-dosing and corresponding to a daily AUC of 
25.318.56 Mh (n=6). 
 the day 7/day 1 AUC(0-24h) ratio was around 3, in line with what was expected 
considering the schedule and the half-life of the compound that at this dose level was on 
average 33.3 hours. 
Overall, at similar doses administered with different schedules, comparable PHA-848125AC 
PK profile was observed across studies. 
For more details on PHA-848125AC, please refer to Investigator Brochure for PHA 
848125AC, Version 7, 2011 [23]. 
 


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Table 1. PHA-848125AC pharmacokinetic data from CDKO-125a-001 study 
CDKO-125a-001 first schedule (7 days on, 7 days off q2wks) 
Day 
 
Dose 
(mg/day) 
No. of 
Pts 
Cmax 
(M) 
AUC0-t(24h) 
(M h) 
tmax (h) 
t1/2,z 
(h) 
1 
50 
3 
0.20.06 
2.560.52 
3.351.17 
N/A 
7 
50 
3 
0.40.15 
6.842.21 
3.331.15 
32.812.2 
1 
100 
6 
0.440.07 
6.192.26 
3.52.51 
N/A 
7 
100 
6 
1.20.47 
19.910.5 
2.761.89 
38.29.28 
1 
150 
6 
0.660.24 
8.862.64 
2.51.22 
N/A 
7 
150 
6 
1.470.51 
25.38.54 
2.51.22 
33.37.08 
1 
200 
6 
0.560.11 
8.411.68 
41.26 
N/A 
7 
200 
6 
1.680.17 
29.24.5 
4.331.51 
31.84.68 
1 
300 
1 
1.15 
22.3 
2 
N/A 
7 
300 
1 
5.12 
83.6 
4 
31.3 
CDKO-125a-001 second schedule (4 days on, 3 days off x 3wks q4wks) 
Day 
 
Dose 
(mg/day) 
No. of 
Pts 
Cmax 
(M) 
AUC0-t(24h) 
(M h) 
tmax (h) 
t1/2,z 
(h) 
1 
150 
3 
0.42±0.1 
6.67±1.72 
4±0 
N/A 
18 
150 
3 
1.08±0.07 
19.5±4.27 
3.13±1.96 
41±3.01 
1 
180 
1 
0.55 
6.67±1.72 
2 
N/A 
18 
180 
1 
1.22 (Day 4) 
6.67±1.72 
4 
-- 
1 
200 
4 
0.79±0.5 
9.58±7.34 
2±0 
N/A 
18 
200 
3 
2.33±0.58 
33.3±2.56 
1.71±0.44 
25.9±8.38 
N/A: not applicable 
 
Table 2. PHA-848125AC pharmacokinetic data from CDKO-125a-002 study 
CDKO-125a-002 (14 days on, 7 days off q3wks) 
Day 
 
Dose 
(mg/m2/day) 
No. of 
Pts 
Cmax 
(M) 
AUC0-t(24h) 
(M h) 
tmax (h) 
t1/2,z 
(h) 
1 
18 
5 
0.103±0.042 
1.7±0.487 
4.8±1.09 
N/A 
14 
18 
4 
0.248±0.064 
4.08±1.23 
2.5±1 
40.1±6.68 
N/A: not applicable 
 
 


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Table 3. PHA-848125AC pharmacokinetic data from CDKO-125a-003 study 
CDKO-125a-003 first schedule (21 days on, 7 days off q4wks) 
Day 
 
Dose 
(mg/m2/day) 
No. of 
Pts 
Cmax 
(M) 
AUC0-t(24h) 
(M h) 
tmax (h) 
t1/2,z 
(h) 
1 
16 
7 
0.220.28 
2.542.92 
2.861.57 
N/A 
21 
16 
6 
0.250.08 
4.071.29 
2.961.15 
33.610 
1 
24 
6 
0.20.09 
2.480.92 
1.781.26 
N/A 
21 
24 
5 
0.420.2 
6.242.44 
2.432.05 
37.15.77 
CDKO-125a-003 second schedule (14 days on, 7 days off q3wks) 
Day 
 
Dose 
(mg/m2/day) 
No. of 
Pts 
Cmax 
(M) 
AUC0-t(24h) 
(M h) 
tmax (h) 
t1/2,z 
(h) 
1 
24 
3 
0.180.05 
2.320.54 
2.31.5 
N/A 
14 
24 
3 
0.450.22 
7.13.94 
1.70.6 
41.24.26 
1 
48 
3 
0.310.09 
4.51.43 
2.81.4 
N/A 
14 
48 
3 
0.70.44 
1.277.9 
3.31.2 
28.91.6 
N/A: not applicable 
 
3.3. Rationale for the use of PHA-848125AC in Thymic Carcinoma 
Chemotherapy was shown to have significant antitumor activity against unresectable, 
recurrent or metastatic thymomas and thymic carcinomas, but an optimal treatment strategy 
has not been determined and other drugs are needed to improve the outcome of patients with 
advanced invasive tumors [10]. 
In recent years, a few studies on molecular changes in thymomas point to alterations that 
may be of use in selecting patients for targeted therapies [4-8]. Unfortunately for some of 
them, such as KIT and EGFR inhibitors, the reported results seem to be discouraging [12-
14]. In addition, despite a lack of correlation of thymidilate synthase expression with 
thymoma clinicopathological characteristics, pemetrexed obtained interesting responses in 
stage IVA thymomas, but not in thymic carcinomas [20]. 
The pyrazoloquinazoline PHA-848125 is a compound counteracting the effects of some of 
the other so far identified, but not yet exploited, molecular alterations found in thymoma and 
thymic carcinoma, e.g. underexpressed p21 and p27 and overexpressed TRKA [7,8]. These 
targets are not yet been investigated in therapeutic intent clinical trials. 
In fact, p21 and p27 encode natural potent cyclin-dependent kinase inhibitors and their 
ablation in the cancer cell results in an activation of cyclin E/CDK2 or cyclin D/CDK4 
complexes and thus in uncontrolled cell cycle progression and cell proliferation [24-32], 
while TRKA activation promotes tumor growth [33], probably through MAPK pathway 
activation. PHA-848125 potently inhibits both the CDK/Cyclin complexes and TRKA, 


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proposing in this way to be a “selective dual inhibitor” and appearing particularly attractive 
in this disease. 
The preliminary results in early clinical trials on thymic carcinomas patients (2 out of 3 
patients with clinical benefit) support the hypothesis that PHA-848125 could be of 
therapeutic value for patients with this tumor type. 
An exploratory analysis on the relationship of molecular features of p53 (natural regulator of 
p21), p21, p27, cyclin D1, p75, TRKA and other genes/proteins involved in the PHA-
848125AC mechanism of action with treatment efficacy variables will be possibly 
performed in tumor biopsies of consenting patients obtained before study entry. 
4. TRIAL OBJECTIVES AND ENDPOINTS 
4.1. Objectives 
4.1.1. Primary Objective 
 Assessment of the antitumor activity of PHA-848125AC as second-line treatment in 
patients with recurrent or metastatic, unresectable thymic carcinoma previously treated 
with chemotherapy. Antitumor activity will be evaluated on the basis of the progression-
free survival status at 3 months. 
4.1.2. Secondary Objectives 
 Assessment of additional measures of tumor control to further characterize the efficacy 
profile of PHA-848125AC in recurrent or metastatic, unresectable thymic carcinoma 
previously treated with chemotherapy. 
 Evaluation of the safety profile of repeated administrations of PHA-848125AC in 
patients with recurrent or metastatic, unresectable thymic carcinoma previously treated 
with chemotherapy. 
4.1.3. Exploratory Objective 
 Relationship of baseline molecular features in tumor biopsies of p53, p21, p27, cyclin 
D1, p75, TRKA and other genes/proteins involved in the PHA-848125AC mechanism of 
action with treatment efficacy. 
4.2. Endpoints  
4.2.1. Primary Endpoint 
 Progression-free survival rate at 3 months (PFS-3 rate). The PFS-3 rate, will be 
calculated as the proportion of evaluable patients (see Section 12.2) known to be alive 


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and progression-free at ≥ 3 months since study treatment start out of the total number of 
evaluable patients. 
4.2.2. Secondary Endpoints 
 Confirmed Objective Response Rate (CR + PR) according to RECIST guideline (version 
1.1). 
 Disease Control Rate (Confirmed Objective Response Rate +  6 weeks SD rate). 
 Progression-free survival, calculated as the time from the date of treatment start to the 
date of first documentation of objective progression or of death due to any cause, 
whichever comes first.  
 Duration of Response, measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded on study). 
 Overall Survival (OS), i.e. the time from the date of treatment start to the date of death 
from any cause. 
 Overall safety profile, evaluated on the basis of laboratory and clinical safety parameters 
(i.e. hematology and blood chemistry, urinalysis, vital signs, ophthalmologic 
examinations and adverse events emerging during the trial).  The National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 
will be used for the severity grading of adverse events and of hematological and blood 
chemistry abnormalities. 
4.2.3. Exploratory Endpoint 
 Baseline characterization of selected biomarkers (p53, p21, p27, cyclin D1, p75, TRKA 
and other genes/proteins involved in the PHA-848125AC mechanism of action) in tumor 
tissue of consenting patients. Assessments will be done on paraffin embedded blocks, 
obtained from all patients before study entry, by IHC and other possible techniques, such 
as FISH and PCR. 
5. TRIAL DESIGN AND DESIGN RATIONALE 
In consideration of the exploratory nature of the study, the Simon’s optimal 2 stage design is 
adopted for this single-arm, open-label, multicentre phase II clinical trial of PHA-848125AC 
administered to patients with recurrent or metastatic, unresectable thymic carcinoma 
previously treated with chemotherapy (only one prior systemic therapy allowed).  
The intent of the study is to assess the antitumor activity of PHA-848125AC and ultimately 
to improve the outcome of patients with thymic carcinoma who have already exploited one 
chemotherapy option. To this purpose, the progression free survival rate at 3 months is 
considered to be an appropriate primary endpoint. 


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Patients will receive repeated cycles of PHA-848125AC administered orally once daily at 
the flat dose of 150 mg/day, according to a 7 days on / 7 days off schedule in 2-week cycles. 
A treatment cycle will therefore comprise 7 days of PHA-848125AC administration (Days 1 
to 7) followed by 7 days of rest (Days 8 to 14) for a total of a 14 days period (2-week cycle). 
The 150 mg/day dose has been selected based on the results of the first single agent Phase I 
study in solid tumor patients (CDKO-125a-001), where PHA-848125AC was administered 
with the same schedule, at escalating dose levels, ranging from 50 to 300 mg/day: the dose 
of 150 mg/day was assessed as the dose recommended for Phase II investigations (RP2D); 
this dose was associated with mild/moderate reversible adverse events, mostly represented 
by maximum grade 2 nausea and/or vomiting and/or diarrhea and maximum grade 2 
neurological effects. 
Patients may continue on study treatment until disease progression, patient refusal or 
withdrawal of patient consent, or the occurrence of unacceptable toxicity and will be 
followed up for survival up to the end of the study and in any case for no more than 2 years 
from the end of treatment. 
Patients remaining on treatment longer than 6 cycles of treatment  are allowed to come back 
to the site once every 3 cycles (once every 1.5 month) for safety evaluation, drug dispensing, 
oncologic assessment and ocular examination. At the end of each cycle instead of the site 
visit the patient is required to perform the laboratory tests locally.  Also a phone interview 
will be performed by the Investigator to clarify the toxicity experienced by the patient during 
the observation period. The Investigator must document in writing the results of the phone 
call with the patient in the medical chart. Data are to be reported in the CRF. 
Only after evaluation of the laboratories’ results and of the patient’s safety performed by 
phone, the Investigator can decide if the patient may continue with the treatment. 
Otherwise, if the Investigator deems necessary to physically visit the patient (especially for 
the evaluation of his/her neurological status) or he has any doubt about the capability of the 
self-evaluation for a specific patient, it is left to the Investigator’s discretion the possibility 
to require that the patient reaches the site before continuing the treatment. 
A cut-off date is planned on 31 May 2017 in order to proceed with clinical database closure 
and preparation of the clinical study report. 
The management of patients after the cut-off date of 31 May 2017 should be conducted as 
per Section 9.5. 
The total number of evaluable patients for the primary efficacy analysis ranges from 17 (if 
the trial stops at the end of the 1st stage) to 54 (if the trial proceeds up to the completion of 
the 2nd stage). Accounting for a 10%-15% proportion of non evaluable patients, up to 20 
patients could be required in the 1st stage of the study and up to 60 patients could be 
required for completing the trial (1st and 2nd stage). 


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For statistical considerations, see Section 12. 
5.1. Confirmation of histological diagnosis 
Histological confirmation of thymic carcinoma for all patients will be obtained by an 
Independent Review Committee during the course of the study, based on paraffin embedded 
tumor tissue slides retrieved from the patients.  
6. SUBJECT SELECTION 
This clinical trial can fulfill its objectives only if appropriate subjects are enrolled.  The 
following eligibility criteria are designed to select subjects for whom protocol treatment is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject.  
Eligibility criteria may not be waived by the investigator and are subject to review in the 
case of a Good Clinical Practices (GCP) or a regulatory authority audit.  Any questions 
regarding a subject’s eligibility should be discussed with NMS Study Management prior to 
enrollment. 
6.1. Subject Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:  
1. Signed and dated IRB/IEC-approved Informed Consent. 
2. Histologically or cytologically proven diagnosis of unresectable B3 thymoma or thymic 
carcinoma recurrent or progressing after prior chemotherapy (only one prior systemic 
therapy allowed). 
3. Presence of measurable disease defined as at least one lesion that can be accurately 
measured by CT scan in at least one dimension, as > 10 mm for non nodal lesions 
(longest diameter to be recorded) and  15 mm for lymph nodal lesions (short axis to be 
recorded). (CT scan is the desirable method for lesion measurement. Other measurement 
techniques [eg MRI] are acceptable [but not for lung lesions] provided that the size of 
the measurable lesion is twice the slice thickness of the MRI). 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
4. Age  18 years. 
5. ECOG performance status 0-1. 
6. Estimated life expectancy of at least 3 months. 
7. Negative pregnancy test (if female in reproductive years). 


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8. Agreement upon the use of effective contraceptive methods (hormonal or barrier method 
of birth control, or abstinence) prior to study entry and for the duration of study 
participation, if men and women of child producing potential. 
9. Adequate liver function: 
 Total Serum Bilirubin            1.5 x upper limit of normal (ULN) 
 Transaminases (AST/ALT)    2.5 ULN (if liver metastases are present, then  5  
 
 
 
 
 ULN is allowed) 
 ALP 
 
 
           2.5 ULN (if liver and/or bone metastases are present, 
 
 
 
 
  then  5 ULN is allowed). 
10. Adequate renal function: 
 Serum Creatinine 
           ULN 
or 
Creatinine Clearance calculated by Cockcroft and Gault’s formula > 60 mL/min. 
11. Adequate hematologic status: 
 ANC   
 
           1,500 cells/mm3  
 Platelet Count  
           100,000 cells/mm3 
 Hemoglobin     
           9.0 g/dL.  
12. At the time of start of treatment, at least 2 weeks must have elapsed since completion of 
prior chemotherapy, minor surgery, radiotherapy (provided that no more than 25% of 
bone marrow reserve has been irradiated). 
13. With the exception of alopecia, resolution of all acute toxic effects of any prior 
chemotherapy, surgery or radiotherapy to NCI CTC (Version 3.0) grade  1 and to the 
baseline laboratory values as defined in Inclusion Criteria Number 9, 10, 11. 
14. Able and willing to comply with scheduled visits, therapy plans, and laboratory tests 
required in this protocol. 
15. Capability to swallow capsules intact (without chewing, crushing, or opening). 


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6.2. Subject Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment: 
1. Any of the following in the past 6 months: myocardial infarction, uncontrolled cardiac 
arrhythmia, unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, cerebrovascular accident or transient ischemic attack, 
pulmonary embolism, deep vein thrombosis. 
2. Grade >1 retinopathy as determined by an ophthalmologist. 
3. Known brain metastases. 
4. Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment. 
5. Active, uncontrolled bacterial, viral, or fungal infections. 
6. Known infection with HIV, active hepatitis B or hepatitis C. 
7. Pregnant or breast feeding women. 
8. Previous (within the last 5 years) or current malignancies at other sites, except for 
adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the 
cervix uteri. 
9. Current enrollment in or participation in another therapeutic clinical trial within 4 weeks 
preceding treatment start. 
10. Diabetes mellitus uncontrolled. 
11. Gastrointestinal disease (e.g. Crohn’s disease, ulcerative colitis, or short gut syndrome) 
that would impact on drug absorption. 
12. Patients under treatment with anticoagulants or with coagulation disorders or with signs 
of hemorrhage at baseline. 
13. Patients with previous history or current presence of neurological disorders, including 
epilepsy (although controlled by anticonvulsant therapy), Parkinson’s disease and extra-
pyramidal syndromes. 
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or may interfere with the 
interpretation of study results and, in the judgment of the Investigator, would make the 
patient inappropriate for entry into this study or could compromise protocol objectives in 
the opinion of the Investigator and/or the Sponsor. 


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7. SCHEDULE OF EVENTS 
The following table summarizes information on the timing of study assessments. 
SCHEDULE OF EVENTS 
Protocol Activities 
and Forms to Be Completed 
Pre 
Treatment 
Treatment 
Post Treatment 
Cycles 
Last 
Cycle 
 21 
Days 
 7 
Days 
Week 1 
Day 1 (*) 
Week 2 
between Days 
11-14 
AE 
FU 
(§) 
Follow up 
Informed Consent 1 
X 
 
 
 
 
 
 
Medical/ Oncologic History & 
Physical Examination 2 
X 
 
 
X 
X 
 
 
Vital Signs 3 
 
X 
X 
 
 
 
 
ECG 4 
X 
 
As medically indicated 
X 
 
 
Chest X-Ray 5 
X 
 
 
 
X 
 
 
Ophthalmologic exam. 6 
X 
 
 
X (even cycles)  
X 
 
 
Laboratory Assessments 
Serum/ Urine Pregnancy Test 7 
 
X 
 
 
 
 
 
Urinalysis 8 
 
X 
X (*)  
X (even cycles)  
X 
 
 
Hematology 9 
 
X 
X (*) 
X 
 
 
 
Blood Chemistry 10 
 
X 
X (*) 
X 
 
 
 
Coagulation 11 
 
X 
X (*) 
X (even cycles)  
X 
 
 
Tumor Assessments 
Tumor Imaging: 
chest/abdomen/pelvic CT scan or 
MRI 12 
X 
 
 
q6wks 
X 
 
q6wks 
Survival 13 
 
 
 
 
 
 
q6wks 
(+ q6mos) 
Other Clinical Assessments 
Adverse Event Assessment  
(including neurological status 
evaluation)  14 
 
X 
X 
 
X 
 
Concomitant Medications 15 
 
X 
X 
 
 
 
Special Studies 
Biomarker Status Assessment 16 
X 
Pharmacokinetic Blood Sampling 17 
 
 
As needed 
 
 
Histological confirmation 18 
X 
Study Treatment 
Enrollment 19 
 
X 
 
 
 
 
 
PHA-848125AC Administration 20 
 
 
Once daily for 7 
cons. days 
(D1 to D7) 
 
 
 
 
Footnotes for Schedule of Events 
1. Informed Consent: Every patient must sign the informed consent to participate in this trial before starting any trial related 
procedures. After signature, a Patient Screening Number is assigned centrally by CLIOSS on behalf ofTiziana Life Sciences, 
PLC. 
2. Medical/Oncology History & Physical Examination: Includes oncologic history, history of other disease processes 
(active, controlled or resolved) and concomitant illnesses (all of them at pretreatment only).  Physical examination will be done 
at pretreatment, and, on treatment, at the end of each cycle (see Section 11.4.3 Other safety assessments). For patients 
remaining on treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, the physical 
examination will be done in concomitance with the visit to the site (once every 3 cycles, 1.5 months).  Oncologic and non-
oncologic medical history, including prior antitumor treatments/procedures, are to be reported in the relevant case report form 
(CRF).  
Following approval of Amendment 4, management  of patients should be as per Section 9.5 


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3. Vital signs: Blood pressure/pulse (supine): at baseline and on Day 1 of each treatment cycle, before treatment 
administration. Height (in cm or inches): at baseline only.  Weight (in kilograms or pounds): at baseline and on Day 1 of each 
treatment cycle. ECOG performance status: at baseline and on Day 1 of each treatment cycle. Temperature (in °C or in °F): at 
baseline and on Day 1 of each treatment cycle. For patients remaining on treatment for a period of time more than 6 cycles 
and come back to the site every 3 cycles, vital signs (including blood pressure/pulse, weight, ECOG performance status and 
temperature) will be done in concomitance with the visit to the site (once every 3 cycles, 1.5 months). 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
4. ECG: 12-lead study. To be done at baseline, at the end of the last cycle and to be repeated during treatment as medically 
indicated. 
5. Chest X-Ray: Mandatory at screening visit and at the end of last cycle as safety assessment.  
6. Ophthalmologic Examination: to be conducted at baseline, at the end of even cycles (between days 11 and 14) and at 
the end of last cycle. For patients remaining on treatment for a period of time more than 6 cycles and come back to the site 
every 3 cycles, opthalmological examination will be done in concomitance with the visit to the site (once every 3 cycles, 1.5 
months). Includes visual acuity test and fundoscopic examination by an ophthalmologist. Additional assessments will be 
performed if clinically indicated. Ophthalmologic evaluations will be possibly done by the same ophthalmologist for a given 
patient. Following approval of Amendment 4, management  of patients should be as per Section 9.5 
7. Pregnancy Test: For women of reproductive potential.  Must be done within 7 days prior to initial study treatment. 
8. Urinalysis: pH, dipstick for glucose, protein and blood. To be done at baseline and at the end of last cycle. During 
treatment, should be performed at the end of even cycles (between days 11 and 14). For patients remaining on treatment for a 
period of time more than 6 cycles and come back to the site every 3 cycles, the urinalysis tests may be done locally when the 
visit to the site is not planned  (one visit planned to the site every three cycles, 1.5 months) and must be sent to the site for 
safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
9. Hematology (local laboratory): Hemoglobin, erythrocytes (RBC), white blood cell (WBC) with differential count (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, differential other cells), platelets (PLTs). To be done at baseline and 
between Day 11-14 of each cycle. In case of toxicity preventing re-treatment, hematology should be re-assessed on Day 1 of 
the next cycle before starting treatment. For patients remaining on treatment for a period of time more than 6 cycles and come 
back to the site every 3 cycles, the hematological tests may be done locally when the visit to the site is not planned  (one visit 
planned to the site every three cycles, 1.5 months) and must be sent to the site for safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
10. Blood Chemistry (local laboratory): sodium, potassium, chloride, magnesium, blood urea nitrogen (BUN) or urea, 
creatinine, albumin, AST/SGOT, ALT/SGPT, Alkaline Phosphatase (ALP), total bilirubin, creatinine clearance (calculated by 
Cockroft and Gault’s formula), amylase and lipase.  
To be done at baseline and between Day 11-14 of each cycle. In case of toxicity preventing re-treatment, blood chemistry 
should be re-assessed on Day 1 of the next cycle before starting treatment. For patients remaining on treatment for a period 
of time more than 6 cycles and come back to the site every 3 cycles, the biochemical tests may be done locally when the visit 
to the site is not planned  (one visit planned to the site every three cycles, 1.5 months) and must be sent to the site for safety 
evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
11. Coagulation: INR (International Normalized Ratio), activated partial thromboplastin time (APTT in seconds). To be done 
at baseline, at the end of last cycle and, during treatment, at the end of even cycles (between Days 11 and 14). For patients 
remaining on treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, the coagulation tests 
may be done locally when the visit to the site is not planned (one visit planned to the site every three cycles, 1.5 months) and 
must be sent to the site for safety evaluation and reported on CRF. 
Following approval of Amendment 4, management  of patients should be as per Section 9.5 
12. Tumor imaging: chest/abdomen/pelvic CT scan/ MRI : At baseline, to be done within 21 days before Day 1; during the 
treatment period (irrespectively from cycles duration), the first one to be done 6 weeks (between days 42 and 48) after first 
drug administration, the second one to be done 3 months (between days 92 and 98) after first drug administration, 
following ones to be repeated every 6 weeks (between days 42 and 48) after the previous one, and at end of last cycle (if not 
done in the previous 4 weeks). During Follow Up, to be performed every 6 weeks, until PD or until a new antitumor therapy 
starts. Patients with responding tumors (complete or partial response) must have response confirmed by CT scan at least 4 
weeks after the 1st documentation of response. The same method of assessment and the same technique should be used to 
characterize and follow the same lesion at baseline and during treatment. CT scan is the desirable method for lesion 
measurement. Other measurement techniques (eg MRI) are acceptable (but not for lung lesions) provided that the size of the 
measurable lesion is twice the slice thickness of the MRI. After data cut-off of 31 May 2017, the patients should perfom 
CT scan according to routine clinical practice and/or at investigator’s discretion. 
13. Survival: To be assessed during Follow Up every 6 weeks until PD or until a new antitumor therapy starts; every 6 months 
thereafter, up to 2 years from the end of treatment.  
Following approval of Amendment 4, management  of patients should be as per Section 9.5 


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14. Adverse Event Assessment (including neurological status evaluation): Events should be assessed and documented 
at each scheduled clinic visit since patient signs the Informed Consent: before treatment administration at baseline (baseline 
signs and symptoms), at the end of each treatment cycle, and 28 days after the last dose of study drug administration. For 
patients remaining on treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, the events 
will be assessed by phone call if the visit to the site is not planned (one visit planned to the site every three cycles, 1.5 
months). The phone call information will be reported in the medical chart and included in the CRF.  
Patients must be followed for adverse events also until every ongoing drug-related toxicities and serious adverse events have 
resolved or the investigator assesses them as “chronic” or “stable”. However, if the patient begins a new anticancer therapy 
before 28 days after the last dose of study drug administration, the adverse event reporting period will end at the time the new 
treatment is started. AEs will be recorded in the relevant CRF pages. 
After cut-off date of 31 May 2017, AE/SAE data will be no longer collected into the CRF, but assessments information 
should continue to be collected into the patient’s medical notes.  
After protocol Amendment 5 approval, only SAEs will continue to be reported to CLIOSS Pharmacovigilance for 
patients still receiving treatment, up to 28 days after milciclib discontinuation, according to Section 9.5. 
15. Concomitant Medications: all concomitant medications should be reported in the relevant CRF, including supportive 
care drugs, and drugs used for treating adverse events or chronic diseases. For patients remaining on treatment for a period 
of time more than 6 cycles and come back to the site every 3 cycles, the concomitant medications will be assessed by phone 
call if the visit to the site is not planned (one visit planned to the site every three cycles, 1.5 months). The phone call 
information will be collected in the medical chart and included in the CRF. Following approval of Amendment 4, 
management  of patients should be as per Section 9.5 
16. Biomarker Status Assessment: retrieval of tumor paraffin embedded blocks (slides), obtained from consenting patients 
before study entry (if available) and characterization of baseline molecular features of p53, p21, p27, cyclin D1, p75, TRKA 
and other genes/proteins involved in the PHA-848125AC mechanism of action.   
17. Pharmacokinetics: blood samples may be collected if, in the opinion of the Investigator and of the Sponsor, an 
evaluation of PK parameters is needed for safety reasons. 
18. Histological confirmation: histological confirmation of diagnosis of thymic carcinoma for all patients will be obtained by 
an Independent Review Committee during the course of the study, based on paraffin embedded tumor tissue slides retrieved 
from patients. 
19. Enrollment: The Investigator is requested to sign a Request For Enrollment form. His/her signature is the guarantee that 
all the eligibility criteria are met. Patient Number is assigned by the Sponsor. Treatment must be administered within 7 days 
from patient enrollment. 
20. PHA-848125AC administration: The study drug will be administered at 150 mg (flat dose) once daily for 7 consecutive 
days of each treatment cycle (from day 1 to Day 7). After an overnight fasting with free access to water, patients will take the 
study drug with a large glass of plain water without ice. A light breakfast can be served 1.5-2 hours later. PHA-848125AC 
capsules have to be stored under refrigerated conditions (5  3 °C; 36-46 °F) and out of reach of children 
(*) Cycle 1, Day 1 assessments: hematology, blood chemistry, urinalysis and coagulation do not need to be repeated before 
treatment on Cycle 1, Day 1 if they were performed during screening within 1 week before first study drug administration. 
Cycle > 1, Day 1 assessments: hematology and blood chemistry do not need to be repeated before treatment on Cycles> 1, 
Day 1 if no toxicity preventing re-treatment resulted from laboratory assessments done within the previous 4 days. 
(§) AE FU: end of adverse events reporting period (to be done 28 days after last study drug administration) and follow up of 
unresolved drug related/serious AEs. 
After data cut-off of 31 May 2017, AE/SAE data and related follow up will be no longer collected into the CRF, but 
assessments information should continue to be collected into the patient’s medical notes.  
After approval of Amendment 4 to the protocol, only SAEs should be reported to CLIOSS Pharmacovigilance for 
patients still receiving study treatment, up to 28 days after discontinuation of milciclib, according to Section 9.5. 


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8. ENROLLMENT PROCEDURES 
The informed consent should be signed and dated before starting any trial specific 
procedures. After signature of informed consent, the patient will be registered with a 
patient’s screening number centrally assigned by CLIOSS on behalf of Tiziana (details 
reported in the Study Manual). Upon completion of screening evaluation, the patient, if 
eligible, will be enrolled and assigned a patient number to be carried out during the trial. 
In order to obtain screening number and then patient number for each patient, the 
Investigator will fill in a registration/enrollment form and fax it to the CLIOSS study 
management (details reported in the Study Manual).  Investigator’s signature on the 
registration/enrollment form is the guarantee that all the eligibility criteria are met. A reply 
by fax will be sent within 1 working day. The time between enrollment and initiation of 
treatment should not be longer than 7 days. 
Enrollment will be competitive among the participating sites. 
CLIOSS will inform all sites on a regular basis about the enrollment status. 
9. TREATMENT  
Only qualified personnel familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents.  
9.1. Trial Products  
9.1.1. Description 
PHA-848125AC is formulated as hard gelatin capsules containing 10 mg, 50 mg and 100 
mg, respectively, of active ingredient. 
The three different strengths are distinguishable each other by the different color and 
capsules sizes: 10 mg capsules are size 4 hard gelatin capsules, opaque Swedish orange cap 
and opaque caramel body; 50 mg capsules are size 2 hard gelatin capsules, opaque Swedish 
orange cap and body; 100 mg capsules are size 1 hard gelatin capsules, opaque white cap 
and body. All the described capsules contain a pale yellow to yellow powder. 
PHA-848125AC 10 mg, 50 mg and 100 mg capsules are packaged in white High Density 
Polyethylene (HDPE) bottles with twist off plastic caps. 
New capsule formulations have been developed in order to have a formulation suitable for 
an automatic filling process, whereas the original formulations are filled with a 
semiautomatic capsule filling machine. 


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For more details on the new formulations, see PHA-848125AC Investigator Brochure, 
Version 7, 2011 [23]. 
9.1.2. Drug Preparation/Administration/Dispensing 
PHA-848125AC will be administered as home-based treatment. The Investigator (or 
delegate) will dispense to the patient the doses of PHA-848125AC covering no more than 
two cycles at a time during the first three months of treatment (6 cycles) and covering three 
cycles at a time after three months of treatment (for patients who continue treatment after 6 
cycles and come back to the site every 3 cycles). The daily doses will be made out of a 
number of capsules, according to the dose (in mg/day) at which the patient has been assigned 
for a given cycle.  
The study medication has to be stored under refrigerated conditions (5  3 °C; 36-46 °F), in 
the original packaging, out of the reach and sight of children. 
Original IMP Packaging 
As each capsule of PHA-848125AC is individually packaged in a bottle (the primary 
packaging), the daily dose of PHA-848125AC will consist of a number of bottles packed 
together in an outer packaging (bag) and the 7 bags will be stored in a weekly container 
(box). At each cycle, patients will take the assigned daily dose for 7 consecutive days (from 
Day 1 to Day 7) and will be instructed not to take the study drug for the subsequent 7 days 
(i.e. Days 8-14), so to ensure a 7-day resting period. 
A secondary packaging (box) will be used to store stocks of bottles in the pharmacy of the 
participating institutions only. 
Primary, secondary and outer packaging, and weekly container will be labeled with the 
relevant information. 
New IMP Packaging 
A new IMP packaging, currently under preparation, will be introduced and will consist of 
one PHA-848125AC capsule of each strength individually packaged in a labeled bottle (the 
primary packaging) and each bottle inserted in one labeled small single carton (the 
secondary packaging).  
The Sponsor has considered to simplify the original IMP packaging above described, so that 
no repacking activities for patient doses preparation should occur at clinical trial sites. The 
original IMP packaging will be used in the clinical trial until the new IMP packaging will be 
available.  
The different IMP strengths (50 mg and 100 mg) will be easily distinguished by using 
different colors for labels stuck on primary and secondary packaging. 


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As each capsule of PHA-848125AC is individually packaged in a bottle/single carton, the 
daily dose of PHA-848125AC will consist of a number of bottles/cartons (e.g. for a full dose 
of 150 mg/day: 1 bottle containing one 50 mg capsule in a single small carton and 1 bottle 
containing one 100 mg capsule in a single small carton). At each cycle, patients will take the 
assigned daily dose for 7 consecutive days (from Day 1 to Day 7) and will be instructed not 
to take the study drug for the subsequent 7 days (i.e. Days 8-14), so to ensure a 7-day resting 
period. 
9.1.3. Patient Education & Information 
All patients will receive their doses of PHA-848125AC together with a patient’s diary, 
which includes also the instructions relevant to study drug administration. The site personnel 
handing the study medication to patients must ensure that they fully understand that the 
treatment period (cycle) comprises 14 days, consisting of 7 days of daily administration 
(from Day 1 to Day 7), followed by a 7-day resting period, from Day 8 to Day 14. Extension 
of treatment period to Days >7 is not allowed, even in case of missed doses. 
Additionally, the patients should be informed: 
 to take the study drug every day as prescribed by their doctor. Some patients may find 
particularly hard to remember the idea of repeated short courses of treatment with 'gaps' 
between them. 
 to take the study drug at the same time each day (1.5-2 hours before breakfast with a 
glass of plain water without ice; water is allowed during fasting period). 
 if the patient forgets to take the study drug at the usual time, to take it between meals at 
any time during the same day and record the events on the patient’s diary. 
 if the patient misses one day, to take the normal amount the next day, if scheduled. Not 
to double the daily prescribed dose of the study drug and to track the number of capsules 
missed and the reason for it in the patient’s diary. 
 if vomiting occurs during or after having taken the daily dose, not to take extra capsules 
that day and to take the normal amount the next day, if scheduled. Not to double the 
daily prescribed dose of the study drug and record the events in the patient’s diary. 
 to adhere to the principles of safe handling and storage of the study medication. 
Breaking/crushing or opening the capsules must be avoided. In such cases, record of the 
broken capsules should be kept in the patient’s diary. In case of opening of the capsules, 
to avoid contact or inhalation. In case of skin contact, to wash the affected area with 
plenty of water or soap and water. In case of eye-contact, to rinse thoroughly with plenty 
of water and seek medical advice as soon as possible. 
 to return all packaging (bottles, bags and carton boxes for the original IMP packaging 
and bottles and single cartons for the new IMP packaging) as well as not-taken capsules 
(if applicable) and the patient diary to the site personnel. 


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As much of this information as possible should first be given at the pre-treatment visit and 
reinforced on subsequent visits. 
9.2. Procedure for Handling Drug Spills 
Precautions for drug handling of cytotoxic agents should be followed for PHA-848125AC. 
In case of opening of the capsules, avoid contact or inhalation. In case of skin contact, the 
affected area should be washed with plenty of water or soap and water. Any contaminated 
clothing should be removed. In case of eye-contact, rinse thoroughly with plenty of water. 
Seek medical advice as soon as possible. 
9.3. Storage and Stability 
PHA-848125AC is to be stored under refrigerated conditions (5  3 °C; 36-46 °F) and in the 
original packaging, out of the reach and sight of children. 
To ensure optimal environmental and patient exposure protection, the packaging has been 
designed as a single use one. 
On the basis of the available supportive stability results, a provisional shelf-life of  48 
months is assigned to both 50 mg  and 100 mg capsules, when stored at 5  3 °C (36-46 °F) 
in the original packaging. 
Concurrent stability studies on the clinical batches of the current formulation will be carried 
out in order to evaluate the chemical and physical parameters, and the expiry date will be 
extended accordingly with the stability results.  Any unexpected finding will be promptly 
communicated to the investigators and to the Health Authorities. 
9.3.1. Source of Drug 
NerPharMa (NMS Group), on behalf of the Sponsor Tiziana Life Sciences PLC will supply 
PHA-848125AC (milciclib maleate) free of charge. Additional supply may be obtained by 
contacting CLIOSS (see Study Manual for contact information). 
9.3.2. Drug Accountability 
PHA-848125AC must not be used outside the context of this protocol.  Under no 
circumstances should the Investigator or site personnel supply study product to other 
Investigators or clinics, or allow the supplies to be used other than as directed by this 
protocol without prior authorization from the Sponsor. 
Adequate records on receipt, use, return, loss, or other disposition of medication must be 
maintained. A specific drug accountability form supplied by the Sponsor or computer 
records used by the pharmacy at the investigational site, can be used to provide drug 
accountability information. In either case, information describing study drug supplies and 


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their disposition, subject by subject, must be provided, signed by the Investigator (or the 
pharmacist or other person who dispensed the drug) and collected by the study monitor. 
Requisite data includes relevant dates, quantities, batches or code numbers, and subject 
identification for subjects who received study drug. 
At the end of the study and upon authorization of the Sponsor, the study drug may be 
destroyed at the site as dictated by the appropriate standard procedures of the participating 
institutions.  Destruction must be documented.  Alternatively, all unused product will be 
collected by the local monitor and returned to NerPharMa. 
If disposed locally, all used bottles and containers of study product should be discarded 
according to the standard institutional policy. 
Study drug handling and accountability after the cut-off date of 31 May 2017 should 
continue as described above. 
9.4. Treatment Administration 
9.4.1. Treatment Dose and Schedule 
PHA-848125AC will be administered orally at the dose of 150 mg/day (flat dose) once daily 
for 7 consecutive days of each treatment cycle. A treatment cycle will comprise 7 days of 
PHA-848125AC administration (Day 1 to 7) followed by 7 days of rest for a total of 14 days 
(2 weeks) period. 
After an overnight fasting, with free access to water, patients will take the study drug with a 
large glass of plain water without ice. A light breakfast can be served 1.5-2 hours after study 
drug intake. 
9.4.2. Duration of Treatment  
Each patient will remain on treatment until disease progression, patient refusal, consent 
withdrawal, or the occurrence of unacceptable toxicity or of any other criteria for withdrawal 
as detailed in Section 10. 
At the end of the treatment period, all patients will be followed for survival every 6 months 
up to 2 years after the end of treatment. Anyhow, if a patient stops the treatment before any 
documentation of PD, the follow up will be initially performed at 6-week intervals and will 
include a complete oncological assessment up to documentation of PD or the start of another 
antitumor therapy, then it will be continued for survival only every 6 months.  
Patients still on treatment after the cut-off date of 30 April 2017, will be managed according 
to Section 9.5. 


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9.4.3. Dose Modifications 
Dose modifications may occur as a consequence of drug-related toxicities, during a cycle or 
at the start of a new cycle. In the event of multiple toxicities, dose modifications should be 
applied based upon the most severe toxicity observed and attributable to PHA-848125AC. 
As far as dose reductions are concerned, a dose reduction to the dose level of 100 mg/day 
(i.e. –33%) is recommended in case of poor tolerability of the full dose of 150 mg/day. 
The dose of 100 mg/day (mean Day 7 AUC 19.9 M·h) was successfully used for 20 cycles 
in keeping disease control in a patient with colorectal cancer, initially treated at 150 mg/day 
for 7 cycles in the CDKO-125a-001 study. 
Doses reduced for drug-related toxicity should not be re-escalated. Any exception is to be 
discussed between the Investigator and the Sponsor. 
Table 4 describes the recommended dose modifications during the treatment cycles and at 
the start of any new cycle. 
Note: the dose adjustments in the third column are intended as referred to the dose of Day 
1 of the previous cycle. 


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Table 4. Criteria for PHA-848125AC Dose Modifications 
Toxicity (Graded as per NCI CTCAE Criteria, 
Version 3.0) 
During Treatment Cycle 
Dose Adjustment for Next 
Treatment Cycle (after recovery 
from toxicities to grade 1, or to 
baseline values) ¶ 
Hematologic  
 
 
Grade 0 or Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 Neutropenia (ANC < 1500-1000/mm
3) 
and/or Grade 2 Thrombocytopenia (platelet 
count <75000-50000/mm3) 
If occurs during treatment, maintain 
daily dose level 
Monitor until resolved to grade 1 
Maintain dose level 
Grade 3 Neutropenia (ANC <1000-500/mm
3) 
If occurs during treatment, 
decrease daily dose by one dose 
level  
Monitor until resolved to grade 1 
Maintain dose level 
Grade 3 Thrombocytopenia (platelet count 
<50000-25000/mm3), uncomplicated or lasting 
less than 5 days 
If occurs during treatment, 
decrease daily dose by one dose 
level 
Monitor until resolved to grade 1 
Maintain dose level 
Grade 4 Neutropenia (ANC < 1000/mm
3) 
lasting < 7 days 
If occurs during treatment, 
decrease the daily dose  by one 
dose level 
Monitor until resolved to grade  1  
Maintain dose level 
Grade 4 Neutropenia (ANC < 1000/mm
3)  
lasting 7 days or more 
 
 
Febrile neutropenia 
(ANC <1,000/mm3 and fever of unknown origin 
38.5C) 
 
 
Neutropenic infection: grade  3 (i.e. infection 
documented clinically or microbiologically with 
grade 3 or grade 4 neutropenia) 
If occurs during treatment, interrupt 
the treatment 
Monitor until resolved to grade 1 
 1 dose level 
Grade  3 Thrombocytopenia (platelet count 
<50000/mm
3) uncomplicated lasting 5 days or 
more, or associated with bleeding and/or 
requiring transfusion  
 
 
Any other grade 4 hematological toxicity 
 
 
Nausea and/or Vomiting  
 
 
Grade 1 or 2 in absence of antiemetics 
If occurs during treatment, maintain 
daily dose level and add 
antiemetics, if needed. 
If occurs during rest period, add 
antiemetics, if needed 
Maintain dose level with 
antiemetics §, if needed 
Grade 3 in absence of antiemetics 
If occurs during treatment, 
decrease the daily dose by one 
dose level, add antiemetics. 
If occurs during rest period, add 
antiemetics 
Monitor until resolved to grade 1 
Maintain dose level with 
antiemetics § 
Grade 3 in presence of antiemetics § 
If occurs during treatment, interrupt 
treatment 
Monitor until resolved to grade 1 
 1 dose level  


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Toxicity (Graded as per NCI CTCAE Criteria, 
Version 3.0) 
During Treatment Cycle 
Dose Adjustment for Next 
Treatment Cycle (after recovery 
from toxicities to grade 1, or to 
baseline values) ¶ 
 
Diarrhea 
 
 
Grade 1 or 2 (in absence or presence of 
management of the event §) 
If occurs during treatment, maintain 
daily dose level, add/adjust 
antidiarrheal treatment, if needed. 
If occurs during rest period, 
add/adjust antidiarrheal treatment, 
if needed 
Maintain dose level 
Grade 3 despite optimal management of the 
event § 
If occurs during treatment, interrupt  
treatment 
Monitor until resolved to grade 1 
 1 dose level 
Neurologic 
 
 
Grade 0, 1 or no worsening compared to 
baseline 
Maintain dose level 
Maintain dose level 
Grade 2 tremors 
If occurs during treatment, interrupt  
treatment 
 1 dose level or discontinue 
study treatment (Investigator to 
discuss with the Sponsor) 
Grade > 2 tremors or any other Grade  2 
neurological toxicity 
Discontinue study treatment  
(Investigator to discuss with the 
Sponsor) 
Discontinue study treatment 
(Investigator to discuss with the 
Sponsor) 
Ocular/Visual 
 
 
Grade 0  
Maintain dose level 
Maintain dose level 
Increase of 1 or more grades retinopathy by 
ophthalmologic examination compared to 
baseline  
Discontinue study treatment 
Discontinue study treatment 
Other non hematological toxicity (except alopecia) 
Grade 0, 1 
Maintain dose level 
Maintain dose level 
Grade 2 
If occurs during treatment, maintain  
or decrease the daily dose by 1 
dose level, if clinically indicated 
Monitor until resolved to grade 1 
Maintain dose level 
Grade  3 
If occurs during treatment, interrupt 
treatment 
Monitor until resolved to grade 1 
 1 dose level  
Failure to recover 
 
 
Failure to recover to grade  1 toxicity (except 
alopecia) or to baseline values, if grade 2 is 
allowed at study entry, after delaying the 
initiation of next cycle by > 2 weeks 
Monitor until resolved to grade 1 
 1 dose level  (Investigator to 
discuss with the Sponsor) 
¶ : the dose adjustments in the third column are intended as referred to the dose of Day 1 of the previous cycle. 
§  For prophylaxis and management of the events, see Concomitant Medications and Other Therapy, Section  9.4.9. 
Abbreviations: ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events, NCI = 
National Cancer Institute 
 


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9.4.4. Retreatment and Dose Delay 
A new cycle of treatment may begin when the ANC is  1500/mm3, the platelet count is 
 100,000/mm3, and the non-hematologic toxicities are  grade 1, except for alopecia (for 
which a grade > 1 is allowed) and for ocular toxicity (for which a worsening retinopathy of 1 
or more grades compared to baseline implies study treatment discontinuation) or are 
recovered to baseline values, if grade 2 is allowed at study entry. If these conditions have not 
been met, treatment should be delayed for 1 or 2 weeks to allow for recovery. If after a 
maximum of a 2-week delay all toxicities (except for alopecia and for toxicities for which 
grade 2 is allowed at study entry) are  grade 1, then proceed with treatment as outlined in 
the Dose Modification Table 4.  An increased delay > 2 weeks is to be discussed between 
the Investigators and the Sponsor on a case by case basis. 
9.4.5. Overdose Instructions 
There are no known antidotes for milciclib maleate PHA-848125AC.  In the case of an 
overdose of PHA-848125AC, neurological toxicity (tremors and ataxia) and gastrointestinal 
toxicity are among the expected effects. The Sponsor study management should be contacted 
to discuss the details of any overdose. 
9.4.6. Unblinding  
Not applicable in this study. 
9.4.7. Assessment and Management of Potential CNS Toxicity 
Signs of CNS toxicity, including tremors, hyperactivity and ultimately convulsions have 
been observed during the toxicology evaluations of PHA-848125AC administered at high 
single or high repeated doses attaining daily systemic exposures  30M.h. In all species, 
this pattern of toxicity was reversible and not accompanied by morphological/pathological 
findings. 
In humans, reversible tremors and ataxia have been reported in the CDKO-125a-001 study 
(see Section 3.2.7). Resolution of both events in approximately 7-8 days was reported, upon 
study treatment discontinuation. 
Tremors which can be induced by other drugs include enhanced physiologic tremor, rest 
tremor, and action tremor. Signs and symptoms of drug-induced tremors depend on the drug 
used and on a patient's predisposition to its side effects. Cessation of the causative agent may 
improve drug-induced tremor symptoms. Table 5 lists drugs that may induce tremor, along 
with the types of tremors and neurologic signs they produce. 


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Table 5. Drug-induced Tremors and Corresponding Neurologic Signs 
Drug/Drug Class 
Tremor Type 
Neurologic Signs 
Neuroleptics 
Rest, postural 
Extrapyramidal 
Metoclopramide 
Rest, postural 
Extrapyramidal 
Lithium 
Rest, postural, action 
Extrapyramidal 
Theophylline 
Postural 
None 
Bronchodilators 
Postural, action 
None 
Valproate 
Postural 
Rarely parkinsonism 
Amiodarone 
Postural 
Rarely parkinsonism 
 
During visits, patients treated with PHA-848125AC will undergo regular clinical 
examination, which includes the assessment of clinical tremors and associated signs and 
symptoms. Patients should be examined during rest, when assuming various positions and 
when moving.  Tremors will be graded according to NCI CTCAE version 3.0 grading 
system as follows: 
Tremor Grades, NCI CTCAE Version 3.0 
0. Absent 
1. Mild and brief or intermittent but not interfering with function 
2. Moderate tremor interfering with function, but not interfering with ADL 
3. Severe tremor interfering with ADL 
4. Disabling 
 
PHA-848125AC dose modifications for neurologic adverse events attributable to the study 
drug are detailed in Table 4. 
Pharmacological management of neurological adverse events, such as tremors and/or 
convulsions, should refer to institutional and/or published interventional protocols [35,36]. 
9.4.8. Assessment of Potential Ocular Toxicity 
Ocular toxicity has been reported in rats treated for prolonged period of time (daily 
treatments for 3 consecutive weeks + 1 week of rest x 3 cycles or daily treatments for 4 
consecutive weeks) at doses associated with daily AUCs close to 25 M·h, as well as in rats 
given daily treatments for 2 consecutive weeks +1 week of rest for 5 cycles at doses 
associated to AUC of about 32 M·h. 
No ocular toxicity was observed in rats with a 7-day repeat treatment schedule up to doses 
associated to a daily AUC of about 50M·h or up to doses associated to a daily AUC of 
about 10 Mh in the 4-week schedule and up to doses associated to daily AUC of about 12 
M·h. in the 3-week schedule. 


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Despite clinical manifestations of ocular toxicity were not observed in the clinical studies so 
far, a potential ocular toxicity cannot be excluded. During visits, patients treated with PHA-
848125AC will undergo regular clinical examinations, i.e. ophthalmologic examination 
(visual acuity test and funduscopic examination), at the end of even cycles (see Schedule of 
Events in Section 7 and also Section 11.4.3). 
Retinopathy will be graded according to NCI CTCAE version 3.0 grading system as follows: 
Retinopathy Grades, NCI CTCAE Version 3.0 
0. 
Absent 
1. 
Asymptomatic 
2. 
Symptomatic with moderate decrease in visual acuity (20/40 or better) 
3. 
Symptomatic with marked decrease in visual acuity (worse than 20/40) 
4. 
Blindness (20/200 or worse) 
 
Grade 1 retinopathy is allowed at study entry since it is an asymptomatic event occurring in 
relation to common medical conditions such as hypertension [37,38]. It is recognized that 
several patients in their 50s and 60s with underlying hypertension may present asymptomatic 
retinopathy. Such a status is to be regarded as a condition which does not prevent patients’ 
enrollment in the study, being not clinically significant. 
Ophtalmologic evaluations will be possibly done by the same ophthalmologist for a given 
patient. 
The increase of 1 or more grades retinopathy by ophthalmologic examination will require 
immediate study drug discontinuation. 
Management of ocular adverse events should refer to institutional interventional protocols. 
9.4.9. Assessment of Potential, Thrombotic Microangiopathy/Hemolytic Uremic 
Syndrome 
Two patients, both treated in the CDKO-125a-004 combination study with gemcitabine (‘A 
Phase I Dose-Escalation Study of Oral PHA-848125AC Administered in Combination with 
Gemcitabine in Adult Patients with Advanced/Metastatic Solid Tumors'), developed 
Thrombotic Microangiopathy/Hemolytic Uremic Syndrome (TMA/HUS). 
The two cases were considered to be probably related to gemcitabine and unlikely related to 
PHA-848125AC by the participating Investigator, and occurred in patients with very 
prolonged and high exposure to both drugs (after 14 and 21 months on treatment, 
respectively); both patients recovered in the opinion of the Investigator, and only one of 
them required plasmapheresis. No other cases of TMA/HUS were reported in any of the 
other studies completed or ongoing with PHA-848125AC (all single agent studies). Anyway, 
taking into consideration the small number of patients treated so far at this stage of 
development of PHA-848125AC (about 200 patients), a contribution of the study drug on 


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the two observed TMA/HUS events cannot be completely ruled out. As a consequence, 
special attention should be paid to the following events: 
 Progressive increase of anemia up to CTC Grade  3 no otherwise explained 
 Progressive platelets decrease up to CTC Grade  2 
 Increase of creatinine (shift to CTC Grade 2) or calculated creatinine clearance 
diminished by  25% vs baseline 
 Presence of hematuria or proteinuria 
 Appearance of high blood pressure in a patient with unknown history or with high blood 
pressure previously well controlled with medications  
 Appearance of oedema concomitant to proteinuria 
Whenever  2 of the above listed alterations appear concomitantly for the first time, or at 
any time if the Investigator judges it appropriate, study drug administration is to be 
temporarily held, until further evaluations are done. The latter ones consisting of the search 
of schistocytes in the peripheral blood smear, the count of reticulocytes in the peripheral 
blood, coagulation test, total LDH and 24-hour proteinuria [39]. Routine Hematology, Blood 
Chemistry and Urinalysis tests foreseen by study protocol, should also be repeated at the 
time when this evaluation is performed. 
If based on the above examinations MTA/HUS can be ruled out, study drug administration 
can be resumed, adopting the dose modifications outlined in Table 4 for drug-related 
toxicities, as applicable. 
In case of suspicion or evidence of MTA/HUS, study drug has to be discontinued. 
9.4.10. Concomitant Medications and Other Therapy 
All concomitant medications must be entered into the CRF.  
After the data cut-off of 31 May 2017 and protocol Amendment 4 is approved at the 
investigational site, data will be no longer collected into the CRF, and information on 
concomitant medications should continue to be recorded into the patient’s medical notes 
only.  
Directives for supportive care are outlined below. 
9.4.10.1. Antiemetics 
Prophylactic therapy with antiemetics is allowed starting from the first onset of emesis. 
Pharmacological management of nausea and/or vomiting may refer to institutional and/or 
published guidelines for treatment [40,41]. 


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9.4.10.2. Antidiarrheals 
Treatment with loperamide might be started at the occurrence of grade 1 diarrhea (increase 
of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline). 
Loperamide should be taken in the following manner: 4 mg at the first onset of diarrhea, 
then 2 mg every 2 hours. This therapy should continue for 12 hours after the last liquid stool.  
Patients may take loperamide 4 mg every 4 hours during the night. In no instance should 
loperamide be administered for more than 48 consecutive hours because of the risk of 
paralytic ileus. 
Other antidiarrhetic agents and/or antibiotics used by the Institutions are allowed. 
Patients should be instructed to refer to the center in case of diarrhea lasting > 24 hours 
despite optimal supportive care or diarrhea with fever. 
9.4.10.3. Antiacids 
Patients with chronic/ intensive use of H2-receptor antagonists, proton pump inhibitors, 
antacids, should take these drugs at a time point far from PHA-848125AC intake (at least 3-
4 hours) during the day, or the night before treatment, to avoid any potential effect on 
PHA-848125AC absorption. 
9.4.10.4. Hematopoietic Growth Factors 
Hematopoietic growth factors may be used as medically indicated in patients with relevant 
neutropenic complications, such as tissue infection, sepsis, etc., at the Investigator’s 
discretion. Red blood cell and/or platelets transfusion should be considered at the 
Investigator’s discretion in patients with significant anemia and/or thrombocytopenia. 
9.4.10.5. Anticoagulants 
Concomitant anticoagulant treatment is not recommended.  
9.4.10.6. Inhibitors or Inducers of CYP3A4 
Significant drug-drug interactions with inhibitors or inducers of CYP3A4 are not expected 
(see Section 3.2.4). Therefore, there are no specific contraindications to the use of inhibitors 
or inducers of CYP3A4. 
9.4.10.7. Steroids 
Concurrent use of steroids for treatment of a pre-existing autoimmune disorder or as 
antiemetic therapy is allowed. 


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9.4.10.8. Other Permitted Concomitant Medications 
Therapies considered necessary for the patient’s well being may be given at the discretion of 
the Investigator, i.e. chronic treatments for concomitant medical conditions, as well as 
agents required for life-threatening medical problems, analgesics etc. Patients should be 
advised to contact the treating physician before starting any new drug. 
9.4.10.9. Concomitant Radiotherapy 
Palliative radiotherapy to specific sites is permitted if considered medically necessary by the 
treating physician. However, the irradiated area should be as small as possible, and involve 
≤20% of the bone marrow reserve [Appendix 2]. During the period of irradiation and for 2 
weeks after, chemotherapy should be withheld. If irradiation-related toxicities (other than 
xerostomia) have not normalized to pre-irradiation levels after these 2 weeks of rest, the 
patient should be removed from the study. Radiotherapy should be avoided for at least 5 
days after the last dose of PHA-848125AC. 
9.4.10.10. Other Anticancer or Experimental Therapy 
No other approved or investigational anticancer treatment will be permitted during the study 
period including chemotherapy, biological response modifiers, hormones or immunotherapy. 
No other investigational drug may be used during therapy on this protocol. Simultaneous 
participation in other clinical treatment study protocols is not allowed. 
9.5. Management of Patients after Data Cut-Off 
Patients still receiving milciclib maleate at the cut-off date of 31 May 2017 can continue 
with their treatment, and will continue with their protocolled scheduled visits to the site until 
they meet any discontinuation criteria as per Section 10.  
However, after protocol Amendment 4 is approved at the investigational site, data will be no 
longer collected into the CRF, and assessments information should continue to be recorded 
into the patient’s medical notes only. After protocol Amendment 4 approval, the patients 
should attend visit according to routine clinical practice and/or at investigator’s discretion, 
until they meet any discontinuation criteria as per Section 10. 
After cut-off date of 31 May 2017, SAEs will continue to be reported as per protocol for 
patients still receiving study treatment, up to 28 days after discontinuation of milciclib. 
Drug supply will be granted by the Sponsor free of charge, and accountability should 
continue to be performed until the patient stops study treatment completely. 
The end of the study is defined as the date of the last visit of the last patient, occurring when 
all patients have discontinued study treatment.  


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10. SUBJECT WITHDRAWAL FROM STUDY PARTICIPATION 
Patients may continue with therapy unless any of the following occurs: 
 Disease progression at any time 
 Unacceptable toxicity dictating cessation of treatment 
 Changing in medical status of the patient (including pregnancy) such that the 
Investigator believes that patient safety will be compromised or that it would be in the 
best interest of the patient to stop treatment  
 Withdrawal of consent (includes any reason why the patient decides to discontinue 
completely his/her study participation and does not wish that the Sponsor follows 
him/her to collect information regarding disease status. In this case no further evaluation 
should be performed and no attempts should be made to collect additional data) 
 Patient’s refusal to continue the study treatment (includes any patient who does not want 
to be treated anymore in the frame of this study but accepts that the Sponsor continues to 
follow him/her in order to collect information regarding disease status). Applicable only 
for patients treated pre-Amendment 4. 
 Non-compliance by the patient with protocol requirements. Applicable only for patients 
treated pre-Amendment 4. 
 Patient lost to follow up. If a patient does not return for a scheduled visit, every effort 
should be made to contact the patient. In any circumstance, every effort should be made 
to document patient outcome. Applicable only for patients treated pre-Amendment 4. 
11. ASSESSMENTS  
11.1. Timing of Assessments 
Section 7 summarizes information on the timing of study assessments.  
11.2. Efficacy Assessments 
The determination of antitumor efficacy will be based on objective tumor assessments made 
according to the RECIST guideline (version 1.1) [34]. 
11.2.1. Tumor Imaging 
Tumor imaging by chest/abdomen/pelvic CT scan or MRI: the baseline tumor 
assessment by CT scan or MRI has to be performed within 3 weeks prior to the treatment 
start; during the treatment period (irrespectively of cycles duration) the first assessments will 
be performed 6 weeks (between days 42 and 48) after first drug administration, the second 
one 3 months (between days 92 and 98) after first drug administration, the following 
ones every 6 weeks (between days 42 and 48) after the previous one (or whenever a clinical 


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deterioration will be observed) and at end of last cycle (if not done in the previous 4 weeks). 
For patients with responding tumors (complete or partial response), response confirmation 
must be performed no less than 4 weeks after the criteria for response are first met. 
In addition, in patients withdrawn from study treatment for causes other than disease 
progression, tumor response will have to be reassessed at the time of study drug 
discontinuation, unless a tumor assessment was performed within the previous 4 weeks. In 
these patients, regular tumor imaging assessments are to be performed every 6 weeks during 
follow-up, until PD or until a new antitumor therapy starts. 
The same method and technique (CT scan, spiral CT scan or MRI) should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging-
based evaluation, over clinical examination, is the required technique when both could be 
used to assess the antitumor effect of the treatment. 
CT scan is the desirable method for lesion measurement. CT scans should have a maximum 
slices thickness of 5 mm and a minimum size for a measurable lesion is twice that: 10 mm 
(even if slice thickness is <5 mm). If scanners with slice thickness > 5 mm are used, to 
qualify for a measurable lesion, the minimum lesion size must have a longest diameter twice 
the actual slice thickness. MRI is acceptable (but not for lung lesions), provided that the size 
of the measurable lesion is twice the slice thickness of the MRI. 
All patients’ files and scans must be available for source verification. 
11.2.1.1. Measurability of Tumor Lesions 
At baseline, tumor lesions will be categorized by the Investigator as measurable or non-
measurable by the RECIST guideline (version 1.1) criteria as described below. 
Measurable:  
Tumour lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:  
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). In case of MRI, the 
size of the measurable lesion must be twice the slice thickness of the MRI and a minimum of 
10 mm. 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Non-Measurable: 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 


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nodes with 10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Special considerations regarding lesion measurability: 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• “Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  
When effusions are known to be a potential adverse effect of treatment, the 
cytological/histological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or SD is 
mandatory to differentiate between response or SD and PD. 
11.2.1.2. Recording Tumor Measurements 
Target lesions. When more than one measurable lesion is present at baseline, all lesions up 
to a maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline (this means in instances where patients have only one or two organ 
sites involved a maximum of two and four lesions respectively will be recorded). Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 


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reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion which can be measured reproducibly should be selected.  
Pathological nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of 15 mm by CT scan. Only the short axis of these 
nodes will contribute to the baseline sum. The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT 
scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, 
sagittal or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum. 
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline, including pathological lymph nodes with 
short axis 10 mm but <15 mm (nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed). 
Measurements are not required and these lesions should be followed as “present”, “absent”, 
or in rare cases “unequivocal progression”. In addition, it is possible to record multiple non-
target lesions involving the same organ as a single item on the case record form (e.g. 
“multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). 
11.2.1.3. Target Lesions Tumor Response 
Complete response (CR) is defined as disappearance of all target lesions and reduction in 
short axis to <10 mm of any pathological lymph nodes (whether target or non-target). 
Partial response (PR) is defined as at least 30% decrease in the sum of the diameters of the 
target lesions, taking as a reference the baseline sum diameters. 
Progressive disease (PD) is defined as at least 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new 
lesions is also considered progression). 
Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 


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Special notes on the assessment of target lesions 
Lymph nodes: lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when 
lymph nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become “too small to measure”: while on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan 
that the radiologist may not feel comfortable assigning an exact measure and may report 
them as being ‘too small to measure’. When this occurs it is important that a value be 
recorded on the case report form. If it is the opinion of the radiologist that the lesion has 
likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned. (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned in this circumstance as 
well). This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false responses or 
progressions based upon measurement error. To reiterate, however, if the radiologist is able 
to provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: when non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid 
in obtaining maximal diameter measurements of each individual lesion. If the lesions have 
truly coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximal longest diameter for the “coalesced lesion”. 
11.2.1.4. Non Target Lesions Tumor Response 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete response (CR) is defined as the disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 
mm short axis). 
Non-CR/Non-PD is defined as a persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 


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Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression). 
Special notes on assessment of progression of non-target disease 
To achieve “unequivocal progression” on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease such that, even in presence of 
SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest increase in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
11.2.1.5. Confirmation of Tumor Response 
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed > 4 weeks after the criteria for response are first met 
by the same tumor imaging technique used at baseline and on treatment (eg CT scan or 
MRI).   
In case of SD, measurements must have met the SD criteria at least once after study entry at 
the minimum interval of 6 weeks. 
11.2.1.6. Determination of Overall Response by RECIST (version 1.1) 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  The overall assessment of response will involve all parameters as depicted in 
Table 6. 
Table 6. Response Criteria 
Target Lesions 1 
Non-Target Lesions 2 
New Lesions 3 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any response 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
1 Measurable lesions only  
2 May include measurable lesions not followed as target lesions or non-measurable lesions 
3 Measurable or non-measurable lesions 
Abbreviations:  CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease, NE = 
inevaluable 
 


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The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation (achievement 
of both measurement and confirmation criteria, depending on the nature of the study and the 
protocol requirement).  The patient’s best overall response assignment will depend on the 
findings of both target and non-target disease and will also take into consideration the 
appearance of new lesions. In the case of SD, follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 6 weeks. 
Table 7. Best overall response when confirmation of CR and PR required 
Overall response 
First time point 
Overall response 
Subsequent time point 
 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether 
minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were 
likely still present and in fact the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration” (see Study Manual specific data collection instructions).  
Of note, every effort should be made to document the objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such 
patients is to be determined by evaluation of target and non-target disease. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy before assigning a status of 
CR. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic 


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changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
11.3. Outcomes Research Assessments 
Not applicable in this study. 
11.4. Safety Assessments   
11.4.1. Adverse Event Assessment  
11.4.1.1. Definition of Adverse Events 
11.4.1.1.1. Adverse Event 
According to ICH definition an AE is defined as any untoward medical occurrence in a 
patient or a clinical trial subject administered a medicinal product and which does not 
necessarily have to have a causal relationship with the use of the product. An adverse event 
can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), 
symptom, or diagnosis temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.  
Any untoward medical occurrence, which occurs outside the period of subject follow-up 
defined in the protocol (28 days after the last treatment administration for the present study, 
see Section 11.4.1.3), is not considered an AE. Symptoms or medically significant 
laboratory or instrumental (e.g. electrocardiograph) abnormalities of a pre-existing condition 
should not be considered an AE. However, occurrences of new symptoms, laboratory or 
instrumental abnormalities, as well as worsening of pre-existing ones, are considered AEs. 
In this trial, the following should not be reported as adverse event: 
 The general wording “Progression of the disease”.  
Note: the specific symptoms of the disease worsening have to be considered as adverse 
events.  
 Uncomplicated and asymptomatic abnormal laboratory findings.  
Note: abnormal laboratory findings have to be considered as adverse events when they 
cause treatment discontinuation or when require clinical intervention (e.g., 
hospitalization for further investigation or management of the laboratory abnormality).   
11.4.1.1.2. Serious Adverse Events 
A serious adverse event is an adverse event that falls into one or more of the following 
categories:  


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 Results in death 
 Is life-threatening, i.e., is an event which, in the view of the Investigator, places the 
subject at immediate risk of death from the event as it occurred (it does not include 
an event which hypothetically might have caused death if it was more severe) 
 Requires inpatient hospitalization or prolongation of existing hospitalization  
 Results in persistent or significant disability/incapacity, where disability is defined as 
a substantial disruption of a person’s ability to conduct normal life functions, either 
reported or defined as per clinical judgment 
 Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child) 
 Is any other important medical event, i.e., may not result in death, be life-threatening, 
or require hospitalization, but based upon appropriate medical judgment, it may 
jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the points above.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, and blood dyscrasias or convulsions that do not result in inpatient 
hospitalization. 
A non-serious adverse event is any adverse event that does not meet the criteria listed above 
for a serious adverse event or the outcome (i.e., subject treatment, life-threatening condition, 
hospitalization, recovery) cannot be determined with the information provided. 
Each adverse event has to be classified by the Investigator as serious or non-serious. This 
classification of seriousness of the event determines the reporting procedures to be followed.  
In this trial the following do not have to be classified as Serious Adverse Events: 
 Admission to hospital required by the protocol. 
 Events definitely related to disease progression. 
All deaths occurring during the reporting period have to be reported as SAEs, even if 
due to disease progression. 
11.4.1.2. Eliciting Adverse Event Information 
The Investigator has to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject using concise medical terminology.  In addition, 
each trial subject will be questioned about adverse events at each clinic visit following the 
signature of the informed consent. The question asked will be “Since your last clinical visit 
have you had any health problems?” 


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11.4.1.3. Adverse Event Reporting Period 
Adverse event reporting period: 
The adverse event reporting period for this trial begins upon signing of informed consent 
form and ends 28 days after the last treatment administration. 
. 
However, if the patient begins a new anticancer therapy before 28 days after the last dose of 
study treatment administration, the adverse event reporting period will end at the time the 
new treatment is started. 
All adverse events that occur in trial subjects during the adverse event reporting period must 
be reported to CLIOSS (delegated by the Sponsor), whether or not the event is considered 
related to the study treatment.  
Adverse event follow up after the end of the reporting period: 
The following events should be followed after the end of the reporting period (i.e., 28 days 
after the last treatment administration): 
1. All serious adverse events with outcome “not recovered” or “unknown” at the end of the 
reporting period. 
2. Those non-serious events whose relationship with investigational study treatment has 
been classified as “Unlikely”, “Possible”, “Probable” and “Definite” with outcome ‘ not 
recovered’ at the end of the reporting period. 
Such events should be followed until they resolve, the patient begins a new anticancer 
therapy or the Investigator determines, whenever possible, that they have become “chronic” 
or “stable”. Resolution of such events is to be documented on the appropriate report form. 
In addition, if, after the end of the reporting period, suspected serious adverse reactions or 
deaths are reported to the Investigator and he/she believes that they are related to the 
investigational product, it is the Investigator’s responsibility to report this suspected serious 
adverse reactions to CLIOSS Pharmacovigilance. Such suspected serious adverse reactions 
will be reported using a Serious Adverse Event Report Form or any other way chosen by the 
Investigator.  
After the cut-off date of 31 May 2017 and protocol Amendment 4 approval, SAEs will 
continue to be reported to CLIOSS Pharmacovigilance for patients continuing treatment, 
until 28 days after study treatment is discontinued, according to Section 9.5. 


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11.4.1.4. Reporting Requirements 
Each adverse event has to be classified by the Investigator as SERIOUS or NON SERIOUS.  
The seriousness of the event determines the reporting procedures to be followed. If a serious 
adverse event occurs, the CLIOSS Pharmacovigilance (delegated by the Sponsor) has to be 
notified, by Fax (+39 0331 581681) or by e-mail (drugsafety@clioss.com) using the 
designated form, within 24 hours of awareness of the event by the Investigator. The initial 
report should be followed by submission of more detailed adverse event information within 
5 calendar days after the Investigator first became aware of the serious adverse event. 
Reporting requirements for adverse events are summarized in the following table. 
Table 8. Reporting requirements for adverse events 
Gravity 
Reporting Time 
Type of Report 
SERIOUS 
Within 24 hours 
Initial report on designated serious adverse event 
form (SAER-F) 
Within 5 calendar days 
Follow-up/Final report on designated serious 
adverse event form (SAER-F) 
NONSERIOUS 
Per case report form submission 
procedure 
Study case report forms 
 
Serious adverse events should also be recorded on appropriate section of the case report 
form. 
In the rare event that the Investigator does not become aware of the occurrence of a serious 
adverse event immediately (for example, if an outpatient trial subject initially seeks 
treatment elsewhere), the Investigator should report the event within 24 hours after learning 
of it and document his/her first awareness of the adverse event. 
Non serious adverse events have to be recorded on the study case report forms. 
11.4.1.5. Recording Adverse Events in the Case Report Forms 
Information on adverse events must be evaluated by a physician and recorded in a source 
document such as the hospital file.  Adverse events are to be recorded on the case report 
forms as above specified.  The Investigator will also be asked to assess the relationship 
between the adverse event and the investigational medication. 
 Preexisting Conditions 
In this trial, a pre-existing condition (i.e., a disorder present before an adverse event occurs 
and recorded on the pretreatment medical history/physical examination form) should not be 
reported as an adverse event unless the condition worsens or episodes increase in frequency 
during the adverse event reporting period. 
 Baseline Signs and Symptoms 


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All Signs and Symptoms (either tumor-related or not tumor-related) collected at baseline 
should not be reported anymore during the study except in case they worsen in severity or in 
frequency. 
 Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should 
not be reported as adverse events.  However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of adverse event.  For example, 
an acute appendicitis that begins during the adverse event reporting period should be 
reported as the adverse event and the resulting appendectomy should be recorded in the 
source documents.  
After cut-off date of 31 May 2017, AE/SAE data will be no longer collected into the CRF, 
but assessments information should continue to be collected into the patient’s medical notes. 
11.4.1.6. Grading of Adverse Event Severity 
The severity of adverse events will be graded using the Common Terminology Criteria for 
Adverse Events (CTCAE, Version 3.0) of the US National Cancer Institute. See the website: 
http://ctep.info.nih.gov/reporting/ctc.html. For each event, the highest severity grade attained 
should be reported. 
Schedule of adverse events safety assessment is reported in Section 7, Schedule of Events. 
For events not reported in the CTCAE Version 3.0, the Investigator will use the grade or 
adjectives reported in Table 9: 
Table 9. Grading of Adverse Event Severity for Events not reported in the CTCAE 
Version 3.0 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Does not interfere with patient’s usual function 
Grade 2 
Moderate 
Interferes to some extent with patient’s usual function 
Grade 3 
Severe 
Interferes significantly with patient’s usual function 
Grade 4 
Life-threatening 
Results in threatening to life or in an incapacitating disability 
Grade 5 
Death 
Results in death 
 
Note the distinction between the seriousness and the intensity of an adverse event.  Severe is 
a measure of intensity; thus, a severe reaction is not necessarily a serious reaction.  For 
example, a headache may be severe in intensity but would not be classified as serious unless 
it met one of the criteria for serious events listed in paragraph (see Section 11.4.1.1.2). 
11.4.1.6.1. Relationship to the Investigational product 
The causality between each adverse event and the investigational product should be 
classified according to the following terms: 


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Unrelated: the event is a pre-dose event or is definitely due to causes separate from the 
administration of the investigational product, i.e.: documented pre-existing condition, 
concomitant medication, the subject’s clinical state or the event is judged as not related and 
does not fall under any of the above points. 
Unlikely: an event for which the exclusion of drug causality seems most plausible, whilst 
other drugs or underlying disease provide plausible explanation. 
Possible: a clinical event, including laboratory test abnormality, with a reasonable temporal 
sequence from administration of the investigational product and with a known response 
pattern to the investigational product, but the event could have been caused by subject’s 
clinical state, other therapy administered or diagnostic/interventional procedure. Information 
on drug withdrawal may be lacking or unclear. 
Probable: a clinical event, including laboratory test abnormality, with a reasonable temporal 
sequence from administration of the investigational product and with a known response 
pattern to the investigational product, but the event cannot be reasonably explained by the 
known characteristics of the subject’s clinical state, other therapy administered or 
diagnostic/interventional procedure and for which there is evidence of partial or complete 
disappearance of the event after withdrawal of the product (positive dechallenge). 
Definite: a clinical event that follows a reasonable temporal sequence from administration of 
the drug or in which the drug level has been established in body fluids or tissues; that 
follows a known response pattern to the suspected drug; and that is confirmed by 
improvement on withdrawal (positive dechallenge) or reducing the dose, and reappearance 
of the event after reintroduction of the drug (positive rechallenge). 
11.4.1.7. Exposure In Utero 
The Investigator will be asked to submit an Exposure in Utero Form in the cases reported 
below: 
 a trial patient becomes or is found to be pregnant while receiving an investigational 
medication/product or within 90 days of its discontinuation 
 a partner of a male patient becomes or is found to be pregnant, while the patient is 
receiving an investigational medication/product or within 90 days of discontinuing 
the investigational medication/product. 
This must be done irrespective of whether an adverse event has occurred and within 24 
hours of awareness of the pregnancy. The information submitted should include the 
estimated date of delivery (see below for information related to induced termination of 
pregnancy). However if the patient begins a new anticancer therapy before 90 days after the 
last dose of study treatment administration, the exposure in utero reporting period will end at 
the time the new treatment is started.  


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The Investigator will follow the patient until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify the CLIOSS Pharmacovigilance of the 
outcome within 5 days or as specified below. The Investigator will provide this information 
as a follow up to the initial Exposure in Utero form. The reason(s) for an induced abortion 
must be specified.  
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the Investigator should follow the procedures for 
reporting serious adverse events, i.e., report the event to Nerviano Medical Sciences (as 
described in Section 11.4.1.4, Reporting Requirements).  
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant must pass before an 
Exposure in Utero Form can be completed). The “normality” of an aborted fetus can be 
assessed by gross visual inspection unless pre-abortion laboratory findings are suggestive of 
a congenital anomaly.  
Additional information about pregnancy outcomes that are classified as serious adverse 
events follows:  
 “Spontaneous abortion” includes miscarriage and missed abortion. 
 All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events. In addition, any infant death after 1 month that 
the investigator assesses as possibly related to the in utero exposure to the investigational 
medication should also be reported. 
11.4.2. Laboratory Safety Assessments 
Laboratory safety assessments will include repeated evaluation of hematology and 
biochemistry parameters, urinalyses and pregnancy test that after the cut-off date of 31 May 
2017 will be done according to routine clinical practice and/or at investigator’s discretion. 
The results of these exams should be recorded only in the patient’s medical notes..  
Hematology tests include: hemoglobin, erythrocytes (RBC), white blood cell (WBC) with 
differential count (neutrophils, lymphocytes, monocytes, eosinophils, basophils, differential 
other cells), platelets (PLTs). 
They will be performed during screening period and repeated during treatment between the 
Days 11 and 14 of all cycles. If toxicity preventing re-treatment results from the Day 11-14 
assessment, hematology should be repeated as needed to monitor for recovery. 
Hematology tests will be done also on Day 1 of cycles, before study drug administration, 
only in case toxicity preventing re-treatment resulted from the assessment done within the 
previous 4 days at the end of the prior cycle.  
For patients remaining on treatment for a period of time more than 6 cycles and come back 


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to the site every 3 cycles, the hematological tests may be done locally when the visit to the 
site is not planned (one visit planned to the site every three cycles, 1.5 months) and must be 
sent to the site for safety evaluation and reported on CRF. 
Blood chemistry tests include: sodium, potassium, chloride, magnesium, blood urea nitrogen 
(BUN) or urea, creatinine, albumin, AST/SGOT, ALT/SGPT, Alkaline Phosphatase (ALP), 
total bilirubin, creatinine clearance (calculated by the Cockroft and Gault’s formula), 
amylase and lipase. 
They will be performed during screening period and repeated during treatment between the 
Days 11 and 14 of all cycles. If toxicity preventing re-treatment results from the Day 11-14 
assessment, blood chemistry should be repeated as needed to monitor for recovery. 
Blood chemistry tests will be done also on Day 1 of cycles, before study drug 
administration, only in case toxicity preventing re-treatment resulted from the assessment 
done within the previous 4 days at the end of the prior cycle. For patients remaining on 
treatment for a period of time more than 6 cycles and come back to the site every 3 cycles, 
the biochemical tests may be done locally when the visit to the site is not planned  (one visit 
planned to the site every three cycles, 1.5 months) and must be sent to the site for safety 
evaluation and reported on CRF. 
Coagulation tests include: INR (International Normalized Ratio) and activated partial 
thromboplastin time (APTT, in seconds). To be done at baseline, at the end of last cycle and, 
during treatment, at the end of even cycles (between Days 11 and 14). For patients 
remaining on treatment for a period of time more than 6 cycles and come back to the site 
every 3 cycles, the coagulation tests may be done locally when the visit to the site is not 
planned (one visit planned to the site every three cycles, 1.5 months) and must be sent to the 
site for safety evaluation and reported on CRF. 
Urinalysis includes: pH, dipstick for glucose, protein and blood.  It will be performed at 
baseline and at the end of last cycle. During treatment, should be performed at the end of 
even cycles (between Days 11 and 14). For patients remaining on treatment for a period of 
time more than 6 cycles and come back to the site very 3 cycles, the urinalysis tests may be 
done locally when the visit to the site is not planned (one visit planned to the site every three 
cycles, 1.5 months) and must be sent to the site for safety evaluation and reported on CRF. 
Serum/urine pregnancy test is indicated only for women of reproductive potential and is to 
be carried out within 7 days prior to the first treatment administration. 
The timing and specific requirements for each laboratory safety evaluation are given in 
Section 7, Schedule of Events. 
Specific analyses to be performed in presence of events indicative of, or suggestive of, 
MTA/HUS (see Section 9.4.9): search of schistocytes in the peripheral blood smear, count of 
reticulocytes in the peripheral blood, coagulation test, total LDH and 24-hour proteinuria. 


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Routine Hematology, Blood Chemistry and Urinalysis tests, foreseen by the study protocol, 
should also be repeated at the time when this evaluation is performed. 
11.4.3. Other Safety Assessments 
The following safety assessments will also be performed, according to timing reported in 
Section 7, Schedule of Events: 
Physical examination will be done at pretreatment and on treatment at the end of each cycle. 
Any abnormality at pretreatment should be reported in the Baseline Signs and Symptoms 
CRF page and on treatment in the AE CRF page. For patients still on treatment at the cut-off 
date of 31 May 2017, assessments data should be recorded only in the patient’s medical 
notes. 
Vital Signs: Blood pressure/pulse (supine) is to be monitored at baseline and on Day 1 of 
each treatment cycle, before treatment administration; height (in cm or inches) will be 
measured at baseline only; weight (in kg or pounds) will be assessed at baseline and on Day 
1 of each treatment cycle; ECOG performance status will be monitored at baseline and on 
Day 1 of each treatment cycle; temperature (in °C or °F) will be measured at baseline and on 
Day 1 of each treatment cycle. 
ECG (12-lead) will be carried out at the pretreatment visit and at the end of last cycle. To be 
repeated during treatment as medically indicated. 
Chest X-ray will be carried out, for safety assessment, at the pretreatment visit and at the end 
of last cycle. 
Ophthalmologic examination will include visual acuity test and fundoscopic examination 
and will be carried out at the pretreatment visit, at the end of even cycles (between Days 11 
and 14) and at the end of last cycle by an ophthalmologist. Additional assessments will be 
performed if clinically indicated.  
Ophthalmologic evaluations will be done by the same ophthalmologist for a given patient. 
For patients still on treatment at the cut-off date of 31 May 2017, data should be recorded 
only in the patient’s medical notes. 
Neurological status evaluation: at each scheduled clinical visit (at baseline, at the end of 
each treatment cycle, and 28 days after the last dose of study drug administration) patients 
will undergo regular clinical examination, including the assessment of clinical tremors and 
associated signs and symptoms. Patients should be examined during rest, when assuming 
various positions and when moving (see also Section 9.4.7, Assessment and Management 
ofPotential CNS Toxicity). Any sign and symptom of neurological toxicity should be 
recorded in the Adverse Events CRF pages of the relevant cycle.  For patients still on 
treatment at the cut-off date of 31 May 2017, no AEs will be collected in the CRF, and all 
evaluations should be recorded only in the patient’s medical notes. 


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11.5. Other Assessments 
11.5.1. Confirmation of histological diagnosis 
Histological confirmation of diagnosis of thymic carcinoma for all patients will be obtained 
by an Independent Review Committee during the course of the study, based on paraffin 
embedded tumor tissue slides retrieved from patients. 
11.5.2. Pharmacokinetics 
No blood sampling is expected during the study for pharmacokinetics analysis. Blood 
samples may be collected if, in the opinion of the Investigator and of the Sponsor, an 
evaluation of the systemic exposure of PHA-848125AC is needed for safety reasons. In such 
case the IRB will be notified. 
If applicable, the actual time of sample collection has to be recorded in the Case Report 
Form. 
11.5.3. Laboratory Exploratory Studies on Tumor Specimens 
11.5.3.1. Collection of Tumor Specimen(s) 
Paraffin-embedded tissue blocks or derived slides containing the original diagnostic tumor 
samples from consenting patients will be procured from the institutions where the diagnostic 
procedures were performed. 
Tumor blocks or derived slides will be shipped by a commercial courier under controlled 
temperature conditions in protective packaging. 
11.5.3.2. Molecular characterization of patient’s tumors 
Molecular analysis of p53, p21, p27, cyclin D1, p75, TRKA and other genes/proteins 
involved in the PHA-848125AC mechanism of action on paraffin-embedded tissues of 
consenting patients will be performed in designated facilities in NMS and NIH/NCI. 
12. STATISTICAL METHODS 
12.1. Sample Size Calculation 
In consideration of the exploratory nature of the study, the Simon’s optimal 2-stage design 
[42] is adopted for this single-arm, open-label, multicentre phase II clinical trial. 
The total number of evaluable patients for the primary efficacy analysis ranges from 17 (if 
the trial stops at the end of the 1st step) to 54 (if the trial proceeds up to the completion of 
the 2nd step). Accounting for a 10%-15% proportion of non evaluable patients, up to 20 


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patients could be required in the 1st stage of the study and up to 60 patients could be required 
for completing the trial (1st and 2nd stage). 
The primary endpoint of the study is the progression-free survival status at 3 months and the 
primary efficacy analysis will be performed on the proportion of successes (i.e. patients alive 
and in a progression-free status at 3 months since treatment start) out of the total number of 
evaluable patients (PFS-3 rate). 
Considering a 33% PFS-3 rate as clinically interesting, against a clinically uninteresting 
hypothesis of a PFS-3 rate no higher than 17%, the system of hypotheses to be tested is: 
H0:  p  p0,   p0 = 0.17      vs.      H1:  p  p1,    p1= 0.33 
The analysis will be performed at the overall level  = 0.05 (1-sided). 
The design below outlined will provide 80% power (1-β) not to reject the treatment as 
insufficiently effective, if the true PFS-3 rate is 33% or higher.   
In the first stage, 17 evaluable patients are to be assessed. If  3 successes are observed, the 
study treatment will be considered as providing insufficient evidence of efficacy and the trial 
will be terminated.  
If at least 4 successes are observed in the 1st stage, patients’ enrollment will proceed up to an 
overall enrollment of 54 evaluable patients. At the final analysis,  14/54 successes (PFS-3 
rate ≥ 25.9%) will be required to reject the null hypothesis and suggest that the drug might 
have an interesting level of efficacy.  The progression free survival at 3 months will be 
evaluated based on the antitumor activity evaluated during the oncologic assessment at 3 
months after first drug administration. The oncologic assessment will be performed 
preferably between 92-98 days from treatment start, but all patients with assessments 
performed up to 134 days will be considered evaluable for the primary end-point. 
 
H0    vs.    H1 
  
(1-sided)  
power  
(1-) 
1st Stage (*) 
2nd Stage 
Pts 
STOP and  
Reject drug 
Pts 
Reject drug 
Do not reject drug 
p0  0.17  vs.  p1  0.33 
    ( PFS-3 rate ) 
0.05 
0.80 
17 
evaluable 
pts 
 3  / 17 
successes 
54 
evaluable 
pts 
 13 / 54 succ. 
(PFS-3 rate 24.1%) 
 14 / 54 succ. 
(PFS-3 rate  25.9%) 
(*) Probability of Early Termination: PET=0.675,  if the drug is actually ineffective;   
      Probability to continue the trial > 0.863,  if the true PFS-3 rate is at least 33%:  
Expected sample size assuming ineffective drug: 29 
No. of enrolled patients:  20 patients in the 1st stage,  60 patients overall  (if 10%-15% inevaluable patients)  


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12.2. Definition of Analyzed Study Populations 
For the purpose of the analysis, the following patient populations are defined and the 
endpoints, to be analyzed in these populations, are specified: 
 Screened Patients:  This population will include all subjects who are screened about 
their eligibility for the trial, regardless of whether or not they will be enrolled in the 
study.  This population will be evaluated in the analysis of patients’ disposition. 
 Enrolled Patients:  This population will include all subjects who are enrolled in the trial, 
regardless of whether subjects receive the study drug or not.  This population will be 
evaluated in the analysis of patients’ disposition. 
 Treated Patients: The treated patient population consists of all enrolled patients who 
actually receive at least one study drug administration. This population will be evaluated 
in the analysis of patient disposition, baseline characteristics, treatment efficacy and 
safety and treatment exposure. 
 Patients Evaluable for Efficacy Analysis:  This is the patient population for the primary 
efficacy analysis of PFS-3 rate and consists of all treated patients who fulfill the 
following additional conditions:  
 They have received histological confirmation of thymic carcinoma by an 
Independent Review Committee 
 They receive at least 80% of drug in the first two cycles overall. 
 They have baseline and 1 on-treatment tumor/oncologic assessment(s) or die before 
tumor re-assessment. 
If deemed of clinical interest, patient disposition, baseline characteristics, treatment 
efficacy and safety and treatment exposure will be analyzed also in this population. 
12.3. Analyses 
12.3.1. Study Conduct and Subject Disposition 
Patients’ disposition will be presented in frequency distribution tables and individual data 
listings.  All screened patients will be included in this evaluation. Violations of eligibility 
criteria at study entry as recorded in the relevant sections of the CRF will be documented. 
Reasons for stopping treatment will be summarized as frequency distribution in the treated 
patient population and, if clinically interesting, in other patient subsets (e.g. evaluable 
patients). 
12.3.2. Baseline Characteristics 
Descriptive statistics of the baseline characteristics will be generated in the treated patient 
population and, if clinically interesting, in other patient subsets (e.g. evaluable patients). 
Frequency distributions will be presented for the categorical / categorized variables.  


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Summary statistics including mean, standard deviation, median, minimum, maximum and 
the number of assessed patients will be calculated, as appropriate, for the quantitative 
variables.  Individual data will be presented in listings. 
12.3.3. Treatment Administration/Compliance 
The treatment exposure and the compliance with study treatment will be descriptively 
analyzed in the treated patient population and, if clinically interesting, in other patient 
subsets (e.g. evaluable patients). Descriptive statistics (e.g. min, max, mean, standard 
deviation, and median value) will be calculated on a per-patient basis for the following 
variables: the number of cycles administered, the overall duration of treatment, the actual 
and total doses administered, and the absolute and relative dose intensity. Frequency 
distributions of patients and/or cycles will be used to describe dose modifications, delays 
and omissions, as well as the reasons for deviation from the planned therapy. These data will 
be presented as reported in the relevant CRF sections. 
12.3.4. Efficacy Analyses 
Primary Efficacy Endpoint 
For the primary efficacy analysis, the primary endpoint, i.e. the PFS-3 rate, will be 
calculated as the proportion of evaluable patients (see Section 12.2) known to be alive and 
progression-free at ≥ 3 months since study treatment start out of the total number of 
evaluable patients (see Section 4.2.1). Decision rules will be applied in the primary efficacy 
analysis as described in Section 12.1, i.e.: 
 At least 4 / 17 evaluable patients alive and progression free at  3 months are required 
not to early terminate the trial and reject the drug at the end of the first step.  
 At least 14 / 54 evaluable patients alive and progression free at  3 months are required 
at the end of the second step to reject the null hypothesis of a PFS-3 rate as low as 17%, 
at the 1-sided α-level of 0.05.   
Supportive analyses of the primary endpoint will include the estimation of the PFS-3 rate 
together with its exact, two-tail, 95% confidence interval and the estimation of the PFS 
curve by the Kaplan-Meier method [43] in both the evaluable and the treated patient 
population. 
Other Efficacy Endpoints 
The secondary efficacy endpoints outlined in section 4.2.2 and including the confirmed 
objective response rate, the disease control rate, the duration of response and the overall 
survival will be analyzed in both the evaluable and the treated patient population as follows: 
Objective tumor response rate: Point and 95% confidence interval estimates will be 
calculated for the objective tumor response rate (confirmed CRs or PRs).  The analysis will 


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be performed in the evaluable and in the treated patient populations.  The estimates of the 
rates of unconfirmed tumor objective responses will also be provided and considered as 
supportive. 
Disease control rate: Point and 95% confidence interval estimates will be calculated for the 
disease control rate (confirmed CRs / PRs and SD  6 weeks).  The analysis will be 
performed in the evaluable and in the treated patient populations.   
Time-to-event endpoints:  For the other secondary endpoints, duration of response (in 
patients achieving a confirmed objective tumor response by RECIST version 1.1 criteria) 
and overall survival (OS), individual calculated times will be presented in patients’ data 
listings together with the identification of censored vs. failure status. Kaplan-Meier curves 
will be estimated for OS in both the evaluable and the treated patient populations.   
All collected efficacy data will be presented in individual patients’ data listings. 
12.3.5. Outcomes Research Analyses 
Not applicable in this study. 
12.3.6. Safety Analyses 
Safety data will be evaluated in the treated patient population and, if clinically interesting, in 
other patient subsets (e.g. evaluable patients). 
The adverse events (AEs) will be coded by the Medical Dictionary for Regulatory Activities 
(MedDRA) and their severity graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0.  The MedDRA preferred term and system organ 
class (SOC) will be used to identify and group events in data listings and descriptive 
analyses. All reported baseline signs and symptoms and on-treatment adverse events will be 
reported in the patients’ data listings. The analysis will address all the events that are 
recorded on treatment (i.e. from cycle 1, on). The raw incidence of each sign/symptom, of 
the subsets of events grouped by system organ class and, in general, the raw incidence of any 
AE, will be calculated. In this analysis, every patient will be accounted for on the basis of 
the worst CTCAE grade reported during the whole period, within the considered category 
(e.g. the analyzed sign/symptom or system organ class).  The following subsets of AEs will 
also be specifically considered: serious AEs, AEs with CTCAE grade 3-5, AEs with a 
relationship to study treatment classified by the Investigator as possible or probable or 
definite and AEs reported as leading to discontinuation from treatment. 
Raw incidence of death will be calculated.  Deaths will also be described in terms of 
relationship to the study treatment and according to the time from treatment stop. 
Laboratory test values will be graded according to the NCI CTCAE scale, v3.0, whenever 
possible. For each laboratory test included in the NCI CTCAE system, the incidence of 


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abnormalities will be evaluated by considering the worst occurrence for each patient 
throughout the whole treatment period. The frequency distributions of cycles according to 
the worst CTCAE grade will also be calculated for selected parameters, as clinically 
indicated. Preliminary conversions of reported values from the originally reported units to a 
set of predefined units will be applied to facilitate the comparison.  For selected parameters 
descriptive analysis of shifts relative to baseline will be performed if deemed of clinical 
relevance. Coagulation tests will be evaluated with respect to the corresponding baseline 
values and to the recorded normal ranges. Urinary parameters will be documented in patient 
data listings. 
Ophthalmologic examinations will be summarized in terms of normal / abnormal findings.  
Shift tables comparing patients’ worst assessments after treatment initiation to the 
corresponding baseline assessments will be built. 
All collected safety data (including vital signs, ECG, ophthalmologic evaluations, laboratory 
tests and adverse events) will be presented in individual patients’ data listings. Identification 
of clinically relevant values and calculation of changes from baseline will be provided in the 
listings for those parameters and conditions deemed of clinical relevance. 
12.3.7. Analyses of Other Endpoints 
12.3.7.1. Baseline Expression of Molecular Markers in Tumor Biopsies 
The collection of these data is foreseen only in the consenting patients with available tumor 
samples. 
Descriptive statistics of molecular features of p53, p21, p27, cyclin D1, p75, TRKA and 
other genes/proteins involved in the PHA-84125AC mechanism of action in the available 
tumor samples will be presented. Exploratory analyses on the relationship between these 
markers and treatment efficacy variables (e.g. PFS-3, PFS, objective tumor response, OS) 
will be performed only if sufficient data are collected. 
12.3.7.2. Pharmacokinetics 
Plasma levels versus sampling times will be presented in tabular and graphic form, if 
applicable. 
12.3.7.3. Concomitant Medications and Post-Treatment Anti-tumor Therapies 
Individual patients’ data listings will be prepared to document the administration of 
concomitant medications. 
Patients starting antitumor therapies during follow-up will be identified in a patients’ data 
listing. 


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12.4. Interim Analysis Plan 
Not Applicable in this study. 
12.5. Data Monitoring Committee 
Not applicable. 
13. END OF STUDY 
After approval of Amendment 4, the end of the trial is defined as the last visit of the last 
patient, occurring when all patients have discontinued study therapy. 
14. QUALITY CONTROL AND QUALITY ASSURANCE 
Monitoring visits to the trial site will be made periodically during the trial to ensure that 
GCPs and all aspects of the protocol are followed.  Source documents will be reviewed for 
verification of agreement with data on case report forms.  The investigator/institution 
guarantees direct access to source documents by the Sponsor and appropriate regulatory 
authorities. 
The trial site may also be subject to review by the institutional review board 
(IRB)/independent ethics committee (IEC) to quality assurance audits performed by the 
Sponsor, and/or to inspection by appropriate regulatory authorities to assure compliance 
with proper trial conduct. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process 
15. DATA HANDLING AND RECORD KEEPING 
15.1. Case Report Forms  
A case report form is required and should be completed for each included subject.  The 
completed original case report forms are the sole property of Tiziana Life Sciences, PLC and 
should not be made available in any form to third parties, except for authorized 
representatives of appropriate regulatory authorities, without written permission from 
Tiziana Life Sciences. 
It is the investigator's responsibility to ensure completion and to review and approve all case 
report forms.  Case report forms must be signed by the investigator or by an authorized staff 
member.  These signatures serve to attest that the information contained on the case report 
forms is true.  At all times, the investigator has final personal responsibility for the accuracy 
and authenticity of all clinical and laboratory data entered on the case report forms.  Subject 


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source documents are the physician's subject records maintained at the study site.  In most 
cases, the source documents will be the hospital's or the physician's chart.  In cases where 
the source documents are the hospital or the physician's chart, the information collected on 
the case report forms must match those charts.  In some cases, a portion of the source 
documents for a given study/site may be the case report forms.  The investigator must agree 
which items will be recorded in the source documents and for which items the case report 
form will stand as the source document.  
For patients still on treatment at the cut-off date of 31 May 2017, data should be recorded 
only in the patient’s medical notes. 
15.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or Tiziana Life Sciences, 
PLC, the investigator agrees to keep records, including the identity of all participating 
subjects (sufficient information to link records, case report forms and hospital records), all 
original signed informed consent forms, copies of all case report forms, source documents, 
and detailed records of treatment disposition.  The records should be retained by the 
investigator according to local regulations or as specified in the Clinical Trial Agreement, 
whichever is longer.   
If the investigator relocates, retires, or for any reason withdraws from the study, the Sponsor 
should be prospectively notified.  The study records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to Tiziana Life sciences, PLC.  
The investigator must obtain the Sponsor written permission before disposing of any 
records. .  
For patients still on treatment at the cut-off date of 31 May 2017, data should be recorded 
only in the patient’s medical notes. 
16. ETHICS 
16.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval of the trial protocol, protocol amendments, informed consent forms, and other 
relevant documents (eg, advertisements), if applicable, must be obtained from the IRB/IEC 
according to applicable regulatory requirements. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval 
is where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and the local Nerviano Medical 
Sciences site personnel as soon as the change has been implemented. 


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16.2. Ethical Conduct of the Trial 
The trial will be performed in accordance with International Conference on Harmonization 
Good Clinical Practice guidelines, the Declaration of Helsinki (1996 Version), and 
applicable local regulatory requirements and laws. 
16.3. Subject Information and Consent 
It is the responsibility of the Investigator to give each subject (or the subject’s acceptable 
representative) full and adequate verbal and written information regarding the objective and 
procedures of the trial and the possible risks involved.  This information must be provided to 
the subject prior to undertaking any trial-related procedure.  The subjects must be informed 
about their right to withdraw from the trial at any time.  Written subject information, 
approved by the IRB/IEC, must be given to each subject before any trial-related procedure is 
undertaken. The written subject information must not be changed without prior approval by 
NMS and the IRB/IEC. Furthermore, it is the responsibility of the Investigator to obtain 
signed and dated informed consent from all subjects, and a signature from the persons 
conducting the informed consent discussion, prior to undertaking any trial-related procedure. 
A recommended informed consent sample is provided in Appendix 1 of this protocol. 
17. SPONSOR DISCONTINUATION CRITERIA 
Tiziana Life Sciences, PLC reserves the right to discontinue the trial prior to inclusion of the 
intended number of subjects, but intends only to exercise this right for valid scientific or 
administrative reasons.  After such a decision, the Investigator must contact all participating 
subjects within a time period set by the Sponsor.  In any case, for patients on treatment, the 
Sponsor will guarantee the supply of PHA-848125AC until the patients will benefit from 
this product. As directed by the Sponsor, all study materials must be collected and all case 
report forms completed to the greatest extent possible. 
18. DISSEMINATION AND PUBLICATION OF RESULTS 
The conditions regulating dissemination of the information derived from this clinical study 
are described in the Clinical Trial Agreement. Presentations, abstracts, publications of the 
study results are to be submitted to the Sponsor for internal review procedure, at least 1 
month before submission. 


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19. REFERENCES 
1. 
NCI PDQ [Physician Data Query] ®, last modified 05/08/2008 
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Malignant thymoma in the United States: demographic patterns in incidence and 
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Wright C. Management of thymomas. Crit. Rev. Oncol. Hematol., 2008; 65(2): 109-20 
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Henley JD, Cummings OW, Loehrer PJ Sr. Tyrosine kinase receptor expression in 
thymomas. J Cancer Res Clin Oncol 2004; 130:222–224. 
5. 
Pan CC, Chen CH, Wang LS, Lee JY, Chiang H. Expression of apoptosis-related 
markers and HER-2/neu in thymic epithelial tumours. Histopathol 2003; 43:165–172. 
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Sasaki H, Fukai I, Kiriyama M, Kaji M, Yano M, Yamakawa Y, Fujii Y. Thymidylate 
synthase and dihydropyrimidine dehydrogenase mRNA levels in thymoma. Surg Today 
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7. 
Baldi A, Ambrogi V, Mineo D, Mellone P, Campioni M, Citro G, and Mineo TC. 
Analysis of Cell Cycle Regulator Proteins in Encapsulated Thymomas. Clin Cancer 
Res 2005;11(14) July 15, 2005  
8. 
Kim DJ, Yang WI, Kim SH, Park IK, Chung KY. Expression of neurotrophin receptors 
in surgically resected thymic epithelial tumors. Eur. J. Cardiothorac. Surg., 2005; 
28(4): 611-6 
9. 
Kondo K. Optimal therapy for thymoma. J. Med. Invest., 2008; 55(1-2): 17-28 
10. Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, Miyazawa N. 
Multidisciplinary treatment for advanced invasive thymoma with cisplatin, 
doxorubicin, and methylprednisolone. J. Thorac. Oncol. 2007; 2(1): 73-8 
11. Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol, 2005; 17:140-146 
12. Kurup A, Burns M, Dropcho S, Pao W, Loehrer PJ. Phase II study of gefitinib 
treatment in advanced thymic malignancies. JCO 23 (16S, Part I of II, June 1 
Supplement), ASCO 2005: Abs. 7068  
13. Salter JT, Lewis D, Yiannoutsos C, Loehrer PJ, Risley L, Chiorean EG. Imatinib for 
the treatment of thymic carcinoma. JCO 26: ASCO 2008 (May 20 Supplement): Abs. 
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14. Bedano PM, Perkins S, Burns M, Kessler K, Nelson R, Schneider BP, Risley L, 
Dropcho S, Loehrer PJ. A Phase II trial of erlotinib plus bevacizumab in patients with 
recurrent thymoma or thymic carcinoma. JCO 26: ASCO 2008 (May 20 Supplement): 
Abs. 19027 
15. Ströbel P, Hartmann M, Jakob A, Mikesch K, Brink I, Dirnhofer S, Marx A. Thymic 
carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J 
Med. 2004 Jun 17;350(25):2625-6. 
16. Bisagni G, Rossi G, Cavazza A, Sartori G, Gardini G, Boni C. Long lasting response to 
the multikinase inhibitor by 43-9006 (Sorafenib) in a heavily pretreated metastatic 
thymic carcinoma. J Thorac Oncol. 2009 Jun;4(6):773-5.  
17. Koizumi T, Takabayashi Y, Yamagishi S, Tsushima K, Takamizawa A, Tsukadaira A, 
Yamamoto H, Yamazaki Y, Yamaguchi S, Fujimoto K, Kubo K, Hirose Y, Hirayama J, 
Saegusa H. Chemotherapy for advanced thymic carcinoma: clinical response to 
cisplatin, doxorubicin, vincristine and cyclophosphamide  (ADOC chemotherapy). Am 
J Clin Oncol, 2002; 25(3): 266-8 
18. Magois E, Guigay J, Blancard PS, Margey J, Milleron B, Lher P, Jounieaux V. 
Multimodal treatment for thymic carcinoma: Report of nine cases. Lung Cancer, 2008; 
59 (1): 126-32 
19. Igawa S, Murakami H, Takahashi T, Nakamura Y, Tsuya A, Naito T, Kaira K, Ono A, 
Shukuya T, Tamiya A, Endo M, Yamamoto N. Efficacy of chemotherapy with 
carboplatin and paclitaxel for unresectable thymic carcinoma. Lung Cancer 2009 Apr 
29 [Epub ahead of print] 
20. Loehrer PJ, Yiannoutsos C, Dropcho S, Burns M, Helft P, Chiorean EG, Nelson RP. A 
Phase II trial of pemetrexed in patients with recurrent thymoma or thymic carcinoma. 
JCO 24 (18S, Part I, June 20 Supplement): ASCO 2006, Abs. # 7079 
21. Palmieri G, Merola C, Petillo L, Merola G, Federico P, Leopardo D, Marino M, 
Montella L. Gemcitabine-capecitabine in platinum-refractory patients with thymic 
epithelial tumors. ASCO 2009, Abs. # 7590 
22. Giaccone G, Rajan A, Carter C, Kelly R, Berman A, Spittler J, Espinoza-Delgado I, 
Lee M, Trepel J, Loehrer P. Phase II study of the histone deacetylase inhibitor 
belinostat in thymic malignancies. ASCO 2009, Abs.# 7589   
23. Investigator Brochure for PHA-848125AC, Version 7. Nerviano Medical Sciences; 
2011. Document No CDKO-125a-IB7. 
24. Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. 
Genes Dev 2004;18(22):2699-2711. 


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25. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat 
Rev Cancer 2001;1(3):222-231. 
26. Shapiro GI. Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment. J 
Clin Oncol 2006;24(11):1770-1783. 
27. Malumbres M, Barbacid M. Cell cycle kinases in cancer. Curr Opin Genet Dev 
2007;17(1):60-65. 
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29. Swanton C. Cell-cycle targeted therapies. Lancet Oncol 2004;5(1):27-36. 
30. Slingerland J, Pagano M. Regulation of the Cdk inhibitor p27 and its deregulation in 
cancer. J Cell Physiol 2000;183:10-17. 
31. Desdouets C, Bréchot C. p27: a pleiotropic regulator of cellular phenotype and a target 
for cell cycle dysregulation in cancer. Pathol Biol 2000;48:203-210. 
32. Adams PD. Regulation of the retinoblastoma tumor suppressor protein by cyclins/cdks.  
Biochimica et Biophysica Acta 2001;1471:M123-133. 
33. Hondermarck H. Nerve growth factor: the dark side of the icon. Am J Pathol. 2008 
Apr;172(4):865-7. 
34. Eisenhauer EA,  Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D and Verweij J. New response evaluation criteria in solid tumours: Revised 
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35. Marik PE. The management of Status Epilepticus, Chest 2004;126:582-591. 
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Recommendations of the Epilepsy Foundation of America's Working Group on Status 
Epilepticus.  JAMA 1993;270:854-859. 
37. Marmor MF, Holder GE, Seeliger MW, and Yamamoto S. Standard for Clinical 
Electroretinography (2004 update). Document approved by the International society for 
Clinical Electrophysiology of Vision in Nagoya, Japan on April 4, 2003. Documenta 
Ophthalmologica 2004;108:107-114. 
38. Wong TY, Mitchell P. Hypertensive Retinopathy. N Engl J Med 2004;351:2310-2317. 


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39. Desramé J, Duvic C, Béchade D et al. Is the frequency of hemolytic uremic syndrome 
as a complication of gemcitabine underestimated? The role of systematic screening. 
Gastroenterol Clin Biol. 2006 Feb;30(2):332-4. 
40. Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow 
GR, Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM. American Society of 
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2006;24(18): 2932-2947. 
41. The Antiemetic Subcommittee of the Multinational Association of Supportive Care in 
Cancer (MASCC). Prevention of chemotherapy– and radiotherapy-induced emesis: 
results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol 
2006;17:20-28. 
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43. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc 1958; 53:457-481. 


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APPENDICES 
Appendix 1. Recommended Informed Consent Form 
Appendix 2. The Distribution of Active Bone Marrow in the Adult 


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Appendix 1. Recommended Informed Consent Form 


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Patient Information and Informed Consent 
__________________________________________________________________________ 
Phase II study of oral PHA-848125AC in patients with thymic carcinoma previously 
treated with chemotherapy. 
Protocol No. CDKO-125a-006 
Institution/Hospital: 
Investigator: 
Sponsor: 
Tiziana Life Sciences, PLC 
__________________________________________________________________________ 
You are being asked if you want to take part in a research study using an experimental drug 
called PHA-848125AC. Whether you take part or not is entirely your decision.  You may 
decide to participate to the study or not to take part at all.  If you decide to participate to the 
study, you may end your participation at any time.  In any case, your decision will not affect 
your regular medical care or any benefit to which you are otherwise entitled.  If there is 
anything you do not understand about this study after reading this information, please ask 
your study doctor or study staff member. 
Why is this study being done? 
PHA-848125AC is a new drug selected for clinical evaluation because of its antitumor 
activity in experimental models. This drug acts by blocking specific proteins (called cyclin-
dependent kinases) involved in the control of cell division.  In the case of tumor cells such 
control is altered and leads to abnormal cell replication.  Experiments have shown that the 
addition of PHA-848125AC may block this uncontrolled proliferation.  Treatment with 
PHA-848125AC might possibly have a positive effect on your disease. 
This drug was evaluated in a number of clinical studies in the US and in Europe, with 
different schedules of administration. As of November 2011, PHA-848125AC has been 
administered to approximately 200 patients with various solid tumors. Currently, two studies 
are ongoing, including this one. 
The most relevant side effects encountered so far in the evaluation in humans were transient 
nausea and/or vomiting and /or diarrhea and neurological toxicity, mainly represented by 
transient tremors and ataxia (incoordination). Fatigue has been frequently reported. See also 
section “Risks” here below. 
Two objective tumor responses were obtained so far in the US study, in two out of three 
patients affected by thymic carcinomas. 


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This is the first study with PHA-848125AC specifically dedicated to patients with thymic 
carcinoma. 
This study is called phase II clinical study. Patients will be all treated at the same dose of 
PHA-848125AC; this dose has been selected based on results of the first clinical study in 
solid tumors patients where patients treated at this dose had mild/moderate reversible 
adverse events, represented by nausea, vomiting, diarrhea and tremors.  
The dose of PHA-848125AC will never be increased and could be reduced based on the 
tolerability of the patient. 
The purpose of this study is to help researchers to: 
- evaluate if PHA-848125AC can be effective as a treatment for thymic carcinoma 
- get additional information on the side effects of PHA-848125AC.  
If you decide to take part in this clinical study, you will get PHA-848125AC every day for 7 
consecutive days and then you will not take the drug from day 8 to day 14. A period of 14 
days (2 weeks) is called a cycle.  You will take the study medicine by oral route.  The 
number of cycles you may receive will depend both on the observed side effects and the 
evolution of your disease. 
During your stay in the study you will be also followed regularly for the status of your 
disease. 
This study is conducted in US and Europe. A total of about 60 patients will participate. 
This is what will happen if you decide to be in this study 
Your doctor will talk to you about your disease, ask you questions about your health, and 
give you a physical exam.  Blood will be taken from one of your veins and you will be asked 
to give a urine sample for laboratory tests. Electrocardiogram and ocular examination will be 
carried out. The ocular examination includes a fundoscopic examination and a visual acuity 
test. The funduscopic examination will consist of projection of a light from an 
ophthalmoscope through the pupil to view the back (fundus) of the eyeball. The examination 
will take few minutes and will not be painful. The exam may be preceded by drops in the 
eye, to dilate pupils. Visual acuity test measures the smallest letters that you can read on a 
standardized chart at a standard distance. 
During the course of this study, blood samples will be periodically taken. These regular 
blood tests, as well as other examinations, will be performed to check that the study 
medicine is not adversely affecting your bone marrow, kidneys, liver and other organs. At 
each sampling, the volume of blood taken for these analyses will be about 5 mL. 
There is the possibility, for safety reasons, that a few additional 5 ml blood samples may be 
required by the Investigator and the Sponsor to investigate the presence of PHA-848125AC 


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in your body.  
Part of your tumor tissue (paraffin embedded block), previously taken at the time of 
diagnosis of your disease, will be used to confirm histological diagnosis by an independent 
group of experts.       
You will also have other tests and activities to monitor your disease and the possible effects 
of the treatment as shown in the following table: 
Schedule of Visits/Tests 
Activity 
Before you 
begin  
the study 
During the 
study 
End of 
treatment 
After end of 
treatment 
period 
Discussion With Nurse/Study Doctor 
X 
X 
X 
X 
Medical/Oncology history/Physical exam 
X 
X 
X 
 
Confirmation of histological diagnosis  
 
X 
 
 
Vital signs 
X 
X 
X 
X 
Pregnancy Test 
X 
 
 
 
Blood Samples 
X 
X 
X 
 
Urine Samples 
X 
X 
X 
 
Chest X-Ray and ECG 
X 
 
X 
 
Ophthalmologic visit 
X 
X 
X 
 
Other exams to follow your disease (CT 
scan or MRI) 
X 
X 
X 
X 
Anything the study doctor believes is 
medically needed 
As needed 
 
Your doctor will ask you to record your daily drug intake in a diary. 
The effect of the study medicine on your disease will be assessed periodically by a CT scan 
or MRI. 
The administration of PHA-848125AC will continue as long as you can tolerate the 
experimental compound and if there are no indications that the disease is worsening. If 
unacceptable side-effects occur, the study medicine will be stopped and appropriate medical 
care will be provided. If your disease becomes worse during treatment, you will be told, the 
treatment will be stopped and alternate medical care will be provided. 
Experimental Aspects of the Trial 
Analysis of the basal molecular markers of the tumor 
Alteration of some genes is very common in human cancers, including thymic carcinoma. 


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It would be of value to know if the cells of your tumor have this kind of alteration, to study 
the relationship between the affected genes and the study treatment efficacy. 
To do so, a sample of your tumor tissue is needed: it is possible that a sample of your tumor 
has already been collected in the past, if you had a surgery or a biopsy, or that it may be 
requested by your doctor to understand the status of your disease before entering this study. 
If you give your consent (or you consented for this study earlier), part of your tumor sample 
will be analyzed also in this study to determine some molecular features of p53, p21, p27, 
cyclin D1, p75, TRKA, and other genes/proteins involved in the PHA-84125AC mechanism 
of action. 
The possible correlation between these molecular features and the effect of PHA-848125AC 
on the disease may be of help to support in the future the choice of the best treatment option 
for patients having thymic carcinoma. 
________________________________________________________________________________________ 
Your Responsibilities 
If you decide to be in this study, you will have to: 
 Keep all scheduled appointments. 
 Tell your doctor about any other medicines that you take, even if it is medicine you buy 
without a prescription or it is an herbal remedy. 
 Tell your doctor about any medical problems you have. 
 Adopt effective contraceptive methods if you are sexually fertile while on the study and 
for 90 days after you leave the study. 
 Avoid, if you are female, becoming pregnant while on the study and for 90 days after 
you leave the study. 
 Avoid, if you are male, father a child while on the study and for 90 days after you leave 
the study. 
 Avoid breast-feeding while you are taking the study medicine. 
If you do not follow the items listed above, you may be removed from the study. 
________________________________________________________________________________________ 
Other Treatments 
There may be other ways to treat your disease. Your doctor can tell you more about these 
other treatments and their side effects. 


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Benefits 
The medicine that you are given might help you with your disease, but this cannot be 
guaranteed. However, even if you does not benefit personally from being in this study, 
having you take part in this study will help researchers find out if PHA-848125AC will help 
other people who are affected by thymic carcinoma.  
Of note, two objective tumor responses were obtained so far in a previous study performed 
in the US, in two out of three patients affected by thymic carcinomas. 
If you are in this clinical study, you will get free medical examinations and laboratory tests 
that are not part of the routine care for your condition. You will not have to pay for the 
medicine. 
Risks 
The medicine you receive may cause side effects in human beings. Since PHA-848125AC is 
an experimental drug, these side effects in humans are not fully known. If you have any side 
effects, your doctor may stop or temporarily interrupt the treatment, or give you other drugs 
to make them less serious and to make you more comfortable. 
The most common side effects seen in animals after treatment with PHA-848125AC were: 
anemia, thrombocytopenia, neutropenia, lymphopenia, diarrhea, nausea and vomiting. These 
events were almost completely reversible. Ocular and central nervous system (CNS) toxicity 
were reported in animals at high doses or after prolonged administration, as well as 
congestions and/or hemorrhages (including hemorrhagic diarrhea, hemorrhages in the heart), 
gastrointestinal (GI) tract ulceration, bleeding and infection. 
The most relevant side effects encountered so far in the evaluation in humans were transient 
nausea and/or vomiting and /or diarrhea and neurological toxicity, mainly represented by 
transient tremors and ataxia (incoordination) and less frequent episodes of dizziness. The 
neurological symptoms gradually improved in all patients after temporary suspension of the 
study drug. Fatigue is a side effects reported in about half of patients. Hematological toxicity 
was sporadically reported, consisting especially in mild/moderate anemia (low hemoglobin) 
and neutropenia (low neutrophils). A prolonged elevation in liver enxymes was occasionally 
observed with the schedule adopted in the present study (7 days on / 7 days off), however, 
with a more prolonged treatment schedules (eg a schedule encompassing 14 consecutive 
days every 3 weeks), alterations of liver function tests were more frequently reported. Some 
episodes of transient elevation of lipase (a pancreatic enzyme), without clinical symptoms, 
have been reported, as well as mild transient elevations of creatinine (a parameter indicative 
of renal function status). There could be the possibility that the daily dose of study drug is 
reduced after recovery of adverse effects in order to continue study treatment at a better 
tolerated dose. 
Ocular toxicity was never encountered so far, with the exception of a worsening of the 


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electroretinography examination during treatment compared to baseline in one diabetic 
patient treated at 24 mg/m2/day for 21 consecutive days and in a second patient treated at 72 
mg/m2/day for 14 consecutive days (dose then reduced to 48 mg/m2/day in the two 
subsequent cycles). Both patients, however, did not show any ocular clinical symptoms.  
Two cases of TMA/HUS (Thrombotic Microangiopathy/Haemolytic Uraemic Syndrome) 
occurred in two different patients, both treated for more than a year, in a study administering 
PHA-848125AC together with Gemcitabine, a drug approved for the treatment of different 
tumor types, which is known to produce HUS. Both patients recovered. 
There may be some side effects that researchers do not yet know about. If researchers learn 
important new information that could change your decision to continue to take part in the 
study, your study doctor will tell you in a timely manner. PHA-848125AC might not work 
for you or might not work as well as other medicines you have received in the past. 
Your study doctor will be checking you closely to see if you are having any side effects. 
Your study doctor may give you medicines to help with side effects. Many side effects stop 
after the treatment is stopped. Your study doctor may also change the schedule or the 
amount of study treatment to reduce side effects. 
The risks of having blood taken from your vein include pain, bruising, or infection at the site 
where the blood was taken, and fainting. 
Stopping Early 
You may decide to leave the study at any time without any disadvantage to you. You are not 
obliged to provide reason for your withdrawal. 
Your doctor may also decide to remove you from the study if you fail to follow instructions, 
for medical reasons, or for other reasons.  There is also the possibility the study could be 
stopped by the Sponsor before your participation is complete.  If this would happen and if 
this is because of non-medical reasons, and you are benefiting by the study treatment, the 
supply of PHA-848125AC will be guaranteed.  From that moment on, the treatment will be 
under the responsibility of your doctor. 
If you leave the study for any reason, you will be asked to return to the study doctor to bring 
back any left study medicine and to complete the final study activities.  All study 
information that is collected about you until the time you leave the study and refuse further 
evaluations will be kept and used by the Sponsor. 
________________________________________________________________________________________ 
Pregnancy 
You must avoid becoming pregnant while you are in this study.  If you become pregnant 
while you are in the study or within 90 days after completing your participation, you must 


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tell your study doctor.  Your doctor must then report the outcome of your pregnancy to the 
Sponsor. 
Similarly, if you are male, you must avoid making a partner become pregnant while you are 
in the study. If you make a partner pregnant while you are in the study, or within 90 days 
after completing your participation, you must tell the study doctor. The study doctor must 
then report this and also the outcome of the pregnancy to the Sponsor. 
________________________________________________________________________________________ 
Compensation 
Every effort will be made to prevent research related injury.  If any injury is due to your 
participation in this study you will receive emergency care.  The Sponsor has insurance that 
covers any research-related injury you should suffer. The term “research-related injury” 
means physical injury caused by the product or procedures required by the trial which are 
different from the medical treatment you would have received if you had not participated in 
the trial. 
You will not be paid for participating in this trial. You will not need to pay for the study 
medicine and for any tests or procedures which are “research-related”. 
Confidentiality and Data Privacy 
Your doctor will record the study information described above on case report forms that will 
be sent to the study Sponsor.  In these case report forms, you will only be identified with a 
study subject number.  All records in which your name appears will be kept by your doctor 
and be kept confidential.  Your name will never appear on any Sponsor forms or in a report 
or publication. 
The study Sponsor will use the information recorded on the case report form to support new 
approvals for medical use of the PHA-848125AC and for any required regulatory reporting 
of side effects.  The information may be transferred and exported by the Sponsor to other 
entities within the Sponsor organization, to its business partners, and to regulatory 
authorities, on a global basis. 
Authorized persons from the Sponsor, governmental regulatory agencies, and/or the ethics 
committees may need to look at the medical records kept by your doctor to verify the 
information on the case report forms. 
By signing this informed consent form you agree to allow this review of your records as well 
as to the processing and transfer of your personal information as described above. 


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Storage and Analysis of Biological Samples 
Eventual blood samples collected for safety reason to investigate the presence of PHA-
848125AC in your body will be sent to the Sponsor for analysis in Accelera Srl and storage 
in a secure place to ensure protection of your confidentiality. 
Tumor samples to be analyzed for the characterization of molecular markers will be sent to 
the Sponsor for analysis and storage in a secure place to ensure protection of your 
confidentiality. 


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__________________________________________________________________________ 
If You Have Questions 
For questions about your responsibilities or study activities, please contact: 
 
 
 
 
 
 
at 
 
 
 
 
 
 
For questions about your rights as a participant in this study, please contact 
 
 
 
 
 
 
at 
 
 
 
 
 
 
For questions about possible injury due to activities in this study, please contact 
 
 
 
 
 
 
at 
 
 
 
 
 
 


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Patient’s Statement 
 
 I voluntarily agree to participate in this study 
 I understand that the study Sponsor may stop the study at any time 
 I have read and understood this statement of informed consent and the risks described 
 I understand that I will receive a signed and dated copy of this consent form 
 I understand that I may withdraw my consent at any time 
 I also voluntary 
 
agree   
 
or  
 
not agree  
 
 
to have my tumor tissue analyzed for molecular features. 
 I have had a chance to ask questions and understand the answers given to all of my 
questions 
 
 
 
Signature of study patient:  
 
 
 
 
 
 Date:   
 
 
Printed name of study patient:  
 
 
 
 
 
 
**************************************** 
 
Signature of person conducting informed consent discussion:   
 
 
 
 
Printed name of person conducting informed consent discussion:   
 
 
 
Date:    
 
 
 


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Appendix 2.  The Distribution of Active Bone Marrow in the Adult 


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The distribution of bone marrow in the adult 
Site 
Marrow 
Weight (g) 
Fraction Red 
Marrow - Age 40 
Red Marrow 
Weight -Age 40 (g) 
% Total Red 
Marrow 
Head 
 
 
136.6 
13.1 
Cranium 
165.8 
0.75 
124.3 
 
Mandible 
16.4 
0.75 
12.3 
 
Upper Limb Girdle 
 
 
86.7 
8.3 
2 Humerus, head & neck 
26.5 
0.75 
20.0 
 
2 Scapulae 
67.4 
0.75 
50.5 
 
2 Clavicles 
21.6 
0.75 
16.2 
 
Sternum 
39.0 
0.6 
23.4 
2.3 
Ribs 
 
 
82.6 
7.9 
1 pair 
10.2 
All 0.4 
4.1 
 
2 
12.6 
 
5.0 
 
3 
16.0 
 
6.4 
 
4 
18.6 
 
7.4 
 
5 
23.8 
 
9.5 
 
6 
23.6 
 
9.4 
 
7 
25.0 
 
10.0 
 
8 
24.0 
 
9.6 
 
9 
21.2 
 
8.5 
 
10 
16.0 
 
6.4 
 
11 
11.2 
 
4.5 
 
12 
4.6 
 
1.8 
 
Vertebrae  (Cervical) 
 
 
35.8 
3.4 
1 
6.6 
All 0.75 
5.0 
 
2 
8.4 
 
6.3 
 
3 
5.4 
 
4.1 
 
4 
5.7 
 
4.3 
 
5 
5.8 
 
4.4 
 
6 
7.0 
 
5.3 
 
7 
8.5 
 
6.4 
 
Vertebrae (Thoracic) 
 
 
147.9 
14.1 
1 pair 
10.8 
All 0.75 
8.1 
 
2 
11.7 
 
8.8 
 
3 
11.4 
 
8.5 
 
4 
12.2 
 
9.1 
 
5 
13.4 
 
10.1 
 
6 
15.3 
 
11.5 
 
7 
16.1 
 
12.1 
 
8 
18.5 
 
13.9 
 
9 
19.7 
 
14.8 
 
10 
21.2 
 
15.9 
 
11 
21.7 
 
16.3 
 
12 
25.0 
 
18.8 
 


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The distribution of bone marrow in the adult 
Site 
Marrow 
Weight (g) 
Fraction Red 
Marrow - Age 40 
Red Marrow 
Weight -Age 40 (g) 
% Total Red 
Marrow 
Vertebrae (Lumbar) 
 
 
114.1 
10.9 
1 pair 
27.8 
All 0.75 
20.8 
 
2 
29.1 
 
21.8 
 
3 
31.8 
 
23.8 
 
4 
32.1 
 
24.1 
 
5 
31.4 
 
23.6 
 
Sacrum 
194.0 
0.75 
145.6 
13.9 
Lower limb girdle 
 
 
273.0 
26.1 
2 os coxae 
310.6 
0.75 
233.0 
 
2 femoral head & neck 
53.0 
0.75 
40.0 
 
Total 
1497.7 
 
1045.7 
100.0 
 
R.E. ELLIS - The Distribution of Active Bone Marrow in the Adult. Phy. Med. Biol. 5, 255 – 258, 1961 

SAP_001.pdf: 
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ANALYSIS DISPLAY PLAN 
ALGORITHMS 
 
 
 
Compound: 
PHA-848125AC 
Protocol No.: 
CDKO-125a-006 
Protocol title: 
Phase II Study of Oral PHA-848125AC in Patients with Thymic Carcinoma Previously Treated with Chemotherapy 
Clinical phase: 
Phase II 
Author: 
Miriam Fossati, Anna Petroccione  
 
 
 
 
 
 
 
 


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PATIENT POPULATIONS ..................................................................................................................................................................................... 10 
Registered /Screened Patients ............................................................................................................................................................................. 10 
Screening Failure (Y/N) ...................................................................................................................................................................................... 10 
Enrolled Patients (Y/N) ....................................................................................................................................................................................... 10 
Treated Patients ................................................................................................................................................................................................... 10 
Not Treated Patients ............................................................................................................................................................................................ 10 
Evaluable Patients for Efficacy Analysis and Reasons for Non- Evaluability ............................................................................................... 10 
Age/Sex/Race ........................................................................................................................................................................................................ 11 
PATIENT DISPOSITION ........................................................................................................................................................................................ 11 
Patient Status on Treatment ............................................................................................................................................................................... 11 
Off Treatment Reason not Provided .................................................................................................................................................................. 12 
Duration of Treatment ........................................................................................................................................................................................ 12 
Patient Status on FU ............................................................................................................................................................................................ 12 
Patient Status on Study ....................................................................................................................................................................................... 12 
Last Recorded Date ............................................................................................................................................................................................. 13 
Last Recorded Date Flag ..................................................................................................................................................................................... 13 
Time on Study (days weeks months) .................................................................................................................................................................. 13 
Off Study Reason not Provided .......................................................................................................................................................................... 14 
PROTOCOL DEVIATIONS ..................................................................................................................................................................................... 14 
Inclusion / Exclusion Criteria ID ........................................................................................................................................................................ 14 
Protocol Deviations Flag ..................................................................................................................................................................................... 14 
DEMOGRAPHY AND BASELINE ......................................................................................................................................................................... 14 


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Tumor History: Primary Diagnosis, Diagnosis at Study Entry and History of Other Cancer(s) .......................................................................... 14 
Derived Date of Primary Diagnosis .................................................................................................................................................................... 14 
(Derived) Date of Primary Diagnosis: Weeks/Months to Tr. Start Date and Flag ........................................................................................ 15 
Derived Date of Diagnosis at Study Entry ......................................................................................................................................................... 15 
(Derived) Date of Diagnosis at Study Entry: Weeks/Months to Tr. Start Date and Flag ............................................................................. 15 
Time (weeks/months) from Primary Diagnosis to Diagnosis at Study Entry and Flag ................................................................................ 15 
(Derived) Other Cancer (previous): Yes / No; Yes Value Derived and Flag ................................................................................................. 15 
Derived Date of Other Cancer Diagnosis .......................................................................................................................................................... 15 
(Derived) Date of Other Cancer Diagnosis: Weeks/Months to Tr. Start Date and Flag .............................................................................. 16 
Tumor History: Independent Review Committee Confirmation ............................................................................................................................. 16 
Tumor History: Prior Antitumor Treatment / Procedures ...................................................................................................................................... 16 
Prior Antitumor Treatment / Procedures: Yes / No; Yes Value Derived and Flag ....................................................................................... 16 
Derived Prior Antitumor Treatment/Procedures Start and Stop Date .......................................................................................................... 16 
Weeks/Months from (Derived) Prior Antitumor Treatment/Procedures Stop Date to Tr. Start Date and Flag ....................................... 18 
Duration (weeks/months) of Prior Antitumor Treatment/Procedures and Flag ........................................................................................... 18 
Time (weeks/months) since Previous Antitumor Treatment/Procedures and Flag ....................................................................................... 18 
Prior Antitumor Treatment / Procedures Classification ................................................................................................................................. 18 
Prior Systemic Therapies, Prior Surgeries, Prior Radiotherapies: Yes / No; Yes Value Derived and Flag ............................................... 19 
General Medical History and Physical Examination .............................................................................................................................................. 20 
Any Relevant Diagnosis: Yes / No; Yes Value Derived and Flag .................................................................................................................... 20 
TREATMENT ADMINISTRATION ....................................................................................................................................................................... 20 
Treatment and Schedule ..................................................................................................................................................................................... 20 
Regimen (mg/day) ................................................................................................................................................................................................ 20 


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First Dose Date (Tr. Start Date) ......................................................................................................................................................................... 20 
Last Dose Date (Tr. Last Date) ........................................................................................................................................................................... 20 
Start Date of a Cycle ............................................................................................................................................................................................ 20 
Total no. of Cycles ................................................................................................................................................................................................ 20 
Number of Days of Treatment ............................................................................................................................................................................ 20 
Time on Treatment (days weeks months) .......................................................................................................................................................... 21 
Derived date of end of treatment ........................................................................................................................................................................ 21 
Duration of a Cycle (weeks) (Duration for cycle x) .......................................................................................................................................... 21 
Treatment Duration (weeks) (for the whole treatment period) ....................................................................................................................... 22 
Intended Dose (mg) (at cycle x) .......................................................................................................................................................................... 22 
Intended Dose (mg) (whole treatment period) .................................................................................................................................................. 22 
Taken  Dose (mg) per Day or Cycle (at cycle x) ................................................................................................................................................ 22 
Administered Dose (mg) (whole treatment period) .......................................................................................................................................... 22 
BSA (m2, calculated) at cycle x .......................................................................................................................................................................... 22 
Dose (mg/m2, calculated) per Day or Cycle and Flag ...................................................................................................................................... 23 
% Scheduled Dose ................................................................................................................................................................................................ 23 
Classification of Cycles by Percentage of Scheduled Dose ............................................................................................................................... 23 
Cumulative Dose (mg) ......................................................................................................................................................................................... 23 
Absolute Dose Intensity (mg/wk) (at cycle x) .................................................................................................................................................... 23 
Absolute Dose Intensity (mg/wk) for whole treatment period ......................................................................................................................... 23 
Intended Dose Intensity (mg/wk) ....................................................................................................................................................................... 24 
Relative Dose Intensity (%) ................................................................................................................................................................................ 24 
Treatment Modifications ..................................................................................................................................................................................... 24 


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Reasons for Treatment Modification ................................................................................................................................................................. 24 
TREATMENT EFFICACY ...................................................................................................................................................................................... 25 
Tumor Lesions ..................................................................................................................................................................................................... 25 
Population to be Analyzed .................................................................................................................................................................................. 25 
Oncologic Assessment: Time of Assessment ...................................................................................................................................................... 25 
Lesion Assessment .................................................................................................................................................................................................... 25 
Premise .................................................................................................................................................................................................................. 25 
Weeks to/from Treatment Start from/to Lesion Assessment Date: ................................................................................................................ 25 
Lesion Flag for Different Method ...................................................................................................................................................................... 26 
Individual Target Lesion: Evaluability for % Change .................................................................................................................................... 26 
Individual Target Lesion: %Change from Baseline ......................................................................................................................................... 26 
All Target Lesions: Evaluability for %Change. ............................................................................................................................................... 26 
All Target Lesions: Sum of Measures ................................................................................................................................................................ 26 
All Target Lesions: % Change from Baseline ................................................................................................................................................... 26 
All Target Lesions: Nadir (Y/N) ......................................................................................................................................................................... 27 
All Target Lesions: % Change from Nadir ....................................................................................................................................................... 27 
Tumor Response Status ............................................................................................................................................................................................ 27 
Assessment Date (calculated) .............................................................................................................................................................................. 27 
Weeks from Treatment Start .............................................................................................................................................................................. 27 
Date of documented PD and Flags ..................................................................................................................................................................... 27 
Time (Days, Weeks and Months) to PD ............................................................................................................................................................. 27 
Best Overall Response (Confirmed) ................................................................................................................................................................... 27 
Date of First Response and Flag ......................................................................................................................................................................... 28 


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Date of Confirmed Response and Flag .............................................................................................................................................................. 28 
Best Unconfirmed Tumor Response .................................................................................................................................................................. 28 
Date of Last Oncologic Assessment before PD .................................................................................................................................................. 28 
Durations ................................................................................................................................................................................................................... 28 
Premise .................................................................................................................................................................................................................. 28 
Failure/Censored Patients ................................................................................................................................................................................... 28 
Date of Failure ...................................................................................................................................................................................................... 29 
Date of Censoring ................................................................................................................................................................................................ 29 
Response Duration and Censored Patients Flag ............................................................................................................................................... 29 
Progression Free Survival (PFS) and PFR at 3 months ......................................................................................................................................... 29 
Premise .................................................................................................................................................................................................................. 29 
Failure/Censored Patients ................................................................................................................................................................................... 30 
Date of Failure ...................................................................................................................................................................................................... 30 
Date of Censoring ................................................................................................................................................................................................ 30 
Progression Free Survival (PFS) ........................................................................................................................................................................ 30 
Progression Free Survival Rate at 3 Months .................................................................................................................................................... 31 
Overall Survival (OS) ................................................................................................................................................................................................ 31 
Premise .................................................................................................................................................................................................................. 31 
Failure/Censored Patients ................................................................................................................................................................................... 31 
Overall Survival and Censored Patients Flag ................................................................................................................................................... 31 
Summary Statistics for Time to Events Endpoints: Flag for Censored Patients ................................................................................................... 32 
ADVERSE EVENTS (AES) ..................................................................................................................................................................................... 32 
Safety Population ................................................................................................................................................................................................. 32 


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AE terminology criteria: MedDRA and aggregation levels for the analysis .................................................................................................. 32 
On treatment Adverse Event .............................................................................................................................................................................. 32 
Maximum CTC grade by patient and MedDRA Preferred Term .................................................................................................................. 32 
Maximum CTC grade by patient and System Organ Class (SOC) ................................................................................................................ 32 
Maximum CTC grade by patient ....................................................................................................................................................................... 32 
Aes: CTC Grade >= 3 Flag ................................................................................................................................................................................. 32 
Aes in Follow-up Flag .......................................................................................................................................................................................... 33 
Deaths ........................................................................................................................................................................................................................ 33 
Date of Death ........................................................................................................................................................................................................ 33 
Patient Died .......................................................................................................................................................................................................... 33 
CRF Source .......................................................................................................................................................................................................... 33 
Days from Last Treatment Administration and Flag ...................................................................................................................................... 33 
Most Probable Cause of Death ........................................................................................................................................................................... 33 
Relationship to Study Drug of Death ................................................................................................................................................................. 34 
Autopsy Performed: ‘Yes’ Value Derived ......................................................................................................................................................... 34 
Hospitalization .......................................................................................................................................................................................................... 34 
Duration (Days) .................................................................................................................................................................................................... 34 
Weeks from First Dose Date ............................................................................................................................................................................... 34 
LABORATORY TESTS ............................................................................................................................................................................................ 34 
Safety Population ................................................................................................................................................................................................. 34 
Reference Document for CTC Grade Calculation ........................................................................................................................................... 34 
Low / High ( L/H) Flag ........................................................................................................................................................................................ 35 
Variables to used for CTC grade calculation .................................................................................................................................................... 35 


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Converted Value, Unit and Range Limits ......................................................................................................................................................... 35 
Allocation of Lab. Tests to the Relevant Study Period ..................................................................................................................................... 36 
Allocation of Lab. Tests Reported at Cycles with Missing Treatment Dose or Date .................................................................................... 37 
Allocation of Lab. Tests Reported at 28 days AE Visit .................................................................................................................................... 37 
Laboratory test day ............................................................................................................................................................................................. 37 
Cycles with at Least One Assessment ................................................................................................................................................................ 37 
Treated Patients with at least one Assessment .................................................................................................................................................. 37 
Baseline Data: Value, Unit, CTC Grade and Date ........................................................................................................................................... 37 
Worst CTC grade ................................................................................................................................................................................................ 38 
Lab. CTC Grade 3 – 4 Flag ................................................................................................................................................................................. 38 
OTHER SAFETY ASSESSMENTS ........................................................................................................................................................................ 38 
Temperature .............................................................................................................................................................................................................. 38 
Blood Pressure .......................................................................................................................................................................................................... 38 
Blood Pressure Flags ........................................................................................................................................................................................... 38 
Blood Pressure: Normal and Abnormal Values ............................................................................................................................................... 38 
Electrocardiogram .................................................................................................................................................................................................... 39 
Electrocardiogram: Category ............................................................................................................................................................................. 39 
Electrocardiogram: ‘Yes’ Value Derived .......................................................................................................................................................... 39 
Electrocardiogram: Abnormalities not Present at Pretreatment ................................................................................................................... 39 
Electrocardiogram: Tracing Abnormalities (Y/N) ........................................................................................................................................... 39 
Chest X-Ray ............................................................................................................................................................................................................... 39 
Days to/from Treatment Start ............................................................................................................................................................................ 39 
Pregnancy Test .......................................................................................................................................................................................................... 39 


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OTHER INFORMATION ........................................................................................................................................................................................ 40 
Other Anti-tumor Therapies at Follow-up ............................................................................................................................................................... 40 
‘Yes’ Value Derived ............................................................................................................................................................................................. 40 
Days from Last Treatment Administration ...................................................................................................................................................... 40 
Concomitant Medications ......................................................................................................................................................................................... 40 
Any Concomitant Medications?: ‘Yes’ Value Derived .................................................................................................................................... 40 
Duration (days) .................................................................................................................................................................................................... 40 
Weeks from Tr. Start Date ................................................................................................................................................................................. 40 
Concomitant Radiotherapies .................................................................................................................................................................................... 40 
Any Concomitant Radiotherapies?: ‘Yes’ Value Derived ............................................................................................................................... 40 
Duration (days) .................................................................................................................................................................................................... 40 
Weeks from Tr. Start Date ................................................................................................................................................................................. 40 
Blood Derivatives ...................................................................................................................................................................................................... 41 
Weeks from Tr. Start Date ................................................................................................................................................................................. 41 
REVISION HISTORY .............................................................................................................................................................................................. 42 
 


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ALGORITHMS 
PATIENT POPULATIONS 
Registered /Screened Patients 
Patients with at least one information in any section of the CRF, except the one of laboratory normal range. 
Screening Failure (Y/N) 
Y: 
if the pt no. begins with ‘S’   (screening failure) 
N: 
else.                                        (enrolled patient) 
Enrolled Patients (Y/N) 
The information is collected on the enrollment form. 
N: 
if the pt no. begins with ‘S’   (screening failure) 
Y: 
else.                                        (enrolled patient) 
Treated Patients  
All recorded patients with at least one administration of study treatment (i.e. administered dose (mg) > 0 in at least one cycle). 
Not Treated Patients 
As per difference between Enrolled and Treated Patients. 
Evaluable Patients for Efficacy Analysis and Reasons for Non- Evaluability    
A patient is considered evaluable for the efficacy analysis in compliance with the protocol if:  
 
1.  
at least two out of three histological confirmation of thymic carcinoma were received by and Independent Reviewer Committee (see “Demography and  
 
 
Baseline” Section) (evaluability criterion 1) 
 
2. 
the patient received at least 80% of the intended dose for the first two treatment cycles (evaluability criterion 2) 
 
3. 
a baseline tumor/oncologic assessment was performed (evaluability criterion 3) 
4 
at least one on treatment oncologic assessment was performed (evaluability criterion 4.1) OR the patient died before the first scheduled oncologic  
 
 
assessment (6 weeks after treatment start  (evaluability criterion 4.2) 
 
 
Note: evaluability criterion 2: (Administered dose (mg) (Cycle1+ Cycle2) * 100) / Intended Dose (mg) (Cycle1+ Cycle2))  ≥  80%  (see “Treatment Administration” Section). 
 
Therefore a variable indicating patient’s evaluability will be derived as “Yes” if:  


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evaluability criterion 1 AND  evaluability criterion 2 AND evaluability criterion 3 AND evaluability criterion 4.1 are met 
 
OR 
 
 
evaluability criterion 1 AND evaluability criterion 2 AND evaluability criterion 3 AND evaluability criterion 4.2 are met 
 
Else, patient’s evaluability will be derived as “No”.  
 
Accordingly, reasons for non-evaluability will be derived as: 
R1 if  evaluability criterion 1 is violated 
R2 if  evaluability criterion 2 is violated 
R3 if  evaluability criterion 3 is violated 
R4 if  evaluability criterion 4.1 AND evaluability criterion 4.2 are both violated otherwise R4.1 or R4.2 depending of sub criterion violated. 
 
More than one reason for non evaluability may exist 
Age/Sex/Race 
This variable is derived by concatenating Age (years) and the first character of the variables Sex and Race. 
PATIENT DISPOSITION 
Patient Status on Treatment 
Patient Status on Treatment is to be classified as the following: 
 Not treated:  Not treated as defined above in patient population section.  
 Still On treatment (Still on Tr.): Treated patients as defined above in the patient population section AND  
 
no Off Treatment Reason Form AND 
 
no End of AE Reporting Period Form filled in AND 
 
no Follow-up visit AND 
 
no Off Study Reason Form AND 
 
patient died = No (see algorithm on the adverse event section). 
 Off treatment (Off Tr.): Treated patients as defined above in the patient population section AND  
 
Off Treatment Reason Form present OR 
 
End of AE Reporting Period Form filled in OR 
 
Follow-up visit OR 
 
Off Study Reason Form present OR  
 
patient died = Yes (see algorithm on the adverse event section) 
 
A control listing may be built with all variables needed to implement the algorithm. 


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Off Treatment Reason not Provided 
Classify and report the patient as ‘Reason Not Provided’ if the patient’s status is Off Treatment and one of the following two situations occurs: 
1 The Off Treatment Reason Form is available but the reason is missing 
OR   
2 the Off Treatment Reason Form is not in the DB. 
Duration of Treatment 
Treatment Duration (weeks) = (<Derived date of the end of treatment> - <Study treatment start date>) / 7  
For derivation of the Date of the End of Treatment see corresponding section under Treatment Administration section 
Patient Status on FU 
Patient Status on FU is to be defined only for ‘Off Treatment Patients’ (see definition above) as follows: 
No FU: No follow up visits  
 
Still on FU (On FU): At least one follow up visit AND  
 
no lost to FU information in survival FU status form AND 
 
no lost to follow up recorded in Off Treatment Reason form AND 
 
no Off Study Reason AND 
 
patient died=No (see algorithm on the adverse event section) 
 
Off FU (Off FU): At least one follow up visit AND 
 
lost to FU information in survival FU status form OR 
 
Off Study Reason OR  
 
patient died = Yes (see algorithm on the adverse event section))  
 
Note: A control listing may be built with all variables needed to implement the algorithm. 
Patient Status on Study 
Patient Status on Study is to be classified as the following: 
 
Still On Study (On):  no off study reason AND 
 
pt died = ‘N’  
 
Off Study (Off):   off study reason present OR 
 
pt died = ‘Y’  
 
Note: A control listing may be built with all variables needed to implement the algorithm. 


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Last Recorded Date  
Is the date of death for dead patients or the date when the patient was lastly reported alive for the patients with no death reported. The latter date is the latest among the 
following dates recorded on the CRF: 
 
 “Last known alive date” or “alive as of” reported in the Follow-up Survival Status Forms; 
 
Date when Consent was withdrawn by the patient reported in the Off Study Reason Form; 
 
Date when Investigator’s Decision was taken to withdraw patient from study  in the Off Study Reason Form; 
 
Date of ‘End of AE Reporting Period’ visit in the End of AE Reporting Period Form; 
 
AEs start and stop dates reported in the Adverse Event Forms, including last AE Follow-up Form, if any; 
 
Dates of start and stop of concomitant medication reported in the Concomitant Medication Form, if any; 
 
Dates of start and stop of concomitant radiotherapy reported in the Concomitant Radiotherapy Form, if any; 
 
Dates of  Specimen Collection recorded in the Laboratory Results Forms (any panel); 
 
Dates of  Biopsy in the Biopsy Shipment Form;  
 
Date(s) of Specimen Collection in the Pharmacokinetics form; 
 
Dates when Oncologic Assessments reported in the Oncologic Assessment Form were performed, if any, including follow-up; 
 
Dates of Vital Signs measurements recorded in the Vital Signs Section, log included; 
 
Last date when study treatment was administered as recorded in the Drug “X” Administration Form; 
 
Date of Admission and date of Discharge to/from the hospital recorded in the Hospitalization Form; 
 
Date of CR/PR, either first or confirming scan whichever is the latest, reported in the Best Overall Tumor Response Form; 
 
Date of PD in Response Status Forms; 
 
Dates of assessment in the Medical History & Physical Examination Form; 
 
Dates  of Performance Status recorded in the Outcome Measurements Section; 
 
Dates of ECG assessments recorded in the Electrocardiogram Form; 
 
Date(s) of Assessment in the CT-Scan /Chest X-ray Form; 
 
Date(s) of Assessment in the Visual Acuity and Fundoscopic Examination Form whichever is the latest; 
 
Date(s) of Transfusion in the Blood Derivatives Form; 
 
Date(s) of Other Antitumor Therapies at Follow-up; 
 
For calculation of the date of death see section “DEATH“ below. 
 
Note: A control listing may be built with all variables needed to implement the algorithm. 
Last Recorded Date Flag 
A flag (§) is to be derived if “Last Recorded Date” is posterior to the “Investigator’s Decision” date or the “Consent Withdrawn” date in Off Study form. 
Time on Study (days weeks months) 
It is the time interval between the Date of Informed Consent and the Last Recorded Date  
Last Recorded Date- Informed Consent Date  
 
(days) 


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(Last Recorded Date- Informed Consent Date) / 7  
 
(weeks) 
((Last Recorded Date- Informed Consent Date) *12) / 365.25  
(months) 
Off Study Reason not Provided 
If the form Off Study Reason is in the DB and no reason is marked, classify and report the patient as ‘Reason Not Provided’. 
 
PROTOCOL DEVIATIONS 
Inclusion / Exclusion Criteria ID 
In the listings incl. criteria are sequentially numbered as “ICxx” (e.g. IC01); excl. criteria are sequentially numbered as “ECxx” (e.g. EC10). 
A few inclusion criteria are reported in the CRF Inclusion / Exclusion criteria pages as ‘documented elsewhere on CRF pages’ and are derived at the OC DB level in a 
specific variable.  
The answers to Inclusion / Exclusion criteria are typically ‘Yes’ or ‘No’. 
Protocol Deviations Flag 
All ‘No’ answers to inclusion criteria (I) or derived inclusion (DI) criteria and all ‘Yes’ answers to exclusion criteria (E) are to be marked by a *. 
DEMOGRAPHY AND BASELINE 
Tumor History: Primary Diagnosis, Diagnosis at Study Entry and History of Other Cancer(s) 
Derived Date of Primary Diagnosis  
If date of primary diagnosis is incomplete, it will to be derived according to the imputation rules defined below: 
 
Derived Date of Primary Diagnosis 
-   if only day is missing, use day=15 and check the derived date vs. treatment start date. If treatment start date < derived date then use 1 for the missing day.  
-   if both month and day are missing then compare year of treatment start date and year of diagnosis:  
    (a) if year of treatment start date > year of diagnosis then impute 30 June;  
    (b) if year of treatment start date = year of diagnosis then impute 01 January. 
 
In the listing, dates are to be reported as they are, i.e. with no day/month imputation. 


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(Derived) Date of Primary Diagnosis: Weeks/Months to Tr. Start Date and Flag  
Weeks to tr. start = (treatment start date) – [derived] date of primary diagnosis) / 7 
Months to tr. start = (treatment start date) – [derived] date of primary diagnosis) * 12 / 365.25 
Estimated times should be identified by a flag variable and by an ‘*’ in the listings. 
Derived Date of Diagnosis at Study Entry 
If date of diagnosis at study entry is incomplete, it will to be derived according to the imputation rules defined below: 
 
Derived Date of Diagnosis at Study Entry 
-   if only day is missing, use day=15 and check the derived date vs. (treatment start date). If (treatment start date) < derived date then use 1 for the missing day.  
-   if both month and day are missing then  stop further computations 
     
In the listing, dates are to be reported as they are, i.e. with no day  imputation. 
(Derived) Date of Diagnosis at Study Entry: Weeks/Months to Tr. Start Date and Flag  
Weeks to tr. start = (treatment start date) – [derived] date of diagnosis at study entry) / 7 
Months to tr. start = (treatment start date)– [derived] date of diagnosis at study entry) * 12 / 365.25 
Estimated times should be identified by a flag variable and by an ‘*’ in the listings. 
Time (weeks/months) from Primary Diagnosis to Diagnosis at Study Entry and Flag 
Time (weeks) = ([derived] date of diagnosis at study entry - [derived] date of primary diagnosis) / 7 
Time (months) = ([derived] date of diagnosis at study entry - [derived] date of primary diagnosis) * 12 / 365.25  
Estimated times should be identified by a flag variable and by an ‘*’ in the listings. 
(Derived) Other Cancer (previous): Yes / No; Yes Value Derived and Flag 
-- Pts are classified and counted as ‘Yes’ if: ‘Yes’ answers to the ‘yes/no’ initial question (e.g. “Has the pt had previous history…..?”)  OR  at least one detail is reported  in 
the form. Missing or ‘No’ answers to the ‘yes/no’ initial question should be changed into ‘Yes’ (derived Yes).  
-- Pts are classified as ‘No’ if: ‘No’ answers to the ‘yes/no’ initial question  AND  no details are reported in the form. 
 
Derived ‘Yes’ is to be identified by ‘*’. 
Derived Date of Other Cancer Diagnosis  
If date of other cancer diagnosis is incomplete, it will to be derived according to the imputation rules defined below: 
 
Derived Date of Other Cancer Diagnosis 
-   if only day is missing, use day=15 and check the derived date vs. treatment start date. If (treatment start date) < derived date then use 1 for the missing day.  
-   if both month and day are missing then compare year of treatment start date and year of diagnosis:  


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    (a) if year of treatment start date > year of diagnosis then impute 30 June;  
    (b) if year of treatment start date = year of diagnosis then impute 01 January. 
 
In the listing, dates are to be reported as they are, i.e. with no day/month imputation. 
(Derived) Date of Other Cancer Diagnosis: Weeks/Months to Tr. Start Date and Flag  
Weeks to tr. start = (treatment start date) – [derived] date of other cancer diagnosis) / 7 
Months to tr. start = (treatment start date) – [derived] date of other cancer diagnosis) * 12 / 365.25 
Estimated times should be identified by a flag variable and by an ‘*’ in the listings. 
Tumor History: Independent Review Committee Confirmation  
Diagnosis confirmation of thymic carcinoma by the independent review committee is collected on three separate form, one for each reviewer.  
Thymic carcinoma diagnosis is confirmed by the reviewer if (s)he ticked either “B3 - Well-differentiated thymic carcinoma” or  “C - Thymic carcinoma” as tumor type at 
diagnosis. 
 
Overall Confirmed Thymic Carcinoma Type at Diagnosis and Flag 
For each patient derive the Overall Confirmed Thymic Carcinoma Type as the thymic carcinoma type (see above) indicated by  at least two out of the three reviewers. In this 
case  Thymic Carcinoma Confirmed Flag =Y. 
If no thymic carcinoma type was indicated by more than one reviewer, thymic carcinoma will not be confirmed and Overall Confirmed Thymic Carcinoma Type is not to be 
derived.  In this case Thymic Carcinoma Confirmed Flag =N. 
 
Tumor History: Prior Antitumor Treatment / Procedures  
Prior Antitumor Treatment / Procedures: Yes / No; Yes Value Derived and Flag 
- 
Pts are classified and counted as ‘Yes’ if:  
‘Yes’ answers to the ‘yes/no’ initial question (e.g. “Has the pt had antitumor treatment/procedures……”)   
OR   
at least one detail is reported  in the form. Missing or ‘No’ answers to the ‘yes/no’ initial question should be changed into ‘Yes’ (derived Yes).  
- 
Pts are classified as ‘No’ if: ‘No’ answers to the ‘yes/no’ initial question  AND  no details are reported in the form. 
 
Derived ‘Yes’ is to be identified by ‘*’. 
Derived Prior Antitumor Treatment/Procedures Start and Stop Date 
In order to compute time from previous antitumor treatment/procedure, duration of prior antitumor treatment/procedure and  time to treatment start it’s necessary to derive the 
prior antitumor treatment/procedure start and stop dates when 


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one or both are incomplete in the CRF (see Scenario 1)  
OR 
one (and only one) of them is completely missing in the CRF (see Scenario 2).   
 
Both derived date of prior treatment/procedures start and derived date of prior treatment/procedures stop should be stored in the analysis database. 
In the listings, however, dates are to be reported as they are in the CRF. 
 
Scenario 1:   
Both prior treatment/procedure start and stop date are recorded in the CRF page for a given Chronological Seq no but one of them is incomplete 
 
If T/P start date is incomplete then:  
o 
if only day is missing, use day = 1 for the missing day.  
o 
if both month and day are missing, then impute 01 January. 
 
If T/P stop date is incomplete then: 
o 
 if only day is missing, use day=15 and check the derived T/P stop date vs. treatment start date.  
If treatment start date  < derived T/P stop date then use 1 for the missing day.  
o 
 if both month and day are missing then compare year of treatment start date and year of T/P stop:  
(a) 
if year of treatment start date > year of T/P stop then impute 30 June;  
(b) 
if year of treatment start date = year of T/P stop then impute 01 January. 
 
At the end of the imputation process, verify that the following relation holds:  
 
(derived) T/P start date </= (derived)  T/P stop date < treatment start date  
If (derived) T/P start date < treatment start date AND (derived) T/P stop date < (derived) T/P start date then: 
 
(derived) T/P stop date = (derived) T/P start date.  
 
If both start and stop date are partially missing stop the derivation process?? 
 
Scenario 2:  
Only the prior treatment/procedure start date or the prior treatment/procedure stop date is recorded in the CRF page for a given Chronological Seq no.  
 
If the above date is incomplete then:  
o 
 if only day is missing, use day=15 and check the derived T/P date vs. treatment start date. If treatment start date < derived T/P date then use 1 for the missing day.  
o 
if both month and day are missing then compare year of treatment start date and year of T/P:  
(a) 
if year of treatment start date > year of T/P then impute 30 June;  
(b) 
if year of treatment start date = year of T/P then impute 01 January. 
 
At the end of the imputation process assigned the derived T/P date value both to (derived) T/P stop date and (derived) T/P start date. 
If stop date is NA, stop date is set equal to start date for further the purpose of further computations. 


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Weeks/Months from (Derived) Prior Antitumor Treatment/Procedures Stop Date to Tr. Start Date and Flag  
Weeks to tr. start = (treatment start date – [derived] date of prior treatment/procedure stop) / 7 
Months to tr. start = (treatment start date – [derived] date of prior treatment/procedure stop) * 12 / 365.25 
Estimated times should be identified by a flag variable and by an ‘*’ in the listings. 
If, for a given Chronological Seq no., stop date is NA AND start date is a valid date (eg surgeries), then ‘*’ will not be printed in the listings as stop is assumed to be 
coincident with start date. 
Duration (weeks/months) of Prior Antitumor Treatment/Procedures and Flag  
Duration (weeks) = ([derived] prior treatment/procedure Stop date - [derived] prior treatment/procedure Start date] / 7 
Duration (months) = ([derived] prior treatment/procedure Stop date - [derived] prior treatment/procedure Start date] *12 / 365.25 
Estimated times should be identified by a flag variable and by an ‘*’ in the listings (asterisks are not to be reported if  either Start Date or Stop Date are NA). 
 
 
Time (weeks/months) since Previous Antitumor Treatment/Procedures and Flag 
Time (weeks) = ([derived] prior treatment/procedure Start date at Current Chron. Seq. No - [derived] prior treatment/procedure Stop date of Previous Chron. Seq. No) / 7 
Time (months) = ([derived] prior treatment/procedure Start date at Current Chron. Seq. No - [derived] prior treatment/procedure Stop date of Previous Chron. Seq. No) *12 / 
365.25 
Estimated times should be identified by a flag variable and by an ‘*’ in the listings. If, for a given Chronological Seq no, stop date is NA AND start date is a valid date (eg 
surgeries), then ‘*’ will not be printed in the listings as stop is assumed to be coincident with start date. 
 
If  both (Derived) Start Date at Current Chronological Sequence No. and (Derived) Stop date at Previous Chron. Sequence No. are incomplete, (Derived) Time since previous 
Antitumor Treatment will not be calculated because it may be negative-valued. 
Prior Antitumor Treatment / Procedures Classification 
 
Each type of therapy recorded on the prior antitumor treatment/procedure CFR will be classified according to the following schema: 
 
Type of therapy 
Classification 
1=Surgery 
Surgery 
2=Chemotherapy 
Systemic therapy 
3=Hormone therapy 
Systemic therapy 
4=Immune therapy 
Systemic therapy 
5=Local or loco-regional therapy 
Systemic therapy 
6=Radiation therapy 
Radiotherapy 
7=Genetic therapy 
Systemic therapy 
8=Other Physical Treatments 
Systemic therapy 


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9=Sensitizer 
Radiotherapy 
10=Targeted therapy 
Systemic therapy 
 
This classification will allow the matching between the general information of each type of prior antitumor treatment/procedure and the respective details reported in the 
specific CRF sections (e.g.: details of ‘Chemotherapy’ will be found in the ‘Prior Systemic Therapy’ CRF ). 
Prior Systemic Therapies, Prior Surgeries, Prior Radiotherapies: Yes / No; Yes Value Derived and Flag  
To identify  whether the patient had any  prior systemic therapies, any surgery, any radiotherapies proceed as follows: 
 
Step 1: 
(example for Prior Surgery) 
Derive Step1_flag_sur =’Yes’ if ‘Yes’ answers to the ‘yes/no’ initial question (e.g. in the case of  Surgery: “Was any prior surgery reported in the prior antitumor 
treatment/procedure form?”)  OR  at least one detail is reported  in the form. Missing or ‘No’ answers to the ‘yes/no’ initial question should be changed into ‘Yes’ (derived 
Yes) 
Derive Step1_flag_sur=’No’ if ‘No’ answers to the ‘yes/no’ initial question  AND  no details are reported in the form. 
Derived ‘Yes’ is to be identified by ‘*’. 
 
Similarly, create the appropriate Step1_flag_xxx for each of these sections: Prior Systemic Therapies, Prior Surgeries, Prior Radiotherapies. 
 
Step 2: 
(example for Prior Surgery) 
derive Step2_flag_sur  by selecting the ‘Prior Antitumor Treatment / Procedures Derived Flag’ (see derivation above) when type of therapy is classified as ‘Surgery’  (see 
‘Prior Antitumor Treatment/Procedure Classification’ schema above)  
 
Similarly, derive the approriate Step2_flag_xxx for each type of therapy according to their classification (‘Systemic Therapy’, ‘Surgery’, ‘Radiotherapy’.  
 
Step 3: 
After the derivation of Step1_flag_xxx and Step2_flag_xxx for each of these topics:  Prior Systemic Therapies, Prior Surgeries, Prior Radiotherapies, 
o 
Pts are classified and counted as  ‘Yes’ (‘Yes’ or derived ‘Yes’) if Step1_flag_xxx = ‘Yes’ (‘Yes’ or derived ‘Yes’)  OR Step2_flag_ xxx = ‘Yes’ (‘Yes’ or derived 
‘Yes’) 
o 
Pts are classified as ‘No’, else. 
 
Derived ‘Yes’ is to be identified by ‘*’. 


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General Medical History and Physical Examination 
Any Relevant Diagnosis: Yes / No; Yes Value Derived and Flag 
o 
Pts are classified and counted as ‘Yes’ if: ‘Yes’ answers to the ‘yes/no’ initial question (e.g. “Has the pt had Any Relevant Medical History?”)  OR  at least one 
detail is reported  in the form. Missing or ‘No’ answers to the ‘yes/no’ initial question should be changed into ‘Yes’ (derived Yes).  
o 
Pts are classified as ‘No’ if: ‘No’ answers to the ‘yes/no’ initial question AND no details are reported in the form. 
 
Derived ‘Yes’ is to be identified by ‘*’. 
TREATMENT ADMINISTRATION 
Treatment and Schedule  
Regimen/Schedule  
The treatment schedule is “150 mg/day x 7 days q 2 wks” 
The per protocol cycle duration in days is 14 
The per protocol no. of drug administrations per cycle is 7 
Regimen (mg/day) 
It is the dose reported on the section ‘Patient Enrollment’ of the CRF and corresponds to the daily intended dose, i.e.  150 mg/day for 7 days every 14 days. 
First Dose Date (Tr. Start Date) 
The first date of administration where an administered dose (mg) > 0 is reported is taken as the date of the first study treatment administration  
Last Dose Date (Tr. Last Date) 
The last date of administration where an administered dose (mg) > 0 is reported is taken as the date of the last study treatment administration 
Start Date of a Cycle 
It’s the date of the first study drug administration within the specific cycle, i.e. when the first administered dose (mg) > 0 is reported. 
Total no. of Cycles 
For each patient, it’s the number of cycles with an administered dose (mg) > 0. 
Number of Days of Treatment 
For each cycle is the number of days with an administered dose (mg) > 0. 


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Time on Treatment (days weeks months)  
From first dose date to last dose date: 
 
(Last dose date- first dose date)+1   
(days)   
[(Last dose date- first dose date)+1]/7 
(weeks) 
[(Last dose date- first dose date)+1] *12 / 365.25  
(months) 
Derived date of end of treatment 
The derivation of the date of end of treatment is necessary to derive both the duration of the last cycle of treatment and the duration of the whole treatment period. For each 
patient the date of end of treatment will be derived as follows. 
 
1- Compute <derived EOT_1> as the maximum among the following dates: 
 
-  date of vital signs and date of performance status assessment in last treatment cycle 
 
-  last date of tr. admin in last treatment cycle 
 
-  last date of lab. assessment in last treatment cycle (any panel) 
 
-  last date of any other assessment (including Visual Acuity and Fundoscopic Examination) in last treatment cycle 
 
-  last date of any specimen collection (pharmacokinetics) in last treatment cycle 
 
-  date of ecg in last treatment cycle 
 
-  date of CT Scan / X ray in last treatment cycle 
 
-  date of Physical Examination in last treatment cycle 
 
-  (derived) date of per_protocol_end_of_last_cycle as:  date of first administration of last cycle + (  <per protocol cycle duration> – 1  ) 
2- Compute <derived EOT_2> as the minimum among the following dates: 
 
-  Date of death (see sections ‘Death’) 
 
-  End Date of an AE with action taken =’drug permanently withdrawn’  
 
-  Consent Withdrawn date in the Off Study Reason form (dataset STST) 
 
-  Investigator’s decision date in the Off Study Reason form (dataset STST)  
 
-  Alive as of date in the Status at Follow-up form  
 
-  Last known alive date in the Status at Follow-up  
 
-  Other Antitumor Therapies date at Follow-up 
 
3 -Finally compute <Derived date of end of treatment> as the min(<derived EOT_1>, <derived EOT_2>) 
Duration of a Cycle (weeks) (Duration for cycle x) 
Duration of cycle x (weeks) = (Start date of cycle <‘x+1’>  -  Start date of cycle <x>) / 7    
For the last cycle of treatment: 
(a) As a general rule:          duration of last cycle (weeks) = (Derived date of end of treatment - Start date of the last cycle ) / 7   
(b) For the purpose of calculating Dose Intensity:          duration of last cycle (weeks) = per protocol cycle duration (weeks)  
 


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In the listing reporting dose intensity derivations, for the last cycle of treatment, the duration based on the derived end of treatment is to be displayed together with the per 
protocol cycle duration displayed within brackets. 
Treatment Duration (weeks) (for the whole treatment period) 
Treatment Duration (weeks) = (Derived date of the end of treatment  - Study treatment start date) / 7  
For the purpose of calculating Dose Intensity:  
 
Treatment Duration (weeks) = [(Start date of the last cycle + per protocol cycle duration in days) – Study treatment start date] / 7   
 
e.g.: 
study treatment start date = 01 MAR 2007 
 
start date of the last cycle = 01 JUL 2007 
 
per protocol cycle duration = 2 weeks (i.e. 14 days) 
 
=>  treatment duration = (01 JUL 2007 + 14 days) – 01 MAR 2007 = 136 days  ~ 19.43 weeks  
 
 
In the listing reporting dose intensity, the whole treatment duration based on the derived date of end of treatment is to be displayed, together with the per protocol whole 
treatment duration displayed within brackets. 
Intended Dose (mg) (at cycle x) 
Intended dose (mg) = Assigned Dose Level (mg/day) * n (where n is the per protocol no. of drug administrations per cycle). 
Intended Dose (mg) (whole treatment period) 
For each patient the Intended Dose (mg) for the whole treatment period is the sum of all the Intended doses (mg) (at cycle x)   
Taken  Dose (mg) per Day or Cycle (at cycle x) 
Taken dose (mg) per day: as reported for each day on the treatment CRF page.  
Taken dose (mg) per cycle: it’s the sum of all administered doses per day reported on the CRF for that cycle. 
Administered Dose (mg) (whole treatment period)  
For each patient the Administered Dose (mg) for the whole treatment period is the sum of all the Administered Doses (mg) (at cycle x). 
BSA (m2, calculated) at cycle x 
Create a calculated BSA using the following formula: 
 
BSA=Weight in Kg**0.425 * Height in cm**0.725*71.84/10000 
(DuBois&DuBois formula)    
where weight is the one reported at the cycle on the CRF and height is reported at the pretreatment visit. 
 If height or weight at cycle is missing, BSA CANNOT BE CALCULATED. 


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Dose (mg/m2, calculated) per Day or Cycle and Flag  
Dose (mg/m2, calculated) = Administered dose (mg) per day or cycle / BSA reported at cycle on the treatment CRF page.  
 
If BSA reported at cycle on the treatment CRF page is missing, use BSA(m2, calculated). If both of them are missing  then: 
 
a)  at cycles > 1 use BSA of previous cycle: BSA reported on the treatment CRF or, if this is missing, BSA (m2, calculated) 
b)  at cycle 1 derive the BSA using the weight and height reported at pretreatment using the formula specified above. 
 
Under the circumstances a) or b) Dose (mg/m2 calculated) will have to be flagged and identified in the listings, e.g. by ‘*’. 
% Scheduled Dose 
At each cycle:  
 
% Schedule Dose = Administered dose (mg) per Cycle (see above) * 100) / Intended Dose (mg) 
Classification of Cycles by Percentage of Scheduled Dose 
For the frequency distribution table of cycles by % of scheduled dose the following categories are used: 
 
“Full Dose”                     when  % scheduled dose of the cycle   GE   95%   
 
“80% - < Full Dose”      when  80% LE   % scheduled dose of the cycle   LT   95% 
              “50% - < 80%”:              when  50%   LE   % scheduled dose of the cycle   LT   80% 
 
 
“<50%”                          when  % scheduled dose of the cycle   LT   50% 
Cumulative Dose (mg) 
Cumulative Dose (mg) is the cumulative sum of all doses, from start of treatment either up to end of each treatment cycle OR to the end of the treatment, as required by the 
analysis and the output to be displayed, where dose is defined as: 
 
<Administered Dose (mg) per Cycle>  
Absolute Dose Intensity (mg/wk) (at cycle x)  
Absolute Dose Intensity (mg/wk) (at cycle x) = Administered Dose (mg) per Cycle (see above) / duration of the cycle in weeks  
 
<duration of the cycle in weeks (see above)>  for the last cycle of treatment: the per protocol cycle duration is to be used. 
Absolute Dose Intensity (mg/wk) for whole treatment period  
Absolute Dose Intensity (mg/wk) (for whole treatment period) = Cumulative Dose (mg) for the whole treatment period (see above) / treatment duration in weeks 
 
<treatment duration in weeks (see above)> =    [(Start date of the last cycle + <per protocol cycle duration in days>) – Study treatment start date] / 7 


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Intended Dose Intensity (mg/wk) 
Intended Dose Intensity (mg/wk) = Intended Dose (mg) (see above) / < per protocol cycle duration in weeks > 
Relative Dose Intensity (%) 
Relative Dose Intensity (%) = Absolute Dose Intensity (mg/wk) / Intended Dose Intensity (mg/wk) * 100. 
It may be calculated for a cycle as well as for the whole treatment period. 
Treatment Modifications  
Treatment modification can occur at the start of each cycle > 1 or within any cycle. Treatment modifications are derived as follows. 
 
At Cycle Start:  
 
“Treatment Delay (Yes/No)” must be derived as ‘Yes’ if ‘Yes’ is recorded in the CRF or at least one reason for treatment delay is recorded. 
 
“Dose Reduction (Yes/No)” must be derived as ‘Yes’ if ‘Yes’ is recorded in the CRF or at least one reason for dose reduced is recorded.  
 
Within Cycle: 
 
“Intra Cycle Treatment Modification (Yes/No)” must be derived as ‘Yes’ if ‘Yes’ is recorded in the CRF or at least one reason for intra-cycle modification is 
 
recorded. 
 
“Any Modification (Yes/No)” must be derived as ‘Yes’ if at least one Treatment Modification <At Cycle Start> and/or  <Within Cycle> is recorded or derived. 
Reasons for Treatment Modification 
For each toxicity class (i.e. hemat./non-hemat./other) the number of patients for whom the analyzed toxicity was reported at least once will be counted regardless of the kind 
of treatment modification and how many times this kind of toxicity was reported. 
If a patient had a treatment modification and no reason was specified at any cycle of treatment, then the patient will be classified as ‘Unknown Reason’ in the relevant 
frequency distribution table. 
 


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 TREATMENT EFFICACY  
Tumor Lesions 
Population to be Analyzed 
Efficacy listings are to be produced for treated patients, while tables will be produced both for treated and for evaluable patients (see definitions of evaluable patient in the 
patient population section).  
Oncologic Assessment: Time of Assessment 
As per protocol, during the treatment period, irrespectively of cycles duration, the first assessments will be performed 6 weeks (between days 42 and 48) after first drug 
administration, the second one 3 months (between days 92 and 98) after first drug administration, the following ones every 6 weeks (between days 42 and 48) after the 
previous one (or whenever a clinical deterioration will be observed) and at end of last cycle (if not done in the previous 4 weeks). Patients off-treatment without progressing 
before the 3rd month oncologic assessment should have been scheduled at the time of endpoint assessment, unless a new antitumor therapy started.  In addition regular 
oncologic assessments of patients withdrawn from study treatment for causes other than disease progression will continue every 6 weeks during follow-up, until PD or until a 
new antitumor therapy starts. The corresponding information will be collected on the appropriate forms placed outside the treatment cycles. 
Lesion Assessment  
Premise  
Lesions and responses are defined as per RECIST 1.1 criteria  
 
The presence of a lesion is indicated by a lesion number on the CRF. The same lesion number identifies the same lesion throughout the whole study period. 
 
The “individual target lesion” analyses ( % change from baseline) will be performed only if the individual target lesion is considered as evaluable, i.e. if the criteria of 
evaluability for % change described in the algorithm “Individual Target Lesion: Evaluability for % Change” are fulfilled.  
 
The “all target lesions” analyses (sum of measures, % change from baseline, best and worst % Change from baseline, Nadir and %change from Nadir ) will be performed only 
if the set of  “all target lesions” is considered as evaluable, i.e. if the criteria of evaluability for % change described in the algorithm “All Target Lesions: Evaluability for % 
Change” are fulfilled..  
Weeks to/from Treatment Start from/to Lesion Assessment Date:  
At pre-treatment: (date of lesion assessment – first dose date) / 7  
On-Treatment: [(date of lesion assessment – first dose date)] / 7 


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Lesion Flag for Different Method  
For each patient, assessment and lesion, a flag is to be derived if the assessment method for that lesion at the current assessment is different from the method used at the 
pretreatment (reference assessment). 
Individual Target Lesion: Evaluability for % Change 
At each assessment after treatment start, a target lesion is considered as ‘evaluable’ for % change if: 
a) The lesion is reported both at pretreatment and at the analyzed visit with the same method and with valid measurements  
OR 
b) The lesion is a new lesion with valid, non missing method and measurement at the analyzed assessment 
 
Otherwise the lesion will be classified as ‘not evaluable’ and will not be processed for % change calculation [e.g. the method differs from baseline method, or the lesion is 
labeled as not assessed, or lesion’s measurement is not reported either at the analyzed visit or at baseline].  
    
Individual Target Lesion: %Change from Baseline  
At each assessment after treatment start:  
 
 
%Change from Baseline = (measure at the current assessment  – measure at pretreatment) * 100 / measure at pretreatment.   
 
Notes: % change for new lesions is not to be calculated: they will be taken into account only for % change of all target lesions 
All Target Lesions: Evaluability for %Change. 
At each assessment after treatment initiation, the set of all target lesions is considered as evaluable for % change if: 
a) 
All lesions assessed at pretreatment are also assessed at the analyzed visit AND 
b) 
There is no lesion at the current assessment which is classified as ‘non evaluable’ (see above). 
All Target Lesions: Sum of Measures  
At each assessment (pretreatment included):  
 
Sum of measures: sum (all target lesions measures). 
 
Note: In the afore described sum, take into account also new target lesions. In the sum of measures take into account also lymph nodes  
All Target Lesions: % Change from Baseline  
At each assessment after treatment start as: 
 
%Change from Baseline = (Sum of measures at current assessment – sum of measures at pretreatment)*100 / sum of measures at pretreatment. 


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All Target Lesions: Nadir (Y/N) 
The lowest value of all sums of measures reported throughout the whole study period (baseline included). In the relevant listing a ‘Y’ is to be put beside the “all target” value 
corresponding to the nadir value. Only ‘Y’ values are to be printed. 
All Target Lesions: % Change from Nadir 
(Current sum of measures – all target lesions nadir value) * 100 / all target lesions nadir value. 
It is applicable only for study periods following the visit at which the nadir measure is reported. 
 
Tumor Response Status 
Assessment Date (calculated) 
For each visit when a tumor assessment is performed, derive the assessment date as: min (target and non target lesions assessment dates) among valid dates. In absence of a 
valid date no date is surrogated. 
Weeks from Treatment Start 
[(Assessment date (calc.) – first dose date)] / 7. 
Date of documented PD and Flags  
The date of PD is to be derived as the earliest date-out of the valid ones- among all tumor lesion assessments (non-target lesions included) performed at the (first) assessment 
when PD was reported in the Response Status form (page 3 of 3 of onc. assessment CRFs). In absence of a valid date no date is surrogated. 
 
Date of PD > start date of the first anti-tumor therapy at follow-up is to be marked with § 
A control listing is to be built with all the variables needed to implement the algorithm. 
Time (Days, Weeks and Months) to PD  
For Overall Response in Study Period:  
[(date of documented PD - first dose date)]  (days) 
[(date of documented PD - first dose date)] / 7   (weeks) 
[(date of documented PD - first dose date)] * 12 / 365.25    
(months) 
Best Overall Response (Confirmed) 
It’s the best overall tumor response reported  on treatment for each patient and collected on the corresponding CRF   
In addition to individual response categories recorded on the CRF, for the purpose of table display assign the following categories: 
- Objective response = yes  if patient attained as best response either PR or CR 
- Disease Control = yes if patient attained as best response either PR or CR or SD 


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Date of First Response and Flag 
For responding patients only  
If a patient has a ‘CR’ or a ‘PR’ as a best overall tumor response, the date of start of response should be reported (as date of first onset scan on the CRF best overall response 
form). If missing, then it’s to be estimated as follows:     
max (all tumor lesion assessment dates) at the first tumor assessment visit with an overall response = best overall tumor response.  
Estimated dates of first response are to be identified by *. 
Note: A control listing is to be built with all the variables needed to implement the algorithm 
Date of Confirmed Response and Flag 
For responding patients only  
If a patient has a ‘CR’ or a ‘PR’ as a best overall tumor response, the date of the confirmed response should be reported (as date of confirming scan on the CRF best overall 
response  form). If missing, then it’s to be estimated as follows:   
max (all tumor lesion assessment dates) at the second tumor assessment visit with an overall response = best overall tumor response. 
Estimated dates of confirmed response are to be identified by *. 
Note: A control listing is to be built with all the variables needed to implement the algorithm. 
Best Unconfirmed Tumor Response  
It’s the ‘best’ response among all the overall responses reported on the Response Status Forms at each assessment for the patient. 
Example: pt X1 has performed three oncologic assessments; on the first assessment the overall response is ‘SD’, on the second assessment is ‘PR’, on the third assessment is 
‘PD’, hence the best unconfirmed tumor response will be ‘PR’. 
Date of Last Oncologic Assessment before PD   
It is the Assessment Date (calculated) (see above) of the most recent oncologic assessment with overall tumor response = ‘CR’ or ‘PR’ or ‘SD’. 
Durations  
Premise  
Duration of response, duration of stable disease and time to progression are to be calculated and saved in DB as days, weeks and months. 
Failure/Censored Patients   
The patients are classified as failure (failure = 1) if: 
o 
they experienced Progressive Disease (independently of the presence of a date of PD) AND (no new anti-tumor therapy is reported at Follow Up OR it is reported 
with a non valid date)  
OR  
o 
date of Progressive Disease ≤  Start Date of first new anti-tumor therapy reported at Follow Up (both dates must be valid) 
OR 


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o 
they experienced Death with cause  “Progressive Disease” or missing   (independently of the presence of a date of Death) AND NO new anti-tumor therapy is 
reported at Follow Up.  
 
Patients will be classified as censored (i.e. failure = 0) if they are not failures.  
 
A control listing may be built with all the variables needed to implement the algorithm. 
Date of Failure  
For failure patients it is the earliest, non missing date between: 
1) 
Date of PD 
2) 
Date of Death with cause “Progressive Disease” or missing  
Note that date of failure could be missing.  
Date of Censoring 
For censored patients:  
1) Start date of first new anti-tumor therapy at Follow Up 
 
OR  
2) Date of “Last Oncologic Assessment before PD” if no new anti-tumor therapy is reported at Follow Up OR it is reported with a non valid date. 
Note that date of censored could be missing.  
Response Duration and Censored Patients Flag   
For responding patients only  
1) For failure patients: 
 
(date of failure – start of response)  
2) For censored patients: 
 
(date of censoring - start of response)  
 
For censored patients only: at the end of calculation, if duration of response is missing then set its value to 1.  
For failure patients, if date of failure is missing, duration of response won’t be computed and will result in a missing value.  
In the listing the response duration of censored patients will be identified by a + (e.g. ‘5 +’) 
Progression Free Survival (PFS) and PFR at 3 months 
Premise  
Progression free survival is to be calculated and saved in DB as days, weeks and months.  


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Failure/Censored Patients   
The patients are classified as failure (failure = 1) if: 
o 
they experienced Progressive Disease (independently of the presence of a date of PD) AND (no new anti-tumor therapy is reported at Follow Up OR it is reported 
with a non valid date)  
OR  
o 
date of Progressive Disease ≤  Start Date of first new anti-tumor therapy reported at Follow Up 
OR 
o 
they died  (independently of the presence of a date of Death)  
 
Patients will be classified as censored (i.e. failure = 0) if they are not failures.  
 
A control listing may be built with all the variables needed to implement the algorithm. 
Date of Failure  
For failure patients it is the earliest, non missing date between: 
1) 
Date of  PD 
2) 
Date of  Death  
Note that date of failure could be missing .  
Date of Censoring 
For censored patients:  
o 
Start date of first new anti-tumor therapy at Follow Up 
 
OR  
o 
 Date of “Last Oncologic Assessment” if no new anti-tumor therapy is reported at Follow Up OR it is reported with a non valid date. 
 
Note that date of censoring could be missing .  
Progression Free Survival (PFS) 
1) For failure patients: 
 
(date of failure – treatment start date)  
2) For censored patients 
 
(date of censoring - treatment start date)  
 
If at the end of calculation progression free survival is missing, then set its value to 1 regardless of whether the patient is censored or failure. 


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Progression Free Survival Rate at 3 Months 
Per protocol 3rd month assessment should have been performed  between 92 and 134  days since treatment start, therefore a patient’s status regarding progression free survival 
at 3 months will be determined according to the following rules:  
 
1) For failure patients 
 
‘Success’:  if 134  (date of “Last Oncologic  Assessment before PD OR before death” – first dose date)  ≥ 92.  
 
 
‘Failure’: 
Otherwise 
 
2) For censored patients: 
 
‘Success’ if:  
134  PFS ≥ 92 days 
 
 
‘Failure’: 
Otherwise 
 
Note. For the purpose of Interim Analysis the primary endpoint PFS rate at 3 months will be evaluated on the first 17 treated and evaluable patients irrespectively they were 
observed for 3 months or they failed earlier. If 3 or fewer patients out of the first 17 are progression-free at 3 months, the study  will stop for futility as soon as this can be 
determined. If 4 or more patients out of 17 are progression free, the trial will be continued until 54 evaluable patients are available.  
The rules to define the patient’s status regarding progression free survival at 3 months are the same as reported above in this paragraph. 
Overall Survival (OS)  
Premise  
Overall survival is to be calculated and saved in DB as days, weeks and months. 
Failure/Censored Patients 
A variable (failure) is to be derived to identify failure and censored patients. 
1) Patients will be classified as failure (i.e. failure = 1) if: 
 
pt died = ‘Y’  
2) Patients will be classified as censored (i.e. failure = 0) if they are not failures. 
Overall Survival and Censored Patients Flag 
1) For failure patients: 
 
(Death date – study treatment start date)  
2) For censored patients: 
 
(Last recorded date – study treatment start date)  
If at the end of calculation survival is missing, then set its value to 1 regardless of whether the patient is censored or failure  
In the listing overall survival for censored patients will be identified by a + (e.g. ‘5 +’) 


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Summary Statistics for Time to Events Endpoints: Flag for Censored Patients 
For all time to event endpoints (i.e.: progression free survival, overall survival, duration of response). 
Derive a flag if the statistics refer to censored patients when calculating MIN and MAX of time to event endpoints,. 
ADVERSE EVENTS (AES) 
Safety Population 
All treated patients. The safety population will be used as the denominator to calculate percentages. 
AE terminology criteria: MedDRA and aggregation levels for the analysis 
AEs are recorded in the DB as reported in the CRF (Investigator’s Term) and coded according to MedDRA (MedDRA Code and Preferred Term). For each MedDRA 
Preferred Term, the corresponding MedDRA System Organ Class (SOC) is also recorded in the DB. 
In the analyses, aggregations both by MedDRA Preferred Term (Aes) and  MedDRA System Organ Class (SOC) will be provided. 
On treatment Adverse Event 
As per protocol all adverse events recorded on treatment (recorded in the AE forms from cycle 1 on, follow-up excluded) will be classified as ‘on treatment Aes’ and 
considered in the analysis, regardless of whether they were also recorded as baseline signs and symptoms in the pre-treatment CRF. 
Maximum CTC grade by patient and MedDRA Preferred Term 
For each patient and for each MedDRA Preferred Term, derive the maximum CTC grade for the on treatment records. In the relevant analyses the patients will be classified 
according to this derived variable and counted for each MedDRA Preferred Term. 
Maximum CTC grade by patient and System Organ Class (SOC) 
For each patient and for each system organ class (SOC), derive the maximum CTC grade for the on treatment records. In the relevant analyses the patients will be classified 
according to this derived variable and counted for each SOC. 
Maximum CTC grade by patient 
For each patient derive the maximum CTC grade by patient, independently of the event/system, for the on treatment records. In the relevant analyses the patients will be 
classified according to this derived variable. 
Aes: CTC Grade >= 3 Flag 
Any ctc grade >/= 3 is to be marked by *. 


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Aes in Follow-up Flag 
Aes not recovered in Follow-up are identified by §. 
Deaths 
Date of Death 
As a general rule the date of death will be defined as: 
 
(1) min (Date of death on CRF Death form, date(s) of death on survival follow-up forms) 
If the date of death (1) is not available, it will be derived as 
 
(2) min [Stop date(s) of AE with death as outcome (CRF Adverse Event form)or with CTC grade=5] 
Patient Died 
Patient died = Yes: 
 
if a death date (see definition above) is not missing  
 
or at least one information on death is reported in death form or in survival follow-up forms 
 
or at least one AE has outcome=death or CTC grade=5. 
Patient died = No: 
 
if a death date (see definition above) is missing  
 
and no information on death is reported in death form nor in survival follow-up forms 
 
and no AE with outcome = death nor CTC grade=5. 
CRF Source 
If death date is obtained from the death form, then CRF Source = ‘(Death)’;  
else if death date is obtained from the survival follow-up forms then CRF Source = ‘(FU)’; 
else if death date is obtained from the AE forms then CRF Source = ‘(AE)’. 
Days from Last Treatment Administration and Flag 
Days from last treatment administration = Date of Death (see definition above) – Treatment Last date 
If patient died = ‘Y’ and date of death is missing then  
Days from last treatment administration = Unknown 
 
A flag (*) is to be derived if difference is <= 28. 
Most Probable Cause of Death 
If death date is obtained from the death form, select the most probable cause reported in the same form, along with the corresponding details; 
else if death date is obtained from the survival follow-up forms, select the most probable cause reported in the same form, along with the corresponding details; 
else if death date is obtained from the AE forms, set ‘Adverse Event’ as the most probable cause, without any details. 


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If most probable cause of death = missing then report it as ‘Unknown’ in the analysis tables. 
Relationship to Study Drug of Death 
If death date is obtained from the death form, select the relationship reported in the same form. 
Else if death date is obtained from the AE forms, select the relationship of the adverse event reported in the same form. 
If relationship of death to study drug  = missing and most probable cause of death is not PD, then report it as ‘Unknown’ in the outputs. 
 
If death date is obtained from the survival follow-up forms (where relationship to study drug  is not reported) and most probable cause of death is not PD, then report it as 
‘Unknown’ in the outputs. 
Autopsy Performed: ‘Yes’ Value Derived 
Autopsy Performed: derive value ‘Y’ if date of autopsy and/or autopsy results is reported. 
Hospitalization 
Duration (Days)  
((Date of Discharge – Date of Admission) + 1) is calculated if Ongoing not equal to ‘Yes’ or if Date of Discharge is not missing. 
Weeks from First Dose Date 
[(Date of admission – First Dose Date) + 1] / 7   
LABORATORY TESTS 
Safety Population 
In principle, the outputs concerning laboratory examinations will be based on all patients who took any drug ever (Treated Patients). In most of the summary displays (e.g. 
contingency table) the number of Treated Patients is going to be the reference population for safety analyses. However, when specified, the subset of treated patients with at 
least one non-missing lab. Assessment (for the test under analysis within the time window to be displayed, e.g. cycle 1, cycles > 1, whole treatment period) may be 
considered, instead of the whole set of treated patients. 
Reference Document for CTC Grade Calculation 
The document to be referred to is the NCI CTCAE v.3.0 (http://ctep.cancer.gov/reporting/ctc_v30.html grading system. Not all the laboratory assays have a corresponding 
grading according to CTC. Also for some of the assays, the CTC reference document reports absolute values as thresholds that define the boundaries of the grade category, 
whereas the boundaries of many other assays are defined as multiples of either Upper or Lower Limit of Normality (LLN,ULN). 


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Additionally, although variations outside the normality ranges are pathological in both directions (above and below the limits) for the majority of the assays, in most cases the 
CTC grade has been defined in one direction only. For those assays whose abnormality is determined by two-way modifications ( e.g. Calcium, Sodium) both abnormalities 
are to be analysed independently and the worst CTC grade should be calculated both for variations above and below the limit of normality. A variation that is abnormal in one 
direction is to be considered normal in the opposite one. 
See CTC classification for references of lab. Assays  with bidirectional CTC grade defined. 
Low / High ( L/H) Flag 
This flag is stored in the Oracle DB  and it marks the values according to where they fall with respect to their range of normality; it is derived as follows: 
- <flag> = ‘L’   if:  [both < value > and <lower range limit > are not missing]   and   <value> LT <lower range limit>   
- <flag> = ‘H’   if:  [both < value > and <upper range limit > are not missing]   and  <value> GT <upper range limit>  
otherwise the flag will be N (printed as missing in some of the outputs). 
Variables to used for CTC grade calculation 
CTC grade is not collected on the CRF or stored in the Oracle DB, rather it is calculated as part of the analysis of safety data; the calculation will move from the following  
variables stored in the OC DB:  
 
LBFCTC = Flag identifying lab tests included in the reference document. 
 
LBVCTC = Assay Value Converted into CTC Unit. 
 
RGLCTC = Low Value Converted into CTC Unit. 
 
RGHCTC = High Value Converted into CTC Unit. 
 
LBUCTC = Standard CTC Unit. 
 
CTC units are the units associated to the boundary values reported in the reference document. 
For those laboratory tests whose CTC boundary values are expressed in absolute value and for which in the reference document two different values and units were available 
(e.g. conventional and standard international), conventional units were preferred, therefore the above variables contain the conventional value, ranges and unit. 
For those laboratory tests whose CTC boundary values are expressed as multiples of ULN and LLN (mainly belonging to Blood Chemistry, see below) the above variables 
contain the collected value, ranges and unit. 
Converted Value, Unit and Range Limits 
To the purpose of data presentation and analysis, each laboratory test should be expressed in the same unit across patients within the same test. Therefore a set of derived 
variables (converted value, unit and range limits) containing the harmonized values units and ranges is to be created according to the following rules. 
For those test that belong to the CTC classification system the choice of units has been based on those reported in the reference document in the definition of the thresholds. 
For all the other tests the conventional units are to be used.  
In details: 
Hematology: 
 
For lab. Tests reported in the reference document use the CTC Value and Unit variables (LBVCTC and LBUCTC). 
Warning for the programmer: if the collected value of Neutrophils and Lymphocytes (and/ or other ones to be specified) was originally expressed as % of  WBC, the 
value stored in the OC variable LBVCTC and LBUCTC have already been converted in absolute count /mm3, but the lab. Assay codes (‘NEUT’ and ‘LYM’) have 
not been changed accordingly in ‘NEUTX’ and ‘LYMX’ respectively. 


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 
For lab. Tests not reported in the reference document the converted value will be expressed in the same unit of WBC (i.e. absolute count /mm3), in particular, if 
Eosinophils, Basophils, Monocytes are expressed as % over the total count of WBC, they will be converted in absolute values. In summary: 
 
 
WBC total count  *  Lab. Test / 100 
if the collected value is expressed as percentage of the WBC value; 
 
 
Lab. Test * 1000  
 
 
if the collected value is expressed as 103/mm3   or as 109/L. 
For Blasts, Nucleated RBCs, Plasma Cells, Atypical Cells the set of derived variables containing the harmonized values, units and ranges will be a copy of the 
Conventional set. 
 
Blood Chemistry: 
 
For lab. Tests reported in the reference document whose CTC grades class boundaries are expressed in absolute value (e.g. Albumin, Uric Acid, Calcium, 
Phosphorus Inorganic, Potassium, Sodium,…) use the CTC Value and Unit variables. 
 
For lab. Tests reported in the reference document whose CTC grades are expressed as multiple of ULN and LLN (e.g: Alkaline Phosphatase, AST, ALT, Bilirubin, 
Creatinine….) use the Conventional Value and Unit variables.  
 
For lab. Tests not reported in the reference document use the Conventional Value and Unit variables. 
 
Coagulation: 
 
For lab. Tests reported in the reference document (e.g. INR and aPTT) whose CTC grades are expressed as multiple of ULN and LLN use the Conventional Value 
and Unit variables. 
 
For lab. Tests not reported in the reference document (e.g. PT and PT % of control) use the Conventional Value and Unit variables. 
 
Allocation of Lab. Tests to the Relevant Study Period 
Laboratory tests are key examinations for the evaluation of the safety of the patients on treatment with the experimental compound(s)/regimen. 
Blood samples are repeatedly collected during study conduct according to study specific schedule of events as outlined in the protocol. Lab assessments scheduled at the end 
of each cycle (or at baseline when cycle 1 is considered) should be performed on the day before first day of cycle or at latest on the same day, but in any case before actual 
treatment administration. As per CRF compilation instructions, these assessments belong to the cycle that is about to complete and not to the cycle that is about to start. 
In other words, if a lab assessment is performed on the same day of first drug administration of the cycle, it is considered to have been performed before that the drug 
administration took place. 
Based on this assumption, whether or not the assessments were recorded at the right cycle in the CRF, in the individual data listing the values will be reported within the 
study period of pertinence and analysed consistently.  
To this purpose the assessments performed on the same date as the first day of treatment administration in the cycle are to be allocated as follows should they be recorded in 
the wrong cycle in the CRF. 
Cycle 1:  
 
If lab. Assessment dateCycle 1 is not missing and if (assessment dateCycle 1) ≤ (treatment dateCycle 1) then lab. AssessmentCycle 1 should be considered along with 
pretreatment laboratory assessment. 
 
Else if (assessment dateCycle 1) > (treatment dateCycle 1) then no allocation should be performed and the specific lab. AssessmentCycle 1 should be considered along with 
all other cycle 1 lab. Assessments. 
Any Cycle >1:  


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 
If lab assessment dateCycle x is not missing and if (assessment dateCycle X) ≤  (treatment dateCycle X) then lab assessmentCycle X should be allocated to the previous cycle 
X-1 with a valid treatment administration record, and considered along with the lab assessments of Cycle (X-1) for the data analysis. 
 
Otherwise no allocation should occur and the specific lab. AssessmentCycle X should be considered along with all other cycle X lab. Assessments. 
 
Allocation of lab. Tests to the relevant study period is the first step to be performed. Both original and allocated cycles values should be stored as two distinct variables in the 
analysis database. 
Allocation of Lab. Tests Reported at Cycles with Missing Treatment Dose or Date 
Lab. Tests recorded at a cycle for which the total administered dose is missing or the cycle start date is missing should be allocated to the previous available cycle with a valid 
treatment administration record and should be considered together with the tests of that cycle of treatment.  
Allocation of Lab. Tests Reported at 28 days AE Visit 
Lab. Tests performed at the 28 days AE visit are expected to be reported in the CRF as assessments of last cycle, therefore no action is taken. 
Laboratory test day  
Laboratory test day is calculated after the allocation process as : 
 
(lab.assessment date – treatment start date) before first study drug administration ( i.e. when lab.assessment date  treatment start date)  
 
 
 
 
 
(lab.assessment date – start date of cycle) + 1 on treatment (i.e. when lab.assessment date > treatment start date)  
 
 
 
 
where: start date of cycle is the date of the first dose administration in the cycle to which the test was allocated 
 
If lab. Assessment date is missing laboratory test day is not to be derived. 
Cycles with at Least One Assessment 
Treatment cycles with at least one assessment:  for each laboratory test it is a cycle with a valid (non missing) value for the given test after the allocation process. 
Treated Patients with at least one Assessment  
Treated patients with at least one cycle with at least one assessment for the specific laboratory test  
Baseline Data: Value, Unit, CTC Grade and Date 
After the allocation process, for each analyzed test, select the most recent value among the pretreatment assessment(s). 
The following information should be recorded in the analysis database: Baseline Value, Unit, CTC Grade and Date. 


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Worst CTC grade 
For lab. Test included in the NCI CTCAE v.3.0 reference document, it is the first occurrence, after the allocation process, of the highest CTC grade observed during the time 
window of reference, i.e.: baseline, cycle 1, cycles >1, all cycles.  
Lab. CTC Grade 3 – 4 Flag 
In the listings all occurrences of CTC grades 3 or 4 must be flagged, e.g. by an asterisk: for instance   “3  * ” or  “4  * ” 
 
OTHER SAFETY ASSESSMENTS 
Temperature 
In the Outputs use “Temperature in Celsius”. 
Blood Pressure 
Blood Pressure Flags 
At pretreatment   
At pretreatment  a ‘*’  sign is to be derived to identify systolic blood pressure  140 mmHg OR diastolic blood pressure  90 mmHg  
 
On Treatment  
(1) Systolic Blood Pressure  140 mmHg  
OR 
(2) Diastolic Blood Pressure  90 mmHg   
OR  
(3) Systolic Blood Pressure – Baseline Systolic Blood Pressure 20 mmHg.  
OR  
(4) Diastolic Blood Pressure – Baseline Diastolic Blood Pressure 10 mmHg. 
A ‘*’ sign is to be derived for (1) and (2), a ‘§’ sign is to be derived for (3) and (4). 
Blood Pressure: Normal and Abnormal Values  
‘Normal’: if systolic blood pressure < 140 AND diastolic blood pressure < 90. 
‘Abnormal’: Else, if not normal (systolic blood pressure  140 OR diastolic blood pressure  90. 
‘Unknown’: both values missing 
 
Tabular display 


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At pretreatment: 
Consider the most recent not “Unknown” of the assessments (if more than one) performed at pretreatment  
Worst Assessment on treatment: 
“Abnormal” if at least one assessment on treatment is “Abnormal”. Else “Normal”. 
Electrocardiogram 
Electrocardiogram: Category 
If abnormality code begins with ‘A’ then category = Rhythm 
If abnormality code begins with ‘B’ then category = P-wave morphology 
If abnormality code begins with ‘C’ then category = Conduction   
If abnormality code begins with ‘D’ then category = QRS 
If abnormality code begins with ‘E’ then category = ST-T wave 
In the summary tables, pts are counted for each reported category.  If multiple abnormalities are reported in a category, the pt is counted once in the category. 
Electrocardiogram: ‘Yes’ Value Derived 
If any specific abnormality is marked on CRF, the patient is to be classified as ‘YES’ even though a missing or NO answer was reported to the initial question. In the outputs 
Derived ‘Y’ are to be identified by * 
Electrocardiogram: Abnormalities not Present at Pretreatment 
Abnormalities recorded after treatment start that were not already present at pretreatment  are to be identified by *. 
Electrocardiogram: Tracing Abnormalities (Y/N) 
Tabular display 
On treatment: Any abnormality = ‘YES’ / ‘Abnormal’ if at least one abnormality was recorded on the CRF or was derived (see above) after treatment start 
Chest X-Ray  
Days to/from Treatment Start 
At pretreatment:   (Date of Chest X-Ray – Study Treatment Start Date)  
At any other assessment time:  ((Date of Chest X-Ray – Study Treatment Start Date) + 1) 
Pregnancy Test 
Positive results are to be identified by ‘*’.  


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OTHER INFORMATION 
Other Anti-tumor Therapies at Follow-up 
‘Yes’ Value Derived  
If any details are reported in CRF, the patient is to be classified as ‘YES’ even though a missing or NO answer was reported in the CRF  
Days from Last Treatment Administration  
Days from last treatment administration = Date of start of other anti-tumor therapies at FU– Treatment Last date. 
If date of start of other anti-tumor therapies at FU is incomplete no calculation will be done. 
Concomitant Medications 
Any Concomitant Medications?: ‘Yes’ Value Derived 
If any details are reported in CRF, the patient is to be classified as ‘YES’ even though a missing or NO answer was reported in the CRF  
Duration (days) 
((Concomitant Medication Stop Date – Concomitant Medication Start Date) +1) is calculated if stop date is not missing.     
Weeks from Tr. Start Date 
[(Concomitant Medication Start Date – Treatment Start Date) + 1] / 7    
Concomitant Radiotherapies 
Any Concomitant Radiotherapies?: ‘Yes’ Value Derived 
If any details are reported in CRF, the patient is to be classified as ‘YES’ even though a missing or NO answer was reported in the CRF  
Duration (days) 
((Concomitant Radiotherapy End Date – Concomitant Radiotherapy Start Date) +1) is calculated if end date is not missing.  
Weeks from Tr. Start Date 
[(Concomitant Radiotherapy Start Date – Treatment Start Date) + 1] / 7   


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Blood Derivatives  
Weeks from Tr. Start Date 
[(Blood Derivatives Date – Treatment Start Date) + 1] / 7   


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REVISION HISTORY 
 
Version Date 
Reviewed by:  
(Printed name) 
Reason for change 
1.0 
8th   July 2013 
 
First release of document 
 
 
 
 
 
Reviewed and Approved by: 
 
Role 
 
Printed Name 
 
Signature 
 
Date 
Statistician 
Anna Petroccione 
 
 
  
CL 
Marcella Martignoni