Clinical trial NCT00378482
Conditions: Colorectal Neoplasms Melanoma Prostatic Neoplasms Renal Cell Carcinoma Neoplasms Patients Who Have/Have Had Melanoma and Other Tumors
Keywords: Melanoma and other tumors
Sponsor: AstraZeneca
Start date: 2007-03-05; Completion date: 2023-10-27
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is intended to provide access to tremelimumab for patients who have previously received tremelimumab in a clinical trial.

Detailed description:

Arms: arm 1: Drug: CP-675,206 (Tremelimumab)
Interventions: intervention 1: CP-675,206 (Tremelimumab)
Intervention descriptions: intervention 1: 15 mg/kg IV every 3 months as long as required

Protocol documents:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
A ROLLOVER PROTOCOL FOR PATIENTS WHO RECEIVED 
TREMELIMUMAB (CP-675,206) IN OTHER PROTOCOLS 
 
Compound:  
CP-675,206 
Compound Name (if applicable):  
Tremelimumab 
Sponsor 
AstraZeneca AB, 
151 85 Södertälje, Sweden 
US IND Number (if applicable):  
BB-10096  
EudraCT number: 
2008-000989-23 
Protocol Number:  
D4881C00024 
Phase:  
Phase 2  
Version and Date:  
Amendment 2  
26 December 2019 
 
Amendment 1 
04 March 2008 
 
Original Protocol 
02 August 2006 
 
 
This document contains confidential information belonging to AstraZeneca.  Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it 
for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, 
AstraZeneca must be promptly notified.  
 
 
 


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SUMMARY  
Indication:  
This trial will enroll subjects who received tremelimumab (previously known as CP-275,206) 
in other trials and are no longer going to receive tremelimumab in the other trial.  
Rationale:  
Tremelimumab is a fully human monoclonal antibody. It binds to the CTLA4 molecule, 
which is expressed on the surface of activated T lymphocytes. The binding of CTLA4 to its 
target ligands (B7-1 and B7-2) provides a negative regulatory signal, which limits T-cell 
activation.  Tremelimumab antagonizes binding of CTLA4 to B7 ligands and enhances 
human T-cell activation as demonstrated by increased cytokine (interleukin-2, interferon-
gamma) production in vitro in whole blood or peripheral blood mononuclear cells cultures.  
Tremelimumab is thought to stimulate subjects’ immune systems to attack their tumors by 
blocking a negative regulatory signal, as mentioned above.    
The anti-tumor activity of antibodies to CTLA4 has been demonstrated in a variety of murine 
tumor models. Tremelimumab has also been shown to induce durable tumor responses in 
subjects with metastatic melanoma in Phase 1 and Phase 2 clinical studies.    
More complete information is available in the current tremelimumab Investigator Brochure.  
Objectives:   
Primary Objective  
x 
To allow access to tremelimumab for subjects who received tremelimumab in other trials  
Secondary Objectives  
x 
To follow long-term survival and tumor status of subjects treated with tremelimumab in 
other trials  
x 
To monitor the safety and tolerability of tremelimumab  
 
Trial Design:  
This is a multi-center, international, open label study.  Eligible subjects are those who have 
received tremelimumab in another protocol but are no longer going to receive tremelimumab 
in the other trial.  All subjects who are enrolled in this trial will have the opportunity to 
receive tremelimumab.  Doses may be delayed under certain circumstances at the discretion 
of the investigator.  Subjects not receiving tremelimumab should be seen in the clinic or 
contacted at least every 6 months to determine their tumor status until the time of final 
analysis.    


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Endpoints:  
Safety Endpoints  
x 
Serious adverse events  
x 
Grade 3 or 4 tremelimumab-related adverse events  
x 
Immune-mediated adverse events  
x 
Hypersensitivity reactions to tremelimumab  
 
Efficacy Endpoints  
x 
Tumor status: alive with disease (AWD) or no evidence of disease (NED)  
x 
Survival  
 
Trial Treatments:  
Subjects who received a single dose of tremelimumab or who received 15 mg/kg every 90 
days in another study will receive intravenous administration of tremelimumab at a dose of 
15 mg/kg on Day 1 of each 90-day cycle.  To allow for possible change in body weight over 
time, subjects should be weighed within 10 days prior to each cycle and the administered 
dose of tremelimumab should be recalculated.  
Subjects who have been receiving a different dosing regimen of tremelimumab in a prior 
study may have the option of continuing with their prior dosing regimen or switching to the 
regimen of 15 mg/kg each 90 days.  
For subjects on a 90-day (or 3-month) dosing regimen, doses should not be given less than 86 
days from the previous dose.  For subjects on other dosing schedules, doses should not be 
given more than 2 days prior to the scheduled dose.   
Doses may be delayed under certain circumstances at the discretion of the investigator: 
x 
Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related AE. 
x 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing will 
resume as soon as feasible.  
 
Subjects not receiving tremelimumab should be seen in the clinic or contacted at least every 6 
months to determine their tumor status until the time of the final analysis.    
 
 


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Statistical Methods:  
Sample Size  
The number of subjects enrolled in this study will be determined by the number of subjects 
who received tremelimumab in other tremelimumab trials who wish to participate and who 
meet the eligibility criteria.   
No statistical methods will be employed to test a specific hypothesis in this study.  Only 
descriptive statistics will be provided for safety (number and percentage of subjects with 
adverse events) and survival (median, range, 95 percent confidence interval) end-points. 
 
 


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Table 1 
Schedule of Activities 
D4881C00024 
 
 
First Cycle 1  
Subsequent Cycles  
Follow-Up Off  
Tremelimumab  
Treatment 10  
Protocol Activities  
Prior to  
Enrollment 
Up to 10 
days  
before 
dose  
Day 1  
Within 10 
days prior to 
Day 1 of 
next cycle  
Day 1 or 
up to 72 
hours  
before 
dose  
Within 10 
days prior 
to next 
dose 
90 Days 
post-dose 
 
Every 6 
Months 
SCREENING/BASELINE  
  
  
  
  
  
  
  
  
Informed Consent 2  
X  
  
  
  
  
  
  
  
Contraception Counseling 3  
X  
  
  
  
  
  
  
  
Demographics  
X  
  
  
  
  
  
  
  
Medical History  
X  
  
  
  
  
  
  
  
SAFETY ASSESSMENTS  
  
  
  
  
  
  
  
  
Adverse Event  
Assessment 4  
  
  
Post-dose 
  
X  
  
X  
  
Review  
Concomitant Medications 5  
  
  
X  
  
X  
  
  
  
Weight  
  
X  
  
X  
  
X  
  
  
Vital Signs 6  
  
  
X  
  
X  
  
  
  
Pregnancy Test 7  
  
X  
  
X  
  
X  
  
  
Laboratory Assessments 8  
  
X  
  
X  
  
X  
  
  
STUDY TREATMENT  
  
  
  
  
  
  
  
  
Review Redosing Criteria  
  
  
X  
  
X  
  
  
  
Tremelimumab 
Administration  
  
  
X  
  
X  
  
  
  
SURVIVAL AND TUMOR 
STATUS  
  
  
  
  
  
  
  
  
Record Tumor Assessment 9  
  
X  
  
X  
  
X  
  
X  
FU for survival 10  
  
  
  
  
  
  
  
X 
  
 
 
 
 
 
 


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Footnotes to Schedule of Activities:    
1. Cycle: For subjects on a 90-day (or 3-month) dosing regimen, doses should not be given less than 86 days 
from the previous dose.  For subjects on other schedules, doses should not be given more than 2 days 
prior to the scheduled dose.  
2. Informed Consent: All subjects must sign an informed consent document prior to any study-related 
procedures that are not considered standard of care.  
3. Contraception Counseling:  All women of childbearing potential must agree to practice a form of effective 
contraception for 12 months following any dose of study drug.  
4. Adverse Event Assessment: Following the first dose, serious adverse events, tremelimumab-related grade 
3 and 4 events, immune-mediated adverse events, and hypersensitivity reactions to tremelimumab should 
be assessed and documented during the study reporting period. See Section 8.2, Reporting Period.  All 
reported study drug-related adverse events must be followed until the event has resolved, returned to 
baseline or has been deemed irreversible, or until the subject dies.    
5. Concomitant Medications:  Review medications taken by the subject since the last visit to determine 
whether treatment with tremelimumab is contraindicated.  See Section 5.3, Concomitant Medications.  
6. Vital Signs:  Vital signs, including temperature, blood pressure (sitting), and heart rate.  During 
tremelimumab infusions, routine monitoring of the subjects’ blood pressure, heart rate, and temperature 
should be recorded prior to treatment and monitored as needed during drug infusion and for 
approximately 1 hour post-infusion. Patients experiencing symptoms or changes in their vital signs should 
be monitored more frequently as needed   
7. Pregnancy Test: For women of childbearing potential.  Serum or urine.  Results must be available prior to 
dosing.  Pregnancy tests may also be repeated during the study as per request of IEC/IRBs or if required 
by local regulations.  Subjects who become pregnant must not receive further treatment while they are 
pregnant.  
8. Laboratory Assessments:   Blood Chemistry: Lipase, Amylase, AST (SGOT), ALT (SGPT), 
Alkaline Phosphatase (ALP),  
Gamma-Glutamine Transferase (GGT), Lactic Acid Dehydrogenase (LDH)    
Thyroid Function: T3, T4, TSH   
Hematology: WBC with differential count and Absolute Neutrophil Count (ANC), RBC count, 
Hemoglobin, Hematocrit, Platelet Count  
9. Tumor Assessment:  The results of any tumor assessments should be reviewed, and the tumor status (NED 
or AWD) and date of assessment should be recorded. If the patient begins a new treatment for their  
tumor, the start date and type of treatment will be recorded on the CRF. See Section 7.4 Tumor 
Assessments.  
10. Follow-Up:  Subjects (or their physicians) should be seen or contacted at least every 6 months to collect 
information on date of death, cause of death, and tumor status.  If the patient begins a new treatment for 
their tumor, the start date and type of treatment will be recorded on the CRF.  If there is evidence of 
continuing study drug-related toxicity, the subject should continue to be followed at intervals deemed 
medically appropriate by the investigator.  This information may be obtained by telephone interview.  
  
 
 
 


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 TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................ 10 
1.1 
Background ....................................................................................................... 10 
1.1.1 
Rationale for this Trial ...................................................................................... 10 
1.1.2 
Clinical Data for Tremelimumab ....................................................................... 10 
1.2 
Tremelimumab Risks and Precautions ............................................................... 10 
2 
TRIAL OBJECTIVES ....................................................................................... 11 
2.1 
Primary Objective ............................................................................................. 11 
2.2 
Secondary Objectives ........................................................................................ 11 
3 
TRIAL DESIGN ............................................................................................... 11 
3.1 
Endpoints .......................................................................................................... 11 
3.1.1 
Safety Endpoints ............................................................................................... 11 
3.1.2 
Efficacy Endpoints ............................................................................................ 12 
4 
SUBJECT SELECTION ................................................................................... 12 
4.1 
Inclusion Criteria............................................................................................... 12 
4.2 
Exclusion Criteria ............................................................................................. 12 
4.3 
Randomization Criteria ..................................................................................... 12 
4.4 
Life Style Guidelines ......................................................................................... 12 
5 
TRIAL TREATMENTS .................................................................................... 13 
5.1 
Allocation to Treatment ..................................................................................... 13 
5.2 
Drug Supplies ................................................................................................... 13 
5.2.1 
Formulation and Packaging ............................................................................... 13 
5.2.2 
Preparation and Dispensing ............................................................................... 14 
5.2.3 
Administration .................................................................................................. 14 
5.2.3.1 
Dose Delays and Re-Dosing Criteria for Tremelimumab ................................... 14 
5.2.3.2 
Stopping Rules for Adverse Events ................................................................... 15 
5.2.4 
Compliance ....................................................................................................... 15 
5.2.5 
Drug Storage and Drug Accountability .............................................................. 15 
5.2.6 
Treatment after the End of the Study ................................................................. 15 
5.3 
Concomitant Medication(s) ............................................................................... 16 
5.4 
Management of Toxicity and Dose Modification Information of 
Tremelimumab .................................................................................................. 17 
5.4.1 
Management of Hypersensitivity Reactions to Tremelimumab .......................... 17 
5.4.2 
Medication Errors ............................................................................................. 18 
6 
TRIAL PROCEDURES .................................................................................... 19 
6.1 
Screening .......................................................................................................... 19 
6.2 
Treatment Period ............................................................................................... 19 
6.3 
End of Treatment .............................................................................................. 19 
6.4 
Follow-up Assessments ..................................................................................... 20 


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7 
ASSESSMENTS ............................................................................................... 20 
7.1 
Baseline Demographics ..................................................................................... 21 
7.2 
Subject History.................................................................................................. 21 
7.3 
Laboratories ...................................................................................................... 21 
7.4 
Tumor Assessments .......................................................................................... 21 
8 
ADVERSE EVENT REPORTING .................................................................... 21 
8.1 
Adverse Events ................................................................................................. 21 
8.2 
Reporting Period ............................................................................................... 22 
8.2.1 
Immediate Reporting of Serious Adverse Events ............................................... 22 
8.2.2 
Reporting of Adverse Events on Case Report Forms ......................................... 22 
8.3 
Definition of an Adverse Event ......................................................................... 22 
8.4 
Abnormal Test Findings .................................................................................... 23 
8.5 
Serious Adverse Events ..................................................................................... 23 
8.6 
Hospitalization .................................................................................................. 24 
8.7 
Severity Assessment .......................................................................................... 25 
8.8 
Causality Assessment ........................................................................................ 26 
8.9 
Exposure in Utero ............................................................................................. 26 
8.10 
Withdrawal Due to Adverse Events (See also End of Treatment, Section 6.3) ... 27 
8.11 
Eliciting Adverse Event Information ................................................................. 27 
8.12 
Reporting Requirements .................................................................................... 28 
8.12.1 
Serious Adverse Event Reporting Requirements ................................................ 28 
8.12.2 
Non-Serious Adverse Event Reporting Requirements ........................................ 28 
9 
DATA ANALYSIS/STATISTICAL METHODS .............................................. 29 
9.1 
Sample Size Determination ............................................................................... 29 
9.2 
Efficacy Analysis .............................................................................................. 29 
9.3 
Safety Analysis ................................................................................................. 29 
9.4 
Interim Analysis ................................................................................................ 29 
9.5 
Data Monitoring Committee .............................................................................. 29 
10 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 29 
11 
DATA HANDLING AND RECORD KEEPING .............................................. 30 
11.1 
Case Report Forms/Electronic Data Record ....................................................... 30 
11.2 
Record Retention............................................................................................... 30 
12 
ETHICS ............................................................................................................ 31 
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ........... 31 
12.2 
Ethical Conduct of the Trial .............................................................................. 31 
12.3 
Subject Information and Consent ....................................................................... 31 
13 
DEFINITION OF END OF TRIAL ................................................................... 31 
13.1 
End of Trial in a Member State ......................................................................... 31 


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13.2 
End of Trial in all Participating Countries ......................................................... 32 
14 
SPONSOR DISCONTINUATION CRITERIA ................................................. 32 
15 
PUBLICATION OF TRIAL RESULTS ............................................................ 32 
16 
REFERENCES ................................................................................................. 33 
LIST OF TABLES 
Table 1 
Schedule of Activities ................................................................................ 5 
Table 2 
Examples of Allowed Concomitant Anti-Cancer Therapies ...................... 16 
 
LIST OF APPENDICES 
Appendix 1 
List of Abbreviations................................................................................ 34 
Appendix 2 
CLINICAL PROTOCOL AMENDMENT 1 ............................................ 35 
Appendix 3 
CLINICAL PROTOCOL AMENDMENT 2 ............................................ 43 
Appendix 4 
Medication Error ...................................................................................... 54 
 
  
 


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1 
INTRODUCTION  
1.1 
Background 
Rationale for tremelimumab (previously known as CP-675,206) in Melanoma and Other 
Tumors:  
Tremelimumab is a fully human monoclonal antibody.  It binds to the CTLA4 molecule, 
which is expressed on the surface of activated T lymphocytes.  The binding of CTLA4 to its 
target ligands (B7-1 and B7-2) provides a negative regulatory signal, which limits T-cell 
activation. Tremelimumab antagonizes binding of CTLA4 to B7 ligands and enhances human 
T-cell activation as demonstrated by increased cytokine (interleukin-2, interferon-gamma) 
production in vitro in whole blood or peripheral blood mononuclear cells cultures.  
Tremelimumab is thought to stimulate subjects’ immune systems to attack their tumors by 
blocking a negative regulatory signal, as mentioned above.    
The anti-tumor activity of antibodies to CTLA4 has been demonstrated in a variety of murine 
tumor models. Tremelimumab has also been shown to induce durable tumor responses in 
subjects with metastatic melanoma in Phase 1 and Phase 2 clinical studies.    
1.1.1 
Rationale for this Trial 
Tremelimumab has been and will be tested in multiple clinical trials. Each of the protocols 
allows the administration of a limited number of doses of tremelimumab.  This rollover 
protocol will allow continued access to tremelimumab for subjects who have received it in 
other trials, until this agent becomes commercially available or development is discontinued.  
Some subjects who were treated in early phase trials have experienced long term survival 
and/or durable tumor responses.1 This protocol will allow long-term follow-up of subjects for 
survival and tumor status.  
1.1.2 
Clinical Data for Tremelimumab  
The results of previous clinical trials are summarized in the current Investigators Brochure.   
1.2 
Tremelimumab Risks and Precautions 
Risks with tremelimumab monotherapy include, but are not limited to, gastrointenstinal 
effects (colitis, diarrhea, enterocolitis, intestinal perforation, and large intestinal perforation); 
endocrine disorders (hypo- and hyperthyroidism, hypophysitis, and adrenal insufficiency); 
skin effects (rash and pruritus); lipase and/or amylase elevations and clinical manifestations 
of pancreatitis; hepatic events (including immune-mediated hepatitis and liver enzyme 
elevations); pneumonitis and ILD; neurotoxicity (including encephalitis, peripheral motor 
and sensory neuropathies, and Guillain-Barré syndrome); thrombocytopenia, anemia, and 
neutropenia; infusion-related reactions and hypersensitivity/anaphylactic reactions; renal 
events (including nephritis/autoimmune nephritis and acute kidney injury); autoimmune 


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arthritis, Sjogren’s syndrome; giant cell temporal arteritis, and ulcerative colitis; and 
hyperglycemia and diabetes mellitus.  
For information on all identified and potential risks for tremelimumab, please always refer to 
the current version of the tremelimumab IB. 
In monotherapy clinical studies, AEs reported at an incidence of > 20% include events such 
as diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, and vomiting. Approximately 
16% of patients experienced an AE that resulted in permanent discontinuation of 
tremelimumab, and approximately 45% of patients experienced an SAE. Please see the 
current version of the tremelimumab IB for a detailed summary of tremelimumab 
monotherapy data, including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
tremelimumab program. 
 
2 
TRIAL OBJECTIVES  
2.1 
Primary Objective 
x To allow access to tremelimumab for subjects who received tremelimumab in other 
trials  
2.2 
Secondary Objectives 
x To follow long-term survival and tumor status of subjects treated with tremelimumab 
in other trials  
x To monitor the safety and tolerability of tremelimumab  
3 
TRIAL DESIGN  
This is a multi-center, international, open label study.  Eligible subjects are those who have 
received tremelimumab in another protocol but are no longer going to receive tremelimumab 
in the other trial.  This protocol will allow continued access to tremelimumab for subjects 
who have received it in other trials, until this agent becomes commercially available or 
development is discontinued.  
3.1 
Endpoints 
3.1.1 
Safety Endpoints 
x Serious adverse events 
x Grade 3 or 4 tremelimumab-related adverse events 
x Immune-mediated adverse events 
x Hypersensitivity reactions to tremelimumab 
 


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3.1.2 
Efficacy Endpoints 
x Tumor status: alive with disease (AWD) or no evidence of disease (NED)  
x Survival  
 
4 
SUBJECT SELECTION  
It is expected that patients in ongoing trials will not be eligible except in extraordinary 
circumstances.  
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.  
4.1 
Inclusion Criteria   
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial:  
1 
The subject received tremelimumab in another protocol.   
2 
Females of childbearing potential must agree to practice a form of effective 
contraception for 12 months following any dose of study drug.  The definition of 
effective contraception will be based on the judgment of the investigator.    
3 
Subject must be willing and able to provide written informed consent and to comply 
with scheduled visits and other trial procedures.  
 
4.2 
Exclusion Criteria  
There are no exclusion criteria.    
Note that subjects must meet all of the redosing criteria (Section 5.2.3.1 and 5.2.3.2) in order 
to receive any dose of tremelimumab in this study.  
4.3 
Randomization Criteria   
The Sponsor must approve the enrollment of each patient.  Subjects must withdraw from 
treatment in their other tremelimumab trial prior to enrollment in this study.  
4.4 
Life Style Guidelines   
Females of childbearing potential must agree to practice a form of effective contraception for 
12 months following any dose of study drug.  The definition of effective contraception will 
be based on the judgment of the investigator.   


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5 
TRIAL TREATMENTS  
Subjects who received a single dose of tremelimumab or who received 15 mg/kg every 90 
days in another study will receive intravenous administration of tremelimumab at a dose of 
15 mg/kg on Day 1 of each 90-day cycle. To allow for possible change in body weight over 
time, subjects should be weighed within 10 days prior to each cycle and the administered 
dose of tremelimumab should be recalculated.  
Subjects who have been receiving a different dosing regimen of tremelimumab in a prior 
study may have the option of continuing with the prior dosing regimen or of switching to the 
regimen of 15 mg/kg each 90 days.  
For subjects on a 90-day or 3-month dosing regimen, doses should not be given less than 86 
days from the previous dose.  For subjects on other schedules, doses should not be given 
before 2 days prior to the scheduled dose.   
Doses may be delayed under certain circumstances at the discretion of the investigator: 
x Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related AE. 
x If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.   
 
Subjects not receiving tremelimumab should be seen in clinic or contacted at least every 6 
months to record their tumor status until the time of the final analysis.    
 
5.1 
Allocation to Treatment  
This is an open label trial.  Allocation to study treatment will take place during the enrollment 
process. Please refer to the Study Manual for details.  
Subjects must withdraw from treatment in their other tremelimumab trial prior to enrollment 
in this study.  
5.2 
Drug Supplies  
5.2.1 
Formulation and Packaging   
Tremelimumab is supplied as a sterile solution, packaged in 20 mL clear glass vials with a 
rubber stopper and an aluminum seal.  Each vial contains 20 mg/mL of tremelimumab (with 
a nominal fill of 400 mg per vial), in 20 mM Histidine buffer, pH 5.5, with 84 mg/mL 
Trehalose dehydrate, 0.2 mg/ml Polysorbate 80 and 0.1 mg/mL diSodiumEDTA dehydrate.   
The standard supply of tremelimumab is delivered to the investigator site in a white carton 
with 4 vials of tremelimumab within foam inserts. The vial and carton labels identify 
tremelimumab as “tremelimumab (clonal), 20 mg/ml IV VialSolution 400 mg/vial”.  The 


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lastest formulation, packaging and labeling will be provided in an updated Investigational 
Product Manual. Labels for the investigational product will be prepared in accordance with 
Good Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill 
GMP Annex 13 requirements for labeling. Label text will be translated into local languages, 
as required. 
5.2.2 
Preparation and Dispensing  
Specific preparation instructions are provided in the most current version of the 
Investigational Product Manual.  A member of the Pharmacy or Clinical Research Unit staff 
with appropriate training and experience must prepare all supplies.  
5.2.3 
Administration  
Tremelimumab may be diluted with sterile normal saline (supplied by the investigator) prior 
to administration according to specific instructions in the Investigational Product Manual.  
Tremelimumab should be administered open label as an intravenous solution followed by 
observation.  Specific dosing and administration instructions are provided in the most current 
version of the Investigational Product Manual.  
Although tremelimumab is a fully human monoclonal antibody, immunogenicity remains a 
possibility, so acute and subacute hypersensitivity reactions are possible. The subjects’ blood 
pressure, heart rate, and temperature should be recorded prior to treatment and monitored as 
needed during drug infusion and for approximately 1-hour post-infusion.    
Medications to treat hypersensitivity reactions should be available, such as IV saline, 
acetaminophen, and emergency drugs, including subcutaneous epinephrine, 
diphenhydramine, methylprednisolone, and nebulized albuterol.  See Section 5.4.1 for 
guidelines on management of hypersensitivity reactions.  If a hypersensitivity reaction 
attributed to tremelimumab occurs, the investigator must report this to the AstraZeneca study 
physician.    
5.2.3.1 
Dose Delays and Re-Dosing Criteria for Tremelimumab  
The initiation of a cycle may be delayed to allow recovery from treatment-related toxicity.  
There is a concern that subjects with active brain metastases may be at risk for increased 
intracranial pressure if treated with tremelimumab. Subjects with brain metastases must not 
receive tremelimumab until after the metastases have been adequately treated with surgery 
and/or radiation.  
Subjects must not receive tremelimumab while pregnant or breast-feeding. Females of 
childbearing potential must have a negative serum or urine pregnancy test within 10 days 
prior to each dose. Females who have undergone surgical sterilization or who have been 
postmenopausal for at least 2 years are not considered to be of childbearing potential. 
For details on dosing delays and re-dosing criteria, please refer to the Dosing Modification 
and Toxicity Management Guidelines, which is delivered as an Annex document.  


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5.2.3.2 
Stopping Rules for Adverse Events  
Subjects who experience any of the following adverse events at any time during the previous 
cycle must not receive further dosing with tremelimumab unless the investigator discusses 
the case with the AstraZeneca study physician and has provided a written action plan.  
• 
Hypersensitivity to tremelimumab, Grade 3 (see Section 5.4.1)  
• 
Hypersensitivity to tremelimumab, Grade 2, and symptoms reappear after infusion 
restarted  
• 
Melanoma associated retinopathy, Grade 2 or above  
• 
Uveitis, Grade 2 or above  
• 
Diverticulitis  
• 
Immune-mediated thrombocytopenia  
5.2.4 
Compliance  
Tremelimumab will be administered in the clinic by study personnel.  The dose administered 
will be recorded in the subject records and in the Case Report Form (CRF).  
5.2.5 
Drug Storage and Drug Accountability   
Tremelimumab must be stored at 2°C to 8°C (36°F to 46°F).  It is important that the 
formulation is not frozen.  The investigator or an approved representative (e.g., pharmacist) 
must ensure that all study drug is stored in a secured area, under recommended storage 
conditions and in accordance with applicable regulatory requirements.    
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational product(s). Drug accountability forms used must identify 
the investigational product, including batch or code numbers, and account for its disposition 
on a subject-by-subject basis, including specific dates and quantities. The forms must be 
signed by the individual who dispensed the drug, and copies must be provided to 
AstraZeneca.  
At the end of the trial, AstraZeneca will provide instructions as to disposition of any unused 
investigational product. If AstraZeneca authorizes destruction at the trial site, the investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by AstraZeneca.  
Destruction must be adequately documented.  
5.2.6 
Treatment after the End of the Study 
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving tremelimumab therapy up to the time that they discontinue the treatment for 
whatever reason (see Section 6.3). At the time of the final analysis and thereafter: 


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x Assessment will revert to standard of care at particular site 
x There would be no more data collection except for SAE reporting. Clinical study 
database would be closed 
x Paper form process would be used for SAE reporting. All SAEs, overdoses and 
pregnancies would be reported until 90 days after last dose 
x Drug dispensation and reconciliation will be handled by site on each patient's visit 
x Study would be opened until last patient treated. Final last subject last visit will be 
defined as last patient's treatment discontinuation 
 
5.3 
Concomitant Medication(s)  
Concomitant medications to treat the subject’s primary malignancy are not allowed unless 
these drugs were allowed in the subject’s original protocol; AstraZeneca does not supply 
these concomitant medications for this protocol.  Examples of allowed concomitant anti-
cancer therapy include:  
Table 2 
Examples of Allowed Concomitant Anti-Cancer Therapies 
Protocol #  
Indication  
Allowed Anti-Cancer Therapy  
A3671006  
Breast Cancer  
exemestane (Aromasin)  
Patients from Renal Cell Carcinoma studies should not receive sunitinib within 3 months of a 
dose of tremelimumab, as acute renal failure has been reported with combination therapy of 
tremelimumab and sunitinib. It is unknown whether there could be a safety issue with 
combination of tremelimumab and other tyrosine kinase inhibitors.  
Since the anti-tumor activity of tremelimumab is thought to involve activation of the immune 
system, the use of immunosuppressive drugs should be avoided if alternative treatment is 
available. However, it is recognized that subjects may require immunosuppressive drugs such 
as corticosteroids for management of underlying disease, treatment-related toxicity, or 
unrelated conditions. Topical and inhaled corticosteroids in standard doses are not expected 
to be immunosuppressive.  
It is highly recommended that subjects not receive anti-infective immunizations for at least 6 
months after dosing with tremelimumab, given that the effect of the immunization has not 
been explored under conditions of CTLA4 blockade.    
Concommitant medications should not be recorded on the Case Report Form unless they 
were administered to treat a reportable adverse event (See Section 8.1).  


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5.4 
Management of Toxicity and Dose Modification Information of 
Tremelimumab   
Comprehensive toxicity management guidelines have been developed to assist investigators 
with the recognition and management of toxicities associated with the use of the immune-
checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor) and tremelimumab (CTLA4 
inhibitor).  Given the similar underlying mechanisms of toxicities observed with these two 
compounds, these guidelines are applicable to the management of patients receiving either 
drug as monotherapy or in combination.  Additionally, these guidelines are applicable when 
either drug is used alone or in combination and is administered concurrently or sequentially 
with other anti-cancer drugs (i.e. antineoplastic chemotherapy, targeted agents), as part of a 
protocol specific treatment regimen.  The TMGs provide information for the management of 
immune-mediated reactions, infusion-related reactions, and non-immune mediated reactions 
that may be observed with checkpoint inhibitor monotherapy or combination checkpoint 
inhibitor regimens, with specific instructions for dose modifications (including 
discontinuations) and treatment interventions.  Investigators are advised however to use local 
practice guidelines and consult local references for the management of toxicities observed 
with other cancer treatment. The most current version of the TMGs entitled “Dosing 
Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, 
and Non-Immune Mediated Reactions (MEDI4736) Monotherapy or Combination Therapy 
with Tremelimumab or Tremelimumab Monotherapy” is provided to the investigative site as 
an Annex document and is maintained within the Site Master File.  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
imAE diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related. In addition, there are certain circumstances in which 
tremelimumab should be permanently discontinued (see Section 5.2.3.2 of this protocol and 
the Dosing Modification and Toxicity Management Guidelines).  Following the first dose of 
IP, subsequent administration of tremelimumab can be modified based on toxicities observed 
as described in the Dosing Modification and Toxicity Management Guidelines. These 
guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to tremelimumab monotherapy  regimen by the reporting 
Investigator.  
Dose reductions are not permitted. In case of doubt, the Investigator should consult with 
the Study Physician. 
5.4.1 
Management of Hypersensitivity Reactions to Tremelimumab  
In case of hypersensitivity reactions, the Investigator should institute treatment measures 
deemed medically appropriate and notify the AstraZeneca Clinician of the event.  The 
following treatment recommendations may be applicable and can be adopted at the 
investigator’s judgment:3, 4   


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CTCAE v.3.0 Grade 1 Allergy (transient flushing or rash, drug fever <38°C):  
x Supervise at the bedside.  
CTCAE v.3.0 Grade 2 Allergy (urticaria, drug fever ˰38°C, and/or asymptomatic 
bronchospasm):  
x Interrupt the infusion of tremelimumab and disconnect infusion tubing from subject.  
x Administer IV antihistamines (diphenhydramine 25-50 mg and ranitidine 50 mg or 
cimetidine 300 mg).  
x After recovery of symptoms, resume the infusion at half the initial infusion rate.  If no 
further symptoms appear, complete the administration of the dose.  If symptoms 
reappear, stop infusion and discontinue the subject from treatment.  
x CTCAE v.3.0 Grade 3 or 4 Allergy (symptomatic bronchospasm requiring parenteral 
medication(s) with or without urticaria; allergy-related edema/angioedema; 
hypotension; anaphylaxis):  
x Stop the infusion of tremelimumab and disconnect infusion tubing from subject.  
x Administer epinephrine (1:10,000) in 3.5 to 5 mL IV boluses (no more than 6 doses).  
x Administer IV antihistamine (diphenhydramine 50 mg IV push).  
x If wheezing persists: 0.35 mL of inhaled albuterol or other bronchodilators.  
x Consider methylprednisolone 30 to 60 mg IV push, which may prevent recurrent or 
ongoing reactions. 
x Discontinue the subject from treatment    
5.4.2 
Medication Errors 
The definition of a Medication Error can be found in Appendix 4. 
 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, i.e., immediately 
but no later than 24 hours after he/she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.2) and within 30 days for all other 
medication errors. 


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6 
TRIAL PROCEDURES  
6.1 
Screening  
Informed Consent  
All subjects being considered for this study must sign an informed consent document prior to 
any study-related procedures that are not considered to be standard of care and prior to 
receiving study drug.    
Screening assessments are outlined in  
Table 1.  
6.2 
Treatment Period   
All assessments for each cycle are outlined in  
Table 1.  
6.3 
End of Treatment  
Subjects may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons.  If a subject does not return for a scheduled visit, every effort 
should be made to contact the subject. In any circumstance, every effort should be made to 
document subject outcome, if possible. The investigator should inquire about the reason for 
withdrawal, request the subject to return for a final visit, if applicable, and follow-up with the 
subject regarding any unresolved adverse events.  
The investigator must determine the primary reason for discontinuation from treatment in this 
study:     
1. Withdrawal due to adverse event. When a discontinuation is due to a serious adverse 
event (SAE), the serious adverse event must be reported in accordance with the 
reporting requirements and the discontinuation must be reported immediately to the 
AstraZeneca clinical monitor or his/her representative. 
2. Disease progression, unless there is reasonable evidence of clinical benefit to justify 
continuation on protocol. 
3. Subjects may decide to withdraw from treatment at any time. Subjects who withdraw 
from treatment should be followed for tumor assessment and survival. If the subject 
also withdraws consent for disclosure of future information, no further evaluations 
should be performed and no additional data should be collected. The sponsor may 
retain and continue to use any data collected before such withdrawal of consent. 
4. Subjects who begin new investigational therapy, chemotherapy, or other therapy for 
his/her disease must not receive further treatment. 


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5. Subjects may be discontinued from the study for poor compliance at the discretion of 
the investigator. 
6. The investigator should withdraw the subject at any time if he/she believes it is in the 
subject’s best interest to do so. 
7. The subject is lost to follow-up. 
8. The study is terminated by the sponsor. 
Data collection will be stopped, the database locked and the available data summarized once 
eligible patients are no longer available to enter the trial, and all patients have had the 
opportunity to be followed up for approximately 9.5 years.  At this time AstraZeneca will 
continue to supply open-label drug to these patients, up to the time that they discontinue the 
treatment for whatever reason. 
6.4 
Follow-up Assessments  
The post treatment follow-up assessments are outlined in  
Table 1.  
Subjects will be followed for at least 90 days after the last dose of study drug for reportable 
adverse events (See Section 8).  If there is evidence of continuing study drug-related toxicity, 
the subject should continue to be followed at intervals deemed medically appropriate by the 
investigator.  
After withdrawal from study treatment, subjects (or their physicians) should be seen or 
contacted at least every 6 months to collect information on date of death, cause of death, and 
tumor status. This information may be obtained by telephone interview.   
In the event a subject is unable to return to the clinic for the follow-up visit, telephone contact 
with the subject (or their physician) to assess adverse events is expected.  If laboratory 
assessments are needed to follow-up unresolved adverse events, retrieval of assessments 
performed at an institution local to the subject is acceptable.  
The outcome of reportable adverse events with a date of onset during the study period should 
be reevaluated, and any new reportable adverse events should be recorded.  All serious 
adverse events, and those reportable non-serious adverse events assessed by the investigator 
as possibly related to study drug should continue to be followed even after subject 
withdrawal from study.  These adverse events should be followed until they resolve or until 
the investigator assesses them to be “chronic” or “stable.”  


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7 
ASSESSMENTS  
The minimum required screening, on-study and follow-up subject assessments are 
summarized in the Schedule of Activities ( 
Table 1).  
7.1 
Baseline Demographics  
Demographic data will include date of birth.  The subject’s prior tremelimumab study 
number and prior subject ID number in that study will be noted on the Case Report Form 
(CRF).  
7.2 
Subject History  
The subjects’ prior history will include their cancer history, medical history, and dates of 
first and most recent tremelimumab administration.  
7.3 
Laboratories  
Laboratory assessments will include the following: lipase and amylase; liver function tests 
including AST (SGOT), ALT (SGPT), Alkaline Phosphatase (ALP), Gamma-Glutamine  
Transferase (GGT), lactic acid dehydrogenase (LDH); thyroid function tests including T3,  
T4, TSH., hematology tests including WBC with differential count and Absolute Neutrophil 
Count (ANC), RBC count, Hemoglobin, Hematocrit, and Platelet Count.   Investigators 
should review the results of all laboratory tests and use them to make re-dosing decisions.    
All women of childbearing potential must have a serum or urine pregnancy test completed 
within 10 days prior to each administration of tremelimumab.  The pregnancy test must be 
negative, and the results must be available prior to dosing.  Pregnancy tests may also be 
repeated during the study as per request of IEC/IRBs or if required by local regulations.   
Results of routine laboratory assessments will not be collected on the CRFs.  
7.4 
Tumor Assessments  
The subject’s tumor should be assessed according to the investigator’s usual practice.  The 
subject’s tumor status (alive with disease (AWD) or no evidence of disease (NED) and the 
date and type of the most recent tumor assessment should be recorded at each dosing visit 
and follow-up visit.    
Tumor status does not need to be recorded in the CRF for this protocol if it is being recorded 
in the CRFs as part of the post-treatment follow-up for the subject’s prior protocol.  
8 
ADVERSE EVENT REPORTING  
8.1 
Adverse Events  
The following adverse events must be reported as described in the subsequent sections.  


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• 
Serious adverse events  
• 
Grade 3 or 4 tremelimumab-related adverse events  
• 
Immune-mediated adverse events  
• 
Hypersensitivity reactions to tremelimumab  
For all adverse events which meet these criteria, the investigator must pursue and obtain 
information adequate both to determine the outcome of the adverse event and to assess 
whether it meets the criteria for classification as a serious adverse event (See Section 8.5) 
requiring immediate notification to AstraZeneca or its designated representative.  For all 
reported adverse events, sufficient information should be obtained by the investigator to 
determine the causality of the adverse event.  The investigator is required to assess causality.  
For adverse events with a causal relationship to the investigational product, follow-up by the 
investigator is required until the event or its sequelae resolve or stabilize at a level acceptable 
to the investigator, and AstraZeneca concurs with that assessment.  
8.2 
Reporting Period  
8.2.1 
Immediate Reporting of Serious Adverse Events  
Serious adverse events require immediate notification to AstraZeneca or its designated 
representative beginning from the time that the subject provides informed consent for the 
study; and should be reported under the patient’s prior protocol until the patient receives 
investigational product in this study.  SAEs do not require notification if it has been at least 
90 days since the previous dose of tremelimumab, and at least 28 days since any study-
related procedures for the patient.  
8.2.2 
Reporting of Adverse Events on Case Report Forms  
Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of trial treatment.   
An adverse event does not need to be recorded in the CRF for this protocol if it is being 
recorded in the CRF for the patient’s prior protocol.  
If a subject begins a new anticancer therapy, the adverse event reporting period for non-
serious adverse events ends at the time the new treatment is started.  Death must be reported 
if it occurs during the serious adverse event reporting period after the last dose of 
investigational product, irrespective of any intervening treatment.  
8.3 
Definition of an Adverse Event  
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:    
x Abnormal test findings;  


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x Clinically significant symptoms and signs;  
x Changes in physical examination findings;  
x Hypersensitivity.  
Additionally, they may include the signs or symptoms resulting from:  
x Drug overdose;  
x Drug withdrawal;  
x Drug abuse;  
x Drug misuse;  
x Drug interactions;  
x Drug dependency; 
x Extravasation;  
x Exposure in utero.  
Worsening of signs and symptoms of the malignancy under trial should be reported as 
adverse events in the appropriate section of the CRF, providing they meet the reporting 
criteria in Section 8.1.  Disease progression assessed by measurement of malignant lesions on 
radiographs or other methods should not be reported as adverse events.  
8.4 
Abnormal Test Findings  
Abnormal objective test findings meeting the reporting criteria in Section 8.1 should also use 
the following criteria for determining whether an abnormal objective test finding should be 
reported as an adverse event:   
x Test result is associated with accompanying symptoms, and/or  
x Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or  
x Test result leads to a change in trial dosing or discontinuation from the trial, 
significant additional concomitant drug treatment, or other therapy, and/or  
x Test result is considered to be an adverse event by the investigator or sponsor.  
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.  


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8.5 
Serious Adverse Events  
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence 
at any dose that:  
x Results in death;  
x Is life-threatening (immediate risk of death);  
x Requires inpatient hospitalization or prolongation of existing hospitalization;  
x Results in persistent or significant disability/incapacity;  
x Results in congenital anomaly/birth defect.  
Progression of the malignancy under trial (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal during the trial or within the 
safety reporting period. Hospitalization due to signs and symptoms of disease progression 
should not be reported as an SAE. If the malignancy has a fatal outcome during the trial or 
within the safety reporting period, then the event leading to death must be recorded as an AE 
and as an SAE with CTC Grade 5 (see Section 8.7, Severity Assessment).  
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event. An important medical event may not be immediately life-
threatening and/or result in death or hospitalization. However, if it is determined that the 
event may jeopardize the subject and/or may require intervention to prevent one of the other 
outcomes listed in the definition above, the important medical event should be reported as 
serious.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.1  
8.6 
Hospitalization  
AEs reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to 
an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit).  
Hospitalization does not include the following:  
x Rehabilitation facilities;  
x Hospice facilities;  
 
1 21CFR 312.32  


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x Respite care (e.g., caregiver relief);  
x Skilled nursing facilities;  
x Nursing homes;  
x Routine emergency room admissions;  
x Same day surgeries (as outpatient/same day/ambulatory procedures).  
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself an SAE. Examples include:   
x Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition  
(e.g., for work-up of persistent pre-treatment lab abnormality); 
x Social admission (e.g., subject has no place to sleep); 
x Administrative admission (e.g., for yearly physical exam);  
x Protocol-specified admission during a clinical trial (e.g., for a procedure required by 
the trial protocol);  
x Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery);  
x Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.  
x Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.  
8.7 
Severity Assessment  
GRADE  
Clinical Description of Severity  
0   
No Change from Normal or Reference Range (This grade is not included in the 
Version 3.0 document but may be used in certain circumstances.)  
1  
MILD Adverse Event  
2  
MODERATE Adverse Event  


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3  
SEVERE Adverse Event  
4  
LIFE-THREATENING OR DISABLING Adverse Event  
5  
DEATH RELATED TO Adverse Event  
Note the distinction between the severity and the seriousness of an adverse event. A severe 
event is not necessarily a serious event. For example, a headache may be severe (interferes 
significantly with subject’s usual function) but would not be classified as serious unless it 
met one of the criteria for SAEs, listed above.  
8.8 
Causality Assessment  
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious).  An investigator’s causality assessment is the determination of whether 
there exists a reasonable possibility that the investigational product caused or contributed to 
an adverse event.  If the investigator’s final determination of causality is unknown and the 
investigator does not know whether or not investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes.  If the 
investigator’s causality assessment is “unknown but not related to investigational product”, 
this should be clearly documented on trial records.    
In addition, if the investigator determines a serious adverse event is associated with trial 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.  
8.9 
Exposure in Utero  
For investigational products within clinical trials and for marketed products, an exposure 
inutero (EIU) occurs if:  
1) a female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed to (eg, environmental exposure) the investigational product, or the 
female becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure);  
2) a male has been exposed, either due to treatment or environmental, to the 
investigational product prior to or around the time of conception and/or is exposed 
during the partner pregnancy (paternal exposure).  
If any trial subject or trial subject’s partner becomes or is found to be pregnant during the 
trial subject’s treatment with the investigational product, the investigator must submit this 
information to AstraZeneca on an Exposure in Utero Form.  In addition, the investigator must 
submit information regarding environmental exposure to a AstraZeneca product in a pregnant 
woman (eg, a nurse reports that she is pregnant and has been exposed to a cytotoxic product 
by inhalation or spillage) using the Exposure in Utero Form.  This must be done irrespective 
of whether an adverse event has occurred and within 24 hours of awareness of the pregnancy.  


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The information submitted should include the anticipated date of delivery (see below for 
information related to induced termination of pregnancy).  
Follow-up is conducted to obtain pregnancy outcome information on all Exposure in Utero 
reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination (ie, induced abortion) and then notify AstraZeneca 
of the outcome.  The investigator will provide this information as a follow up to the initial 
Exposure in Utero Form.  The reason(s) for an induced abortion should be specified.  An EIU 
report is not created when an ectopic pregnancy report is received since this pregnancy is not 
usually viable.  Rather, a serious adverse event case is created with the event of ectopic 
pregnancy.  
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus, stillbirth or neonatal death]), the investigator should 
follow the procedures for reporting serious adverse events.  
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth  
(ie, no minimum follow-up period of a presumably normal infant is required 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 test 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 be reported.  
8.10 
Withdrawal Due to Adverse Events (See also End of Treatment, 
Section 6.3)  
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page if it meets the protocol-specified criteria for reportable 
adverse events.    
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.  


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8.11 
Eliciting Adverse Event Information  
The investigator is to report all adverse events which meet the criteria for adverse event 
reporting in this trial (Section 8.1 including all directly observed adverse events and all 
adverse events spontaneously reported by the trial subject.  In addition, each trial subject will 
be questioned about adverse events.  
8.12 
Reporting Requirements  
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.  
All adverse events which meet the criteria for adverse event reporting in this trial (Section 
8.1) will be reported on the adverse event page(s) of the CRF.  An adverse event does not 
need to be recorded in the CRF for this protocol if it is being recorded in the CRF for the 
patient’s prior protocol.  It should be noted that the form for collection of serious adverse 
event information is not the same as the adverse event CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same 
adverse event term should be used on both forms.  Adverse events should be reported using 
concise medical terminology on the CRFs as well as on the form for collection of serious 
adverse event information.  
8.12.1 
Serious Adverse Event Reporting Requirements  
If a serious adverse event occurs, AstraZeneca is to be notified within 24 hours of awareness 
of the event by the investigator.  In particular, if the serious adverse event is fatal or life-
threatening, notification to AstraZeneca must be made immediately, irrespective of the extent 
of available adverse event information.  This timeframe also applies to additional new 
information (follow-up) on previously forwarded serious adverse event reports as well as to 
the initial and follow-up reporting of Exposure in Utero cases.    
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient trial subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.  
For all serious adverse events, the investigator is obligated to pursue and provide information 
to AstraZeneca in accordance with the timeframes for reporting specified above.  In addition, 
an investigator may be requested by AstraZeneca to obtain specific additional follow-up 
information in an expedited fashion.  This information may be more detailed than that 
captured on the adverse event case report form.  In general, this will include a description of 
the adverse event in sufficient detail to allow for a complete medical assessment of the case 
and independent determination of possible causality.  Information on other possible causes of 
the event, such as concomitant medications and illnesses must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to AstraZeneca or its designated representative.   


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8.12.2 
Non-Serious Adverse Event Reporting Requirements  
Non-serious adverse events which meet the criteria for adverse event reporting in this trial 
(Section 8.1) are to be reported on the adverse event CRFs, which are to be submitted to 
AstraZeneca.  An adverse event does not need to be recorded in the CRF for this protocol if it 
is being recorded in the CRF for the patient’s prior protocol.  
9 
DATA ANALYSIS/STATISTICAL METHODS  
9.1 
Sample Size Determination  
The number of subjects enrolled in this study will be determined by the number of subjects 
who were administered tremelimumab in prior tremelimumab trials, who wish to participate 
in this trial and who meet the eligibility criteria.    
9.2 
Efficacy Analysis  
No statistical methods will be employed to test a specific hypothesis in this study.  Only 
descriptive statistics will be provided for survival (median, range, 95 percent confidence 
interval) end-points.   
9.3 
Safety Analysis  
No statistical methods will be employed to test a specific hypothesis in this study.  Only 
descriptive statistics will be provided for safety (number and percentage of subjects with 
adverse events) end-points.   
9.4 
Interim Analysis   
Not Applicable  
9.5 
Data Monitoring Committee   
Not Applicable  
10 
QUALITY CONTROL AND QUALITY ASSURANCE  
During trial conduct, AstraZeneca or its agent will conduct periodic monitoring visits to 
ensure that the protocol and GCPs are being followed.  The monitors may review source 
documents to confirm that the data recorded on CRFs is accurate.  The investigator and 
institution will allow AstraZeneca monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.  
The trial site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by AstraZeneca, 
and/or to inspection by appropriate regulatory authorities.  


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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.   
11 
DATA HANDLING AND RECORD KEEPING  
11.1 
Case Report Forms/Electronic Data Record  
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this trial.  
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of AstraZeneca and should not be made available in any 
form to third parties, except for authorized representatives of AstraZeneca or appropriate 
regulatory authorities, without written permission from AstraZeneca.  
It is the investigator’s responsibility to ensure completion and to review and approve all 
CRFs.  CRFs must be signed by the investigator or by an authorized staff member.  These 
signatures serve to attest that the information contained on the CRFs 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 CRFs.  Subject source documents are the physician’s 
subject records maintained at the trial 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 CRFs must match those charts.   
In some cases, the CRF may also serve as the source document.  In these cases, AstraZeneca 
and the investigator must prospectively document which items will be recorded in the source 
documents and for which items the CRF will stand as the source document.  
11.2 
Record Retention  
To enable evaluations and/or audits from regulatory authorities or AstraZeneca, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, serious adverse event forms, source documents, 
and detailed records of treatment disposition.  The records should be retained by the 
investigator according to ICH, local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer.  
If the investigator relocates, retires, or for any reason withdraws from the trial, AstraZeneca 
should be prospectively notified.  The trial records must be transferred to an acceptable 
designee, such as another investigator, another institution, or to AstraZeneca.  The 
investigator must obtain AstraZeneca’s written permission before disposing of any records, 
even if retention requirements have been met.  


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12 
ETHICS  
12.1 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)  
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, informed consent forms, and other relevant documents, eg, 
advertisements, if applicable, from the IRB/IEC.  All correspondence with the IRB/IEC 
should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to AstraZeneca.  
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 AstraZeneca in writing within 5 
working days after the implementation.  
12.2 
Ethical Conduct of the Trial  
The trial will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice guidelines, and applicable local regulatory 
requirements and laws.  
12.3 
Subject Information and Consent  
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures.  In case of data 
transfer, AstraZeneca will maintain high standards of confidentiality and protection of 
subject personal data.  
The informed consent form must be agreed to by AstraZeneca and the IRB/IEC and must be 
in compliance with ICH GCP, local regulatory requirements, and legal requirements.  
The investigator must ensure that each trial subject, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the trial and possible risks 
associated with participation.  The investigator, or a person designated by the investigator, 
will obtain written informed consent from each subject or the subject’s legally acceptable 
representative before any trial-specific activity is performed.  The informed consent form 
used in this trial, and any changes made during the course of the trial, must be prospectively 
approved by both the IRB/IEC and AstraZeneca before use.  The investigator will retain the 
original of each subject’s signed consent form.  


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13 
DEFINITION OF END OF TRIAL   
13.1 
End of Trial in a Member State   
End of Trial in a Member State of the European Union is defined as the date of the last post-
treatment subject follow-up for tumor assessment and survival.  
13.2 
End of Trial in all Participating Countries   
End of Trial in all participating countries is defined as the date of the last post-treatment 
subject follow-up for tumor assessment and survival.  
14 
SPONSOR DISCONTINUATION CRITERIA  
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of 
AstraZeneca.  In addition, AstraZeneca retains the right to discontinue development of 
tremelimumab at any time.  
If a trial is prematurely terminated or discontinued, AstraZeneca will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects within 
60 days.  As directed by AstraZeneca, all trial materials must be collected and all CRFs 
completed to the greatest extent possible.  
15 
PUBLICATION OF TRIAL RESULTS  
Publication of trial results is discussed in the Clinical Study Agreement.  
 


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16 
REFERENCES  
1. 
Ribas A, Camacho LH, Lopez-Berestein G et al.  Anti-tumor Activity in Melanoma and 
Anti-Self Responses in a Phase I trial with the Anti-Cytotoxic T Lymphocyte 
Associated Antigen 4 Monoclonal Antibody CP-675,206.  J Clin Oncol 2005:  Vol 23 
No 35, Dec 10, 2005  
2. 
Yang, James C. MD, "Tumor regression in patients with metastatic renal cancer treated 
with a monoclonal antibody to CTLA4 (MDX-010)".  Developmental Therapeutics: 
Immunotherapy (Scientific Program), 2005 ASCO Annual Meeting.  
3. 
Bookman MA, Kloth DD, Korer PE, et.al. Short-course intravenous prophylaxis for 
paclitaxel-related hypersensitivity reactions. Ann Oncol 1997; 8:611-614.  
4. 
Liberman, P. The use antihistamines in the prevention and treatment of anaphylaxis and 
anaphylactoid reactions. J Allergy Clin Immunology, 1990; 86 (4II Supp): 684-686.  


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Appendix 1 
List of Abbreviations  
 
AE  
adverse event  
ANC  
absolute neutrophil count  
ALT  
alanine aminotransferase  
ALP  
alkaline phosphatase  
AST   
aspartate aminotransferase  
BUN   
blood urea nitrogen  
CRF   
case report form  
CRP   
C reactive protein  
CTCAE   
Common Terminology Criteria for Adverse Events  
CTLA4   
cytotoxic T lymphocyte-associated antigen 4  
DAI  
Dosage and Administration Instructions  
ECG   
electrocardiogram  
FDA   
Food and Drug Administration  
GCP   
Good Clinical Practice  
GGT   
gamma-glutamyl transferase  
ICH   
International Conference on Harmonization  
IEC   
Independent Ethics Committee  
IND   
Investigational New Drug  
IRB   
Institutional Review Board  
IV   
intravenous  
LDH   
lactic acid dehydrogenase  
RBC   
red blood cell  
SAE   
serious adverse event  
SGOT   
serum glutamic-oxaloacetic transaminase (AST)  
SGPT   
serum glutamic-pyruvic transaminase (ALT)  
T3   
triiodothyronine  
T4   
thyroxine  
TSH   
thyroid-stimulating hormone  
ULN   
upper limit of normal  
WBC   
white blood cell count  
  
 


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Appendix 2 
CLINICAL PROTOCOL AMENDMENT 1  
Amendment: 1  
  
Amendment No. 1  
Date 04 March 2008  
  
Previous Amendments:  
Country (ies)  
 
Site(s)  
 
Amendment No.  
Date  
Country (ies)  
Site(s)  
SUMMARY  
Reason(s) for Amendment  
The protocol section(s) that have been amended and the details of the changes are 
summarized in the following sections.  
• 
To add hematology to safety laboratory assessments before each dose.  
• 
To clarify that the single safety reference document for CP-675,206 is the product’s 
Investigators Brochure.   
• 
It will not be required that patients enroll within 3 months of completing treatment in 
their prior protocol.  
• 
To clarify that patients in ongoing trials will not be eligible for this protocol except in 
extraordinary circumstances.  
• 
To clarify that the Sponsor must approve the enrollment of each patient.  
• 
To clarify that if an investigator wishes to re-treat a patient who has experienced an 
adverse event that would otherwise require that the patient stop treatment, the 
investigator must provide the written action plan.  
• 
To add diverticulitis, adverse events requiring infliximab, and immune-mediated 
thrombocytopenia to the list of adverse events that require that the patient stop 
treatment.  
• 
To clarify that concomitant medications should not be recorded on the Case Report 
Form unless they were administered to treat a reportable adverse event.  
• 
To add that patients should be instructed to contact their physician or nurse in case of 
symptoms which could indicate severe colitis.  
• 
To add instructions for use of infliximab to the diarrhea management algorithm.  
• 
To update the number listed on the vial and carton labels.  
• 
To correct typographical errors.  
  
Protocol Section(s) Amended  
The protocol sections that were amended are detailed below.  The format is as follows:  


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The “change from” section represents the current text in the protocol.  Bolded text is used to 
indicate the addition of information to the current text, and strike-out of text (eg, text) is 
used to show the deletion of information from the current text.  
The “change to” section represents the revised text, with the revisions shown in the “change 
from” section in normal text.  
Section <Insert section number> , <Insert section title>   
Change From  
Change To


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1. Section SUMMARY, Footnotes for Schedule of Activities, Numbers 3 and 8  
Change From  
3. Contraception Counseling:  All women of childbearing potential must agree to practice a 
form of effective contraception prior to entry into the study and for 12 months following any 
dose of study drug.  
8. Hematology: WBC with differential count and Absolute Neutrophil Count (ANC), 
RBC count, Hemoglobin, Hematocrit, Platelet Count  
Change To  
3. Contraception Counseling:  All women of childbearing potential must agree to practice a 
form of effective contraception for 12 months following any dose of study drug.  
8. Hematology: WBC with differential count and Absolute Neutrophil Count (ANC), RBC 
count, Hemoglobin, Hematocrit, Platelet Count.  
2. Section 1. INTRODUCTION, 1.2. CP-675,206 Risks and Precautions, Paragraph 7  
Change From  
The single safety reference document for CP-675,206 is the product’s Investigators  
Brochure and its updates as they become available.  Please refer to the Investigators  
BrochureSee the current Investigators Brochure for more information on the safety of CP-
675,206.  
Change To  
The single safety reference document for CP-675,206 is the product’s Investigators Brochure 
and its updates as they become available.  Please refer to the Investigators Brochure.  
3. Section 1. INTRODUCTION, 1.3. Rationale for Dosing Hiatus (“Drug Holiday”), 
Paragraph 2  
Change From  
One subject who participated in a Phase 1 study of CP-675,206 had a complete response after 
a single dose of CP-675,206 and has remained free of disease for more than 2 years.1  All 
Most other subjects who have had objective responses to CP-675,206 have agreed to receive 
additional doses of the agent, and to date mostall responses have been durable (>1 year).  The 
value of subsequent doses is not known, but each additional dose has a risk of side effects.  In 
this study, subjects will be allowed to discontinue therapy with the option of receiving 
additional doses of CP-675,206 at a later time, at the discretion and judgment of the 
investigator.   


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Change To  
One subject who participated in a Phase 1 study of CP-675,206 had a complete response after 
a single dose of CP-675,206 and has remained free of disease for more than 2 years.1  Most 
other subjects who have had objective responses to CP-675,206 have agreed to receive 
additional doses of the agent, and to date most responses have been durable (>1 year).  The 
value of subsequent doses is not known, but each additional dose has a risk of side effects.  In 
this study, subjects will be allowed to discontinue therapy with the option of receiving 
additional doses of CP-675,206 at a later time, at the discretion and judgment of the 
investigator.   
4. Section 4. SUBJECT SELECTION, Paragraph 1  
Change From  
It is expected that subjects will enroll in this protocol within 3 months of completing 
treatment in their prior protocol.  If extenuating circumstances prevent a subject from 
completing treatment in their prior protocol or from enrolling within this timeframe, the 
subject may enroll only with written permission by the Sponsor. It is expected that patients 
in ongoing trials will not be eligible except in extraordinary circumstances.  
Change To  
It is expected that patients in ongoing trials will not be eligible except in extraordinary 
circumstances.  
5. Section 4. SUBJECT SELECTION, 4.3. Randomization Criteria, Paragraph 1, 
Sentence 1  
Addition  
The Sponsor must approve the enrollment of each patient.    
6. Section 5. TRIAL TREATMENTS, 5.2.1. Formulation and Packaging, Paragraph 3  
Change From  
The vial and carton labels identify CP-675,206 as “CP-675,206 (clonal), 20 mg/ml IV Vial  
Solution 400 mg/vial”.  The study number listed on the vial and carton labels is “A367CF”, 
“A367POLS which is a code for pooled clinical supplies that includes Protocol A3671024.  
Change To  
The vial and carton labels identify CP-675,206 as “CP-675,206 (clonal), 20 mg/ml IV Vial  
Solution 400 mg/vial”.  The study number listed on the vial and carton labels is  
“A367POLS”, which is a code for pooled clinical supplies that includes Protocol A3671024.  


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7. Section 5. TRIAL TREATMENTS, 5.2.3.3. Stopping Rules for Adverse Events, 
Paragraph 1 and Bullets 8, 9, and 10  
Change From  
Subjects who experience any of the following adverse events at any time during the previous 
cycle must not receive further dosing with CP-675,206 unless the investigator discusses the 
case with the Pfizer clinician and the Pfizer clinician has provided a written action plan.   
• 
Diverticulitis  
• 
Any adverse event which requires treatment with infliximab  
• 
Immune-mediated thrombocytopenia  
Change To  
Subjects who experience any of the following adverse events at any time during the previous 
cycle must not receive further dosing with CP-675,206 unless the investigator discusses the 
case with the Pfizer clinician and has provided a written action plan.   
• 
Diverticulitis  
• 
Any adverse event which requires treatment with infliximab  
• 
Immune-mediated thrombocytopenia  
8. Section 5. TRIAL TREATMENTS, 5.3. Concomitant Medication(s), Paragraph 4  
Addition  
Concomitant medications should not be recorded on the Case Report Form unless they 
were administered to treat a reportable adverse event (See Section 8.1).  
9. Section 5. TRIAL TREATMENTS, 5.4.1. Management of Diarrhea, Paragraph 1 and 
Table 5  
Change From  
Diarrhea is an expected clinically significant adverse event when treating subjects with 
antiCTLA4 experimental drugs.2  The diarrhea may be severe, may require hospitalization, 
and may result in intestinal perforation.  Patients should be instructed to contact their 
physician or nurse if any of the following occur: diarrhea for the first time during 
treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, 
dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; 
inability to get diarrhea under control within 24 hours; or fever or evidence of 
infection..  The following algorithm (Table 5) is recommended for the treatment of subjects 
who develop diarrhea while on study.  


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Table 5. Diarrhea Algorithm  
Diarrhea Severity and Duration  
Recommendation  
Any change indicative of diarrhea  
Consider use of probiotics   
Grade 1 less than or equal to 14 days  
Consider use of probiotics  
Follow Diarrhea Management Guidelines including  
C. difficile titertoxin, stool tests, oral fluid replacement  
Consider use of mesalamine and/or empiric loperamide  
Grade 1 more than 14 days or   
Grade 2 of any duration   
Consider use of probiotics  
Evaluation of severity by clinician familiar with CP-
675,206-related diarrhea  
Consider IV fluids if indicated  
Consider use of budesonide, olsalazine, or mesalmine  
Consider use of steroids*  
Grade 3 or Grade 4 for any duration   
Or   
Any grade & duration associated with evidence 
of severe enterocolitis including bleeding, 
fever, pain or other signs/symptoms  
Consider use of probiotics  
Evaluation by clinician familiar with CP-675,206-related 
diarrhea  
Consider inpatient hospitalization for IV fluids, 
monitoring  
Consider use of budesonide, olsalazine, mesalamine, or 
octreotide  
Consider use of steroids*  
Consider infliximab if patient is unstable or at risk of 
bowel perforation and not responsive to steroids  
Notify the Pfizer Clinician  
  
Change To  
Diarrhea is an expected clinically significant adverse event when treating subjects with 
antiCTLA4 experimental drugs.2  The diarrhea may be severe, may require hospitalization, 
and may result in intestinal perforation.  Patients should be instructed to contact their 
physician or nurse if any of the following occur: diarrhea for the first time during treatment; 
black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or 
faintness; inability to take fluids by mouth due to nausea or vomiting; inability to get diarrhea 
under control within 24 hours; or fever or evidence of infection..  The following algorithm  
(Table 5) is recommended for the treatment of subjects who develop diarrhea while on study.  
 
Table 5.  Diarrhea Algorithm  


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Diarrhea Severity and Duration  
Recommendation  
Any change indicative of diarrhea  
Consider use of probiotics   
Grade 1 less than or equal to 14 days  
Consider use of probiotics  
C. difficile toxin, oral fluid replacement  
Consider use of mesalamine and/or empiric loperamide  
Grade 1 more than 14 days or   
Grade 2 of any duration   
Consider use of probiotics  
Evaluation of severity by clinician familiar with  
CP-675,206-related diarrhea  
Consider IV fluids if indicated  
Consider use of budesonide, olsalazine, or mesalmine  
Consider use of steroids*  
Grade 3 or Grade 4 for any duration   
Or   
Any grade & duration associated with evidence 
of severe enterocolitis including bleeding, 
fever, pain or other signs/symptoms  
Consider use of probiotics  
Evaluation by clinician familiar with CP-675,206-related 
diarrhea  
Consider inpatient hospitalization for IV fluids, 
monitoring  
Consider use of budesonide, olsalazine, mesalamine, or 
octreotide  
Consider use of steroids*  
Consider infliximab if patient is unstable or at risk of 
bowel perforation and not responsive to steroids  
Notify the Pfizer Clinician  
  
10. Section 7. ASSESSMENTS, 7.3. Laboratories, Paragraph 1  
Change From  
Laboratory assessments will include the following: lipase and amylase; liver function tests 
including AST (SGOT), ALT (SGPT), Alkaline Phosphatase (ALP), Gamma-Glutamine 
Transferase (GGT), lactic acid dehydrogenase (LDH); thyroid function tests including T3, 
T4, TSH., hematology tests including WBC with differential count and Absolute 
Neutrophil Count (ANC), RBC count, Hemoglobin, Hematocrit, and Platelet Count.    
Investigators should use review the results of the all laboratory tests and use them to make 
re-dosing decisions.    
Change To  
Laboratory assessments will include the following: lipase and amylase; liver function tests 
including AST (SGOT), ALT (SGPT), Alkaline Phosphatase (ALP), Gamma-Glutamine 


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Transferase (GGT), lactic acid dehydrogenase (LDH); thyroid function tests including T3, 
T4, TSH., hematology tests including WBC with differential count and Absolute Neutrophil 
Count (ANC), RBC count, Hemoglobin, Hematocrit, and Platelet Count.   Investigators 
should review the results of all laboratory tests and use them to make re-dosing decisions.    
 
11. Section Appendix 1. List of Abbreviations  
 
Addition  
 
         ANC  
absolute neutrophil count 
 
 


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Appendix 3 
CLINICAL PROTOCOL AMENDMENT 2  
Current Amendment: 2 
Amendment No. 2 
Date 26 December 2019  
  
Previous Amendments:  
Country (ies)  
 
Site(s)  
 
Amendment No. 1      Date  04 March 2008 
Country (ies)  
Site(s)  
SUMMARY  
Reason(s) for Amendment  
The protocol section(s) that have been amended and the details of the changes are 
summarized in the following sections.  
• 
To implement the administrative change in 2012 including changes in sponsor, 
compound name, study number, and specific manual name. 
• 
To update safety information of tremelimumab according to changes in Investigator’s 
Brochures of tremelimumab released since last protocol amendment. 
• 
To update that each carton will contain 4 vials of tremelimumab instead of 16. 
• 
To introduce the Safety Management Guidelines (TMG) and to inform that TMG will 
be delivered as a standalone Annex document.  
• 
To provide clarifications of the time database lock and final analysis 
• 
To add language on options patients have after database lock and final analysis. 
 
Protocol Section(s) Amended  
The protocol sections that were amended are detailed below.  The format is as follows:  
The “change from” section represents the current text in the protocol.  Colored and 
underlined text (e.g., text) is used to indicate the addition of information to the current 
text, and colored and strike-out of text (eg, text) is used to show the deletion of 
information from the current text.  
The “change to” section represents the revised text, with the revisions shown in the “change 
from” section in normal text.  
Section <Insert section number> , <Insert section title>   
Change From  
Change To


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1. Entire Protocol 
Change from  
CP-675,206tremelimumab  
Change to 
Tremelimumab 
Change from 
PfizerAstraZeneca 
Change to 
AstraZeneca 
Change from 
A3671024D4881C00024 
Change to 
D4881C00024 
Change from 
Dosage and Administration Instructions Investigational Product Manual 
Change to 
Investigational Product Manual 
2. Section SUMMARY, “Trial Design” 
Change from 
This is a multi-center, international, open label study.  Eligible subjects are those who have 
received CP-675,206tremelimumab in another protocol but are no longer going to receive 
CP-675,206tremelimumab in the other trial.  All subjects who are enrolled in this trial will 
have the opportunity to receive CP-675,206tremelimumab.  Doses may be delayed or 
suspended indefinitely (“dosing hiatus”)under certain circumstances at the discretion of the 
investigator, and the subject may remain in the study..  Subjects not receiving CP-
675,206tremelimumab should be seen in the clinic or contacted at least every 6 months to 
determine their tumor status until the time of final analysis.    
Change to 


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This is a multi-center, international, open label study.  Eligible subjects are those who have 
received tremelimumab in another protocol but are no longer going to receive tremelimumab 
in the other trial.  All subjects who are enrolled in this trial will have the opportunity to 
receive tremelimumab.  Doses may be delayed under certain circumstances at the discretion 
of the investigator.  Subjects not receiving tremelimumab should be seen in the clinic or 
contacted at least every 6 months to determine their tumor status until the time of final 
analysis.    
3. Section SUMMARY, “Trial Treatment”, Fourth paragraph 
Change from  
Doses may be delayed or suspended indefinitely (“dosing hiatus”)under certain 
circumstances at the discretion of the investigator,: 
x Dosing may be delayed per the Dosing Modification and the subject may remain in 
the study.  Dosing Modification and Toxicity Management Guidelines, due to either 
an immune or a non-immune-related AE. 
x If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.  
 
Subjects not receiving CP-675,206tremelimumab should be seen in the clinic or contacted at 
least every 6 months to determine their tumor status.    until the time of the final analysis.    
Change to 
Doses may be delayed under certain circumstances at the discretion of the investigator: 
x Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related AE. 
x If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.  
Subjects not receiving tremelimumab should be seen in the clinic or contacted at least every 6 
months to determine their tumor status until the time of the final analysis.    
4. Section 1.2 “Tremelimumab Risks and Precautions” 
Replace the entire section with  
Risks with tremelimumab monotherapy include, but are not limited to, gastrointestinal effects 
(colitis, diarrhea, enterocolitis, intestinal perforation, and large intestinal perforation); 
endocrine disorders (hypo- and hyperthyroidism, hypophysitis, and adrenal insufficiency); 
skin effects (rash and pruritus); lipase and/or amylase elevations and clinical manifestations 
of pancreatitis; hepatic events (including immune-mediated hepatitis and liver enzyme 


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elevations); pneumonitis and ILD; neurotoxicity (including encephalitis, peripheral motor 
and sensory neuropathies, and Guillain-Barré syndrome); thrombocytopenia, anemia, and 
neutropenia; infusion-related reactions and hypersensitivity/anaphylactic reactions; renal 
events (including nephritis/autoimmune nephritis and acute kidney injury); autoimmune 
arthritis, Sjogren’s syndrome; giant cell temporal arteritis, and ulcerative colitis; and 
hyperglycemia and diabetes mellitus.  
For information on all identified and potential risks for tremelimumab, please always refer to 
the current version of the tremelimumab IB. 
In monotherapy clinical studies, AEs reported at an incidence of > 20% include events such 
as diarrhea, nausea, fatigue, pruritus, decreased appetite, rash, and vomiting. Approximately 
16% of patients experienced an AE that resulted in permanent discontinuation of 
tremelimumab, and approximately 45% of patients experienced an SAE. Please see the 
current version of the tremelimumab IB for a detailed summary of tremelimumab 
monotherapy data, including AEs, SAEs, and CTC Grade 3 to 5 events reported across the 
tremelimumab program. 
 
5. Section 1.3, Rational for Dosing Hiatus (“Drug Holiday”) 
Remove the entire section 
6. Section 5 “TRIAL TREATMENT”, Fourth paragraph 
Change from 
Doses may be delayed or suspended indefinitely (“dosing hiatus”)under certain 
circumstances at the discretion of the investigator,: 
x Dosing may be delayed per the Dosing Modification and the subject may remain in 
the study.  Dosing Modification and Toxicity Management Guidelines, due to either 
an immune or a non-immune-related AE. 
x If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.  
 
Subjects not receiving CP-675,206tremelimumab should be seen in the clinic or contacted at 
least every 6 months to determine their tumor status.    until the time of the final analysis.    
Change to 
Doses may be delayed under certain circumstances at the discretion of the investigator: 
x Dosing may be delayed per the Dosing Modification and Toxicity Management 
Guidelines, due to either an immune or a non-immune-related AE. 


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x If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will resume as soon as feasible.  
Subjects not receiving tremelimumab should be seen in the clinic or contacted at least every 6 
months to determine their tumor status until the time of the final analysis.    
7. Section 5.2.1 “Formulation and Packaging”, Third and fourth paragraph 
Change from 
The vial and carton labels identify CP-675,206tremelimumab as “CP-675,206tremelimumab 
(clonal), 20 mg/ml IV Vial SolutionVialSolution 400 mg/vial”.  The study number listed on 
the vial and carton labels is “A367POLS”, which is a code for pooled clinical supplies that 
includes Protocol A3671024.  
During the course of this trial the formulation, packaging, and/or labeling of CP-675,206 may 
change.  The latestlastest formulation, packaging and labeling will be provided in an updated 
Dosage and Administration Instructions document. Investigational Product Manual. Labels 
for the investigational product will be prepared in accordance with Good Manufacturing 
Practice (GMP) and local regulatory guidelines. The label will fulfill GMP Annex 13 
requirements for labeling. Label text will be translated into local languages, as required. 
Change to  
The vial and carton labels identify tremelimumab as “tremelimumab (clonal), 20 mg/ml IV 
VialSolution 400 mg/vial”.  The lastest formulation, packaging and labeling will be provided 
in an updated Investigational Product Manual. Labels for the investigational product will be 
prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines. The label will fulfill GMP Annex 13 requirements for labeling. Label text will be 
translated into local languages, as required. 
8. Section 5.2.3.1 “Dose Reduction of CP-675,206” 
Move the section to Section 5.4 “Management of Toxicity and Dose Modification 
Information of Tremelimuab” 
9. Section 5.2.3.2 “Dose Delays and Re-Dosing Criteria for of CP-675,206” 
Change from 
5.2.3.1 5.2.3.2. Dose Delays and Re-Dosing Criteria for CP-675,206Tremelimumab  
The initiation of a cycle may be delayed to allow  recovery from treatment-related toxicity.  
All subjects must meet the following criteria for laboratory parameters by the day of dosing, 
as detailed in Table 2, in order to be treated with CP-675,206.   
Table 2.  Re-Dosing Criteria for CP-675,206: Laboratory Parameters  


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Laboratory Parameter  
Re-Dosing Criteria  
Hepatic Function   
(within 10 days)  
  
   
AST, ALT ˯2.5 x ULN (˯5 x ULN if liver 
metastases are present) bilirubin ˯2 x ULN (except 
in subject with Gilbert’s syndrome)  
Amylase and Lipase   
(within 10 days)  
  
  
˯1.5 x ULN or baseline   
For all subjects, treatment-related adverse events must have resolved at least to CTCAE 
Grade 1 or baseline (at the start of this study) and be considered tolerable by the day of 
dosing, in order to be treated with CP-675,206, except as noted in Table 3 and in Section 
5.2.3.3 (Stopping Rules for Adverse Events).  
Table 3.  Re-Dosing Criteria for CP-675,206: Treatment-Related Adverse Events.   
Adverse Event  
Re-Dosing Criteria  
Thyroiditis  
Asymptomatic or stable on thyroid replacement therapy  
Rash  
Tolerable and ˯ Grade 2  
Vitiligo  
May be re-dosed regardless of severity  
All other treatment-related adverse events  
Tolerable and ˯ Grade 1 or baseline  
NOTE:  If a subject has a hypersensitivity reaction to CP-675,206 or a Grade 3 treatment-related toxicity at 
any time during a cycle, the investigator must notify the Pfizer Clinician.  
There is a concern that subjects with active brain metastases may be at risk for increased 
intracranial pressure if treated with CP-675,206. tremelimumab. Subjects with brain 
metastases must not receive CP-675,206tremelimumab until after the metastases have been 
adequately treated with surgery and/or radiation.    
Subjects must not receive CP-675,206tremelimumab while pregnant or breast-feeding.  
Females of childbearing potential must have a negative serum or urine pregnancy test within 
10 days prior to each dose.  Females who have undergone surgical sterilization or who have 
been postmenopausal for at least 2 years are not considered to be of childbearing potential.  
For details on dosing delays and  re-dosing criteria, please refer to the Dosing Modification 
and Toxicity Management Guidelines, which is delivered as an Annex document.  
Change to 
5.2.3.1 Dose Delays and Re-Dosing Criteria for Tremelimumab  
The initiation of a cycle may be delayed to allow recovery from treatment-related toxicity.  
There is a concern that subjects with active brain metastases may be at risk for increased 
intracranial pressure if treated with tremelimumab. Subjects with brain metastases must not 


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receive tremelimumab until after the metastases have been adequately treated with surgery 
and/or radiation.  
Subjects must not receive tremelimumab while pregnant or breast-feeding. Females of 
childbearing potential must have a negative serum or urine pregnancy test within 10 days 
prior to each dose. Females who have undergone surgical sterilization or who have been 
postmenopausal for at least 2 years are not considered to be of childbearing potential. 
For details on dosing delays and  re-dosing criteria, please refer to the Dosing Modification 
and Toxicity Management Guidelines, which is delivered as an Annex document.  
10. Section 5.2.3.3 “Stopping Rules for Adverse Events” 
Change from 
5.2.3.25.2.3.3  Stopping Rules for Adverse Events  
Subjects who experience any of the following adverse events at any time during the previous 
cycle must not receive further dosing with CP-675,206tremelimumab unless the investigator 
discusses the case with the Pfizer clinicianAstraZeneca study physician and has provided a 
written action plan.   
• 
Any Grade 4 CP-675,206-related adverse event  
• 
Hypersensitivity to CP-675,206tremelimumab, Grade 3 (see Section 5.4.21)  
• 
Hypersensitivity to CP-675,206tremelimumab, Grade 2, and symptoms reappear 
after infusion restarted  
• 
Melanoma associated retinopathy, Grade 2 or above  
• 
Uveitis, Grade 2 or above  
• 
Hepatitis, Grade 3  
• 
Diarrhea, Grade 3, requiring treatment with systemic steroids for more than 10 
days in any 3-month period  
• 
Diverticulitis  
• 
Any adverse event which requires treatment with infliximab  
• 
Immune-mediated thrombocytopenia  
Change to 


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5.2.3.2 Stopping Rules for Adverse Events  
Subjects who experience any of the following adverse events at any time during the previous 
cycle must not receive further dosing with tremelimumab unless the investigator discusses 
the case with the AstraZeneca study physician and has provided a written action plan 
• 
Hypersensitivity to tremelimumab, Grade 3 (see Section 5.4.1)  
• 
Hypersensitivity to tremelimumab, Grade 2, and symptoms reappear after 
infusion restarted  
• 
Melanoma associated retinopathy, Grade 2 or above  
• 
Uveitis, Grade 2 or above  
• 
Diverticulitis  
• 
Immune-mediated thrombocytopenia  
11. Section 5.2.6 “Treatment after the End of the Study” 
Add 
After the final analysis, AstraZeneca will continue to supply open-label drug to patients 
receiving tremelimumab therapy up to the time that they discontinue the treatment for 
whatever reason (see Section 6.3). At the time of the final analysis and thereafter: 
x Assessment will revert to standard of care at particular site 
x There would be no more data collection except for SAE reporting. Clinical study 
database would be closed 
x Paper form process would be used for SAE reporting. All SAEs, overdoses and 
pregnancies would be reported until 90 days after last dose 
x Drug dispensation and reconciliation will be handled by site on each patient's visit 
Study would be opened until last patient treated. Final last subject last visit will be defined as 
last patient's treatment discontinuation 
12. Section 5.3 “Concomitant Medication (s)”, Table 4 
Change from  
Protocol #  
Indication  
Allowed Anti-Cancer Therapy  
A3671006  
Breast Cancer  
exemestane (Aromasin)  
A3671025  
Renal Cell Carcinoma  
sunitinib malate (Sutent)  


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Patients from Renal Cell Carcinoma studies should not receive sunitinib within 3 months of a 
dose of tremelimumab, as acute renal failure has been reported with combination therapy of 
tremelimumab and sunitinib. It is unknown whether there could be a safety issue with 
combination of tremelimumab and other tyrosine kinase inhibitors.  
Change to 
Protocol #  
Indication  
Allowed Anti-Cancer Therapy  
A3671006  
Breast Cancer  
exemestane (Aromasin)  
Patients from Renal Cell Carcinoma studies should not receive sunitinib within 3 months of a 
dose of tremelimumab, as acute renal failure has been reported with combination therapy of 
tremelimumab and sunitinib. It is unknown whether there could be a safety issue with 
combination of tremelimumab and other tyrosine kinase inhibitors.  
13. Section 5.4 “Management of Toxicity of CP-675,206” 
Change the Section Title from 
5.4 Management of Toxicity and Dose Modification Information of CP-
675,206Tremelimumab   
Change to 
5.4 Management of Toxicity and Dose Modification Information of CP-
675,206Tremelimumab   
14. Section 5.4 “Management of Toxicity and Dose Modification Information of CP-
675,206Tremelimumab ” 
Replace the introductory text of the Section 5.4 and entire Section 5.4.1 “Management 
of Diarrhea” with 
Comprehensive toxicity management guidelines (TMG) have been developed to assist 
investigators with the recognition and management of toxicities associated with the use of the 
immune-checkpoint inhibitors durvalumab [Medi4736] (PD-L1 inhibitor) and tremelimumab 
(CTLA4 inhibitor).  Given the similar underlying mechanisms of toxicities observed with 
these two compounds, these guidelines are applicable to the management of patients 
receiving either drug as monotherapy or in combination.  Additionally, these guidelines are 
applicable when either drug is used alone or in combination and is administered concurrently 
or sequentially with other anti-cancer drugs (i.e. antineoplastic chemotherapy, targeted 
agents), as part of a protocol specific treatment regimen.  The TMGs provide information for 
the management of immune-mediated reactions, infusion-related reactions, and non-immune 
mediated reactions that may be observed with checkpoint inhibitor monotherapy or 
combination checkpoint inhibitor regimens, with specific instructions for dose modifications 


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(including discontinuations) and treatment interventions.  Investigators are advised however 
to use local practice guidelines and consult local references for the management of toxicities 
observed with other cancer treatment. The most current version of the TMGs entitled 
“Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-
Related, and Non-Immune Mediated Reactions (MEDI4736) Monotherapy or Combination 
Therapy with Tremelimumab or Tremelimumab Monotherapy” is provided to the 
investigative site as an Annex document and is maintained within the Site Master File.  
Patients should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an 
imAE diagnosis. In the absence of a clear alternative etiology, events should be considered 
potentially immune related.  In addition, there are certain circumstances in which 
tremelimumab should be permanently discontinued (see Section 5.2.3.2. of this protocol and 
the Dosing Modification and Toxicity Management Guidelines).  Following the first dose of 
IP, subsequent administration of tremelimumab can be modified based on toxicities observed 
as described in the Dosing Modification and Toxicity Management Guidelines. These 
guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to tremelimumab monotherapy  regimen by the reporting 
Investigator.  
Dose reductions are not permitted. In case of doubt, the Investigator should consult with the 
Study Physician. 
15. Section 5.4 “Mangement of Toxicity of CP-675,206” 
Add  
Section 5.4.2 “Medication Errors” 
The definition of a Medication Error can be found in Appendix 4. 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, i.e., 
immediately but no later than 24 hours after he/she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.2) and within 30 days for all other 
medication errors. 
16. Section 6.3 “End of Treatment” 
Add 


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Data collection will be stopped, the database locked and the available data summarized once 
eligible patients are no longer available to enter the trial, and all patients have had the 
opportunity to be followed up for approximately 9.5 years.  At this time AstraZeneca will 
continue to supply open-label drug to these patients, up to the time that they discontinue the 
treatment for whatever reason. 
15. Section 8.2.1 “Immediate Reporting of Serious Adverse Events” 
Change from 
Serious adverse events require immediate notification to PfizerAstraZeneca or its designated 
representative beginning from the time that the subject provides informed consent for the 
study; and should be reported under the patient’s prior protocol until the patient receives 
investigational product in this study.  SAEs do not require notification if the patientit has 
been placed on drug holiday, at least 90 days have passed since the previous dose of CP-
675,206tremelimumab, and at least 28 days have passed since any study-related procedures 
for the patient.  
Change to 
Serious adverse events require immediate notification to AstraZeneca or its designated 
representative beginning from the time that the subject provides informed consent for the 
study; and should be reported under the patient’s prior protocol until the patient receives 
investigational product in this study.  SAEs do not require notification if it has been at least 
90 days since the previous dose of tremelimumab, and at least 28 days since any study-
related procedures for the patient.  
16. Section 8.2.2 “Reporting of Adverse Events in Case Report Forms” 
Change from 
Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of trial treatment. Collection of new adverse events should 
be discontinued after 90 days post-dose during a drug holiday with the exception that SAEs 
with a suspected causal relationship to CP-675,206 are still reportable. 
Change to 
Adverse events (serious and non-serious) should be recorded on the CRF from the time the 
subject has taken at least one dose of trial treatment. 
17. APPENDIX 4 “Medication Error” 
Added “Appendix 4 Medication Error” 


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Appendix 4 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study drug that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error. 
x 
occurred 
x 
was identified and intercepted before the participant received the drug 
x 
did not occur, but circumstances were recognized that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
x 
Drug name confusion 
x 
Dispensing error e.g.  medication prepared incorrectly, even if it was not actually given 
to the participant 
x 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
x 
Drug not taken as indicated e.g.  tablet dissolved in water when it should be taken as a 
solid tablet  
x 
Drug not stored as instructed e.g.  kept in the fridge when it should be at room 
temperature  
x 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
x 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
x 
Participant accidentally missed drug dose(s) e.g.  forgot to take medication 
x 
Accidental overdose (will be captured as an overdose) 
x 
Participant failed to return unused medication or empty packaging 
x 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product  
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 

SAP_001.pdf: 
Statistical Analysis Plan  
Astra Zeneca / D4881C00024 
Version 2.0/17 February 2020 
 
 
1 
 
 
 
 
 
Statistical Analysis Plan 
 
 
Study code 
D4881C00024 
 
Version 
2.0 
 
Date 
17 February 2020 
 
 
 
 
 
 
A Rollover Protocol For Patients Who Received Tremelimumab (CP-
675,206) In Other Protocols 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Astra Zeneca / D4881C00024 
Version 2.0/17 February 2020 
 
 
2 
 
 
 
 
 
DOCUMENT: 
 Statistical Analysis Plan 
PROTOCOL 
  
Number: 
 D4881C00024  
 
Title: 
 A Rollover Protocol For Patients Who Received 
Tremelimumab (CP-675,206) In Other Protocols 
 
Version / Date: 
 Final  /  02-Aug-2006 
 
 Amendment 1 /  04-Mar-2008 
Amendment 2 / 26 December 2019 
 
  
SAP STATUS 
 Version 2.0 
SAP VERSION 
DATE 
 17 February 2020 
SPONSOR: 
 AstraZeneca AB, 
151 85 Södertälje, Sweden 
PREPARED BY: 
 Quality Data Services, Inc. 
 
  
 




Statistical Analysis Plan  
Astra Zeneca / D4881C00024 
Version 2.0/17 February 2020 
 
 
5 
 
 
 
 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................. 1 
1. LIST OF ABBREVIATIONS ................................................................................. 7 
2. INTRODUCTION .................................................................................................. 9 
2.1. Objective of the Statistical Analysis Plan ...................................................... 9 
3. STUDY OBJECTIVES ......................................................................................... 10 
4. STUDY DESIGN ................................................................................................. 10 
4.1. General Study Design and Plan .................................................................... 10 
4.2. Study Population ........................................................................................... 10 
4.3. Treatment Administration and Duration of Treatment ................................ 10 
4.4. Trial Procedures ............................................................................................. 11 
4.5. End of treatment ............................................................................................ 11 
5. EFFICACY MEASUREMENTS........................................................................... 12 
5.1. Tumor Assessment ........................................................................................ 12 
5.2. Overall Survival .............................................................................................. 12 
6. SAFETY MEASUREMENTS ............................................................................... 12 
6.1. Adverse Events .............................................................................................. 13 
6.2. Hypersensitivity Reactions to Tremelimumab ............................................. 14 
6.3. Clinical Laboratory Assessments ................................................................. 14 
6.4. Vital Sign Measurements ............................................................................... 15 
6.5. Subject History ............................................................................................... 15 
7. GENERAL STATISTICAL CONSIDERATIONS ................................................. 15 
7.1. Determination of Sample Size ....................................................................... 15 


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7.2. Methodology................................................................................................... 15 
7.3. Handling of Dropouts or Missing Data ......................................................... 16 
7.4. Multi-center Studies ....................................................................................... 16 
7.5. Endpoints ....................................................................................................... 16 
7.5.1. Efficacy Endpoints......................................................................................... 16 
7.5.2. Safety Endpoints ........................................................................................... 16 
7.6. Analysis Populations ..................................................................................... 17 
7.6.1. Safety Population .......................................................................................... 17 
7.7. Demographics ................................................................................................ 17 
7.8. Subject Disposition........................................................................................ 17 
7.9. Medical History .............................................................................................. 17 
7.10. Duration of Treatment and Exposure to Study Drug ................................. 17 
7.11. Efficacy Analyses......................................................................................... 18 
7.12. Safety Analysis ............................................................................................ 18 
7.12.1. Prior and Concomitant Medications ............................................................. 18 
7.12.2. Adverse Events ........................................................................................... 19 
7.12.3. Vital Signs ................................................................................................... 20 
8. SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ........ 20 
9. REPORTING CONVENTIONS ........................................................................... 20 
10. REFERENCES .................................................................................................. 21 
11. TABLES, FIGURES, AND LISTINGS ................................................................ 21 
12. APPENDIX A: SCHEDULE OF ASSESSMENTS AND ACTIVITIES .............. 22 
13. DOCUMENT HISTORY .................................................................................... 25 


Statistical Analysis Plan  
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7 
 
 
 
 
 
1.   LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ANC 
Absolute Neutrophil Count 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CI 
confidence interval 
CRF 
Case Report Form 
CRP  
C reactive protein 
CSR 
Clinical Study Report 
CTCAE  
Common Terminology Criteria for Adverse Event 
CTLA4  
cytotoxic T lymphocyte-associated antigen 4 
DAI 
Dosage and Administration Instructions 
ECG  
electrocardiogram 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
GGT  
gamma-glutamyl transferase 
ICH  
International Conference on Harmonization 
IEC  
Independent Ethics Committee 
IND  
Investigational New Drug 
IRB  
Institutional Review Board 
IV  
intravenous 
LDH  
lactic acid dehydrogenase 
RBC  
red blood cell 
SAE  
serious adverse event 
SAP 
Statistical Analysis Plan 


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Version 2.0/17 February 2020 
 
 
8 
 
 
 
 
Abbreviation or 
special term 
Explanation 
SD 
standard deviation 
SGOT  
serum glutamic-oxaloacetic transaminase (AST) 
SGPT  
serum glutamic-pyruvic transaminase (ALT) 
T3  
triiodothyronine 
T4  
thyroxine 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings, figures 
TSH  
thyroid-stimulating hormone 
ULN  
upper limit of normal 
WBC  
white blood cell count 


Statistical Analysis Plan  
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9 
 
 
 
2. INTRODUCTION
2.1. Objective of the Statistical Analysis Plan
This statistical analysis plan (SAP) describes the planned analysis of the safety and efficacy data 
from the study.  A detailed description of the planned tables, figures and listings (TFLs) to be 
presented in the Clinical Study Report (CSR) is provided in the accompanying TFL template 
document.
The intent of this document is to provide guidance for the analysis of data related to safety and 
efficacy to describe any applicable statistical procedures.  In general, the analyses come directly 
from the protocol, unless they have been modified by agreement between the Sponsor and 
  A limited amount of information concerning this study (e.g., 
objectives, study design) is summarized to help the reader interpret the accompanying TFL 
templates.  That information is not a synopsis of the study and does not require review or 
approval because it is simply extracted from the protocol. Attached signatures indicate approval 
of the statistical analysis sections of the SAP, as well as accompanying TFL templates.  These 
sections must be agreed upon prior to database lock.  When the SAP and TFL templates are 
agreed upon and finalized, they will serve as the template for a portion of this study’s clinical 
study report.
This SAP supersedes
the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified.  If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the appropriate section of the CSR.  Any substantial deviations from this 
SAP will be agreed upon between the sponsor and 
  Deviations from this SAP, both 
substantial and non-substantial, will be documented in the CSR.  Any updates to their respective 
analyses, study designs, and TFL presentations after this SAP is finalized and approved will be 
documented in a running Note to the SAP document.
Various outputs may be required during the conduct of this trial which will necessitate the 
production of some but not all of the Figures, Summary Tables and Key Data Tabulations 
detailed in this document.  The SAP will not be updated to reflect these potential changes.


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3.   STUDY OBJECTIVES 
The primary objective is: 
x To allow access to tremelimumab (previously known as CP-675,206) for subjects who 
received tremelimumab in other trials. 
The secondary objectives are: 
x To follow long-term survival and tumor status of subjects treated with tremelimumab in 
other trials 
x To monitor the safety and tolerability of tremelimumab  
 
4.   STUDY DESIGN 
4.1.   General Study Design and Plan 
This is a multi-center, international, open label study.  
4.2.   Study Population 
Eligible subjects are those who have received tremelimumab in another protocol but are no 
longer going to receive tremelimumab in the other trial. All subjects who are enrolled in this trial 
will have the opportunity to receive tremelimumab. Doses may be delayed under certain 
circumstances at the discretion of the investigator. Subjects not receiving tremelimumab should 
be seen in the clinic or contacted at least every 6 months to determine their tumor status until the 
time of final analysis. 
4.3.   Treatment Administration and Duration of Treatment 
Subjects who received a single dose of tremelimumab or who received 15 mg/kg every 90 days 
in another study will receive intravenous administration of tremelimumab at a dose of 15 mg/kg 
on Day 1 of each 90-day cycle.  To allow for possible change in body weight over time, subjects 
will be weighed within 10 days prior to each cycle and the administered dose of tremelimumab 
will be recalculated. 
Subjects who have been receiving a different dosing regimen of tremelimumab in a prior study 
may have the option of continuing with the prior dosing regimen or of switching to the regimen 
of 15 mg/kg each 90 days. 


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For subjects on a 90-day or 3-month dosing regimen, doses should not be given less than 86 days 
from the previous dose.  For subjects on other schedules, doses will not be given before 2 days 
prior to the scheduled dose.  
Doses may be delayed under certain circumstances at the discretion of the investigator.  Subjects 
not receiving tremelimumab should be seen in clinic or contacted at least every 6 months to 
record their tumor status until the time of final analysis. 
No dose reduction of tremelimumab is permitted in the study. 
Dose delays and re-dosing criteria for tremelimumab based on laboratory parameters and based 
on treatment-related adverse events are described in Section 5.2.3.2 of the protocol.  
Dose stopping rules for adverse events are included in Section 5.2.3.3 of the protocol. 
 
4.4.   Trial Procedures  
This study includes a screening period followed by a treatment period with multiple cycles.  See 
Appendix A for the schedule of assessments and activities for each period and cycle. 
 
Subjects will be followed for at least 90 days after the last dose of study drug for reportable 
adverse events.  If there is evidence of continuing study drug-related toxicity, subjects will 
continue to be followed at intervals deemed medically appropriate by the investigator. 
 
4.5.   End of treatment  
Subjects may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, or 
administrative reasons.  If a subject does not return for a scheduled visit, every effort should be 
made to contact the subject.  In any circumstance, every effort should be made to document 
subject outcome, if possible.  The investigator is to inquire about the reason for withdrawal, to 
request the subject to return for a final visit, if applicable, and follow-up with the subject 
regarding any unresolved adverse events. 
 
The following are possible reasons for discontinuation from treatment: 
1. Withdrawal due to adverse event.  
2. Disease progression, unless there is reasonable evidence of clinical benefit to justify 
continuation on protocol. 
3. Subjects may decide to withdraw from treatment at any time. Subjects who withdraw 
from treatment should be followed for tumor assessment and survival.  If the subject also 
withdraws consent for disclosure of future information, no further evaluations should be 


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performed and no additional data should be collected.  The sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
4. Subjects who begin new investigational therapy, chemotherapy, or other therapy for 
his/her disease must not receive further treatment. 
5. Subjects may be discontinued from the study for poor compliance at the discretion of the 
investigator. 
6. The investigator should withdraw the subject at any time if he/she believes it is in the 
subject’s best interest to do so. 
7. The subject is lost to follow-up. 
8. The study is terminated by the sponsor. 
 
Data collection will be stopped, the database locked and the available data summarized once 
eligible patients are no longer available to enter the trial, and all patients have had the 
opportunity to be followed up for approximately 9.5 years.  At this time AstraZeneca will 
continue to supply open-label drug to these patients, up to the time that they discontinue the 
treatment for whatever reason. 
 
5.   EFFICACY MEASUREMENTS  
Efficacy measurements include tumor assessment and overall survival. 
5.1.   Tumor Assessment  
The subject’s tumor will be assessed according to the investigator’s usual practice.  The subject’s 
tumor status (alive with disease [AWD] or no evidence of disease [NED]) and the date and type 
of the most recent tumor assessment should be recorded at each dosing visit and follow-up visit. 
5.2.   Overall Survival 
Subject’s survival will be monitored throughout the trial.  After withdrawal from study 
treatment, subjects (or their physician) will be seen or contacted at least every 6 months to 
collect information on date of death and cause of death.  This information can also be obtained 
by telephone interview. 
 
6.   SAFETY MEASUREMENTS 
Safety will be evaluated by  
 
x All adverse events 
x Serious adverse events 
x Grade 3 or 4 tremelimumab – related adverse events 


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x Immune-mediated adverse events  
x Hypersensitivity reactions to tremelimumab  
x Clinical laboratory tests,  
x Vital signs measurements  
 
6.1.   Adverse Events 
Details about adverse events definitions and reporting requirements are included in Section 8 of 
the protocol.  Adverse events will be assessed throughout treatment period and during follow-up. 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not limited 
to:  abnormal test findings, clinically significant symptoms and signs, changes in physical 
examination findings, hypersensitivity. 
Additionally, they may include the signs or symptoms resulting from: drug overdose, drug 
withdrawal, drug abuse, drug misuse, drug interactions, drug dependency, extravasation, 
exposure in utero. 
Worsening of signs and symptoms of the malignancy under trial will be reported as adverse 
events. 
A treatment-emergent adverse event (TEAE) is defined as any sign or symptom that emerges 
during treatment, having been absent at pretreatment; or re-emerges during treatment, having 
been present at pretreatment but stopped prior to treatment; or worsens in severity during 
treatment relative to the pretreatment state, when the AE is continuous. Adverse events that 
started after a subject‘s last dose but within 7 days of dosing are considered treatment-emergent. 
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence at 
any dose that: results in death; is life-threatening (immediate risk of death); requires inpatient 
hospitalization or prolongation of existing hospitalization; results in persistent or significant 
disability/incapacity; results in congenital anomaly/birth defect.  
Progression of the malignancy under trial (including signs and symptoms of progression) will not 
be reported as a serious adverse event unless the outcome is fatal during the trial or within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease progression will 
not be reported as serious adverse event.  If the malignancy has a fatal outcome during the trial 
or within the safety reporting period, then the event leading to death will be reported as an 
adverse event and as a serious adverse event with CTC Grade 5. 
Severity assessment of adverse events: 


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GRADE 
Clinical Description of Severity 
0  
No Change from Normal or Reference Range  
1 
MILD Adverse Event 
2 
MODERATE Adverse Event 
3 
SEVERE Adverse Event 
4 
LIFE-THREATENING OR DISABLING Adverse Event 
5 
DEATH RELATED TO Adverse Event 
 
If adverse event severity is missing, the respective adverse event will be considered severe. 
Causality will be determined for all adverse events (serious and non-serious) by the investigator.  
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an adverse event.  If the 
investigator’s final determination of causality is unknown, then the event will be handled as 
“related to investigational product”.   
Withdrawal due to insufficient response will not be reported as withdrawal due to adverse 
events.  
Immune-mediated adverse events are those adverse events for which the investigator was not 
able to rule out other possible etiologies.  
6.2.   Hypersensitivity Reactions to Tremelimumab 
The following constitute hypersensitivity reactions to tremelimumab: 
x CTCAE v.3.0 Grade 1 Allergy (transient flushing or rash, drug fever <38°C) 
x CTCAE v.3.0 Grade 2 Allergy (urticaria, drug fever t38°C, and/or asymptomatic 
bronchospasm) 
x CTCAE v.3.0 Grade 3 or 4 Allergy (symptomatic bronchospasm requiring parenteral 
medication(s) with or without urticaria; allergy-related edema/angioedema; hypotension; 
anaphylaxis) 
These will be monitored and recorded throughout the study. 
6.3.   Clinical Laboratory Assessments 


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The protocol specifies the following:  Laboratory assessments will be performed at baseline (up 
to 10 days before dosing in the first cycle) and within 10 days prior to each administration of 
tremelimumab.  They include the following: lipase and amylase; liver function tests including 
AST (SGOT), ALT (SGPT), Alkaline Phosphatase (ALP), Gamma-Glutamine Transferase 
(GGT), lactic acid dehydrogenase (LDH); thyroid function tests including T3, T4, and TSH.
Investigators will use the results of the laboratory tests to make re-dosing decisions.  All women 
of childbearing potential will have a serum or urine pregnancy test completed within 10 days 
prior to each administration of tremelimumab.
The study database does not include laboratory tests results; therefore these will not be 
summarized for the clinical study report.
6.4. Vital Sign Measurements
Vital signs will be measured at on Days 1 on each cycle and will include: temperature, sitting 
systolic and diastolic blood pressure, and heart rate. These vital signs will be recorded prior to 
treatment and monitored as needed during drug infusion and for approximately 1 hour post-
infusion. Height and weight will be collected before Cycle 1.  To allow for possible change in 
body weight over time, subjects will be weighed within 10 days prior to each cycle.
6.5. Subject History
The subjects’ prior history includes their cancer history, medical history, and dates of first and 
most recent tremelimumab administration.
7. GENERAL STATISTICAL CONSIDERATIONS
Statistical analysis and programming of tables and listings will be conducted by 
, using 
  .
7.1. Determination of Sample Size
The number of subjects enrolled in this open-label single-treatment arm study will be determined 
by the number of subjects who received tremelimumab in other tremelimumab trials who wish to 
participate and who meet the eligibility criteria.
7.2. Methodology
No statistical methods will be employed to test a specific hypothesis in this study.  Only 
descriptive statistics will be provided for safety and survival endpoints. 


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Continuous data will be summarized with the following descriptive statistics: number of 
observations, mean, standard deviation (SD), median, minimum, and maximum. Categorical data 
will be summarized with counts and percentages. 
Data listings will be presented by subject and all data will be presented.  Tables will be presented 
summary results for all subjects included in the study. 
7.3.   Handling of Dropouts or Missing Data 
No data imputation will be done for safety parameters except for the adverse events (AEs) with 
missing starting date, missing severity or missing causality.  If the AE onset date is unknown, 
then the date of first study treatment will be used for classification of TEAEs that were 
experienced following administration of study drug. If adverse event severity is missing, the 
respective adverse event will be considered severe.  If the investigator’s final determination of 
causality is unknown, then the event will be handled as “related to investigational product”. 
7.4.   Multi-center Studies 
This is a multi-center study.  Study center will be displayed in the data listings. Summary tables 
will present results for all subjects enrolled in the study.  There are no planned summary results 
by investigative center or by country.   
7.5.   Endpoints 
7.5.1.   Efficacy Endpoints 
Tumor Status: The subject’s tumor will be assessed according to the investigator’s usual practice.  
The possible results for disease status are: evidence of disease, no evidence of disease, 
indeterminate. 
Overall Survival: Subject’s survival will be assessed throughout the study from the first dose till 
the last contact during follow-up post last dose in the last cycle.  After withdrawal from study 
treatment, subjects will be seen or contacted at least every 6 months to collect information on 
date of death and cause of death.  Subjects or their physicians may be contacted via phone to 
collect information on date of death and cause of death.  Subjects lost to follow-up will be 
censored at the time of the last available contact. 
Disease Free Survival will be defined as the time from the first study drug dose to the earliest 
date of evidence of disease (based on tumor status assessment) or death, whichever occurs first. 
7.5.2.   Safety Endpoints 
The following safety endpoints will be summarized for the clinical study report: 
x All adverse events 
x Serious adverse events 


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x Grade 3 or 4 tremelimumab – related adverse events 
x Hypersensitivity reactions to tremelimumab 
x Vital signs measurements  
x Concomitant medications 
7.6.   Analysis Populations 
7.6.1.   Safety Population 
The safety population is defined as all subjects treated with at least one dose of tremelimumab 
during the study. All safety data collected up to the end of the study (i.e., through the last follow-
up evaluation) are included in the safety and efficacy analyses. 
7.7.   Demographics 
The following demographic data: age, height, screening body weight will be summarized 
descriptively as number of subjects, mean, SD, median, minimum, and maximum.  Gender and 
race will be summarized as counts and percentages.   
7.8.   Subject Disposition 
The number of subjects enrolled in the study and included in the safety population will be 
presented overall, by investigative site, and by previous tremelimumab trial. 
Eligibility (inclusion /exclusion) criteria will be listed by subject indicating if all criteria were 
met and if not, which ones were not met. 
Subject disposition at the end of the study will be summarized as: completed or withdrawn.  The 
number of subjects withdrawn from the study will be reported as count and percentage by reason.  
7.9.   Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA®) 
and summarized by system organ class and preferred term for all subjects in the safety 
population.  Medical history reported terms, status (past/present), and other pertinent details will 
be included in the by subject data listing. 
7.10.   Duration of Treatment and Exposure to Study Drug 
Duration of participation in the study (days) will be defined as date of last contact (visit or 
phone) – date of the first dose in the study + 1. 
Duration of exposure (dosing) = date of the last dose – date of the first dose + 1.  This will 
include any unplanned dose interruptions. 


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Duration of participation in the study will be summarized as number of subjects, mean, SD, 
median, minimum, and maximum for all subjects.  Duration of exposure will be summarized as 
number of subjects, mean, SD, median, minimum, and maximum overall and by planned dose. 
Since tremelimumab will be administered in the clinic by study personnel, compliance with 
study drug will not be computed. 
7.11.   Efficacy Analyses 
All efficacy analyses will be performed using safety population. There are no statistical 
hypotheses tested in the study. Efficacy endpoints will be summarized using descriptive statistics 
only. 
Tumor status results will be summarized (counts and percentage) by cycle/visit. 
Survival will be summarized using Kaplan Maier estimate for median time and 95% confidence 
interval. Death is considered to be the “event” for Kaplan Meier analysis.  Subjects who are lost 
to follow-up will be censored at the time of the last known contact.  All other subjects will be 
censored at the time of study completion. 
Disease free survival will be summarized using Kaplan Maier estimate for median time and 95% 
confidence interval. Evidence of disease (based on tumor status assessment) or death are 
considered to be the “event” for Kaplan Meier analysis.  “Event” date will be date when the 
subject’s assessment for tumor is “evidence of disease” or date of death, whichever comes first. 
Subjects who are alive and without evidence of disease or who are lost to follow-up will be 
censored at the time of the last tumor assessment date on or prior to the last known contact.  All 
other subjects will be censored at the time of study completion. 
7.12.   Safety Analysis 
All safety analyses will be conducted on subjects who received at least one dose of protocol 
therapy (Safety Population).  The safety evaluations to be summarized include: AEs, vital signs, 
and concomitant medications. 
 
Safety results will be reported using summary tables and by subject data listings. Continuous 
variables will be summarized using mean, SD, median, minimum, and maximum.  Categorical 
variables will be summarized by presenting the number (frequency) and percentage in each 
category.  
If any screening safety data is repeated, the measurement taken closest to dosing will be used in 
the analysis as pre-study baseline.  If any post-dose safety data is repeated the measurement 
taken first at the particular visit will be used in the analysis.  
7.12.1.   Prior and Concomitant Medications 


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Prior and concomitant therapies as recorded on the CRF will be coded to a World Health 
Organization Drug Dictionary (WHO- DD) term.   
Prior medications are all doses taken prior to the first dose of study medication.  Concomitant 
medications are all doses taken after the first dose of study medication.  If any medications were 
started prior to dosing and were continued after dosing they will be shown in the 
Prior\Concomitant Medications listings and will be included in the concomitant summary table.  
The use of concomitant medications will be summarized as number and percentage of subjects 
taking each medication by ATC Classification. 
7.12.2.   Adverse Events 
Adverse events (AEs) that occur after administration of the first study dose until completion of 
the follow up evaluations will be considered treatment-emergent (TEAE).  If the start date of the 
AE is unknown, it will be assumed to be treatment-emergent. TEAEs will be summarized by 
system-organ-class and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA®). The frequency of subjects who experience TEAEs will be summarized overall. 
Subjects, having the same AE more than once per group, will be counted once for each preferred 
term and once within each system organ class.  
Separate summary tables (number of subjects and percentage) will be prepared for: 
x Serious adverse events 
x Grade 3 or 4 tremelimumab related adverse events 
x Hypersensitivity reactions to tremelimumab: 
o CTCAE v.3.0 Grade 1 Allergy (transient flushing or rash, drug fever <38°C); 
o CTCAE v.3.0 Grade 2 Allergy (urticaria, drug fever t38°C, and/or asymptomatic 
bronchospasm);  
o CTCAE v.3.0 Grade 3 or 4 Allergy (symptomatic bronchospasm requiring 
parenteral 
medication(s) 
with 
or 
without 
urticaria; 
allergy-related 
edema/angioedema; hypotension; anaphylaxis). 
All deaths will be included in a separate by subject data listing which will include date of death, 
cause of death (including specifics for study treatment toxicity, if applicable). Deaths may also 
be summarized by cause of death. 
All AEs are listed by subject, including non-treatment-emergent (i.e., pre-dosing or post-dosing) 
AEs, if applicable. Separate by subject data listings will be provided for subjects who experience 
treatment-emergent SAEs and for TEAEs leading to early termination from the study. 


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Separate summary tables will display the number of subjects and percentage of with treatment-
emergent AEs by maximum severity (grade), treatment-emergent AEs by relationship to study 
drug, and treatment-emergent AEs that led to premature discontinuation of study classified by 
system organ class and preferred term. 
7.12.3. Vital Signs
Vital sign measurements will be summarized using descriptive statistics for each visit and 
measurement time. Individual change from baseline in vital sign measurements will be 
calculated and summarized descriptively.  A by-subject listing of all vital sign measurements will 
be displayed.  Unscheduled visits will only be displayed in the listings.
8. SUMMARY OF CHANGES FROM PROTOCOL-SPECIFIED ANALYSES
SAP includes an additional efficacy endpoint included: Disease free survival.
Clinical laboratory test results are not available in the study database and no summary results 
and/or by subject data listings will be prepared for the study report.
9. REPORTING CONVENTIONS
The mean and median will be displayed to one decimal place greater than the original value and 
the standard deviation will be displayed to two decimal places greater than the original value. All 
statistical programming and analyses will be performed using 
The following standards will be used in the data presentation:
x
Post-text tables should be in landscape format.  Output should adhere to US / International 
Conference on Harmonization (ICH) margins and should not require changes for European 
page size.  For post-text tables, a blank row will separate the header from the content of the 
table listing.  For tables that have “n (%)”, the placement should be centered below “N=xx” 
in the column header.  Frequency tables will be center justified.  Descriptive statistics will be 
decimal aligned.
x
Percentages presented in in-text tables should be rounded to one decimal using the SAS 
rounding function.  If “%” is part of the column heading, do not repeat the “%” sign in the 
body of the table.  Unless specified otherwise, “%” should reflect the total population of the 
treatment groups.  Any deviation from that should be part of the footnote.  For 0 counts, 
leave the corresponding percentage blank.


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x The format for minimum and maximum should be “Min, Max”.  SD should be the default for 
representing scale, unless standard error has been specified.  Standard deviation should be 
abbreviated as “SD”, and presented next to the mean value, without any +/- sign.  The SD 
should have one additional decimal place beyond that of the mean (e.g. mean has one 
decimal place, SD should have two). 
x  “N” will represent the entire treatment group for the population group being analyzed, while 
“n” will represent a subset of the treatment group.  For tables with population designated as a 
row heading, “N” should be used (i.e. tables where all participant data is not available for 
every variable within a treatment group).  As a guideline, if the number is used in a 
denominator it should be presented as “N”.  If the number is used in the numerator, it should 
be presented as an “n”. 
x The heading should consist of four lines.  Line 1:  Sponsor identifier.  Line 2:  Protocol 
identifier.  Line 3: blank line.  Line 4:  Table/Appendix number Table Title – Population.  
The title for in-text tables should begin with the Table/Appendix number. 
x All data listings will be sorted by Subject Number and time point (if applicable). 
x The date format for all dates is DDMMMYYYY.  
A solid line should appear both above and below the column headings of a table.  A solid line 
should appear at the end of the table or at the bottom of each page if the table extends to more 
than one page.  Footnotes should start after the bottom solid line. 
 
10.   REFERENCES 
References are provided in the protocol.  
 
11.   TABLES, FIGURES, AND LISTINGS 
Planned tables, listings and figures for the study report are included in a separate document. 


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12.   APPENDIX A: SCHEDULE OF ASSESSMENTS AND ACTIVITIES 
 
 
 
 
 


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Footnotes: 
 
 


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13. DOCUMENT HISTORY
Version Date
Modified By
Summary of Changes
Draft 2
New efficacy endpoint included: Disease free survival
Version 1.0
Removed analysis section for laboratory test results (not 
available in the database).
Included placeholder for Appendix B for Immune- mediated 
adverse events (to be finalized prior to dbase lock)
Version 1.1
(2020-01-23)
Updated to align with Protocol Amendment 2 (26 December 
2019).
1. Replace CP-675,206 by tremelimumab 
2. Removed “(former A3671024)” from Protocol number
3. Removed Dosing Hiatus 
4. Removed Appendix B, List of Immune-Mediated 
Adverse Event
Version 1.1
(2020-02-17)
1. Add amendment protocol stopping study section to 
SAP 4.5
2. Remove Immune mediated AE from safety endpoint,
summary analysis, Appendix B from the SAP text
Version 2.0
(2020-03-03)
AZ requested to upgrade version from 1.1 to 2.0 to fit the 
publish system