Phase I/IIA, Open-Label, Safety, Tolerability, and Immunogenicity Study of INO-3112 Delivered by Electroporation (EP) in Women With Cervical Cancer After Chemoradiation for Newly Diagnosed Disease or Therapy for Recurrent and/or Persistent Disease
Phase: PHASE1
Conditions: Cervical Cancer
Sponsor: Inovio Pharmaceuticals

 
Official Title: 
PHASE I/IIA, OPEN-LABEL, SAFETY, TOLERABILITY, AND IMMUNOGENICITY 
STUDY OF INO-3112 DELIVERED BY ELECTROPORATION (EP) IN WOMEN 
WITH CERVICAL CANCER AFTER CHEMORADIATION FOR NEWLY DIAGNOSED 
DISEASE OR THERAPY FOR RECURRENT AND/OR PERSISTENT DISEASE 
NCT Number: 
NCT02172911 
 
Document Date: 
 
Protocol Version 2.1: 27 April 2016 
 
 
 
 
 
 
 
 

HPV-004 
PHASE I//IIA, OPEN-LABEL, SAFETY, TOLERABILITY, AND 
IMMUNOGENICITY STUDY OF INO-3112 DELIVERED BY 
ELECTROPORATION (EP) IN WOMEN WITH CERVICAL CANCER AFTER 
CHEMORADIATION FOR NEWLY DIAGNOSED DISEASE OR THERAPY 
FOR RECURRENT AND/OR PERSISTENT DISEASE 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
BB-IND # 15,946 
Version 2.1 
27 April 2016 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-2- 
PHASE I/IIA, OPEN-LABEL, SAFETY, TOLERABILITY, AND 
IMMUNOGENICITY STUDY OF INO-3112 DELIVERED BY 
ELECTROPORATION (EP) IN WOMEN WITH CERVICAL CANCER AFTER 
CHEMORADIATION FOR NEWLY DIAGNOSED DISEASE OR THERAPY 
FOR RECURRENT AND/OR PERSISTENT DISEASE 
Biologic Products:  
INO-3112 (VGX-3100 and INO-9012) 
Protocol Number:  
HPV-004 
Sponsor:  
Inovio Pharmaceuticals, Inc. 
 
660 West Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
Principal Investigator: 
, MD 
Medical Monitor:  
, MD  
 
Version and Date:  
Version 2.1 
27 April 2016  
CONFIDENTIAL 
The information in this document is considered privileged and confidential by 
Inovio Pharmaceuticals and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board/Ethics committee approval and 
informed consent, or as required by local regulatory authorities. Persons to whom 
this information is disclosed must be informed that this information is privileged 
and confidential and that it should not be further disclosed without the written 
permission of Inovio Pharmaceuticals. Any supplemental information added to this 
document 
is 
also 
confidential 
and 
proprietary 
information 
of 
Inovio 
Pharmaceuticals and must be kept in confidence in the same manner as the contents 
of this document. 
  

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-3- 
SUMMARY OF CHANGES 
The following is a list of significant protocol changes from v2.0 dated 12 June 2015 to 
v2.1 dated 27 April 2016. All other changes are administrative and do not significantly 
affect the safety of subjects, study scope, or scientific quality of the protocol.  
 
1. The duration of the study changed from 3 years from last study treatment/EP to 36 
weeks. This change still fulfills the study primary objectives, which include 
safety, tolerability and immunogenicity in subjects with cervical cancer and 
received INO-3112/EP treatment.  
2. Updated the estimated number of Study Centers  
3. Number of subjects to be enrolled in the study changed from 30 to 10 subjects. 
This is mainly due to study primary objectives and the challenge in trial 
operation/enrollment.  
4. Specified in section 6.1.1 and 6.7 that the subjects with HPV-16 and/or HPV-18 
positive from In-situ hybridization (ISH) or polymerase chain reaction (PCR) 
assays will be eligible for the study.  
5. Added the option to conduct Weeks 2, 6, 8 and 10 visits as phone visit or in-
person office visit. This change intends to be more convenient for study subjects.  
6. Eliminated collection of the blood samples at Weeks 2, 4, 6, 10 and 14.  
7. The medical monitor and associated contact information was updated to reflect a 
resourcing update by the Sponsor. All responsibilities of the updated medical 
monitor will remain the same.  
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
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PROTOCOL ACKNOWLEDGEMENT 
 
 
I have read this Protocol and agree that it contains all necessary details for carrying out 
the study described. I understand that it must be reviewed by the Institutional Review 
Board or Independent Ethics Committee overseeing the conduct of the study and 
approved or given favorable opinion before implementation. 
 
The signature of the Principal Investigator and Sponsor below constitute their approval of 
this protocol and proved the necessary assurances that this study will be conducted 
according to The Declaration of Helsinki, GCP, ICH guidelines, local legal and 
regulatory regulations as well as to all stipulations of the protocol in both the clinical and 
administrative sections, including statements regarding confidentiality. 
 
 
 
 
_________________________________ 
 
 
_________________ 
Investigator’s printed name and signature 
 
 
Date 
 
 
 
_________________________________ 
 
 
_________________ 
, MD                                                               Date 
Medical Monitor 
 
 
 
 
 
 
 
 
 
Protocol Number: HPV-004 
Site Number:  
Version Number/Version Date: v2.1/27 April 2016 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-5- 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .............................................................................................. 3 
TABLE OF CONTENTS .................................................................................................. 5 
CLINICAL PROTOCOL SYNOPSIS ................................................................................ 9 
Table 1: HPV-004 Schedule of Events ......................................................................... 14 
1 
INTRODUCTION ............................................................................................. 16 
1.1 
Background and Rationale ................................................................................ 16 
1.1.1 Epidemiology of HPV Infection and Cervical Cancer ..................................... 16 
1.1.2 Primary Prevention of HPV Disease:  Screening and Prophylactic Vaccination
 
16 
1.1.3 Rationale for a HPV Immunotherapy ............................................................... 17 
1.1.4 Target Organ for a Therapeutic HPV Immunotherapy – Skeletal Muscle ....... 20 
1.1.5 Delivery Method – Injection / Electroporation (EP) ........................................ 20 
1.2 
Plasmid DNA Immunotherapy Agents (INO-3112) ......................................... 21 
1.2.1 VGX-3100 ........................................................................................................... 21 
1.2.2 INO-9012 ............................................................................................................. 21 
1.3 
Dose and Regimen Rationale ............................................................................ 21 
1.3.1 Previous Human Experience with VGX-3100 .................................................. 22 
1.3.2 Previous Human Experience with INO-9012 ................................................... 24 
1.4  
Risks/Benefit Assessment ................................................................................. 25 
1.4.1 Current Therapy for Stage IB-IVB Cervical Cancer ........................................ 25 
1.4.2 Rationale for Study Design ............................................................................... 26 
1.4.3 Potential Risks of DNA Immunotherapy Delivery with Electroporation ......... 28 
2 
HYPOTHESIS AND STUDY OBJECTIVES .................................................. 29 
2.1 
Hypothesis ......................................................................................................... 29 
2.2 
Primary Objective .............................................................................................. 29 
2.3 
Secondary Objective .......................................................................................... 29 
2.4 
Exploratory Objective ....................................................................................... 29 
3 
STUDY DESIGN .............................................................................................. 30 
4 
SELECTION AND ENROLLMENT OF SUBJECTS ..................................... 32 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
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4.1 
Inclusion Criteria ............................................................................................... 32 
4.2 
Exclusion Criteria .............................................................................................. 33 
4.3  
Supplementation of Study Subjects ................................................................... 34 
4.4 
Discontinuation/Withdrawal of Study Subjects ................................................ 34 
5 
INVESTIGATIONAL PRODUCTS ................................................................. 35 
5.1 
Investigational Product ...................................................................................... 35 
5.2 
Packaging and Labeling .................................................................................... 36 
5.3 
Handling of INO-3112 ...................................................................................... 36 
5.4 
Dispensing of INO-3112 ................................................................................... 37 
5.5 
Records of INO-3112 Disposition at Investigational Sites ............................... 37 
5.6 
Return and Destruction of Investigational Products .......................................... 37 
5.7 
Use of CELLECTRA-5P Electroporation Device .......................................... 38 
5.8 
Investigational Device Accountability .............................................................. 38 
6 
STUDY PROCEDURES AND TREATMENTS.............................................. 39 
6.1 
Procedure by Visit ............................................................................................. 39 
6.1.1 Screening Evaluations ....................................................................................... 39 
6.1.2 Study Evaluations ............................................................................................. 40 
6.2 
Timing and Evaluations ..................................................................................... 43 
6.2.1 Informed Consent ............................................................................................. 43 
6.2.2 Assignment of Screening/Allocation Numbers ................................................ 43 
6.2.3 Medical History ................................................................................................ 43 
6.2.4 Safety Assessments ........................................................................................... 44 
6.2.4.2  Physical Assessments ...................................................................................... 44 
6.2.4.3  Post-Treatment Reaction Assessment .............................................................. 44 
6.2.4.4  ................................................................................... Participant Reminder Card
 
45 
6.2.4.5  Vital Signs ........................................................................................................ 45 
6.2.4.6  Weight and Height ........................................................................................... 45 
6.2.4.7  12-lead ECGs ................................................................................................... 45 
6.2.4.8  Pregnancy Test ................................................................................................. 45 
6.2.4.9  Laboratory Evaluations .................................................................................... 46 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
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6.2.4.10   .................................................................................................... PET/CT Scan
 
46 
6.3 
Study Treatment/EP with INO-3112 ................................................................. 47 
6.3.1 Management of anxiety and pain due to EP procedure .................................... 47 
6.4 
Assessment of Clinical Adverse Events ............................................................ 48 
6.5 
Assessment of Laboratory Abnormalities ......................................................... 48 
6.6 
Assessment of Injection Site Reactions ............................................................. 48 
6.7 
Cervical Virologic and Peripheral Blood Immunogenicity Assessment ........... 49 
6.8 
Disease Status .................................................................................................... 52 
6.9 
Concomitant Medications/Medical Care ........................................................... 52 
6.10 
Permitted Supportive Therapy .......................................................................... 52 
6.11 
HLA Testing ...................................................................................................... 52 
6.12 
Downloading of EP data from CELLECTRA®-5P device ................................ 52 
6.13 
Restrictions ........................................................................................................ 52 
7 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ......... 53 
7.1 
Safety Parameters .............................................................................................. 53 
7.1.2 Serious Adverse Events (SAEs) ....................................................................... 54 
7.1.3 Severity Codes for AEs ..................................................................................... 55 
7.2 
Causal Relationship of Clinical Material to AEs .............................................. 56 
7.2.1 Abnormal Laboratory Value ............................................................................. 56 
7.2.2 Post-Study Reporting Requirements ................................................................. 57 
7.3 
Methods and Timing of the Collection and Recording of Safety Data ............. 57 
7.4 
Procedures for Documenting Pregnancy During Study .................................... 58 
7.5 
Toxicity Management ........................................................................................ 58 
7.5.1 Criteria for Halting of Study Enrollment .......................................................... 58 
7.5.2 Events Requiring Expedited Reporting ............................................................ 59 
7.5.3 Stopping Rules (Criteria for Pausing of Study) ................................................ 59 
8 
STATISTICAL CONSIDERATIONS .............................................................. 60 
8.1 
Sample Size Considerations .............................................................................. 60 
8.3 
Analysis of Immune Responses ........................................................................ 60 
8.4 
Analysis of Clinical Responses ......................................................................... 60 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-8- 
8.5 
Summary of Demographic and Other Baseline Characteristics ........................ 60 
8.6 
Missing Values .................................................................................................. 60 
8.7 
Site Effects ........................................................................................................ 60 
9 
DATA COLLECTION, MONITORING, AND AE REPORTING .................. 61 
9.1 
Records to Be Kept ............................................................................................ 61 
9.2 
Safety and Quality Monitoring and Record Availability .................................. 61 
9.3 
Adverse Experience (AE) Reporting ................................................................. 62 
9.3.1 Study Reporting Period of Adverse Events ...................................................... 62 
9.3.2 Study Reporting Period of Serious Adverse Events ......................................... 62 
9.3.3 Notification of Serious Adverse Events ............................................................ 63 
9.4 
Reporting of Device Related Complaints .......................................................... 64 
9.5 
Study Discontinuation ....................................................................................... 64 
10 
PUBLICATION OF RESEARCH FINDINGS ................................................. 64 
11 
LIST OF ABBREVIATIONS ........................................................................... 66 
12 
REFERENCES .................................................................................................. 68 
13 
APPENDICES ................................................................................................... 73 
13.1 
Appendix 1: Subject Identification Fax Form ................................................... 73 
13.2 
Appendix 2: ECOG Performance Status ........................................................... 74 
13.3 
Appendix 3: Standard Chemoradiation Guidelines ........................................... 75 
13.4 
Appendix 4:  Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 dated June 14, 2010 ..................................................................... 85 
13.5 
Appendix 5:  Acute Radiation Morbidity Scoring Criteria (RTOG) ................. 86 
13.6 
Appendix 6:  Preparation of Investigational Products ....................................... 88 
13.7 
Appendix 7: CELLECTRA®-5P Error Reporting Form ................................... 89 
13.8 
Appendix 
8: 
New 
York 
Heart 
Association 
(NYHA) 
Functional 
Classification ..................................................................................................... 90 
13.9 
Appendix 9: Participant Reminder Card ........................................................... 91 
13.10 Appendix 10: RECIST ...................................................................................... 92 
 
 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-9- 
 
 
CLINICAL PROTOCOL SYNOPSIS 
Title of Study: Phase I/IIA, Open-Label, Safety, Tolerability, and Immunogenicity Study of INO-
3112 Delivered by Electroporation (EP) in Women with Cervical Cancer after Chemoradiation for 
Newly Diagnosed Disease or Therapy for Recurrent and/or Persistent Disease 
Estimated Number of Study Centers and Countries/Regions: 2 sites (United States)  
Number of Subjects : Approximately 10 subjects 
Study Phase: I/IIa 
Research Hypothesis: Immunotherapy with INO-3112 delivered by intramuscular (IM) injection 
followed by EP with CELLECTRA®-5P will be immunogenic and well tolerated in women with 
newly diagnosed, inoperable cervical cancer associated with HPV-16 and/or HPV-18 after 
completion of standard chemoradiation therapy with curative intent (Cohort 1) or in women with 
persistent and/or recurrent cervical cancer associated with HPV-16 and/or HPV-18 following 
salvage therapy (Cohort 2) and will not be associated with any significant increased toxicity 
compared to that expected/reported with “standard” therapy alone. 
Primary Objective:  
• 
Evaluate the safety and tolerability of immunotherapy with INO-3112 when delivered IM 
followed by EP with CELLECTRA®-5P in women with newly diagnosed, inoperable 
cervical cancer associated with HPV-16 and/or HPV-18 after completion of standard 
chemoradiation therapy with curative intent (Cohort 1) or in women with persistent and/or 
recurrent cervical cancer associated with HPV-16 and/or HPV-18 following salvage 
therapy (Cohort 2) compared to that expected/reported with “standard” therapy alone. 
Secondary Objective: 
• 
Evaluate the cellular and humoral immune responses to immunotherapy with INO-3112 
delivered IM followed by EP with CELLECTRA®-5P in women with newly diagnosed, 
inoperable cervical cancer associated with HPV-16 and/or HPV-18 after completion of 
standard chemoradiation therapy with curative intent (Cohort 1) or in women with 
persistent and/or recurrent cervical cancer associated with HPV-16 and/or HPV-18 
following salvage therapy (Cohort 2). 
Exploratory Objective: 
• 
Evaluate clinical responses (disease-free survival and progression-free survival) following 
treatment with INO-3112 delivered intramuscularly followed by EP with CELLECTRA®-
5P in women with newly diagnosed, inoperable cervical cancer associated with HPV-16 
and/or HPV-18 after completion of standard chemoradiation therapy with curative intent 
(Cohort 1) or in women with persistent and/or recurrent cervical cancer associated with 
HPV-16 and/or HPV-18 following salvage therapy (Cohort 2).  
 
 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-10- 
Study Design: This is a Phase I/IIa, open-label study to evaluate the safety, tolerability, and 
immunogenicity of INO-3112 [6 mg of VGX-3100 (2 separate DNA plasmids encoding E6 and 
E7 proteins of HPV 16 and HPV 18) and 1 mg of INO-9012 (DNA plasmid encoding human 
interleukin 12)] delivered IM by EP in approximately 10 female subjects with biopsy-proven, 
Stage IB-IVB inoperable invasive cervical carcinoma associated with HPV-16 and/or HPV-18 
who have completed treatment with standard chemoradiation therapy with curative intent (Cohort 
1) or in subjects with persistent and/or recurrent cervical cancer  associated with HPV-16 and/or 
HPV-18 following salvage therapy (Cohort 2).   
Eligible subjects who consent to participate in the study will receive a 1.1 mL IM injection of 
INO-3112 in the deltoid followed immediately by EP with CELLECTRA®-5P. If the deltoid is not 
a suitable location, the IM injection should be in the lateral quadriceps followed immediately by 
EP with CELLECTRA®-5P. All subjects (Cohorts 1 and 2) will receive a 4-dose series of INO-
3112. The first study treatment/EP after completion of standard chemoradiation (Cohort 1) or 
salvage  therapy (Cohort 2) will be designated as “Day 0”, the second dose will be administered at 
Week 4, the third dose at Week 8, and the fourth (final) treatment will be administered  at Week 
12.  
Cohort 1:  
Cohort 1 will include subjects with biopsy-proven, Stage IB-IVB inoperable, newly diagnosed, 
invasive cervical carcinoma associated with HPV-16 and/or HPV-18 treated with standard 
chemoradiation therapy with curative intent.  
All subjects in Cohort 1 must receive their first study treatment (Day 0) within 2 weeks after 
completing a course of standard radiation therapy (external beam and brachytherapy) administered 
concurrently with platinum based therapy with curative intent. (Refer to Appendix 3: Standard 
Chemoradiation Guidelines) 
  
Cohort 2: 
Cohort 2 will include subjects with persistent and/or recurrent cervical carcinoma associated with 
HPV-16 and/or HPV-18 treated with salvage therapy (chemotherapy and/or radiation therapy). 
All subjects in Cohort 2 must receive their first study treatment (Day 0) no sooner than 2 weeks 
and no later than 4 weeks after completing a course of salvage therapy. If in the investigators 
opinion, there are no additional salvage therapy options, the subject may be enrolled in Cohort 2 
without having received salvage therapy immediately prior to enrollment.  
Primary Safety Endpoints:   
1. Incidence of adverse events (all, severe [graded per Common Toxicity Criteria for Adverse 
Events (CTCAE) v4.03], unexpected, serious) classified by system organ class (SOC), 
preferred term, severity, and relationship to study medication and schedule 
2. Injection site reactions including pain, tenderness, erythema and induration at the 
administration site 
3. Rates of acute gastrointestinal, genitourinary, or other chemoradiation side effects above the 
expected, graded per Acute Radiation Morbidity Scoring Criteria (RTOG) 
4. Changes in laboratory parameters from baseline 
 
 
 
 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-11- 
 
Study Design Contd.: 
Secondary Immunologic Endpoints:  
1. Antigen-specific cellular immune responses to INO-3112 in blood samples obtained from 
subjects per study schedule: 
a. Interferon-γ secreting T lymphocytes in PBMC by ELISpot 
b. Flow Cytometry for T-cell activation, cytolytic phenotype, and memory phenotype in 
PBMC 
2. Antigen-specific humoral responses to HPV–E6 and –E7 by ELISA per study schedule 
 
Exploratory Clinical Endpoints:  
1. Changes in standard uptake volume (SUV) on PET/CT scans performed at baseline vs follow-
up PET/CT scans obtained at specified time points 
2. Evaluation of subjects relative immune competence longitudinally throughout the study 
starting at the screening visit (for details refer to Section 6.7: Cervical Virologic and 
Peripheral Blood Immunogenicity Assessment)  
3. Changes in cervical histology from the screening biopsy as compared to the week 16 biopsy 
4. Local immune responses to INO-3112 in tumor tissue samples obtained at week 16 
5. Disease-free survival assessed in accordance with  RECIST v1.1 (refer to Appendix 10) as 
follows:  
• 
Clinical evaluations for disease response will be conducted at all study visits (as 
assessed by clinical signs and symptoms of disease progression) 
• 
A baseline PET/CT scan will be obtained on each subject within 4 weeks prior to  
Day 0 and then PET/CT scans for disease progression will be obtained for all subjects 
3-4 months after Day 0 and 3-5 months thereafter per standard of care/in accordance 
with local guidelines and institutional practices. Additional PET/CT scans may be 
obtained at other time points if clinically indicated to confirm a clinical diagnosis of 
disease progression based on signs and symptoms. 
Inclusion Criteria 
a) Written informed consent in accordance with institutional guidelines. If required by local 
law, candidates must also authorize the release and use of protected health information 
(PHI); 
b) Female subjects age 18 years or older;  
c) Histological diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous 
cell carcinoma of the cervix. Not accepted are small cell, clear cell and other rare variants 
of the classical adenocarcinoma; 
d) Histologically confirmed, Stage IB-IVB, invasive cervical carcinoma associated with 
HPV-16 and/or HPV-18  and meeting the following eligibility criteria for either Cohort 1 
or Cohort 2; 
 
 
 
 
 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
-12- 
Inclusion Criteria Contd. 
1. Cohort 1 
• Newly diagnosed inoperable cervical cancer treated with chemoradiation therapy 
with curative intent and a life expectancy of at least 12 months as assessed by the 
investigator. 
o No CNS/spinal metastases 
• Able to initiate study treatment (Day 0) within 2 weeks of completion of last 
chemoradiation treatment; 
o Platinum based treatment (alone or in combination with other drugs); 5 
weekly courses of Cisplatin 40 mg/m2 completed within 10 weeks of its 
initiation 
o Standard radiation therapy (external beam and brachytherapy); completed 
within 10 weeks of its initiation 
o Brachytherapy; must be the last treatment if the subject is receiving 
sequential brachytherapy following the chemoradiation therapy 
2. Cohort 2 
• Persistent and/or recurrent cervical cancer 
o No CNS/spinal metastases 
• Able to initiate study treatment (Day 0) at least 2 weeks after but no more than 4 
weeks after completion of salvage therapy (If in the investigators opinion, there 
are no additional salvage therapy options, the subject may be enrolled in Cohort 
2 without having received salvage therapy immediately prior to enrollment.) 
• Subject has a life expectancy of at least 12 months as assessed by the investigator 
e) ECG with no clinically significant findings as assessed by the investigator performed 
within 30 days of signing the informed consent form (ICF); 
f) Chemistry, liver function tests, renal function, total creatine phosphokinase (CPK) and 
hematology lab results must be ≤ Grade 1 at the time of  screening, in accordance with the 
CTCAE v4.03; 
g) Eastern Cooperative Oncology Group (ECOG) Performance status of ≤ 1;  
h) Adequate venous access for repeated blood sampling according to study schedule; 
i) Women of child-bearing potential must have a negative serum pregnancy test and agree to 
remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), or use two 
medically effective methods of contraception (e.g., oral contraception, barrier methods, 
spermicide, intrauterine device (IUD)). This requirement should be followed from 
screening through 24 weeks after last study treatment/EP. Whole pelvis external beam 
radiation therapy (EBRT) followed by intracavitary (IC) therapy for cervical cancer is 
considered to be an irreversible form of contraception; 
j) Able and willing to comply with all study procedures.  
 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
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Exclusion Criteria: 
a) Pregnancy or breastfeeding; 
b) History of previous therapeutic HPV vaccination (individuals who have been immunized 
with licensed prophylactic HPV vaccines (e.g. Gardasil®, Cervarix®) are not excluded); 
c) Prior exposure to an investigational agent or device within 30 days of signing the ICF.  Of 
note, the subject may participate in observational studies; 
d) Positive serological test for human immunodeficiency virus (HIV), Hepatitis B or 
Hepatitis C or history of HIV infection, Hepatitis B or Hepatitis C (women with cured 
HCV will be allowed; subject must have had an serologic test performed within 12 
months of informed consent); 
e) Prior major surgery within 4 weeks of first study treatment/EP from which the subject has 
not yet recovered to baseline; 
f) High medical risks because of non-malignant systemic disease or with active uncontrolled 
infection; 
g) Current malignancies at other sites, with the exception of adequately treated basal or 
squamous cell carcinoma of the skin; 
- 
Cancer survivors, who have undergone curative therapy for a prior malignancy, have 
no evidence of that disease for five years and are deemed at low risk for recurrence, 
are eligible for the study; 
h) Congestive heart failure or prior history of New York Heart Association (NYHA) class 
III/ IV cardiac disease (refer to Appendix 8); 
i) Any concurrent condition requiring the continued use of systemic or topical steroids at or 
near the injection site, excluding non-systemic (e.g. inhaled and eye drop-containing) 
corticosteroids or the use of other immunosuppressive agents. All other corticosteroids 
must be discontinued > 4 weeks prior to Day 0 of study product administration; 
j) Any cardiac pre-excitation syndromes (such as Wolff-Parkinson-White); 
k) History of seizures (unless seizure free for 5 years); 
l) Less than two acceptable sites exist for IM injection and EP between use of the deltoid 
and lateral quadriceps muscles. A site for injection/EP is not acceptable if there are tattoos 
or scars within 2 cm of the injection/EP site or if there is implanted metal within the same 
limb. Any device implanted in the chest (e.g., cardiac pacemaker or defibrillator) excludes 
the use of the deltoid muscle on the same side of the body; 
m) Administration of any non-study related vaccine within 2 weeks of Day 0;  
n) Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
o) Imprisonment or compulsory detainment (involuntary incarceration) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
p) History of immunosuppressive or autoimmune disease; 
q) Any other illnesses or conditions that in the opinion of the investigator may affect the 
safety of the subject or limit the evaluation of a subject or any study endpoint. 
 

INO-3112 
 
HPV-004 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
v 2.1 
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Table 1: HPV-004 Schedule of Events 
Tests 
S 
D0 
Weeksa 
2 
4 
6 
8 
10 
12 
14 
16 
24 
32 
36 
Study Procedures 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medical and CIN/Cancer history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
Physical exam/assessmentc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical/Clinical assessment 
X 
X 
Xb 
X 
Xb 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
Chemo/RT Effects/Adverse Events 
Xm 
X 
Xb 
X 
  
  
  
  
  
  
  
  
  
Adverse events 
X 
X 
Xb 
X 
Xb 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease Statusd 
X 
  
  
  
  
  
  
  
  
X 
  
X 
X 
Vital signs (Height and Weight)e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Histologic HPV assessmentf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Tumor biopsy collection 
Xl 
  
  
  
  
  
  
  
  
X 
  
  
  
ThinPrep™ sample (if obtainable) 
X 
X 
  
  
  
  
  
  
  
X 
  
  
X 
Digene swab (2) (if obtainable) 
X 
X 
  
  
  
  
  
  
  
X 
  
  
X 
PET/CT scan 
Xn 
  
  
  
  
  
  
  
  
Xp 
  
Xq 
Xq 
Laboratory Procedures 
CBC w/ differential 
X 
Xo 
  
Xo 
  
Xo 
  
Xo 
  
Xo 
  
  
  
Serum chemistryg 
X 
Xo 
  
Xo 
  
Xo 
  
Xo 
  
Xo 
  
  
  
Urinalysish 
X 
  
  
  
  
  
  
  
  
  
  
  
  
CPK 
X 
  
  
  
  
  
  
  
  
Xo 
  
  
  
Pregnancy Testi 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
HIV/ hepatitis serology 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Blood immunologic samplesj, 
X 
X 
  
  
 X 
  
  
  
X 
 X 
 X 
X 
Immunotherapy Procedures 
Immunotherapy/EP 
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
Post treatment reactionk 
  
X 
Xb 
X 
Xb 
X  
Xb 
X 
Xb 
X 
  
  
  
Download EP data 
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
Participant Reminder Card 
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
Review participant reminder card 
  
  
Xb 
X 
Xb 
X  
Xb 
X 
Xb 
X 
  
  
  
 
Wks 2, 6, 8 and 14 visits may be performed as an in-person office visit or a telephone call. After completing 
medical/clinical assessment, reviewing PRC and collecting information on AE with the subject on the 
phone, the investigator will determine whether an office visit is needed for further evaluation.  
Cohort 1: Subjects in Cohort 1 can be screened either prior to initiation of chemoradiation, or during 
chemoradiation and should be enrolled such that their first study treatment (Day 0) will be delivered 
within 2 weeks of completing their chemoradiation therapy;  
Cohort 2: Subjects in Cohort 2 can be screened and enrolled such that their first study treatment (Day 0) is 
no sooner than 2 weeks and no later than 4 weeks after completing the salvage therapy. If in the 

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Date: 27 April 2016 
 
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investigators opinion, there are no additional salvage therapy options, the subject may be enrolled in 
Cohort 2 without having received salvage therapy immediately prior to enrollment. 
a Procedures and visits scheduled from Day 0 through Wk 16 must occur ±1 week of scheduled time. 
Procedures and visits scheduled from Week 24 to Week 36 must occur ± 2 weeks of scheduled time.  
b assessment to be performed if visit done as phone-call 
c Targeted physical examination at all visits except full examination at screening (includes complete 
gynecological exam) and discharge visit 
d Disease status should be categorized into 1) No evidence of disease (NED) 2) Partial Response 3) Stable 
disease 4) Progressive disease 
eTemperature, respiratory rate, blood pressure, heart rate, weight and height. Height collected at screening 
only 
f Paraffin embedded tissue obtained for diagnosis of cervical cancer must be available for HPV testing   
g Serum chemistry includes glucose, albumin, total protein, SGPT, SGOT, alkaline phosphatase, total 
bilirubin, blood urea nitrogen (BUN), calcium, creatinine, electrolytes (sodium, potassium, chloride, carbon 
dioxide or bicarbonate) 
h Urine samples will be tested by dipstick for glucose, protein, and hematuria.  
i Serum pregnancy test required at screening. Urine pregnancy test should be used prior to tumor biopsy and 
prior to each study treatment/EP 
j At least 34 mL (4 x 8.5 mL tubes) whole blood in Acid Citrate Dextrose tubes and 4 mL serum per time 
point. A total of at least 68 mL whole blood and 4 mL serum should be collected prior to dosing on Day 0 
k Assessed 30 to 45 minutes after study treatment/EP and at post-treatment visits 
l A tumor biopsy collection is required at screening if residual tissue and/or unstained slides are not available 
m Chemo/RT effects to be assessed at screening if subject is screened during chemoradiation 
n PET/CT to include standard uptake volume, must be performed within 4 weeks prior to  Day 0 
o All labs for Day 0 and those associated with any treatment visit should be available prior to treatment and 
collected no more than 48 hours prior to treatment  
p PET/CT will be performed 3-4 months after Day 0  
q Not required at study discharge if performed at wk 32 
rImmune competence will be evaluated longitudinally throughout the study from the time of screening visit. 
No additional blood collection required. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 
INTRODUCTION 
1.1 
Background and Rationale 
1.1.1 Epidemiology of HPV Infection and Cervical Cancer 
More than 200 genotypes of human papillomavirus (HPV) are known, of which 
approximately 40 can infect the anogenital mucosa [World Health Organization 
2008]. Persistent infection with oncogenic HPV genotypes is the proximate cause 
of virtually every squamous cervical cancer. HPV types 16 and 18 are the most 
prevalent types of highly oncogenic HPV associated with cervical cancer, 
accounting for approximately two-thirds of all cases of cervical cancer [Munoz 
2003]. 
HPV infection is characterized by ongoing viral replication and shedding, and is 
associated with early pathologic changes (cervical intraepithelial neoplasia; CIN). 
Most genital HPV infections clear spontaneously. Persistent infection with a 
highly oncogenic HPV type is associated with integration of the viral genome into 
the host genome, with subsequent constitutive expression of the viral proteins, E6 
and E7. Expression of these oncoproteins is functionally required for disease 
initiation and persistence, as E6 binds and targets p53 for degradation, and E7 
targets pRb. Viral integration is found in high grade cervical dysplasia (CIN2/3), 
the intraepithelial lesion which is the immediate precursor to invasive disease. 
The vast majority of invasive cancers of the cervix are thought to arise from 
untreated CIN2/3 [Munger 2002]. Because these viral, non-‘self’ proteins are 
functionally required for disease, and are expressed only in diseased tissue, not in 
normal cells, they present compelling antigenic targets for therapeutic 
vaccination. 
1.1.2 Primary Prevention of HPV Disease:  Screening and Prophylactic 
Vaccination 
Despite screening programs that have dramatically reduced the incidence of 
cervical cancer, approximately 12,900 American women are diagnosed with this 
disease annually, and 4100 die from it [ACS 2015]. Worldwide, cervical cancer is 
the fourth most common cancer in women resulting in approximately 268,000 
deaths yearly [GLOBOCAN 2012]. 
In 2006, the U.S. Food and Drug Administration (FDA) licensed a quadrivalent 
HPV vaccine for use in females 9-26 years of age to prevent diseases caused by 
HPV types 6, 11, 16 and 18 [Centers for Disease Control and Prevention 2007]. 
The primary analysis of a prospective, randomized, double-blind, trial involving 
10,565 women 15-26 years of age with no virologic evidence of infection by HPV 
16 or 18, who were randomized 1:1 to receive a 3-dose course of vaccine or 
placebo, found the vaccine efficacy for prevention of the primary composite 
endpoint (prevention of HPV-16 or 18 infection resulting in CIN2 or 3) after 3 
years to be 98% (95% C.I. 86%, 100%) [Future II Study Group 2007]. In October 
2009, a bivalent vaccine was approved for use in women to prevent diseases 
caused by HPV types 16 and 18. 

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Recently available prophylactic HPV vaccines are unlikely to impact the burden 
of disease in the near future; protection is type-specific, and vaccine delivery 
requires intense infrastructure, including the need for three inoculations. Indeed, 
in the United States, only 44% of eligible teen (13-17 years) girls received any 
HPV vaccine, and ~27% completed the three-vaccination series in 2009.  
Furthermore, ensuring vaccination prior to HPV exposure can be challenging 
[CDC 2010]. 
1.1.3 Rationale for a HPV Immunotherapy 
While the currently available prophylactic HPV vaccines are highly effective in 
preventing infection and the development of high-grade CIN caused by HPV 
types 16 and 18, these have no therapeutic effect, and therefore are of no value for 
women already infected with these oncogenic types. Treatment for CIN 2/3 
usually consists of either surgical removal of the affected tissue by cone biopsy or 
a loop electrical excision procedure (LEEP), or ablative therapy via laser, or 
cryotherapy. Invasive cervical cancer may be treated by radical hysterectomy, 
and/or combination radiation and chemotherapy. 
Intraepithelial HPV disease is indolent, and not all CIN 2/3 progress to invasive 
disease. In fact, in immune-competent subjects, spontaneous regression of CIN 
2/3 over a relatively brief timeframe of 6 months is estimated at 30-40% [Trimble 
2005, Castle 2009, Moscicki 2010]. In subjects with CIN 2/3 associated with 
HPV-16, the rate of spontaneous regression is lower, in the range of 25% 
[Trimble 2005, Castle 2009, Moscicki 2010]. Boosting cell-mediated immune 
responses to the early HPV E6 and E7 proteins may lead to elimination of 
immortalized cells and so prevent the development of invasive disease. [Kenter 
2009]. The ability of immunotherapy with VGX-3100 delivered by EP to reverse 
high grade dysplasia is currently being studied in a prospective global, placebo-
controlled, randomized phase 2 study in women with CIN2 and CIN3 associated 
with HPV-16 and/or HPV-18. A pre-planned interim analysis of the study data 
completed in July 2014 revealed that the study met its primary endpoint 
(histopathologic regression of lesions) and secondary endpoint (histopathologic 
regression of lesions in the context of elimination of HPV16 and/or 18 infection) 
demonstrating a highly statistically significant improvement in the VGX-3100 
arm (p<0.017 and p<0.001 respectively). Treatment of HPV16 and/or 18 positive 
patients with CIN2 or 3 was generally safe as evidenced by the lack of statistical 
significance between the frequencies of adverse events reported in the placebo 
arm as compared to the VGX-3100 treated arm. Treatment with VGX-3100 was 
able to induce a robust immune response in the periphery as gauged by IFNg 
ELISpot as well as in the tissue as examined using immunohistochemistry. These 
data reveal the highly promising potential of therapeutic immunization with DNA 
followed by electroporation for the treatment of HPV-16 and/or HPV-18 related 
precancerous cervical disease in women.  
There is early data regarding the use of therapeutic vaccines for cervical cancer 
which does appear to demonstrate some HPV-specific antibody response in pre-

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clinical and early clinical studies [Borysiewicz 1996, Cui 2005, Cui 2006, 
Jochmus 1999, Liu 2000, Ohlschlager 2009, Welters 2008].  
Some clinical studies have employed the combination of radiotherapy with 
immunotherapy and have been shown to induce tumor-specific and innate 
immunity [Chi 2005, Gulley 2005]. Radiation has been shown to increase 
immunogenicity of solid tumors by several mechanisms, including enhancing the 
expression of MHC class I molecules [Reits 2006], as well as increasing 
expression of adhesion molecules by endothelial cells [Gaugler 1997]. These and 
other phenotypic changes subsequent to radiation render established disease more 
susceptible to T-cell-mediated lysis [Garnett 2004]. Chemotherapeutic regimens, 
including cisplatin (CDDP) can also render solid tumors more susceptible to 
immunologic intervention [Gelbard 2006, Matsuzaki 2000].  
However, to date, there are limited data investigating the use of a therapeutic 
vaccine for cervical cancer in the setting of chemoradiotherapy. Encouraging 
synergistic results have been demonstrated in animal models [Tseng 2009]. It was 
observed that TC-1 tumor-bearing mice treated with radiotherapy combined with 
CRT/E7(detox) DNA vaccination generated significant therapeutic anti-tumor 
effects and the highest frequency of E7-specific CD8+ T-cells in the tumors and 
spleens of treated mice. Furthermore, treatment with radiotherapy was shown to 
render the TC-1 tumor cells more susceptible to lysis by E7-specific CTLs 
(cytotoxic T lymphocytes). In addition, it was observed that treatment with 
radiotherapy during the second DNA vaccination generated the highest frequency 
of E7-specific CD8+ T-cells in the tumors and spleens of TC-1 tumor-bearing 
mice. Finally, TC-1 tumor-bearing mice treated with the chemotherapy in 
combination with radiation and CRT/E7(detox) DNA vaccination generated 
significantly enhanced therapeutic anti-tumor effects [Tseng 2009].  
Rationale for DNA based Immunotherapy:  DNA vaccines have several 
advantages over traditional vaccines such as live attenuated virus and recombinant 
protein-based vaccines (engineered specificity, production, safety). To date, DNA 
vaccines have been well-tolerated in humans. In fact, clinical data from hundreds 
of subjects vaccinated with DNA vaccines suggests that intramuscular 
administration alone elicits barely detectable systemic immune responses to 
vaccine antigens. Preclinical safety studies in the literature have not demonstrated 
evidence of plasmid integration [Martin 1999, Nichols 1995]. Similar results were 
obtained in the pre-clinical safety and toxicology studies performed with VGX-
3100 in rabbits. In our studies with VGX-3100, the rates of plasmid clearance 
from the injection site skin and muscle were similar whether the plasmid was 
delivered with or without electroporation suggesting that the delivery method did 
not result in an increased persistence at the injection site. 
Unlike viral vector-based constructs, DNA vaccines can be used for repeated 
administration as the efficacy of plasmid vectors are not influenced by pre-
existing neutralizing antibodies [Chattergoon 1997]. Furthermore, the ability to 
engineer specific targeting of multiple antigenic components allows the inclusion 
of specific immunogens, adjuvants or targeting sequences. VGX-3100 is 

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comprised of plasmids targeting E6 and E7 proteins of both HPV subtypes 16 and 
18, and is delivered via electroporation (EP) using the CELLECTRA-5P 
constant current device. 
Individual candidate vaccine plasmids were developed for both HPV-16 
(pCon16E6E7) and HPV-18 (pCon18E6E7), pre-clinical expression and 
immunogenicity were demonstrated, and then the plasmids were combined and 
formulated to produce VGX-3100. Preclinical toxicology and biodistribution 
studies with VGX-3100 have demonstrated an acceptable safety profile in the 
New Zealand White Rabbit.  
Several pre-clinical studies were performed to further characterize the two 
plasmids. The immunogenicity of DNA delivered by intramuscular (IM) injection 
alone was compared to DNA delivery via electroporation (IM+EP). 
Immunogenicity was compared to vector-alone controls in mice and non-human 
primates (rhesus macaques).  
HPV-16 and HPV-18 E6 and E7 proteins were appropriately expressed and 
processed in two separate animal studies (mouse and rhesus macaques). Indeed in 
both cases, robust cell mediated immune (CMI) responses were elicited. CMI 
responses were enhanced by about 3-fold using EP delivery vs. DNA alone at 
doses as low as 10 µg when delivered by EP. Further, CMI was elicited for both 
the HPV-16 and 18 constructs based on similar ELISpot results.  
A side-by-side comparison at the low DNA dose indicated that the responses were 
approximately 3-fold greater when delivered via IM+EP compared to IM alone. 
Similar levels of CMI responses were elicited when the plasmid DNA was 
delivered at a 10-fold higher dose using IM alone suggesting that the use of EP 
technology will pave the way for development of dose-sparing immunotherapy 
agents. Importantly, in both cases, the epitopes recognized were well 
characterized E6 and E7 epitopes suggesting that normal effective processing of 
antigens occurs following vaccination regardless of whether the antigens were 
delivered via IM+EP or IM alone. This phenomenon has been observed in pre-
clinical studies with other DNA plasmid candidates as well (e.g. influenza, HIV), 
where the magnitude of response is increased when DNA vaccines are delivered 
via EP. 
Finally, efficacy of the pCon16E6E7 plasmid was assessed in a mouse tumor 
challenge model using the TC-1 cell-line which expresses HPV-16 E6 and E7 
proteins [Yan 2009]. Mice were challenged with TC-1 tumor cells at low dose 
(5x104) on Day 0. Three days after TC-1 cell implantation, ten mice were 
immunized with pVAX, a plasmid containing HPV16 E7 only (pE7) and 
pCon16E6E7 and boosted twice on day 10 and 17.  
Only three out of ten mice in pCon16E6E7 vaccinated group developed tumors 49 
days after initial tumor implantation. All mice in the pE7 group eventually 
developed tumors; however, the tumors in this group were smaller than those in 
the control group (p<0.05). In order to further assess the therapeutic potential of 
pCon16E6E7, we performed another tumor regression study by increasing the 

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challenge dose of TC-1 cells to 1x106 and mice were not immunized with 
pCon16E6E7 until the average tumor size was about 6 mm (on day 7). After 
boosting four times, mice in pCon16E6E7 group developed significantly smaller 
tumors compared to those in the control group (p<0.05). Moreover, all mice in 
pCon16E6E7 group survived 49 days after tumor implantation. In contrast, none 
of the mice in the pVAX group survived 28 days after tumor implantation. These 
results indicate that the DNA vaccine pCon16E6E7 induced regression of well-
established tumors in C57BL/6 mice. The efficacy of pCon18E6E7 was not 
assessed due to the lack of a suitable tumor challenge model for HPV-18 related 
tumors [Yan 2009]. 
VGX-3100, HPV therapeutic vaccine is a combination of two plasmids in equal 
quantities (i.e. the 6 mg dose will deliver 3 mg of each pGX3001 and pGX3002 
plasmids):  
a) pGX3001: p16ConE6E7, a plasmid encoding for a synthetic HPV16 
consensus (SynCon™) E6 and E7 fusion gene into a pVAX1 backbone 
(Invitrogen, Carlsbad, CA) under the control of the cytomegalovirus 
immediate-early (CMV) promoter, and  
b) pGX3002: p18ConE6E7, a plasmid encoding for a synthetic HPV18 
consensus (SynCon™) E6 and E7 fusion gene into a pVAX1 backbone 
(Invitrogen, Carlsbad, CA) under the control of the cytomegalovirus 
immediate-early (CMV) promoter. 
Both HPV type 16 and 18 E6 and E7 consensus nucleotide sequences were 
synthetically produced (GeneArt, Germany) after performing multiple alignments 
of the sequences described in the international genetic database (GenBank) for 
HPV type 16 and 18. 
1.1.4 Target Organ for a Therapeutic HPV Immunotherapy – Skeletal 
Muscle 
The skeletal musculature is an excellent candidate for the target tissue of gene 
expression, because muscle fibers have a long lifespan and can be transduced by 
circular plasmids, allowing the gene to be expressed efficiently in 
immunocompetent hosts [Davis 1993; Tripathy 1996]. Furthermore, muscle is 
well vascularized, allowing the newly produced transgene product to gain access 
to the circulation.  
1.1.5 Delivery Method – Injection / Electroporation (EP) 
The use of EP via the CELLECTRA-5P device increases the expression of INO-
3112. EP utilizes a transmembrane electric field pulse to induce microscopic 
pathways (pores) in a bio-membrane. The electric field allows macromolecules, 
ions, and water to pass from one side of the membrane to the other. The presence 
of a constant field influences the kinetics of directional translocation of the 
macromolecular plasmid, such that the plasmid delivery in vivo has been 
sufficient to achieve physiological levels of secreted proteins. Intramuscular 
injection of plasmid followed by EP has been used very successfully to deliver 

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therapeutic genes that encode for a variety of hormones, cytokines or enzymes in 
a variety of species [Prud'homme 2006, 2007]. The design of software that 
enables constant current EP to deliver plasmids allows for the individual 
resistance of the treated muscle to be taken into consideration and yields highly 
efficient in vivo plasmid expression [Khan 2005].  
In a small (10 healthy volunteers) pilot study, pain was evaluated immediately, 5, 
15, 30 minutes and 1 hour after EP with the CELLECTRA device [Diehl 2013]. 
Subjects used a Visual Analog Scale (VAS) questionnaire, 10 cm in length, 
anchored by word descriptors at each end, “No Pain” and “Worst Pain”, to mark 
their pain related to the treatment. Subjects reported a mean (±sem) score of 6.3 
(±0.7) immediately after treatment and 2.8 (±0.5) approximately 5 minutes after 
the procedure. These data showed that the pain associated with electroporation 
was brief and diminished quickly [Diehl 2013]. 
1.2 
Plasmid DNA Immunotherapy Agents (INO-3112) 
1.2.1 VGX-3100 
Chemical name: Circular, double stranded, deoxyribonucleic acid consisting of 
3782 base pairs for the pGX3001 plasmid and 3824 base pairs for the pGX3002 
plasmid. 
Distinguishing name: Eukaryotic expression plasmids containing HPV 16 and 18-
E6 & E7-encoding transcription unit controlled by a synthetic, CMV promoter, 
and elements required for replication and selection in E. coli, namely a pUC 
origin of replication (pUC Ori) and a kanamycin resistance gene (Kan R). 
1.2.2 INO-9012 
Chemical name: Circular, double stranded, deoxyribonucleic acid consisting of 
6259 base pairs for the pGX6001 (also called IL-12 DNA) plasmid. 
Distinguishing name: Eukaryotic expression plasmids containing synthetic IL-12 
p35 light chain and p 40 heavy chain (pGX6001) controlled by a dual promoter 
vector, a bGH poly A tract, bacterial origin of replication to support production of 
the plasmid in E. coli, and a kanamycin resistance gene (Kan R).  
1.3 
Dose and Regimen Rationale 
The doses selected are based on previous human experience and preclinical data 
with VGX-3100 and other DNA vaccines. A total dose of 6 mg VGX-3100 DNA 
has been selected for this study based on the safety and immunogenicity data 
generated in the HPV-001 study, where 6 mg of DNA were delivered IM 
followed by EP, which showed trends toward higher response rates and 
magnitudes of IFN-γ ELISpot responses in the high dose cohort compared to the 
low (0.6 mg) and mid-dose (2 mg) cohorts (Table 1.1) without significant safety 
issues [Bagarazzi, 2012].  
This dose-trend was consistent with prior expectation, a feature of the finding that 
suggests it is a “real” effect rather than random variation. Adverse events from 

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previous human studies with closely related DNA plasmid products have been 
limited to injection site pain from the injection and electroporation procedure. No 
unexpected or severe adverse events were observed in any of the three dose 
cohorts. 
Table 1.1: Percent of subjects responding and average SFU/106 
PBMC in responders for each antigen by cohort in Protocol HPV-
001 Interferon-γ ELISpot  
 
Cohort 
Low 
Mid 
High 
Antige
n 
%RE
SP 
AVG 
%RE
SP 
AVG 
%RE
SP 
AVG 
16E6 
33% 
107 
50% 
243 
50% 
1341 
16E7 
17% 
198 
50% 
104 
67% 
143 
18E6 
50% 
359 
50% 
338 
83% 
664 
18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
 
The IL-12 plasmid dose is based on previous experience in the HVTN-080 study, 
where 1 mg was co-administered with PENNVAX®-B followed by EP. HIV-
specific CD4+ T cell responses were generated in ~81% of PENNVAX®-B + IL-
12 recipients after three vaccinations, compared to 44% with PENNVAX®-B 
alone. Delivery of PENNVAX®-B via EP also increased the frequency of CD8+ T 
cell responses. CD8+ responses were detected in 33% of PENNVAX®-B and 52% 
of PENNVAX®-B + IL-12 recipients after 3 vaccinations. Six months after the 
third vaccination 43% of individuals were still able to respond to HIV peptide 
pools. Overall, 89% of individuals vaccinated with PENNVAX®-B + IL-12 
plasmid followed by EP developed either a CD4+ or CD8+ T-cell response after 
the third vaccination. No unexpected or severe adverse events were observed in 
HVTN-080 or earlier studies of IL-12 DNA delivered without electroporation. 
In summary, a total of 7 mg VGX-3100 + INO-9012 DNA was selected for this 
study based on the safety and immunogenicity data generated in HPV-001, the 
follow-on study HPV-002, and HVTN-080. Additional human experience with 
related DNA plasmids informing the dose is described below. 
1.3.1 Previous Human Experience with VGX-3100 
The clinical experience with VGX-3100 is demonstrated in two phase 1 studies, 
HPV-001 and HPV-002 which enrolled 18  and 13 women, respectively, and a 
phase 2 study, HPV-003, which enrolled 167 women. There have been no 
significant safety findings with very few related Grade 3 Adverse Events (AE’s) 
and no related Grade 4 AE’s or Serious Adverse Events (SAEs) after 551 doses in 
185 subjects. Importantly, the safety profile of the DNA immunogen 
/electroporation technology platform employed in this study has been consistently 
unremarkable in the 580 subjects and 1,548 doses in 16 different studies as of 

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February 4, 2015. (Refer to INO-3112 Investigator’s Brochure v3.0 for additional 
information) 
There were no significant safety findings in the 18 subjects enrolled in HPV-001, 
the phase 1 study of VGX-3100, with only mild to moderate adverse events, 
injection site reactions and laboratory abnormalities which resolved without 
sequelae. All subjects returned home after at least 30 minutes observation in the 
study unit post injection/EP. CPK and ECGs were unremarkable post 
electroporation. Study participants judged the injection/EP to be relatively painful 
(mean VAS score 6.2 immediately after and 2.8 approximately 5 minutes after 
EP) but transient, but did not preclude subsequent injection/EP administration. 
There were no serious adverse events attributed to treatment in any of the subjects 
and there were no early discontinuations in the study. Thirteen women 
participated in HPV-002 in which a fourth dose (6 mg only) of VGX-3100 was 
evaluated and the safety findings were consistent with those observed in the 
parent study, HPV-001.  
The clinical trial experience in HPV-003 with the investigational product to date 
is consistent with those reported previously. No new safety issues have been 
identified with VGX-3100 delivered IM followed by EP with CELLECTRA®-5P, 
and no serious unexpected drug related adverse events, or other events requiring 
expedited reporting, have been reported for subjects dosed with VGX-3100 
delivered IM followed by EP with CELLECTRA®-5P. 
The mechanism of action of VGX-3100 delivered using EP is expected to be 
mediated through a Th1-biased cytolytic T-cell response against the HPV16 and 
HPV18 E6 and E7 proteins. Strong antigen-specific T-cell immune responses 
were observed in not only the phase 1 HPV studies but also in the previous 
studies using the same technology with different antigens for several disease 
indications (e.g. influenza, HIV) [Bagarazzi 2012]. The cellular immunity has 
also been demonstrated to be durable up to 25 months from the initiation of 
therapy [unpublished data]; strongly suggesting the development of long term 
memory cells in the immunized volunteers. In addition, the antigen-specific T-
cells have been shown to exhibit a memory phenotype by flow cytometry 
[Bagarazzi 2012]. Immunoglobulin G-based antibodies have also been measured 
in a high percentage (>90%) of immunized volunteers in the previous human 
studies with this technology [Bagarazzi 2012, unpublished data].  
Ongoing study of VGX-3100 in subjects with for high grade CIN associated with 
HPV-16 and/or HPV-18 (HPV-003) 
All current therapeutic options for cervical dysplasia are destructive, have adverse 
sequelae, and furthermore are not always curative. Among treated high grade CIN 
in immunocompetent women, the overall risk of recurrence is less than ten 
percent when all surgical margins are clear, but increases to approximately 25% 
in women with positive margins. About 90% of recurrences will occur within the 
first year after treatment [Felix 1994]. Moreover, tissue destruction from 
therapeutic interventions can make subsequent detection and treatment of 
recurrent disease difficult, as the healing process draws the transition zone of the 

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cervical epithelium proximally, into the endocervical canal [Ferris 1995]. 
Effective immunotherapy would obviate the need for surgery, to say nothing of 
preventing progression to cervical cancer. Consequently, a placebo-controlled 
phase 2 study is under way to determine if VGX-3100 delivered by EP will result 
in immune-mediated regression of high grade cervical dysplasia when 
administered prior to surgical intervention. The study, known as HPV-003 will 
evaluate histologic regression 6 months after completion of the three dose series.  
A pre-planned interim analysis of the study data completed in July 2014 revealed 
that the study met its primary endpoint (histopathologic regression of lesions) and 
secondary endpoint (histopathologic regression of lesions in the context of 
elimination of HPV16 and/or 18 infection) demonstrating a highly statistically 
significant improvement in the VGX-3100 arm (p<0.017 and p<0.001 
respectively). Treatment of HPV16 and/or 18 positive patients with CIN2 or 3 
was generally safe as evidenced by the lack of statistical significance between the 
frequencies of adverse events reported in the placebo arm as compared to the 
VGX-3100 treated arm. Treatment with VGX-3100 was able to induce a robust 
immune response in the periphery as gauged by IFNγ ELISpot as well as in the 
tissue as examined using immunohistochemistry. These data reveal the highly 
promising potential of therapeutic immunization with DNA followed by 
electroporation for the treatment of HPV-16 and/or HPV-18 related precancerous 
cervical disease in women. 
A logical next step is to determine if INO-3112 delivered by EP could also 
provide clinical benefit for patients with invasive squamous cell carcinoma of the 
cervix. In this setting, the DNA immunogen/EP platform would need to generate 
HPV-specific immune responses to help eliminate residual neoplastic cells after 
standard therapy. This study is designed to assess potential toxicity and 
secondarily immune responses to specific antigens in both blood and locally in the 
cervix, and whether the immune responses are associated with subsequent 
regression of neoplastic cells. 
1.3.2 Previous Human Experience with INO-9012 
The safety profile associated with IM administration of IL-12 plasmid DNA alone 
or followed by EP has been acceptable in clinical studies. Clinical results from 
three different studies substantiate the safety and tolerability profile of IL-12 
plasmid DNA. IL-12 plasmid DNA has been used in several cohorts in the 
following four phase I clinical protocols.   
Protocol # 
Co-administered with 
# subjects received 
IL-12 DNA 
HVTN-060 
HIV-1 gag p37 
80 
HVTN-063 
HIV-1 gag p37 
30 
HVTN-070 
PENNVAX®-B (gag, pol, env) 
30 

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HVTN-080 
PENNVAX®-B (gag, pol, env) 
30 
IL-12 DNA was delivered without EP in HVTN-060, -063 and -070 but was 
followed by EP in HVTN-080. In this protocol, PENNVAX®-B or placebo were 
delivered via IM injection followed by electroporation with the CELLECTRA®-
5P device in 48 healthy volunteers. The regimen consisted of 3 mg of 
PENNVAX®-B with or without plasmid encoding IL-12 at months 0, 1 and 3. 
This study established that a highly engineered DNA vaccine delivered 
intramuscularly followed by EP can induce frequent and robust T-cell responses 
in humans. 
In summary of above clinical studies, no pattern of systemic AEs emerged, and no 
SAEs related to the study products were observed. The plasmid DNA vaccine co-
administered with IL-12 plasmid DNA as a cytokine adjuvant were well-tolerated. 
(See Section 5 of the INO-3112 IB for details for HVTN-080 study) 
1.4  
Risks/Benefit Assessment 
1.4.1 Current Therapy for Stage IB-IVB Cervical Cancer 
All current therapeutic options for cervical cancer involve either surgery with or 
without adjuvant chemotherapy and/or radiation therapy, or definitive radiation 
therapy, or definitive chemoradiation. Current outcomes with either radical 
surgery or standard chemoradiation for invasive cervical cancer results in cure 
rates of approximately 80 to 95 percent in early stage disease (stage I and non-
bulky stage II disease) and approximately 40 to 60 percent for bulky stage II and 
stage III disease [Quinn 2006]. 
Table 1.3: Survival by FIGO stage for patients with cervical cancer: 1999 to 
2001 FIGO statistics 
FIGO stage 
# of 
patients 
Overall survival, % 
1 year 
2 years 
5 years 
IA1 
829 
99.8 
99.5 
97.5 
IA2 
275 
98.5 
96.9 
94.8 
IB1 
3020 
98.2 
95 
89.1 
IB2 
1090 
95.8 
88.3 
75.7 
IIA 
1007 
96.1 
88.3 
73.4 
IIB 
2510 
91.7 
79.8 
65.8 
IIIA 
211 
76.7 
59.8 
39.7 
IIIB 
2028 
77.9 
59.5 
41.5 
IVA 
326 
51.9 
35.1 
22 
IVB 
343 
42.2 
22.7 
9.3 
Original table modified for this publication. From: Quinn MA, Benedet JL, Odicino F, et al. 
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Recurrence rate by stage is as follows: for FIGO stage IB around 10%, for stage 
IIA 17%, for stage IIB 23%, and for stages III and IVA 42% and 74% 
respectively [Perez 1992].  
For early stage disease, the predominant site of disease recurrences is local (i.e. at 
the vaginal apex) or regional (i.e. pelvic sidewall). The risk of persistent or 
recurrent pelvic disease increases with more advanced initial disease stage 
[Morely 1976, Hopkins 1991, Estape 1998].  
The most frequent distant sites of recurrence are the para-aortic lymph nodes 
(81%), lungs (21%), and supraclavicular lymph nodes (7%), whose incidence 
relates to the stage of disease: it is 0–3% in stage IA, 13–16% in stage IB, 22–
31% in stage IIA, 22–26% in stage IIB, 32–39% in stage III and 75% in stage 
IVA [Perez 1995].   
The outcomes for inoperable cervical cancer have improved with the use of 
concurrent chemotherapy during radiation and this multi-modality approach is 
now standard of care [Rose 1999, Morris 1999, Grigsby 2001].  However, as 
noted above, recurrence rates are significant and impact not only survival but also 
quality of life.   
Clearly, there is room to decrease recurrence rates at all stages of disease and 
additional investigations are warranted to further improve outcomes for this 
population. 
1.4.2 Rationale for Study Design 
There are data in patients with pre-invasive lesions that demonstrate the safety of 
immune-based therapy in immune-competent patients.   
In otherwise healthy women whose CIN 2/3 lesions had already been resected, 
treatment with VGX-3100 delivered by EP stimulated both antibody and T-cell 
responses that were detectable in over 80% of subjects, without significant side 
effects. The potential benefit of taking part in this study is that INO-3112 could 
stimulate the immune system to eliminate residual neoplastic cells after standard 
therapy. This study is designed to assess primarily toxicity of treatment with INO-
3112 delivered by EP after such standard therapy and secondarily, immune 
responses to the HPV antigens encoded by VGX-3100 in both peripheral blood 
and locally in the cervix. 
Subjects enrolled in this protocol will undergo close clinical surveillance by 
experienced gynecologic oncologist, radiation oncologists and oncologists. 
Participants will be seen at screening to determine eligibility. Two cohorts will be 
enrolled.   
In Cohort 1, prior to dosing, all subjects will have undergone standard external 
beam radiation therapy administered concurrently with cisplatin over 5 to 6 
weeks, followed by brachytherapy and then a brief rest period (2 weeks or less) 
prior to the study treatment/EP (Day 0) regimen with INO-3112. The first study 
treatment/EP treatment (Day 0) will be administered within two weeks of 
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following Day 0, the third at Week 8 and the fourth (final) treatment will be 
administered at Week 12 following Day 0. 
In cohort 2, subjects with persistent and/or recurrent disease will be treated with 
study treatment/EP following salvage therapy. The first study treatment/EP 
treatment (Day 0) will be administered no earlier than 2 weeks after completing 
salvage therapy, the second study treatment/EP at Week 4 following Day 0, the 
third at Week 8 and the fourth (final) treatment will be administered at Week 12 
following Day 0.  
Participants will be followed as part of this study for 6 months after the last study 
treatment/EP (i.e. Week 12) with INO-3112. 
Radiation therapy has been shown to induce a variety of immune effects within 
the radiation field, including up regulation of major histocompatibility complex 
class I (MHC-I) expression and increased activation of CD8+ cytotoxic T 
lymphocytes (CTL) [Nikitina 2001]. Changes in cytokine and adhesion molecule 
expression facilitate homing of antigen-presenting cells and effector immune cells 
to the induced area [Hong 1995, Hong 1999, Hallahan 1996, Tanigawa 2001]. 
Decreases in CD4+ CD25+ regulatory T cells and myeloid-derived suppressor 
cells (MDSC) have also been noted, which leads to a more robust immune 
response in the irradiated area [Sutmuller 2001]. Apoptotic and necrotic tumor 
cells within the radiation field provide sources of antigens for dendritic cells, 
which in turn activate T cell maturation [Rock 2005]. The dying cells also release 
"danger factors" which can act as immunologic adjuvants to prevent immune 
tolerance to tumor antigens [Matzinger 1994, Galucci 1999, Shi 2002].  
Studies revealed that radiation induces up regulation of death receptors, 
particularly Fas, in tumor cells, which further sensitizes them to the killing action 
of CTL [Sheard 1997, Chakraborty 2002, Garnett 2004]. Fractionated 
radiotherapy is hypothesized to impair the immune response due to deleterious 
effects on infiltrating immune cells whereas hypo-fractionated ablative dosing 
resulted in a superior immune response [Lee 2009]. Thus, concurrent vaccination 
at the end of brachytherapy may have a similarly activating effect on the local 
immune system. Previous murine studies have shown that radiation can heighten 
the immune response to vaccination against HPV oncogenes E6 and E7, and post-
radiation vaccination with a recombinant HPV E6/E7 vector results in a 
significant increase in long-term survival due to cell-mediated killing [Tseng 
2009].  
Delivering the vaccine immediately after the conclusion of brachytherapy to 
harness the immunologic priming effects of radiation and complement the in situ 
immunization may initiate a sustained adaptive immune response against the E6 
and E7-expressing tumor cells. 
Monitoring will include HPV typing at screening/entry. Tumor biopsy, 
ThinPrep™ samples for HPV testing and cytology, and Digene swabs will be 
collected at screening (pre or post-chemoradiation), Day 0 and at Week 16 (one 
month post-dose 4) and week 36. Physical exam, vital signs, ECOG performance 
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study treatment/EP on Day 0 and at specified visits throughout the study. Imaging 
with PET/CT scans will be performed within 4 weeks prior to Day 0 (baseline) 
and 3-4 months after Day 0 and 3-5 month thereafter or at study discharge per 
standard of care or in accordance with local guidelines and institutional practices. 
Investigators will be instructed to use their clinical judgment throughout the 
study.   
1.4.3 Potential Risks of DNA Immunotherapy Delivery with 
Electroporation 
The underlying basis for all studies of plasmid DNA vaccines is the fairly 
substantial safety database that exists for the varied plasmid DNA vaccine 
candidates that have now been studied in both animals and humans. The plasmid 
DNA platform has been utilized for vaccine candidates for a variety of disease 
indications and infectious agents (e.g., HIV, HPV, Influenza, SARS, West Nile 
virus, Ebola among others) in addition to plasmid cytokine adjuvants such as IL-
2, IL-12 and IL-15. 
In two companion papers by Sheets et. al, potential toxicities (both intrinsic and 
immunotoxicities) and biodistribution profiles were compared for 21 different 
plasmid DNA constructs, in 9 separate GLP-compliant studies [Sheets 2006a, 
2006b]. Despite differing plasmid DNA backbones, promoters, and sequence 
inserts, toxicity and biodistribution profiles were similar for all plasmid DNA 
constructs. With respect to the toxicity assessments, the authors reported that 
toxicity was localized to the site of the injection for all 21 plasmid DNA 
constructs. Similarly, all plasmid DNA constructs evaluated showed evidence to 
be localized to the injection site and surrounding tissue in all studies. Based on the 
results of these GLP toxicology and biodistribution studies, Sheets et. al post a 
case for “refinements of preclinical safety protocols over time” as it pertains to 
the development pathway for plasmid DNA vaccine candidates [Sheets 2006a, 
2006b]. 
Further, four separate GLP toxicology and biodistribution studies have been 
performed for eight additional plasmid DNA vaccine candidates developed by 
Inovio with identical backbones delivered by electroporation yielding similar 
toxicity and biodistribution profiles. Intramuscular co-administration of IL-12 
plasmid was evaluated in nonclinical studies to support the studies of 
intramuscular IL-12 plasmid in humans.  
DNA vaccines developed by Inovio have been delivered without electroporation 
(1 study) or using Inovio electroporation devices (11 studies) as shown in Table 
1.4. Inovio electroporation devices have also been used to deliver DNA vaccines 
developed outside of Inovio in three different studies and two studies have 
evaluated the tolerability of Inovio electroporation devices with normal saline. 
Based on clinical experience with INO-3112 from similar protocols using 
electroporation-mediated drug delivery and the overall safety database 
encompassing all studies of Inovio DNA delivered by electroporation with 
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effects or toxicities. Side effects of vaccination with INO-3112 may include 
discomfort related to the electroporation technique, such as transient local edema, 
swelling, or pain.  
In the phase I studies of VGX-3100 delivered by EP in women with a history of 
treated CIN 2/3 there were no serious adverse events attributed to treatment in any 
of the subjects enrolled and no participants discontinued early. 
2 
HYPOTHESIS AND STUDY OBJECTIVES 
2.1 
Hypothesis 
Immunotherapy with INO-3112 delivered by IM injection followed by EP with 
CELLECTRA®-5P will be immunogenic and well tolerated in women with newly 
diagnosed, inoperable cervical cancer associated with HPV-16 and/or HPV-18 
after completion of standard chemoradiation therapy with curative intent (Cohort 
1) or in women with persistent and/or recurrent cervical cancer associated with 
HPV-16 and/or HPV-18 following salvage therapy (Cohort 2)  and will not be 
associated with any significant 
increased 
toxicity 
compared 
to 
that 
expected/reported with “standard” therapy alone. 
2.2 
Primary Objective 
Evaluate the safety and tolerability of immunotherapy with INO-3112 when 
delivered IM followed by EP with CELLECTRA®-5P in women with newly 
diagnosed, inoperable cervical cancer associated with HPV-16 and/or HPV-18 
after completion of standard chemoradiation therapy with curative intent (Cohort 
1) or in women with persistent and/or recurrent cervical cancer associated with 
HPV-16 and/or HPV-18 following salvage therapy (Cohort 2) compared to that 
expected/reported with “standard” therapy alone. 
2.3 
Secondary Objective 
Evaluate the cellular and humoral immune responses to immunotherapy with 
INO-3112 delivered IM followed by EP with CELLECTRA®-5P in women with 
newly diagnosed, inoperable cervical cancer associated with HPV-16 and/or 
HPV-18 after completion of standard chemoradiation therapy with curative intent 
(Cohort 1) or in women with persistent and/or recurrent cervical cancer associated 
with HPV-16 and/or HPV-18 following salvage therapy (Cohort 2).  
2.4 
Exploratory Objective 
Evaluate clinical response (i.e. disease-free survival) following treatment with 
INO-3112 delivered IM followed by EP with CELLECTRA®-5P in women with 
newly diagnosed, inoperable cervical cancer associated with HPV-16 and/or 
HPV-18 after completion of standard chemoradiation therapy with curative intent 
(Cohort 1) or in women with persistent and/or recurrent cervical cancer associated 
with HPV-16 and/or HPV-18 following salvage therapy (Cohort 2). 

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3 
STUDY DESIGN 
This is a Phase I/IIa, open-label study to evaluate the safety, tolerability, and 
immunogenicity of INO-3112 [6 mg of VGX-3100 (2 separate DNA plasmids 
encoding E6 and E7 proteins of HPV 16 and HPV 18) and 1 mg of INO-9012 
(DNA plasmid encoding human interleukin 12)] delivered IM followed by EP in 
approximately 10 female subjects with biopsy-proven, Stage IB-IVB inoperable 
invasive cervical carcinoma associated HPV-16 and/or HPV-18 who have 
completed treatment with standard chemoradiation with curative intent (Cohort 1) 
or in subjects with persistent and/or recurrent cervical cancer associated with 
HPV-16 and/or HPV-18 following salvage therapy (Cohort 2).  
Eligible subjects who consent to participate in the study will receive a 1.1 mL IM 
injection of INO-3112 in the deltoid followed immediately by EP with 
CELLECTRA®-5P. If the deltoid is not a suitable location, the IM injection 
should be in the lateral quadriceps followed immediately by EP with 
CELLECTRA®-5P. All subjects (Cohorts 1 and 2) will receive a 4-dose series of 
INO-3112. The first study treatment/EP after completion of standard 
chemoradiation (Cohort 1) or salvage therapy (Cohort 2) will be designated as 
“Day 0”, the second dose will be administered at Week 4, the third dose at Week 
8, and the fourth (final) treatment will be administered  at Week 12. 
Cohort 1:  
Cohort 1 will include subjects with biopsy-proven, Stage IB-IVB inoperable, 
newly diagnosed invasive cervical carcinoma associated with HPV-16 and/or 
HPV-18 treated with standard chemoradiation therapy with curative intent. 
All subjects in Cohort 1 must receive their initial study treatment (Day 0) within 
2 weeks after completing a course of standard radiation therapy (external beam 
and brachytherapy) administered concurrently with platinum based therapy with 
curative intent.  
Subjects will have received standard external beam radiation therapy administered 
concurrently with cisplatin at 40 mg/m2/week followed by their brachytherapy 
prior to the study treatment with INO-3112. The chemoradiation must be 
completed within 10 weeks of initiation. Standard external beam radiation therapy 
should be delivered to the pelvis +/- para-aortic nodal chain to a total dose of 45 
Gy in 25 fractions, in conjunction with high dose rate (HDR) or low dose rate 
(LDR) brachytherapy to the cervix to deliver a total dose of 80-90 Gy (LDR 
equivalent) to point A. Parametrial and nodal boost should be delivered as 
determined by the disease stage per sequencing outlined in Appendix 3, such that 
brachytherapy will be the last treatment administered. 
Weekly cisplatin chemotherapy at 40 mg/m2 should be administered during 
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Cohort 2:  
Cohort 2 will include subjects with persistent and/or recurrent cervical carcinoma 
associated with HPV-16 and/or HPV-18 who have been treated with salvage 
therapy (chemotherapy and/or radiation therapy).  
All subjects in Cohort 2 must receive their initial study treatment (Day 0) no 
sooner than 2 weeks and no later than 4 weeks after completing a course of 
salvage therapy. If in the investigators opinion, there are no additional salvage 
therapy options, the subject may be enrolled in Cohort 2 without having received 
salvage therapy immediately prior to enrollment.   
Primary Safety Endpoints:  
1. Incidence of adverse events (all, severe [graded per CTCAE v4.03], 
unexpected, serious) classified by system organ class (SOC), preferred term, 
severity, and relationship to study medication and schedule 
2. Injection site reactions including pain, tenderness, erythema and induration at 
administration site 
3. Rates of acute gastrointestinal, genitourinary, or other chemoradiation side 
effects above the expected, graded per Acute Radiation Morbidity Scoring 
Criteria (RTOG) 
4. Changes in laboratory parameters from baseline 
Secondary Immunologic Endpoints:  
1. Antigen-specific cellular immune responses to INO-3112 in blood samples 
obtained from study subjects per study schedule: 
a) 
Interferon-γ secreting T lymphocytes in PBMC by ELISpot 
b) 
Flow Cytometry for T-cell activation, cytolytic phenotype, and 
memory phenotype in PBMC 
2. Antigen-specific humoral responses to HPV–E6 and –E7 by ELISA per study 
schedule 
Exploratory Clinical Endpoints:  
1. Changes in standard uptake volume (SUV) on PET/CT scans performed at 
baseline vs follow-up PET/CT scans obtained at specified time points.  
2. Evaluation of subjects relative immune competence longitudinally throughout 
the study starting at the screening visit (for details refer to Section 6.7: 
Cervical Virologic and Peripheral Blood Immunogenicity Assessment) 
3. Changes in cervical histology from the screening biopsy as compared to the 
week 16 biopsy   
4. Local immune responses to INO-3112 in tumor tissue samples obtained at 
week 16 
5. Disease-free survival assessed in accordance with  RECIST v1.1 (Refer to 
Appendix 10) as follows:  
• Clinical evaluations for disease response will be conducted at all study 
visits, (as assessed by clinical signs and symptoms of disease progression). 

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• A baseline PET/CT scan will be obtained on each subject 1 to 2 weeks 
prior to Day 0 and then PET/CT scans for disease progression will be 
obtained for all subjects 3-4 months after Day 0 and every 3-5 months 
thereafter per standard of care/in accordance with local guidelines and 
institutional practices. Additional PET/CT scans may be obtained at other 
time points if clinically indicated to confirm a clinical diagnosis of disease 
progression based on signs and symptoms. 
 
4 
SELECTION AND ENROLLMENT OF SUBJECTS  
4.1 
Inclusion Criteria 
a) Written informed consent in accordance with institutional guidelines. If required 
by local law, candidates must also authorize the release and use of protected 
health information (PHI); 
b) Female subjects age 18 years or older;  
c) Histological diagnosis of squamous cell carcinoma, adenocarcinoma or 
adenosquamous cell carcinoma of the cervix. Not accepted are small cell, clear 
cell and other rare variants of the classical adenocarcinoma; 
d) Histologically confirmed, Stage IB-IVB, invasive cervical carcinoma associated 
with HPV-16 and/or HPV-18 and meeting the following eligibility criteria for 
either Cohort 1 or Cohort 2; 
1.  Cohort 1 
• Newly diagnosed inoperable cervical cancer treated with chemoradiation 
therapy with curative intent and life expectancy of at least 12 months as 
assessed by the investigator 
o No CNS/spinal metastases 
• Able to initiate study treatment (Day 0) within 2 weeks of completion of 
last chemoradiation treatment; 
o Platinum based treatment (alone or in combination with other 
drugs); 5 weekly courses of Cisplatin 40 mg/m2 completed within 
10 weeks of its initiation 
o Standard radiation therapy (external beam and brachytherapy); 
completed within 10 weeks of its initiation 
o Brachytherapy; must be the last treatment if the subject is receiving 
sequential brachytherapy following the chemoradiation therapy 
2. Cohort 2 
• Persistent and/or recurrent cervical cancer  
o No CNS/spinal metastases 
• Able to initiate study treatment (Day 0) at least 2 weeks but no more than 
4 weeks after completion of salvage therapy (If in the investigators 
opinion, there are no additional salvage therapy options, the subject may 
be enrolled in Cohort 2 without having received salvage therapy 
immediately prior to enrollment.) 
• Subject has a life expectancy of at least 12 months as assessed by the 
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e) ECG with no clinically significant findings as assessed by the investigator 
performed  within 30 days of signing the informed consent form (ICF); 
f) Chemistry, liver function tests, renal function, total CPK and hematology lab 
results must be ≤ Grade 1 at the time of  screening, in accordance with the  
CTCAE v4.03; 
g) Eastern Cooperative Oncology Group (ECOG) Performance status of ≤ 1; ; 
h) Adequate venous access for repeated blood sampling according to study schedule; 
i) Women of child-bearing potential must have a negative serum pregnancy test and 
agree to remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), 
or use two medically effective methods of contraception (e.g., oral contraception, 
barrier methods, spermicide, intrauterine device (IUD)). This requirement should 
be followed from screening through 24 weeks after last study treatment/EP. 
Whole pelvis external beam radiation therapy (EBRT) followed by intracavitary 
(IC) therapy for cervical cancer is considered to be an irreversible form of 
contraception; 
j) Able and willing to comply with all study procedures.  
 
4.2 
Exclusion Criteria 
a) Pregnancy or breastfeeding; 
b) History of previous therapeutic HPV vaccination (individuals who have been 
immunized with licensed prophylactic HPV vaccines (e.g. Gardasil®, Cervarix®) 
are not excluded); 
c) Prior exposure to an investigational agent or device within 30 days of signing the 
ICF.  Of note, the subject may participate in observational studies; 
d) Positive serological test for human immunodeficiency virus (HIV), Hepatitis B or 
Hepatitis C or history of HIV infection, Hepatitis B or Hepatitis C (women with 
cured HCV will be allowed; subject must have had an serologic test performed 
within 12 months of informed consent); 
e) Prior major surgery within 4 weeks of first study treatment/EP from which the 
subject has not yet recovered to baseline; 
f) High medical risks because of non-malignant systemic disease or with active 
uncontrolled infection; 
g) Current malignancies at other sites, with the exception of adequately treated basal 
or squamous cell carcinoma of the skin; 
- Cancer survivors, who have undergone curative therapy for a prior 
malignancy, have no evidence of that disease for five years and are 
deemed at low risk for recurrence, are eligible for the study; 
h) Congestive heart failure or prior history of New York Heart Association (NYHA) 
class III/ IV cardiac disease (refer to Appendix 8); 
i) Any concurrent condition requiring the continued use of systemic or topical 
steroids at or near the injection site, excluding non-systemic (e.g. inhaled and eye 
drop-containing) corticosteroids or the use of other immunosuppressive agents. 
All other corticosteroids must be discontinued > 4 weeks prior to Day 0 of study 
product administration; 
j) Any cardiac pre-excitation syndromes (such as Wolff-Parkinson-White); 

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k) History of seizures (unless seizure free for 5 years); 
l) Less than two acceptable sites exist for IM injection and EP between use of the 
deltoid and lateral quadriceps muscles. A site for injection/EP is not acceptable if 
there are tattoos or scars within 2 cm of the injection/EP site or if there is 
implanted metal within the same limb. Any device implanted in the chest (e.g., 
cardiac pacemaker or defibrillator) excludes the use of the deltoid muscle on the 
same side of the body; 
m) Administration of any non-study related vaccine within 2 weeks of Day 0;  
n) Active drug or alcohol use or dependence that, in the opinion of the investigator, 
would interfere with adherence to study requirements; 
o) Imprisonment or compulsory detainment (involuntary incarceration) for treatment 
of either a psychiatric or physical (i.e. infectious disease) illness; 
p) History of immunosuppressive or autoimmune disease; 
q) Any other illnesses or conditions that in the opinion of the investigator may affect 
the safety of the subject or limit the evaluation of a subject or any study endpoint. 
4.3  
Supplementation of Study Subjects  
Additional subjects may be enrolled with the approval of medical monitor, if 
subjects withdraw prior to completion of the study treatment.   
4.4 
Discontinuation/Withdrawal of Study Subjects 
The subject will be considered to have completed the study when she completes 
all scheduled Study Treatments and follow-up visits or death, whichever occurs 
first. The discharge visit will be the last follow-up visit. If subject discontinues or 
is withdrawn at any time after receipt of Study Treatment, the investigator should 
make every effort to have the subject complete all assessments designated for the 
discharge visit. The investigator will make every effort to have all scheduled 
immune assessment blood sample collected as indicated in the Schedule of 
Events, Table 1 of the Clinical Synopsis. Any adverse events (AEs) present at the 
time of discontinuation/withdrawal should be followed in accordance with the 
safety requirements outlined in Section 7.1 – Safety Parameters.  
If the subject manifests Grade 4 toxicity attributable to study treatment/EP, she 
will not receive further study treatment/EP but will be encouraged to continue 
follow-up safety assessment through study discharge and not discontinue from the 
study. If a subject manifests Grade 3 toxicity attributable to study treatment/EP, 
the medical monitor and PI will discuss whether further treatment should be 
continued for that participant.  
Subjects will be discontinued from the study if there is confirmed disease 
progression or if subject starts new anti-cancer therapy.  
The reason for any discontinuation of study treatment should be discussed with 
the Sponsor’s Medical Monitor within 24 hours. The primary reason for the 
subject discontinuing further study treatments or withdrawal from the study itself 
should be selected from the following standard categories:  

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• Adverse Event (Adverse Reaction): Clinical or laboratory events occurred 
that, in the medical judgment of the investigator for the best interest of the 
subject, are grounds for discontinuation. This includes serious and non-
serious adverse events regardless of relation to study treatment. 
• Death: The subject died. 
• Withdrawal of Consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined 
medical need to withdraw. If the subject gave a reason for withdrawal, it 
should be recorded on the Case Report Form (CRF). This reason does not 
allow for further data collection and should not be selected if follow-up 
data collection of this subject is anticipated by the subject. 
• Protocol Violation: The subject’s findings or conduct failed to meet the 
protocol entry criteria or failed to adhere to the protocol requirements 
(e.g., treatment noncompliance, failure to return for defined number of 
visits). The violation should be discussed with the Sponsor’s Medical 
Monitor prior to discontinuation of Study Treatments or study withdrawal. 
• Lost to Follow-up: The subject fails to attend study visits and study 
personnel are unable to contact the subject after repeated attempts 
including letter sent by certified mail or equivalent. 
• Physician Decision: The subject was terminated for a reason other than 
those listed above by the physician caring for the subject. 
• Other: The subject was terminated for a reason other than those listed 
above, such as termination of study by the Sponsor. 
5 
INVESTIGATIONAL PRODUCTS 
5.1 
Investigational Product  
Investigational product is defined as a pharmaceutical form of an active ingredient 
being tested or used as a reference in the study, whether blinded or unblinded. 
INO-3112 is combination of VGX-3100 and INO-9012. 
VGX-3100, the active investigational product to be used in this study, is a mixture 
of two separate DNA plasmids encoding E6 and E7 proteins of HPV types 16 and 
18. A second investigational product being evaluated for use in combination with 
VGX-3100 is known as INO-9012. INO-9012 is a DNA plasmid expressing the 
p35 and p40 human IL-12 subunits off of separate promoters within the same 
plasmid. 
INO-3112 will be provided by Inovio or its designee. The site pharmacist or 
designee will combine VGX-3100 and INO-9012 into a single syringe to create a 
1.1 mL IM formulation of INO-3112 (see Appendix 6 for details). 
 
Table 5.1 Investigational Products 
VGX-3100 
The plasmid pGX3001 and pGX3002  
Volume per container 
1.0 mL minimum/vial 

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Concentration 
6.0 ± 0.4 mg/mL 
Container Size and Type 
10 mL glass vial 
INO-9012  
The plasmid pGX6001 
Volume per container 
0.2 mL minimum/vial 
Target Concentration 
10.0 ± 0.5 mg/ml 
Container Size and Type 
2 mL glass vial 
 
5.2 
Packaging and Labeling  
This study is open label. Therefore the subject, the Investigator’s site personnel 
and the Sponsor are not blinded to treatment. Each vial will be labeled with a 
single panel label. The following shows text that may be included on the vial 
labels: 
Biologic 
Product 
Specimen Label 
VGX-3100 
 
 
SynCon™ VGX-3100 [6mg/mL] 1 mL/vial 
Lot: VGX-3100. xxxxxx 
Date of Manufacture: DD MMM YY     
Final Retest Date: DD MMM YY  
Store frozen at or below -15C 
CAUTION: New Drug – Limited by Federal Law to Clinical Trial 
Use Only 
Inovio Pharmaceuticals Inc  660 W Germantown Pike, Plymouth 
Meeting, PA 19462 USA 
INO-9012 
 
SynCon™ INO-9012 [10 mg/mL] 
0.2 mL/vial Single Use Vial 
Lot: INO-9012.xxxxxx 
Date of Manufacture: DD MMM YY 
Final Retest Date: DD MMM YY 
Store frozen at or below -15°C 
CAUTION: New Drug – Limited by Federal 
Law to Investigational Use. 
Inovio Pharmaceuticals Inc.  Rev 000 
5.3 
Handling of INO-3112 
Inovio will be responsible for assuring that the quality of the investigational 
products is adequate for the duration of the trial. All study products will be 
shipped frozen on dry ice. If there is no dry ice remaining in the shipment 
container when the shipment is received, the Sponsor or designee should be 
contacted immediately.  
In addition, a temperature monitor will track the temperature of vials and will 
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Investigational product(s) should be stored in a secure area according to local 
regulations. Vials must be stored at -20 °C upon receipt at the clinical site. The 
Sponsor should be notified of any deviations from this recommended storage 
condition.  
A freezer temperature log must be monitored daily and maintained at the site. 
5.4 
Dispensing of INO-3112 
It is the responsibility of the Investigator to ensure that INO-3112 is dispensed to 
study participants. It must be dispensed only from official study sites by 
authorized personnel according to local regulations and must be recorded 
appropriately on the investigational product accountability record.  
Vial contents must be thawed at ambient room temperature and must be 
administered within 4 hours of removal from freezer.    
VGX-3100 and INO-9012 will be combined by the site pharmacist into a single 
syringe for subjects using the procedure outlined in Appendix 6. 
The syringe must be labeled with the date and time it was removed from the 
freezer and a four-hour expiration date and time from the time the vial is removed 
from the freezer. The label should also contain the words “administer as soon as 
possible”. 
5.5 
Records of INO-3112 Disposition at Investigational Sites 
It is the responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where 
investigational product is inventoried and disposed. Records or logs must comply 
with applicable regulations and guidelines, and should include: 
• Amount received and placed in storage area; 
• Amount currently in storage area; 
• Label ID number or batch number and use date or expiry date; 
• Dates and initials of person responsible for each investigational product 
inventory entry/movement; 
• Amount dispensed to each subject, including unique subject identifiers; 
• Amount transferred to another area/site for dispensing or storage; 
• Amount returned to Sponsor; 
• Amount destroyed at study site, if applicable. 
5.6 
Return and Destruction of Investigational Products  
Upon completion or termination of the study, all unused and/or partially used 
investigational product must be returned to Inovio, if not authorized by Inovio or 
local regulations to be destroyed at the site. 
All investigational products returned to Inovio must be accompanied by the 
appropriate documentation. Returned supplies should be in the original 
containers. Empty containers should be retained until final reconciliation 
performed by the Study Monitor, but not be returned to Inovio. It is the 
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provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. The return of unused 
investigational product(s) should be arranged by the responsible Study Monitor.  
If investigational products are to be destroyed on site, it is the Investigator’s 
responsibility to ensure that arrangements have been made for the disposal, 
written authorization has been granted by Inovio, procedures for proper disposal 
have been established according to applicable regulation and guidelines and 
institutional procedures, and appropriate records of the disposal have been 
documented. The unused investigational products can only be destroyed after 
being inspected and reconciled by the responsible Inovio Study Monitor.  
5.7 
Use of CELLECTRA-5P Electroporation Device  
The instructions for use of the CELLECTRA-5P device are located in the 
Operations Manual. Each clinical site will receive training for the use of the 
CELLECTRA-5P device. The following specifications will be used during the 
study: 
 
Number of pulses = 3 
Current Strength = 0.5 Amp 
 
Electroporation pulse duration = 52 milliseconds/pulse 
 
Interval separating pulses = 1 second 
The injection/electroporation procedure must be performed by qualified 
personnel. Any individual designated to perform the procedure should be 
permitted by the relevant local authorities to administer parenteral medications to 
patients (e.g. MD, DO, RN) in addition to receiving device training from sponsor 
personnel. Individuals whose credentials do not meet the relevant local 
requirements may perform the injection/electroporation procedure under the 
conditions below: 
1. The procedure must be performed under the direct supervision of the 
Principal Investigator or an approved Sub-Investigator who has already 
been trained by sponsor personnel.   
2. The CV and any relevant qualifications of the individual have been 
reviewed and approved by the sponsor or its designee to perform the 
procedure. 
Any deviation from the above procedures must be approved by the sponsor or its 
designee. 
5.8 
Investigational Device Accountability 
Each clinical site is responsible for maintaining investigational device 
accountability. This includes recording the CELLECTRA®-5P serial number, IM 
applicator serial number, and IM array lot number used for injection/EP of each 

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subject. Site personnel will be required to download electroporation data and 
provide to Inovio after each treatment.  
6 
STUDY PROCEDURES AND TREATMENTS 
See Table 1 for Schedule of Events showing study procedures and the times at 
which they are to be carried out. 
6.1 
Procedure by Visit 
6.1.1 Screening Evaluations 
Subjects who consent to participate in the study will be eligible for screening and 
will have a tumor biopsy sample (i.e. unstained slides) sent to laboratory for HPV 
assessment that will done either by ISH or PCR. If a subject has documented 
evidence of HPV-16 and/or HPV-18 infection results from cervical specimen 
obtained prior to anti-cancer treatment, then those results will be acceptable. If 
applicable, ThinPrep™ sample should also be sent simultaneously to the central 
lab for HPV assessment by PCR. Another cervical biopsy should be collected at 
screening if residual tissue is not available for additional assessment. The 
screening assessments, if required may be done in two parts. The first part will 
consist of consenting the subject and collecting cervical biopsy samples for HPV 
assessment. The second part of the visit will consist of performing the remaining 
screening assessment.  
Subjects in Cohort 1 can be screened either prior to initiation of chemoradiation 
or during chemoradiation. Subjects should be screened and enrolled such that 
their first study treatment (Day 0) will be delivered within 2 weeks of completing 
their chemoradiation therapy. 
Subjects in Cohort 2 can be screened at any time prior to the date of their first 
study treatment. Subjects should be screened and enrolled such that their first 
study treatment (Day 0) is no sooner than 2 weeks and no later than 4 weeks after 
completing the salvage therapy.  
The following evaluations will be performed at screening visit prior to Day 0: 
o Signed informed consent  
o Histologic diagnosis of cervical cancer  
o Collect demographic information 
o Determination of eligibility per inclusion and exclusion criteria 
o Medical and CIN/cancer history 
o Medical/clinical assessment 
o Adverse event (AE)/Serious adverse event (SAE) assessment  
o Determine disease status 
o Concomitant medications review 
o Assessment 
of 
systemic 
reaction/toxicity/side 
effects 
of 
standard 
(chemoradiation) therapy (only if subject is screened during chemoradiation 
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o Full physical exam to include complete gynecological exam and ECOG 
performance status 
o Vital Signs (including body temperature, respiratory rate, blood pressure, 
heart rate and height/weight) 
o 12-lead ECG 
o HPV assessment 
o Tumor biopsy collection (required only if residual tissue or unstained slides 
are not available at screening) 
o ThinPrep™ sample for HPV testing (if applicable) 
o Digene swab (2 samples) (if applicable) 
o Baseline PET/CT scan (must be performed within 4 weeks prior to Day 0)  
o Complete blood count with differential 
o Serum chemistry evaluation including glucose, albumin, total protein, SGPT, 
SGOT, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), 
calcium, creatinine, electrolytes (chloride, carbon dioxide or bicarbonate, 
potassium, sodium) 
o Baseline CPK  
o Urinalysis 
o Serum pregnancy test  
o HIV, Hepatitis B and C serology (not required if performed within 12 months 
of signing of informed consent) 
o Whole blood and serum for immunologic assays 
6.1.2 Study Evaluations 
Visit dates and windows must be calculated from the date of the Day 0 visit. 
The following study evaluations will be performed on Day 0 prior to study 
treatment/EP 1: 
o Determination of eligibility per inclusion and exclusion criteria 
o Medical/clinical assessment  
o Targeted physical assessment (including ECOG performance status) 
o AE/SAE event assessment 
o Assessment of systemic reaction/toxicity/side effects of standard 
(chemoradiation) therapy to be completed immediately prior to the first study 
treatment/EP on Day 0 
o Concomitant medications review 
o Vital Signs and Weight 
o ThinPrep™ sample for HPV testing (if applicable) 
o Digene swab (2 samples) (if applicable) 
o Complete blood count with differential 
o Serum chemistry evaluation including glucose, albumin, total protein, SGPT, 
SGOT, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), 
calcium, creatinine, electrolytes (chloride, carbon dioxide or bicarbonate, 
potassium, sodium) 
o Urine pregnancy test 
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The following study evaluations will be performed on Day 0, post study 
treatment/EP 1: 
o 
Post-treatment adverse event and injection site reaction assessment within 
30-45 minutes after EP 
o 
Distribute Participant Reminder Card (PRC) 
o 
Download EP data 
 
The following study evaluations will be performed at Weeks 2, 6, 10 and 14 post 
study treatment/EP (± 1 week):  
o Medical/clinical assessment * 
o Targeted physical assessment (including ECOG performance status) 
o Assessment 
of 
systemic 
reaction/toxicity/side 
effects 
of 
standard 
(chemoradiation) therapy 
o Post-treatment injection site reaction assessment* 
o AE/SAE assessment* 
o Concomitant medications review*  
o Review of PRC* 
o Vital Signs and Weight 
 
Weeks 2, 6, 10 and 14 visits may be performed as an in-person office visit or a 
telephone call. The type of visit will be documented on the case report form. All 
study procedures listed above should be performed for an in-person visit. The 
assessments that are required for a telephone call are indicated above with an 
asterisk (*).  
If the visit will be conducted by telephone, the subject should submit their PRC 
(i.e. mail, fax, email) to site personnel prior to the phone visit. If the PRC is not 
received in advance, site personnel should review all PRC elements verbally (see 
Protocol Section 6.2.4.4). The hard copy of the PRC should be collected and 
reviewed at the next in-person study visit. After completing a medical/clinical 
assessment, reviewing the post-vaccination diary and assessing for adverse events 
and injection site reactions with the subject on the phone, the Investigator will 
determine whether an office visit is needed for further evaluation.  
The following study evaluations will be performed on Weeks 4, 8 and 12 prior 
to each study treatment/EP (±1 week): 
o Medical/clinical assessment  
o Targeted physical assessment (including ECOG performance status) 
o Adverse event/serious adverse event assessment 
o Assessment of systemic reaction/toxicity/side effects of standard 
(chemoradiation) therapy at Week 4 only 
o Concomitant medications review 
o Vital Signs and Weight 

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o Complete blood count with differential 
o Serum chemistry evaluation including glucose, albumin, total protein, SGPT, 
SGOT, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), 
calcium, creatinine, electrolytes (chloride, carbon dioxide or bicarbonate, 
potassium, sodium) 
o Urine pregnancy test 
o Whole blood and serum for immunologic assays at Week 8 only 
The following study evaluations will be performed on Weeks 4, 8 and 12 post 
study treatment/EP: 
o 
Post-treatment adverse event and injection site reaction assessment within 
30-45 minutes after EP 
o 
Distribute and review PRC 
o 
Download EP data 
The following study evaluations will be performed on Week 16 (±1 weeks): 
o 
Medical/clinical assessment  
o 
Targeted physical assessment (including ECOG performance status) 
o 
AE/SAE assessment 
o 
Concomitant medications 
o 
Determine disease status 
o 
PET/CT scan (must be done EVERY 3-4 months after Day 0) 
o 
Vital Signs and Weight 
o 
Urine pregnancy test 
o 
Tumor biopsy collection  
o ThinPrep™ sample for HPV testing (if applicable) 
o Digene swab (2 samples) (if applicable) 
o 
Complete blood count with differential 
o 
Serum chemistry evaluation including glucose, albumin, total protein, SGPT, 
SGOT, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), 
calcium, creatinine, electrolytes 
o 
CPK 
o 
Whole blood and serum for immunologic assays 
The following study evaluations will be performed on Weeks 24 (±2 weeks): 
o 
Medical/clinical assessment  
o 
Targeted physical assessment (including ECOG performance status) 
o 
AE/SAE assessment 
o 
Concomitant medications 
o 
Vital Signs and Weight 
o 
Whole blood and serum for immunologic assays  
The following study evaluations will be performed on Weeks 32 (±2 weeks): 
o 
Medical/clinical assessment with ROS 
o 
Targeted physical assessment (including ECOG performance status) 
o 
AE/SAE assessment 
o 
Concomitant medications 

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o 
Vital Signs and Weight 
o 
PET/CT scan 
o 
Whole blood and serum for immunologic assays  
 
The following study evaluations will be performed on Week 36 or discharge 
visit (±2 weeks): 
o 
Medical/clinical assessment  
o 
Full physical exam (including ECOG performance status) 
o 
AE/SAE assessment 
o 
Concomitant medications 
o 
Determine disease status 
o 
Vital Signs and Weight 
o PET/CT scan (not required if performed at wk 32) 
o ThinPrep™ sample for HPV testing (if applicable) 
o Digene swab (2 samples) (if applicable) 
o 
Whole blood and serum for immunologic assays  
 
6.2 
Timing and Evaluations 
6.2.1 Informed Consent 
No study specific-assessments or procedures can be conducted until a signed 
informed consent form (ICF) has been obtained from the subject. 
Study personnel will meet with prospective study subjects, explain the study, and 
provide them with an ICF that describes the screening tests, eligibility criteria for 
entering the study, and study treatments and follow-up procedures.  
6.2.2 Assignment of Screening/Allocation Numbers 
Study personnel will screen subjects and assign unique subject identification 
number (SID). Subject ID numbers are a combination of site number plus a 3-
digit number starting with XX1. Information regarding subject’s screening 
number and screen date must be documented on a screening log.  
When a subject has been deemed eligible by criteria listed in protocol Section 4 - 
Selection and Enrollment of Subjects, the clinical site will contact the Sponsor to 
register the subject and provide the required eligibility information. The site will 
complete a Subject Identification Form (Appendix 1) and fax or email to the 
Sponsor prior to enrolling the subject. The Sponsor will assign the subject a 
unique allocation number based on the cohort the subject will be enrolled and 
return via fax or email the completed form to the site. Once assigned, the 
allocation number cannot be reused for any reason. 
6.2.3 Medical History 
Subjects will be asked to report any current or past medical conditions and 
illnesses at their screening visit and should include treatment detailed information 
on all therapy directed against cervical cancer, or CIN, e.g. past surgical and/or 

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radiation regimens. Any prior chemotherapy or immunotherapies, adjuvants, etc. 
should be recorded on the CRFs. 
Any worsening of a condition recorded in the medical history should be recorded 
as an Adverse Event on the CRFs. 
6.2.4 Safety Assessments 
Safety evaluations and management of toxicities are detailed in Section 7. 
Assessments for safety are described within this section. 
6.2.4.1  Medical and Clinical Assessments 
New onset disease and concomitant medications will be collected on Day 
0 and at all subsequent study visits through discharge.  
Assessment of systemic reaction/toxicity/side effects of standard 
(chemoradiation) therapy will be collected at specified visits and be 
reported using the “Acute Radiation Morbidity Scoring Criteria (RTOG)”, 
(Appendix 5).  
Assessment of all other adverse events will be collected form the time of 
informed consent through discharge and will be will be assessed using the 
CTCAE v4.03 issued by the US Department of Health and Human 
Services on June 14, 2010 (Appendix 4). 
Clinical evaluations for disease response will be conducted at all of the 
study visits (as assessed by clinical signs and symptoms of disease 
progression). PET/CT scans for disease progression will be obtained for 
all subjects 3-5 months after Day 0 and every 3-5 months thereafter per 
standard of care or in accordance with local guidelines and institutional 
practices. 
6.2.4.2  Physical Assessments 
A full examination including complete gynecological exam and ECOG 
performance status will be conducted during screening and study 
discharge. A targeted physical assessment (including ECOG performance) 
will be performed at other visits as determined by the Investigator or 
directed per subject complaints.   
6.2.4.3  Post-Treatment Reaction Assessment 
The Investigator will assess local and systemic reactions post-treatment 
(within 30-45 minutes after study treatment/EP) and at specified visits. 
Any reported local post treatment reactions will be graded per the Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials and any reported systemic post 
treatment reactions will be graded per CTCAE v4.03 and recorded on the 
CRFs (see Section 6.6 for more details). 

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6.2.4.4 Participant Reminder Card  
Subjects will be given an oral thermometer and participant reminder card 
(PRC) at each study treatment/EP visit. Subjects will be instructed to take 
and record their temperature daily (at the same time each day). They will 
also be advised to record local and systemic events on a PRC as shown in 
Appendix 9. 
If Weeks 2, 6, 10 and 12 visits are conducted by telephone, the subject 
should submit their PRC (i.e. mail, fax, email) to the site personnel prior 
to the phone visit. If the PRC is not received in advance, site personnel 
should verbally review all PRC elements listed above. The hard copy of 
the PRC should be collected at the next in-person study visit. Any entry on 
PRC determined to meet the criteria for a Grade 1 or higher adverse event 
should be documented as adverse event. If the PRC entry does not meet 
the criteria of a Grade 1 or higher AE as per the CTCAE v4.0, clinical 
judgment can be used to determine whether the entry should be recorded 
as an AE. For cases where the PRC entry and final AE reporting (i.e., 
grading) do not agree, the reasoning should be recorded in the source 
documents. 
6.2.4.5  Vital Signs 
Vital signs including body temperature, respiration rate, blood pressure 
and heart rate will be measured at all the study visits. 
6.2.4.6  Weight and Height 
Weight (kg) and height (cm) will be collected at the screening visit. 
Weight will be collected at each additional visit from Day 0 through 
discharge. 
6.2.4.7  12-lead ECGs 
An ECG will be performed at screening within 30 days of signing of ICF 
for all subjects to determine subject eligibility. Abnormal ECGs should be 
interpreted as clinically significant or not clinically significant.    
6.2.4.8  Pregnancy Test 
For women of reproductive potential, a negative result for serum 
pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must 
be available at the screening visit and urine β-HCG (pregnancy test) prior 
to each administration of INO-3112 and prior to tumor biopsy collection. 
If at any point, the β-HCG (pregnancy) test is positive, indicating that the 
subject is pregnant, no additional study treatment/EP will be administered, 
but the subject will be followed for the duration of the study and beyond to 
determine the outcome of the pregnancy (with the subject’s consent).  

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6.2.4.9 Laboratory Evaluations 
At screening, blood samples will be collected for serum chemistry and 
hematology. A urine sample will also be obtained to determine eligibility. 
At other visits, blood samples will be collected as specified in Table 1 - 
Schedule of Events. All labs for Day 0 and those associated with any 
treatment visit should be collected no more than 48 hours prior to 
treatment and reviewed/evaluated by the PI prior to treatment.  
Approximately 4 cups of blood will be drawn from each subject during the 
entire duration of the study. 
Complete blood count (CBC)  
White blood cell (WBC) count w/ differential 
Red blood cell (RBC) count 
Hemoglobin, Hematocrit 
Platelet count 
Serum Chemistry 
Glucose 
Albumin 
Total protein 
SGPT (serum glutamic-pyruvic transaminase)/ALT 
SGOT (serum glutamic-oxaloacetic transaminase)/AST 
Alkaline phosphatase 
Bilirubin (total) 
BUN (blood urea nitrogen) 
Calcium 
Creatinine 
Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or 
Bicarbonate) 
CPK (Creatine Phosphokinase) 
Serology (required only at screening if serologic test was performed ≥ 12 
months of informed consent) 
Antibody to HIV 
Hepatitis B surface antigen 
Antibody to Hepatitis C  
Urinalysis  
Urine samples will be tested by dipstick for glucose, protein, and 
hematuria. If abnormal (presence of protein, hematuria, or glucose 
≥ 1+) a microscopic examination will be performed. 
6.2.4.10  PET/CT Scan 
Baseline PET or CT scan must be performed within 4 weeks prior to Day 0.  

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The follow-up scan will be performed 3-4 months after Day 0 to evaluate 
subject disease status. Thereafter, PET/CT scans can be performed 3- 5 
months or at study discharge in accordance with local guidelines and 
institutional practices. 
FDG-PET imaging is based on the increased glucose metabolism of tumor 
cells compared to normal tissue resulting in higher standard uptake volume 
(SUV). Increased SUVmax at diagnosis has been associated with persistent 
abnormal FDG uptake after curative chemoradiation and biopsy-proven 
local recurrence [Kidd 2007]. FDG-PET is already utilized as a follow-up 
evaluation modality in a variety of cancers, including lymphomas, head and 
neck cancers, and breast cancer [Schelling 2000, Smith 2000, Weber 2001, 
Ott 2003, Weber 2003, Brun 2002].  
In a prospective study of cervical cancer patients, FDG-PET was 
demonstrated to be a metabolic biomarker of response and a potential 
prognostic marker for progression-free survival at 3 years [Schwarz 2007]. 
A meta-analysis of 16 studies also demonstrated statistical significance for 
prediction of event-free and overall survival using metabolic response 
derived from PET and PET/CT imaging [Zhao 2013]. 
Studies have previously described the abscopal effect of radiation therapy 
on non-irradiated tumor sites in a variety of cancers [Postow 2012, Prise 
2009]. Post-treatment FDG-PET may further provide elucidation of this 
mechanism by highlighting sites of residual activity. Retrospective and 
prospective studies have demonstrated that the use of positron emission 
tomography (PET) with F-18 fluorodeoxyglucose (FDG) in the post-
therapy evaluation of patients with cervical carcinoma is predictive of 
survival outcome [Grigsby 2004, Grigsby 2003].  
These studies evaluated patients with similar disease stage to our current 
investigation and found that SUV PET response at 3 months after 
chemoradiation correlated with survival and patterns of failure. We propose 
to describe qualitatively the rates of complete metabolic response (CMR), 
partial metabolic response (PMR), and progressive disease (PD) in our 
patient population and compare these rates to patients treated per standard 
of care in the aforementioned studies to preliminarily explore any 
differential outcomes.   
6.3 
Study Treatment/EP with INO-3112  
The timing of the first dose will be designated Day 0. 
6.3.1 Management of anxiety and pain due to EP procedure 
Subjects will be offered topical anesthetic (e.g. EMLA), to prevent significant 
discomfort from the study treatment/EP procedure. If EMLA (lidocaine 2.5% and 
prilocaine 2.5%) is used, an approximately 1.5 cm diameter amount will be 
applied with occlusion to the site of injection ~30 minutes prior to study 
treatment/EP.  

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Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam) for anxiety 
related to the EP procedure. Mild sedatives may be administered approximately 1 
hour prior to EP at Weeks 0, 4, 8 and/or 12. Subjects who receive a mild sedative 
must not be allowed to operate a motor vehicle for 3-4 hours after receiving 
medication and must have arranged transportation to depart the study site. 
Subjects will be offered an analgesic (e.g. ibuprofen, ketorolac) after study 
treatment/EP. [Note: The use of any narcotic (including Tylenol with codeine) for 
pain meets the definition of severe pain (Grade 3) as per the “Guidance for 
Industry - Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials, September 2007” (Table 6.1) and 
therefore do not offer this to the patient unless clinically indicated.] 
Subjects who are allergic to or have contraindications to ibuprofen, ketorolac or 
lorazepam will be offered a suitable alternative.  
6.4 
Assessment of Clinical Adverse Events 
The injection site will be assessed by study personnel prior to and within 30-45 
minutes after study treatment/EP and at next visit prior to study treatment/EP. 
Subjects will also be queried regarding the occurrence of any possible adverse 
events, concomitant medications and new onset chronic disease during their clinic 
visits. Subjects will be reminded to contact study personnel and immediately 
report any event that may happen for the duration of the study. These events will 
be recorded on the subject’s CRF.  
At specific visits the Acute Radiation Morbidity Scoring Criteria (RTOG) 
(Appendix 5) will be used to assess systemic reaction/toxicity/side effects of 
standard (chemoradiation) therapy.  
6.5 
Assessment of Laboratory Abnormalities 
Investigators may use clinical judgment to enroll subjects with isolated Grade 1 
abnormalities in screening CBC, serum chemistry or CPK values if there is no 
indication of disease process in the remainder of the history and physical 
examination.   
Blood will be drawn for serum chemistry, hematology and serology assessments 
as well as pregnancy testing at screening for inclusion into the study as listed in 
sections 6.2.4.8 and 6.2.4.9.  
Urinalysis will be performed at screening to fulfill eligibility criteria. CPK will be 
performed at Screening and Week 16.  
Complete blood count with differential and serum chemistry will be performed at 
each study treatment/EP and Week 16.  
6.6 
Assessment of Injection Site Reactions 
When evaluating injection site reactions throughout the study, the investigator 
will be instructed to use the following grading scale: 

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Table 6.1: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild(1) 
Moderate(2) 
Severe(3) 
Potentially Life 
Threatening(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic 
pain reliever 
>24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Redness* 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
2.5-5 cm and 
does not 
interfere with 
activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
*in addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the 
actual measurement. 
6.7 
Cervical Virologic and Peripheral Blood Immunogenicity Assessment 
Whole blood and serum samples to be tested for antibodies to the HPV E6 and E7 
proteins and/or T-lymphocytes producing IFN-γ will be obtained at baseline 
(Screening and Day 0 prior to dosing) and at each study treatment/ EP and follow-
up visits for the duration of the trial. Other immunological testing may be 
performed to further define the immune responses to the INO-3112. Details of the 
immunology sample collection and shipment will be provided in laboratory 
manual. 
Binding antibody responses against HPV E6 and E7 induced by INO-3112 will be 
measured using ELISA. Commercially available recombinant human HPV-16 and 
HPV-18 proteins will be used to assess induction of binding antibodies to each of 
the antigen components. 
Using antigen-specific IFN-γ ELISpot assays, the number of antigen-specific 
IFN-γ–secreting T-cells in response to stimulation with overlapping peptide 
libraries spanning consensus antigens HPV16 E6, HPV16 E7, HPV18 E6 and 
HPV18 E7 will be determined. As previously described [Bagarazzi et al Sci Tran 
Med]. PBMCs will be incubated with HPV peptide pools at a concentration of 2 
μg/ml. IFN-γ release will be detected after an overnight incubation. Spot forming 
units (SFU) will be adjusted to 1 × 106 PBMCs for each HPV peptide pool.   
Flow cytometric assays will be employed to examine any or all of the following 
characteristics of Study Treatment: induction of T-cells to 1) exhibit phenotypic 

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markers associated with cytolytic potential after short-term stimulation by HPV 
antigen (i.e., CTL phenotyping); 2) remain active in the presence of long-term 
antigen exposure and efficiently synthesize proteins used in lytic activity (i.e., 
Lytic granule loading); and 3) effectively employ lytic degranulation to drive 
killing of target cells expressing HPV antigens (i.e., Killing Assay)  
1. The CTL phenotyping assay employs short term (4-6 hours) in vitro 
stimulation of unfractionated PBMC using peptides spanning HPV antigens 
and appropriate controls. The external cellular markers employed in this 
assay might include CD3, CD4, CD8 (T-cell identification), CD45RO, CCR7 
(memory subset identification) and CD107a (lytic degranulation). The CTL 
Phenotyping assay may additionally analyze the following intracellular 
markers: IFN-γ (Th1 biasing cytokine), Tumor Necrosis Factor-α (TNF-α), 
Granzyme A, Granzyme B and Perforin (involved in lytic degranulation and 
cytotoxic potential). This panel may vary as additional relevant markers are 
identified.  
2. The lytic granule loading assay employs long term (115-120 hours) in vitro 
stimulation of unfractionated PBMC using peptides spanning HPV antigens 
and appropriate controls. The external cellular markers employed in this 
assay might include CD3, CD4, CD8 (T-cell identification) and CD137 (also 
known as 41BB, T-cell activation). The Lytic granule loading assay may 
additionally analyze the following intracellular markers: Granzyme B, 
Perforin and Granulysin (cytotoxic potential). This panel may vary as 
additional relevant markers are identified.  
3. The killing assay employs long term (115-120 hours) in vitro stimulation of 
unfractionated PBMC using peptides spanning HPV antigens. After the 
initial long term incubation, stimulated whole PBMC or CD8+ T-cells 
(hereafter referred to as Effector Cells) are co-incubated for ~1 hr with target 
cells treated with a stain (Target Stain) that differentiates them from Effector 
Cells and have additionally been pulsed with a substrate reagent which is 
activated only by the activity of Granzyme B or a substrate which is activated 
by the activity of terminal caspases involved in the induction and 
perpetuation of apoptosis. Enumeration of target cells identified by the 
Target Stain and the presence of an active substrate reagent within the Target 
population represents a measure of a functional T cell response that is 
capable of Target cell killing. 
A standardized binding ELISA will be performed to measure the anti–
HPV16/HPV-18 E6 or E7 antibody response induced by INO-3112. 96-well 
enzyme immunoassay plates will be coated with HPV16 or HPV18 E6 or E7 
proteins (1 μg/ml). 
PBMC responses against a pool of known antigenic epitopes pooled from 
Cytomegalovirus, Epstein Barr Virus and Influenza (CEF) will be tested in order 
to track general cellular immune competence during the study. Assessment of the 

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response to these reference antigens that are not related to the study antigens will 
give a baseline reading of immunocompetency at study entry.  Observation for 
variation of response against these reference antigens during the progression of 
study treatment may therefore give insight as to general immune competency and 
aid in accounting for variation in response against study antigens encoded by 
INO-3112 in the same manner as HPV response described above. 
Cervical Virologic Assessment 
Subjects must have positive HPV-16 and/or HPV-18 genotype result from ISH or 
PCR assays at screening or prior to screening for inclusion in the study. Subjects 
whose specimens also test positive for other HPV genotypes are not excluded as 
long as they have a positive result for HPV 16 and/or HPV 18. If a subject has 
documented evidence of HPV-16 and/or HPV-18 infection results from cervical 
specimen obtained prior to anti-cancer treatment, then those results will be 
eligible for inclusion in the study. 
If applicable, a liquid based cytology sample (ThinPrep™) will be collected for 
HPV PCR at screening and at Weeks 16 and 36. Samples will be sent to a central 
laboratory to be analyzed for the presence of HPV infection by PCR.  
Cervical Immunologic Assessment  
If applicable, two Digene cervical brushes will be collected at baseline (screening 
and Day 0), Weeks 16 and 36 and will be banked and frozen for immunological 
testing.  
Tissue specimens obtained as routine diagnostic and therapeutic specimens will 
be analyzed to characterize the presence, density, and co-localization of immune 
cell subsets, including macrophages, dendritic cells, T cells (CD8 and regulatory 
T cells), and NK cells. As tissue availability permits, the specimens will also be 
analyzed for cytokine expression.  
At visits where multiple cervical samples are collected, the two Digene cervical 
brushes will be collected prior to the ThinPrep™ sample. 
If adequate residual specimen is available, immunohistochemistry (IHC) studies 
will be performed on either tumor tissue block or unstained slides from tumor(s) 
from the following time points: (1) at screening; (2) at Week 16 (one month post-
dose 4).  
A tumor biopsy will be used to investigate the post-radiation changes at a cellular 
level, with particular focus on the presence and populations of immune cells to 
compare to pre radiation characterization.  
Characterization of the various cell populations present in the primary tumor site 
will allow for elucidation of long-term effects of radiation-induced changes, 
potential cell-mediating killing in microscopic colonies of residual tumor, and 
mechanisms of immune cell interactions in the post-radiation setting. The 
maturation and clonal expansion of T cells in response to repeated 
immunotherapy should result in the production of a memory T cell subset in the 
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Biopsy samples can also be compared to the post-dose peripheral blood samples 
to study shifts in cell populations or HPV-specific proliferative response. In 
addition, biomarkers may be identified as predictors of early response, resistance, 
or recurrence, and contribute to patient outcome stratification. 
6.8 
Disease Status 
Diseases status will be determined based on RECIST (version 1.1). Disease status 
should be categorized into: 
1. No evidence of disease (NED)  
2. Partial Response   
3. Stable disease 
4. Progressive disease 
6.9 
Concomitant Medications/Medical Care 
All medications taken or medical procedures performed within 12 weeks prior to 
Day 0 and during the study must be recorded on the case report forms (CRFs).  
6.10 
Permitted Supportive Therapy 
Anti-emetics, anti-diarrheals, analgesics, nutritional and fluid supplementation, 
and packed red blood cell transfusions are permitted as supportive therapy during 
the study. All medications and interventions must be recorded as concomitant 
medications in the CRFs. 
6.11 
HLA Testing 
A blood sample will be collected at the Day 0 visit and sent to a central laboratory 
for HLA typing. If the subject has a record of previous high resolution HLA 
testing and access to the results, this HLA testing is not required. 
6.12 
Downloading of EP data from CELLECTRA®-5P device 
Within 48 hours following each treatment with INO-3112, data should be 
downloaded from the EP device and the data file that is created should be sent to 
the Sponsor or designee by email to CELLECTRAdata@inovio.com. Instructions 
on how to download the data are provided in Appendix 7. Training will be 
provided. 
6.13 
Restrictions 
Subjects should not be vaccinated (e.g. influenza vaccine) within 2 weeks of 
(before or after) any dose of INO-3112. 
Subjects should not receive a course of systemic corticosteroids (≥2 mg/kg of 
prednisone or equivalent for 5 days) within 2 weeks before or after any dose of 
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7 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
Safety Parameters 
The safety of the INO-3112 DNA plasmid vaccines will be measured and graded 
in accordance with the document entitled “Common Terminology Criteria for 
Adverse Events (CTCAE)”, version 4.03 issued by the US Department of Health 
and Human Services on June 14, 2010 (Appendix 4).  
7.1.1 Adverse Events (AEs) 
 
An adverse event (AE) is defined as any unfavorable and unintended 
change in the structure, function, or chemistry of the body, or worsening 
of a pre-existing condition, temporally associated with the use of a product 
whether or not considered related to the use of the product. In this study, 
such changes will be monitored, classified, and summarized, and as 
Clinical or Laboratory AEs, respectively. Medical condition/diseases 
present before starting the investigational drug will be considered adverse 
events only if they worsen after starting study treatment.  
An unexpected AE is one not identified in the Clinical Investigator’s 
Brochure (CIB) or otherwise not expected from the characteristics of 
the clinical material. AEs include the following: 
• 
Pre- or post-treatment complications that occur as a result of protocol 
mandated procedure during or after the first screening visit (before the 
administration of study drug) 
• 
Any pre-existing condition that increases in severity, or changes in 
nature during or as a consequence of the study drug phase of a human 
clinical trial, will also be considered an AE 
• 
Complications and termination of pregnancy; see Section 7.4 for 
additional information 
• 
All AEs that occur from the study screening visits onwards and 
throughout the duration of the study, including the follow-up off study 
treatment period should be recorded as an AE 
 
AEs do not include the following: 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth 
extraction, transfusion) performed; the condition that leads to the 
procedure is an AE 
• 
Pre-existing diseases or conditions or laboratory abnormalities present 
or detected before the screening visits that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred 
(e.g., hospitalization for elective surgery, social and/or convenience 
admissions). 
• 
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• 
Any medical condition or clinically significant laboratory abnormality 
with an onset date before the consent form is signed and not related to 
a protocol associated procedure is not an AE. It is considered to be 
pre-existing and should be documented on the medical history CRF 
• 
Uncomplicated pregnancy (documented on a pregnancy CRF) 
• 
An induced elective abortion to terminate a pregnancy without medical 
reason (documented on a pregnancy CRF) 
7.1.2 Serious Adverse Events (SAEs) 
A serious adverse event (SAE) is any AE that meets one of the following 
conditions: 
• 
Death during the period of surveillance defined by the protocol; 
• 
Is immediately life-threatening (e.g., subject was, in the view of the 
Investigator, at immediate risk of death from the event as it occurred). 
This does not include an AE that, had it occurred in a more serious form, 
might have caused death; 
• 
An event requiring inpatient hospitalization or prolongation of existing 
hospitalization during the period of protocol defined surveillance 
(including any overnight stay in the hospital, regardless of the length of 
stay, even if the hospitalization is only a precautionary measure to allow 
continued observation. However, hospitalization (including hospitalization 
for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE; 
• 
Results in congenital anomaly or birth defect; 
• 
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions; 
• 
Is an important medical event that may not result in death, be life 
threatening, or require hospitalization, but based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; 
• 
Is medically significant or requires intervention to prevent one or other of 
the outcomes listed above. Examples of “other medically significant 
events” are: 
o Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
o Blood dyscrasias or convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 

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o Development of malignancies 
Clarification of Serious Adverse Events 
• 
Death is an outcome of an AE, and not an adverse event in itself 
• 
The subject may not have been on investigational medicinal product at the 
occurrence of the event. Dosing may have been given as treatment cycles 
or interrupted temporarily before the onset of the SAE, but may have 
contributed to the event 
• 
“Life-threatening” means that the subject was at immediate risk of death 
from the event as it occurred. This does not include an event that might 
have led to death if it had occurred with greater severity 
• 
Complications that occur during hospitalizations are AEs. If a 
complication prolongs the hospitalization, it is an SAE 
• 
Inpatient hospitalization means the subject has been formally admitted to a 
hospital for medical reasons, for any length of time. This may or may not 
be overnight. It does not include presentation and care within an 
emergency department 
The investigator should attempt to establish a diagnosis of the event on the basis 
of signs, symptoms, and/or other clinical information. In such cases, the diagnosis 
should be documented as the AE and/or SAE and not the individual 
signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution. The 
reporting period for SAEs is described in Section 9.3.2. 
7.1.3 Severity Codes for AEs 
Study personnel will grade laboratory AEs and clinical AEs (based on discussions 
with study participants) with respect to the following levels of severity as defined 
in Common Terminology Criteria for adverse events (CTCAE) of the National 
Cancer Institute for reporting of all serious adverse events (SAE) or the Acute 
Radiation Morbidity Scoring Criteria (RTOG).  
• Mild (Grade 1); 
• Moderate (Grade 2) 
• Severe (Grade 3); 
• Potentially Life Threatening (Grade 4) 
• Death (Grade 5) 
A copy of the CTCAE version 4.03 is provided in Appendix 4 and may be 
downloaded 
from 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov/reporting/ctc.html): 
A copy of the Acute Radiation Morbidity Scoring Criteria can be downloaded 
from 
the 
Radiation 
Oncology 
Therapy 
Group 
home 
page 
(http://www.rtog.org/ResearchAssociates/AdverseEventReporting/AcuteRadiatio
nMorbidityScoringCriteria.aspx). 
 

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7.2 
Causal Relationship of Clinical Material to AEs 
A causally related AE is one judged to have a possible, probable or definite 
relationship to the administration of the clinical material (INO-3112). An AE may 
also be assessed as not related to the investigational product. The Investigator is 
responsible for reporting adverse events and judging the relationship between the 
administration of the clinical material and a subsequent AE because the 
investigator is knowledgeable about the subject (e.g., medical history, 
concomitant medications), administers the investigational product, and monitors 
the subject’s response to the investigational product. The Investigator is aware of 
the subject’s clinical state and thus may be sensitive to distinctions between 
events due to the underlying disease process versus events that may be product 
related and may have observed the event. The Sponsor will assess the overall 
safety of the investigational product and determine whether to report 
expeditiously to the FDA. 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where 
applicable); 
• 
Known association of the event with the study drug or with similar 
treatments; 
• 
Known association of the event with the disease under study; 
• 
Presence of risk factors in the Study Subject or use of concomitant 
medications known to increase the occurrence of the event; 
• 
Presence of non-treatment-related factors that are known to be associated 
with the occurrence of the event 
7.2.1 Abnormal Laboratory Value 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, 
laboratory abnormalities (e.g., serum chemistry, hematology, CPK, urinalysis) 
independent of the underlying medical condition that require medical or surgical 
intervention or lead to study treatment interruption or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or 
other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they 
meet the definition of an AE (or SAE) as described in Sections 7.1.1 and 7.1.2. If 
the laboratory abnormality is part of a syndrome, record the syndrome or 
diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality that is new in onset or worsened in severity or 
frequency from the baseline condition and meets one of the following criteria will 
be recorded as an AE: 
• 
Requires therapeutic intervention or diagnostic tests 
• 
Leads to discontinuation of study treatment 
• 
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• 
Is judged by the investigator as clinically significant 
Grade is an essential element of these criteria. Each CTCAE grading term in the 
current version is a unique representation of a specific event used for medical 
documentation and scientific analysis and is a single MedDRA Lowest Level 
Term (LLT).  
Investigators are asked to take the CTCAE grading criteria into account when 
assessing if a laboratory abnormality qualifies as a laboratory AE.  Their clinical 
judgment ultimately determines whether the abnormality in question is “clinically 
significant (CS)” or “not clinically significant (NCS)” and the severity of the 
event. CTCAE grading can be used as a reference when making this 
determination. It is the responsibility of the Investigators to ensure all AEs are 
accurately reported and graded. 
7.2.2 Post-Study Reporting Requirements 
All AEs and SAEs including deaths, regardless of cause or relationship, must be 
reported for subjects on study (including any protocol-required post-treatment 
follow-up). 
Investigators are not obligated to actively seek AEs or SAEs beyond study 
discharge for subjects. However, if the investigator learns of an AE or SAE that 
occurs after the completion or termination visit and the event is deemed by the 
investigator to be probably or possibly related to the Study Treatment, he/she 
should promptly document and report the event to Inovio Pharmaceuticals. 
7.3 
Methods and Timing of the Collection and Recording of Safety Data  
After study treatment/EP: Study subjects will be directly observed by study 
personnel for 30-45 minutes after each administration of study treatment/EP for 
immediate reactions. Injection sites will also be assessed at the subsequent study 
visit. 
The occurrence and severity of any AE during this period or the lack of same will 
be recorded on the appropriate CRF. Subjects will be given an oral thermometer 
and instructed to take and record their temperature daily (at the same time each 
day).  
Days 0-3 following study treatment/EP: Subjects will also be instructed to record 
local and systemic events in a PRC for 3 days following treatment visit as shown 
in Appendix 9. 
Throughout the Study: Subjects will also be queried regarding the occurrence of 
any possible adverse events, concomitant medications and new onset chronic 
disease during their clinic visits. Subjects will be reminded to contact study 
personnel and immediately report any event that may happen for the duration of 
the study. These events will be recorded on the subject’s CRF.  

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At specified visit the Acute Radiation Morbidity Scoring Criteria (RTOG) form 
will be completed for each patient to assess systemic reaction/toxicity/side effects 
of standard (chemoradiation) therapy.  
On study treatment/EP visits, the assessments will be performed prior to dosing. 
Study subjects will be queried at each clinic visit regarding the occurrence of any 
AEs, including SAEs that may have occurred since the last visit. They will be 
reminded to contact study personnel and immediately report any such event that 
happens during the course of the study. These events will be recorded on the 
CRFs.  
7.4 
Procedures for Documenting Pregnancy During Study 
Subjects who are pregnant or expect to become pregnant during the course of the 
study will be excluded from participation in the study. Should a subject become 
pregnant after enrolling in the study, she will not be given any further treatments 
with INO-3112. The Investigator will report this event to Inovio Pharmaceuticals, 
Inc., or its designee, within 24 hours and to the IRB. The Investigator should 
counsel the participant and discuss risks of continuing with the pregnancy and the 
possible effects on the fetus. Sites must request the subject’s permission to query 
pregnancy outcome and follow each subject to determine the outcome of the 
pregnancy. Results will be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study should continue to 
be followed for safety assessments without receiving further treatments. 
Procedures that are contraindicated during pregnancy, including additional 
vaccinations, must not be performed. Investigators should use clinical judgment 
regarding subsequent study-related blood collection based on the presence or 
absence of anemia in each subject. Subjects who are not withdrawn should 
continue to be followed for safety assessments through discharge per protocol.  
All pregnancies that occur from the time of first screening procedure through the 
follow up visits must be reported. Monitoring of the subject and the outcome of 
the pregnancy should be followed by the investigator. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported 
directly to Inovio Pharmaceuticals. 
7.5 
Toxicity Management 
The Sponsor’s Medical Monitor will be responsible for the overall safety 
monitoring of the study.  
7.5.1 Criteria for Halting of Study Enrollment  
Study enrollment (enrollment of new subjects) will be halted if there is a report of 
Grade 3 anaphylaxis from study treatment/EP with INO-3112. The study may 
resume enrollment after the safety data has been reviewed and deemed safe to 
continue by the Medical Monitor and Investigator. 

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7.5.2 Events Requiring Expedited Reporting 
Events requiring expedited reporting (ERER) will be defined as treatment- or EP-
related adverse events including any of the following:  
• Grade 3 or greater injection site pain, tenderness, erythema, and/or 
induration recorded ≥ 1 hour after study treatment (see Table 6.1) 
• Grade 3 or greater fever assessed by the Principal Investigator as 
possibly, probably or definitely related to study treatment  
• Grade 3 or greater systemic symptoms assessed by the Principal 
Investigator as possibly, probably or definitely related to study 
treatment  
as defined in the “Common Terminology Criteria for Adverse Events (CTCAE)”, 
version 4.03 issued by the US Department of Health and Human Services on June 
14, 2010 (Appendix 4). The worse grade for that particular event is to be 
documented on the CRFs. 
Sites should inform the Sponsor of any ERER within 72 hours to discuss whether 
further dosing should continue for that participant. 
7.5.3 Stopping Rules (Criteria for Pausing of Study) 
7.5.3.1 If at any time during the study one third (1/3) or more subjects 
experience an ERER assessed as possibly, probably or definitely 
related to study treatment, further enrollment and study 
treatments will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor and 
Principal Investigator.  
7.5.3.2 After any SAE, potentially life threatening AE or death assessed 
as possibly, probably or definitely related to study treatment, 
further enrollment and study treatments will be halted 
immediately until a thorough investigation has been conducted 
by the Medical Monitor, Principal Investigator and IRB (if 
applicable). 
7.5.3.3 If three or more subjects in this study, experience the same grade 
3 or 4 adverse event, assessed as possibly, probably or definitely 
related to study treatment, further enrollment and study 
treatments will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor and 
Principal Investigator. 
7.5.3.4 In the event of any unexpected Grade 4 toxicities, assessed as 
possibly, probably or definitely related to study treatment, further 
enrollment and study treatments will be halted immediately until 
a thorough investigation has been conducted by the Medical 
Monitor, Principal Investigator and IRB (if applicable). 

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7.5.3.5 The study will be halted for any report of Grade 3 anaphylaxis 
from immunotherapy/EP with INO-3112 in two or more patients 
(as graded per “Common Terminology Criteria for Adverse 
Events (CTCAE)”, version 4.03 issued by the US Department of 
Health and Human Services on June 14, 2010 (Appendix 4)). 
 
8 
STATISTICAL CONSIDERATIONS 
8.1 
Sample Size Considerations 
Per Rose et al., the percentage of patients with grade 3 or 4 hematologic toxicity 
was 23%.  With n=10 patients in this study, there is approximately a 92% chance 
of observing of at least one grade 3 or 4 hematologic toxicity.  If 0 out of 10 
adverse events are observed, the study provides 95% confidence that the true 
proportion of such events is <31%.   
8.2 
Safety Analysis 
With the toxicity results, data from the Acute Radiation Morbidity Scoring 
Criteria and CTCAE will be recorded for each patient during each visit.  For the 
toxicity results, and for AEs and injection site reactions, descriptive statistics will 
be generated tabulating the percentage of subjects with events by type and grade 
along with associated exact 95% Clopper-Pearson confidence intervals. 
8.3 
Analysis of Immune Responses 
Binary responses, i.e., responders/non-responders, will be analyzed by calculating 
the percentage of responders along with associated exact 95% Clopper-Pearson 
confidence intervals.  Continuous responses, e.g., immune levels, will be analyzed 
by calculating the mean or median responses along with associated 95% 
confidence intervals.  
 
8.4 
Analysis of Clinical Responses 
  Disease status frequencies based on RECIST criteria categories will be 
summarized. 
8.5 
Summary of Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized with means, 
medians, standard deviations, ranges or percentages. 
8.6 
Missing Values 
Missing data will not be imputed. 
8.7 
Site Effects 
The data will be summarized by site and compared observationally among sites. 
 

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9 
DATA COLLECTION, MONITORING, AND AE REPORTING 
9.1 
Records to Be Kept 
CRFs will be provided for each subject. Subjects must not be identified by name 
on any CRFs. Subjects will be identified by their subject identification number 
(SID) provided by Inovio Pharmaceuticals, Inc. 
9.2 
Safety and Quality Monitoring and Record Availability 
Monitoring 
Monitoring of the clinical trial will be performed by experienced monitors, who 
will report to the Sponsor. Records for all clinical subjects in this trial will be 
monitored. The following clinical site monitoring tasks will be performed at all 
sites: 
• Prior to trial initiation, a site visit will be conducted to review all relevant 
forms and documentation, to ensure compliance with all applicable 
requirements. 
• All clinical site monitoring visits will be documented.  
• Periodic site visits will be performed on a per dose group basis. 
• The site monitor will be responsible for addressing and documenting the 
following study conduct activities and obligations and will: 
o Assure that the study is being conducted in accordance with the 
protocol, applicable regulatory agency regulations, and IRB policies. 
o Discuss study conduct issues and incidents of noncompliance with the 
Investigator and/or study personnel and document them on the 
resolution trip report. Report any significant unresolved problems 
immediately to the sponsor. 
o Remind the Investigator as necessary of the obligation to immediately 
report SAE and provide subsequent follow-up report of the final 
outcome to the IRB. 
o Review all CRF pages for completeness, logic, and internal 
consistency throughout the study. 
o Assure that the study facilities continue to be acceptable. 
o Compare the study CRFs with source documents to assure that the data 
are accurate and complete and that the protocol is being followed.  
o Assure that investigational product and device accountability and 
reconciliation records are complete and accurate.  
o Assure that all subject specimens are being stored and forwarded 
properly for testing.  
Record Availability  
The investigator will make study documents (e.g., ICFs, drug distribution forms, 
CRFs) and pertinent hospital or clinic records readily available for inspection by 
the local IRB, the site monitors, the FDA, Inovio or its designee or confirmation 
of the study data. 

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9.3 
Adverse Experience (AE) Reporting 
To assure the safety of the participants, information about all AEs (see Section 7.1 
Safety Parameters for definitions), whether volunteered by the subject, discovered 
by investigator or study staff questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded in the 
subject’s source documents and followed as appropriate.  
9.3.1 Study Reporting Period of Adverse Events 
The reporting period for AEs due to chemoradiation therapy toxicity is the 
period immediately following initiation of chemoradiation through the 
Week 4 visit of the study. 
The reporting period for all other AEs is the period immediately following 
informed consent through the end of the study  
9.3.2 Study Reporting Period of Serious Adverse Events 
The reporting period for SAEs (without regard to causality) is the entire 
period following informed consent until the end of the study.  
Each AE will be assessed to determine whether it meets seriousness 
criteria. If the AE is considered serious, the investigator should report this 
event to Inovio Pharmaceuticals as outlined below and also to the Ethics 
Committee according to its standard operating procedures. 
Expectedness of SAEs will be determined by Inovio Pharmaceuticals 
using reference safety information specified in the Investigator’s 
Brochure. An event may qualify for expedited reporting to regulatory 
authorities if it is a SAE, serious adverse drug reaction, or suspected 
unexpected serious adverse reaction (SUSAR) in line with relevant 
legislation. All investigators will receive a safety letter notifying them of 
relevant SUSAR reports. The investigator should notify the Ethics 
Committee as soon as is practical, of serious events in writing where this 
is required by local regulatory authorities, and in accordance with the local 
institutional policy. The investigator should send the initial report to 
sponsor within 24 hours of becoming aware of the event. At minimum, the 
initial report should include the following information: 
• 
Event 
• 
Study code 
• 
Subject number, initials and date of birth 
• 
Investigational study product 
• 
Reporter name and contact information 
In the case of a “minimum report” (one that is solely comprised of the 
information bulleted above), a more detailed follow-up report should be 
sent as soon as more information becomes available but no later than 7 
calendar days after the date of the initial report. Each SAE should be 
followed up until resolution or stabilization and for a reported death, the 

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investigator should provide Inovio Pharmaceuticals and the Ethics 
Committee with any additional requested information (e.g., autopsy 
reports and terminal medical reports). 
The original SAE form should be kept at the study site. Inovio 
Pharmaceuticals or its representative will be responsible for determining 
and in turn, reporting SAEs to regulatory authorities according to the 
applicable regulatory requirements.  
SAEs must be followed by the investigator until resolution, even if this 
extends beyond the study-reporting period. Resolution of an SAE is 
defined as the return to baseline status or stabilization of the condition 
with the expectation that it will remain chronic.  
At any time after completion of the SAE reporting period, if an 
investigator becomes aware of an SAE that is suspected by the 
investigator to be related to Study Treatment, the event should be reported 
to the Sponsor or its designee. 
9.3.3 Notification of Serious Adverse Events 
In accordance with 21 CFR 312.32, the Sponsor shall notify FDA and all 
participating investigators in a written IND safety report of any adverse 
experience associated with the use of the drug that is both serious and 
unexpected. Reports of serious adverse events shall be made as soon as 
possible and in no event later than 7 calendar days if the event is a death or 
is life threatening and 15 calendar days for all other reportable events after 
the Sponsor’s initial receipt of the information. Each written notification 
may be submitted on FDA Form 3500A or in a narrative format and shall 
bear prominent identification of its contents. Each written notification to 
FDA shall be transmitted to the FDA new product review division that has 
responsibility for review of the IND. In each written IND safety report, the 
Sponsor shall identify all safety reports previously filed with the IND 
concerning a similar adverse experience, and shall analyze the significance 
of the adverse experience in light of the previous, similar reports. The 
Sponsor shall also notify FDA by telephone or by facsimile transmission 
of all deaths regardless of causality and any unexpected fatal or life-
threatening experience associated with the use of the drug as soon as 
possible but in no event later than 7 calendar days after the sponsor’s 
initial receipt of the information. Each telephone call or facsimile 
transmission to FDA shall be transmitted to the FDA new product review 
division that has responsibility for review of the IND.  
Follow up information to a safety report shall be submitted as soon as the 
relevant information is available. If the results of a Sponsor’s event 
investigation show that an adverse drug experience not initially 
determined to be reportable is, in fact, reportable, the Sponsor shall report 
such experience in a written safety report as soon as possible, but in no 
event later than 15 calendar days after the determination is made. Results 

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of investigations of other safety information shall be submitted, as 
appropriate, in an information amendment or annual report. 
In the event of death, if an autopsy is performed, a copy of the report 
should be sent to Inovio Pharmaceuticals. 
SAE reporting email: safety@inovio.com  
SAE FAX transmission: 
 
SAE Phone: 
 
SAE MAILING ADDRESS 
Inovio Pharmaceuticals, Inc. 
660 W. Germantown Pike 
Suite 110 
Plymouth Meeting, PA 19462  
MEDICAL MONITOR: 
, MD 
 Mobile 
  
9.4 
Reporting of Device Related Complaints 
Any problems experienced during the treatment procedure including potential 
malfunctions of the CELLECTRA®-5P device, error messages displayed on the 
device screen following treatment or errors that occur during the treatment 
procedure should be reported to the Sponsor or designee immediately for 
evaluation. The error reporting form provided in Appendix 7 should be completed 
and emailed to the Sponsor at 
 
9.5 
Study Discontinuation 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at 
multiple sites for safety or administrative reasons at any time. Should the study be 
terminated and/or the site closed for whatever reason, all documentation and study 
product pertaining to the study must be returned to Inovio Pharmaceuticals or its 
representative. 
10 
PUBLICATION OF RESEARCH FINDINGS 
The results of this trial will be submitted for presentation and/or publication 
within 1 year of study completion and data availability. All data obtained, 
recorded in the CRF and analyzed during the course of this study are the property 
of the Sponsor (Inovio).  Any use of these data must be approved in writing by the 
Sponsor.  At least 60 days before any of the data or results of this study are 
submitted for presentation or publication, the abstract, poster, presentation, or 
manuscript must be sent to the Sponsor for review and approval to determine if 
any confidential information, trade secret, or patentable information is present.  
The Sponsor must approve or deny all requests for data presentation or 

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publication in writing within 30 days. In the event Inovio makes such objection, 
the researcher(s) shall refrain from making such submission for publication or 
presentation for a maximum of three (3) months from the date of receipt of such 
objection in order for patent application(s) directed to the patentable subject 
matter contained in the proposed publication or presentation to be filed with the 
United States Patent and Trademark Office and/or foreign patent office(s).

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11 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CMI 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
CytoMegalo Virus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CT 
Computed Tomography 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
DLT 
Dose Limiting Toxicity 
EBRT 
External Beam Radiation Therapy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
FDG 
Fluordeoxyglucose  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
Human Papillomavirus 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
LEEP 
Loop Electrosurgical Excision Procedure 

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MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
NED 
No Evidence of Disease 
NIH 
National Institutes of Health 
NYHA 
New York Heart Association 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PHI 
Protected Health Information 
PFS 
Progression Free Survival 
PMR 
Partial Metabolic Response 
PRC 
Participant Reminder Card  
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS 
Review of Systems 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome 
SID 
Subject Identification   
SOC 
System Organ Class 
SUV 
Standard Uptake Volume 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WOCBP 
Women of Childbearing Potential 

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12 
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Tomography in Cervical Cancer: A Meta-Analysis. International journal of 
gynecological cancer. 
59. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, et al. (2012) 
Immunologic correlates of the abscopal effect in a patient with melanoma. N. 
Engl. J. Med. 366:925–31. 
60. Prise KM, O'Sullivan JM. (2009) Radiation-induced bystander signalling in 
cancer therapy. Nat. Rev. Cancer, 9: 351–360. 
61. Lee Y, Auh SL, Wang Y et al. Therapeutic effects of ablative radiation on local 
tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 
2009;114:589-95. 
62. Meng, Y., Beckett, M. A., Liang, H., Mauceri, H. J., van Rooijen, N., Cohen, K. 
S., & Weichselbaum, R. R. (2010). Blockade of tumor necrosis factor α signaling 
in tumor-associated macrophages as a radiosensitizing strategy. Cancer 
research,70(4), 1534-1543. 
63. Seung SK, Curti BD, Crittenden M et al. Phase 1 study of stereotactic body 
radiotherapy and interleukin-2--tumor and immunological responses. Sci Transl 
Med 2012;4:137ra74. 
64. Grigsby PW, Siegel BA, Dehdashti F, Rader J, Zoberi I. Posttherapy [18F] 
fluorodeoxyglucose positron emission tomography in carcinoma of the cervix: 
response and outcome. J Clin Oncol. 2004 Jun 1;22(11):2167-71. 
65. Grigsby PW, Siegel BA, Dehdashti F, Mutch DG. Posttherapy surveillance 
monitoring of cervical cancer by FDG-PET. Int J Radiat Oncol Biol Phys. 2003 
Mar 15;55(4):907-13. 
66. Schwarz JK, Siegel BA, Dehdashti F, Grigsby PW. Metabolic response on post-
therapy FDG-PET predicts patterns of failure after radiotherapy for cervical 
cancer. Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):185-90. doi: 
10.1016/j.ijrobp.2011.05.053. 
Epub 
2011 
Oct 
17. 

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13 
APPENDICES 
13.1 
Appendix 1: Subject Identification Fax Form 
 
SCREENING NUMBER: 
 
GENDER: 
 
Date of Birth: 
 
Screening Date: 
 
 
Anticipated Date of Immunotherapy Dose: 
 
Allocation Number (to be completed  by Inovio) 
Allocation Number: 
 
INO initials: ________ 
COMMENTS BOX: 
SITE PERSONNEL REPORTING: 
DATE REPORTED/FAXED: 
 

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13.2 
Appendix 2: ECOG Performance Status 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982. 

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13.3 
Appendix 3: Standard Chemoradiation Guidelines  
Below are standard guidelines for chemoradiation in this patient population. It is highly 
suggested these guidelines be followed.  
I. Standard therapy 
a. Concurrent chemoradiotherapy 
II. Chemotherapy 
a. Cisplatin 
I. Source and Formulation: Cisplatin is commercially available from Bristol-
Myers Oncology and from Pfizer as a dry powder supplied in 10 mg 
and 50 mg vials, and in aqueous solution in 50 mg and 100 mg vials 
with 100 mg mannitol and 90 mg sodium chloride; 10 mg/vial. The 10 
mg and 50 mg vials should be reconstituted with 10 mL or 50 mL 
sterile water for injection USP, respectively. Each mL of the resulting 
solution will contain 1 mg of cisplatin. Reconstitution of powder 
results in a clear colorless solution when completed as recommended. 
NOTE: Aluminum reacts with cisplatin causing precipitation 
formation and loss of potency; therefore, needles or intravenous sets 
containing aluminum parts that may come in contact with the drug 
must not be used for the preparation or administration of cisplatin. 
II. Administration: Patients will be pre-hydrated per institutional guidelines. 
Cisplatin will be dissolved at a concentration of 1 mL of sterile 
water/mg of drug, and the solution will be administered intravenously 
over 45-60 minutes. Supportive treatment will be given according to 
institutional policy. 
III. Storage and Stability: Store at 15º to 20ºC. Unopened vials of dry powder 
are stable for the lot life indicated on the package when stored at room 
temperature. The aqueous solution should be stored at room 
temperature and protected from light. The reconstituted solution is 
stable for 20 hours at room temperature. Do not refrigerate. The 
cisplatin remaining in the amber vial following initial entry is stable 
for 28 days protected from light or for 7 days under fluorescent room 
light. NOTE: Once reconstituted, the solution should be kept at room 
temperature. If the reconstituted solution is refrigerated, a precipitate 
will form. 
IV. Adverse Events: Incidence rates of adverse events associated with 
cisplatin are provided in the product package insert. The following 
events are expected with the administration of cisplatin: 
a. Nephrotoxicity: Dose-related and cumulative renal insufficiency is 
the major dose-limiting adverse events of cisplatin. Renal adverse 
events have been noted in 28-36% of patients treated with a single 
dose of 50 mg/m2. It is first noted in the second week after a dose 
and is manifested as elevated BUN, creatinine, and serum uric 
acid, or as a decrease in creatinine clearance. Because renal 
adverse events become more prolonged and severe with repeated 

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courses of cisplatin, renal function must return to normal before 
another dose can be given. 
b. Ototoxicity: Ototoxicity has been observed in up to 31% of 
patients treated with a single dose of  cisplatin 50 mg/m2. It is 
manifested by tinnitus and/or hearing loss in the high frequency 
range. Deafness has been reported rarely. 
c. Hematologic Toxicity: Myelosuppression occurs in 25-30% of 
patients treated with cisplatin. Nadirs in circulating platelets and 
leukocytes occur between Days 18 and 23 with most patients 
recovering by Day 39. Thrombocytopenia, anemia, neutropenia, 
and fever are also possible adverse events. 
d. Gastrointestinal Toxicity: Marked nausea and vomiting occur in 
almost all patients treated with cisplatin. Diarrhea and anorexia 
have also been reported. 
e. Neurotoxicity: Neurotoxicity usually characterized by peripheral 
neuropathies, has been reported. Neuropathy usually occurs after 
prolonged therapy (4 to 7 months); however, symptoms have been 
reported after a single dose. Muscle cramps, loss of taste, seizures, 
autonomic neuropathy, dorsal column myelopathy, and Lhermitte’s 
sign have also been reported. 
f. Ocular Toxicity: Optic neuritis, papilledema, and cerebral 
blindness have been reported infrequently in patients receiving 
standard recommended doses of cisplatin. Blurred vision and 
altered color perception have been reported after the use of 
regimens with higher doses of cisplatin or greater dose frequency 
than those recommended in the package insert.  
g. Anaphylactic-like Reactions: Anaphylactic-like reactions have 
occasionally been reported in patients previously exposed to 
cisplatin. Symptoms include facial edema, wheezing, tachycardia, 
and hypotension. 
h. Hepatotoxicity: Transient elevations in liver enzymes, especially 
SGOT (AST), and bilirubin, have been reported. 
i. Other Toxicities: Other infrequent toxicities that have been 
reported include cardiac abnormalities, hiccups, elevated serum 
amylase, rash, alopecia, malaise, and asthenia. Rare cases of local 
soft tissue adverse events have occurred. 
V. Mechanism of Action: Primarily causes inhibition of DNA synthesis and, 
to a lesser degree, inhibition of RNA and protein; it has not been 
shown to be cell cycle specific. 
VI. Pharmaceutical data: Cisplatin (cis-diamminedichloroplatinum II) has the 
empiric formula N2CL2 PtH6. It is a planar inorganic compound with 
a molecular weight of 300; soluble in water at a concentration of 1 
mg/mL. The (II) nomenclature denotes the active valence state of the 
platinum. The interatomic distance of the chlorides is 3.3A, which is 
different from the 5-7A interatomic distance of the classic alkylating 
agents. Only the cis-isomer is therapeutically active. 

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VII. 
Supply: This drug is commercially available. 
VIII. Duration of administration: Cisplatin 40 mg/m2 (80 mg max) should be 
administered once weekly during external beam RT (5 cycles only). It 
is recommended that cisplatin be started on day 1 of external beam RT 
but it is acceptable to give cisplatin on days 1, 2, or 3 of external beam 
RT.  Dose modifications and indications for holding cisplatin are 
provided below. 
IX. Dose Modification 
a. Chemotherapy should be held for: 
• 
ANC < 500 /mm3. 
• 
Platelets < 50,000/mm3. 
• 
Febrile neutropenia or bleeding. 
• 
Persistent (>24 hours) grade 3 or 4 nausea and vomiting. 
• 
Renal Failure (creatinine > 2.0 mg% or creatinine clearance < 50 
ml/min). 
b. Cisplatin can be resumed at a dose of 30 mg/m2 (60 mg max) after 
the resolution of: 
• 
Persistent (>24 hours) grade 3 or 4 nausea and vomiting. 
• 
Renal Failure (creatinine > 2.0 mg% or creatinine clearance < 50 
ml/min). 
III. 
Radiation Therapy 
Patients should receive pelvic radiation therapy in combination with cisplatin infusion 
given on a weekly basis for six weeks. The last dose can be given during parametrial 
boost. 
Radiation therapy should be administered to the pelvis with external beam and 
intracavitary techniques.  Radiation therapy may also be administered to the para-aortic 
nodal chain as clinically indicated when there is clinical and/or imaging evidence of 
nodal disease in the high common iliac or para-aortic nodal chain.  Radiation therapy 
must be completed within 10 weeks of its initiation. 
a. Physical Factors 
External beam radiation sources will be linear accelerators which produce 
megavoltage energy radiation beams. SAD (source-axis distance) 100 cm is 
required.  Low-Dose-Rate (LDR) intracavitary radiation may be delivered by 
Cesium-137 sources. High-Dose-Rate (HDR) may also be used using an Iridium-
192 source. 
b. Simulation and Localization 
i. Simulation should be done in the supine position.   
ii. Recommended contrast and markers are intravenous contrast unless medically 
contraindicated, oral contrast, bladder contrast, rectal contrast, and a radio-
opaque cervical marker at the apex of the vagina.  Implanted fiducials are 
optional. 
iii. A gyne swab with CT wire at the tip should be placed into into the vagina 

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iv. A foley catheter should be placed for simulation with both an empty and full 
bladder. Full bladder is recommend to be achieved through injection 120 cc of 
90cc bacteriostatic water and 30 cc of conray through foley into bladder. 
v. Patient should be scanned with both full and empty bladder. Full and empty 
bladder CT scans should be fused. 
vi. Immobilization should be achieved with custom alpha cradles.  
vii. Imaging should include CT simulation using 2-5mm slice thickness from T10 to 
5cm below the ischial tuberosities, or to include the maximal extent of disease. 
viii. Isocenter placement is per the discretion of the treating physicians 
ix. Localization films taken on the simulator and/or treatment machine are 
necessary in all patients.  Polaroid or digital pictures of all treatment portals 
with the patient in the treatment position are recommended.  
Treatment Plan, Dose Specification and Distribution 
i. Depending on the FIGO stage and radiographic extent of disease, patients 
should receive radiation therapy to the pelvis, cervix, gross lymph nodes, and if 
indicated, the paraortic nodal chain. 
ii. The volume irradiated should include the totality of the gross disease locally 
and regionally, as visualized by CT, PET or MRI scanning, the whole uterus, 
paracervical, parametrial and uterosacral ligaments as well as the areas of the 
obturator, hypogastric, external and internal iliac lymph nodes. A margin of 2-3 
cm should be given around the gross disease and 1.5-2 cm around involved 
lymph nodes. 
iii. Patients treated to the whole pelvis +/- paraaortic chain should receive a total 
dose of 4500 cGy in 25 fractions at 180 cGy/fx, using a four field technique or 
intensity modulated radiation therapy (IMRT) throughout the entire treatment 
with all fields treated each day. Gross nodal disease should be treated with 
either a sequential boost or simultaneous integrated boost per the treating 
physician and as determined by proximity of organs at risk. 
iv. If overall treatment time for external pelvic RT exceeds 50 days, then reason for 
the delay must be documented. 
c. Dose Specification 
1. Fractionation: Conventional fractionation should consist of one fraction per day, 
total five fractions per week. 
2. The pelvis and, if indicated, the para-aortic nodal chain, should be treated at a 
dose per fraction of 180 cGy per day. 
3. Sequential or simultaneous integrated boost may be delivered to a maximum of 
65Gy in 1.8-2.5Gy per fraction, while maintaining normal tissue constraints. 
4. Parametrial boost should be delivered sequentially after pelvic/para-aortic 
radiation therapy to a maximum dose of 65Gy to the sidewall.  Point B may be 
used as the calculation point dose site.  The superior border should be reduced to 
include the true pelvis only as defined as 1cm above the inferior aspect of the 
sacroiliac joint. 
d. Target Delineation 
1. General 

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Pelvic MRI and/or PET fusion with the simulation scan is recommended to aid 
target delineation. Fusion should be optimized to match the MRI / PET scan to the 
treatment position. The Gross Tumor Volume (GTV) and Clinical Target Volume 
(CTV) and normal tissues will be contoured on all CT slices in which the 
structures exist. The definition of all volumes will be in accordance with the 1993 
ICRU Report #50: Prescribing, Recording and Reporting Photon Beam Therapy 
(http://www.icru.org/home/reports/prescribing-recording-and-reporting-photon-
beam-therapy-report-50).  
2. GTV Delineation 
The GTV is defined as all known gross disease determined from radiographic 
studies, clinical information, physical examination, endoscopic examination, and 
biopsy results.  
3. CTV Delineation 
The CTV is defined as the gross tumor plus areas containing potential 
microscopic disease, including the cervix, uterus (if present), the superior third of 
the vagina (or half of the vagina, if clinically involved), the parametria, and the 
regional lymph nodes. CTV delineation should follow reported consensus 
guidelines [Small W, Mell LK, Creutzberg C, et al. Consensus recommendations 
for intensity modulated radiation therapy planning for post-operative pelvic 
radiotherapy in endometrial and cervical cancer. Int J Radiat Oncol Biol Phys. 
2008;71:428-34, http://www.ncbi.nlm.nih.gov/pubmed/18037584 and Lim K, 
Small W, Portelance L, et al. Consensus guidelines for delineation of clinical 
target volume for intensity-modulated pelvic radiotherapy for the definitive 
treatment of  cervix cancer  Int J Radiat Oncol Biol Phys. 2009, 
http://www.redjournal.org/article/S0360-3016(09)03587-1/abstract, 
accessed March 25, 2014].  
For patients with distal one third vaginal involvement, the inguinal nodes should 
be contoured continuously from the external iliac nodes to 2 cm caudad to the 
saphenous/femoral junction. For contouring guidelines for patients with inguinal 
nodal involvement, refer to atlases used to treat anal carcinoma [Myerson RJ, 
Garofalo MC, et al. Elective clinical target volumes for conformal therapy in 
anorectal cancer: a radiation therapy oncology group consensus panel contouring 
atlas. 
Int 
J 
Radiat 
Oncol 
Biol 
Phys. 
2009;74:824-30, 
http://www.ncbi.nlm.nih.gov/pubmed/19117696, accessed March 25, 2014].  
4. PTV Delineation 
The Planning Target Volume (PTV) will add a 7-15mm margin around CTV to 
compensate for treatment setup and internal organ motion.  The PTV should be 
manually or automatically trimmed up to 3 mm from the skin surface, if 
necessary, to spare skin, provided that the CTV is still included entirely within the 
PTV. 
e. Normal Tissue Delineation   
            General 
Normal tissues should be contoured on the simulation scan. The tissue within 
the skin surface and outside all other critical normal structures and the PTV is 

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designated as unspecified tissue. Critical normal tissues for IMRT 
optimization will consist of the bowel, bladder, rectum, and bone marrow. 
Femoral heads will be contoured to determine delivered dose but will not be 
used as a planning constraint.  
Bowel 
The bowel should be contoured beginning from the axial slice situated 1 cm 
superior to the superior-most slice containing PTV (if bowel is not present at 
this level, the bowel contour will start from its most superior extent), and will 
continue to its most inferior extent in the pelvis.  Individual loops of bowel 
should not be contoured separately. Rectum should be contoured separately 
from bowel. 
Rectum 
The outer rectal wall should be contoured and will be defined from the level 
of the sigmoid flexure to the anus.   
Bladder 
The outer bladder wall should be contoured, treating the organ as a solid 
continuous structure.    
Bone Marrow 
The outer bone contour should be delineated and filled in, treating the bone 
marrow as a solid continuous structure. The regions contoured should include 
the os coxae, L5 vertebral body, entire sacrum, acetabulae, and proximal 
femora. The superior extent of the bone marrow contour should be at the level 
of the superior border of L5 or the iliac crest, whichever is more superior.  
When the para-aortic nodal chain is treated, the vertebral bodies should be 
contoured to T12 or the most cephalad vertebral level being treated. The 
caudal-most extent of the bone marrow contour should be at the level of the 
ischial tuberosities.  
Femoral Heads 
The outer contours of the femoral heads will be delineated and filled in, 
treating each as a solid continuous structure. Do not include the femoral neck.   
f. Treatment Planning  
   Field Design 
a. Conventional RT consists of a 4-field “box” arrangement using opposed 
AP/PA and lateral fields. For conventional RT, it is permissible to use bone 
landmarks to draw field borders or to use 3-D planning with explicit targeting 
as outlined above, using customized blocking to encompass the PTV. If bone 
landmarks are used, use the following portals: 
• Superior border: L4-5 
• Lateral border: 1-2 cm lateral to the border of the true pelvis 
• Inferior border: Obturator foramen or 4 cm inferior to vaginal cuff, 
whichever is lower 
• Anterior border: line from pubic symphysis to 1 cm anterior to common 
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• Posterior border: draw border posterior to or splitting the sacrum from S1-
S4 
• Custom blocking to shield femoral heads. Do not block the obturator 
foramen or within 1 cm of the common iliac nodes 
b. Intensity-modulated radiation therapy plans may include static field 
arrangements (e.g. 5-9 fields). 
Target coverage requirements 
• The 99% prescription isodose surface will encompass ≥ 90% of the PTV.  
• ≥ 99% of the PTV will receive ≥ 90% of the prescription dose.  
• ≥ 97% of the PTV will receive ≥ 97% of the prescription dose.  
• < 1% of PTV will receive ≥ 115% of the prescription dose.  
• < 10% of the PTV will receive ≥ 110% of the prescription dose.  
• Dose maximum should occur within the PTV  
Normal tissue planning goals for IMRT (soft constraints):  
• Bowel: volume receiving >45 Gy (V45) ≤ 200 cc; V40 < 30%; maximum 
dose < 50 Gy 
• Rectum: V45 < 50%; V30 < 60%; maximum dose < 50 Gy 
• Bone Marrow: V10 < 80%; V20 < 66% 
• Bladder: V45 < 50%; maximum dose < 50 Gy 
• Femoral Head: V30 < 15%; maximum dose < 50 Gy 
Normal tissue requirements for IMRT (hard constraints):  
• Bowel: volume receiving >45 Gy (V45) ≤ 250 cc; maximum dose < 110% 
• Rectum: maximum dose < 110% 
• Bone Marrow: V10 < 90%; V20 < 75% 
• Bladder: maximum dose < 110% 
• Femoral Head: maximum dose < 110% 
Heterogeneity corrections:  Heterogeneity corrections should be applied 
g. External Beam Treatment Modification 
Treatment should be held for ANC <500/mm3, platelets < 20,000 mm3, febrile 
neutropenia, or uncontrolled bleeding. No dose reductions are allowed. Treatment 
will be resumed upon resolution of neutropenia (ANC ≥500/mm3), thrombocytopenia 
(platelets ≥ 20,000 mm3), and febrile neutropenia (temperature<38.0 ° C). 
h. Setup Verification 
Skeletal imaging (e.g., electronic portal MV or kV imaging or CBCT) should be 
performed at least weekly to verify setup accuracy. For patients treated with 
conventional techniques, MV portal verification is recommended at least weekly. 
Daily on-line imaging (image-guided radiotherapy (IGRT)) is allowed but not 
required. 
i. Intracavitary Brachytherapy 
The treating physician should select the dose rate to be used for brachytherapy, either 
HDR or LDR. Orthogonal x-rays, CT, and/or MRI may be used for brachytherapy 

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planning 
j. Low Dose Rate (LDR) Brachytherapy 
Following the completion of external beam RT, the patient will receive 3500-4000 
cGy to Point A by intracavitary implant with Cesium-137. The patient may receive 
this in one or two applications at the discretion of the radiation oncologist. The first 
insertion should be performed promptly upon completion of external beam 
irradiation. If two implants are contemplated, the second implant should be completed 
within three weeks of the completion of external beam irradiation (with total radiation 
treatment time not to exceed 8 weeks). 
Normal Tissue Constraints  
Maximum allowable cumulative doses (external beam + brachytherapy) to normal 
tissues are (in EQD2, α/β=3, T1/2 = 1.5 hours): bladder (ICRU reference point), 85 
Gy; rectum (ICRU reference point), 80 Gy; vaginal surface (reference point), 135 Gy. 
If CT is used for planning it is recommended to keep the maximum bowel dose < 
25% of the brachytherapy prescription dose. Every attempt should be made to deliver 
the full prescription dose, even if the late responding tissues receive a slightly higher 
dose. 
k. High Dose Rate (HDR) Brachytherapy -Iridium-192 as the source for HDR 
brachytherapy. 
HDR Schema -  
Dose should be prescribed to point A. Permissible dose/fractionation schemes are: 
• 5.5 Gy x 6 fractions 
• 5.5 Gy x 5 fractions 
• 6.0 Gy x 5 fractions 
• 6.0 Gy x 6 fractions 
• 7.0 Gy x 3 fractions 
• 7.0 Gy x 4 fractions 
• 7.0 Gy x 5 fractions 
• 7.5 Gy x 3 fractions 
In general, insertions should be separated by a minimum of 48 hours and no more 
than 2 insertions should be performed per week. HDR brachytherapy should start at 
week four of chemoradiation. When HDR brachytherapy begins, at least one insertion 
should be performed per week with no external beam therapy given on the day of the 
insertion. 
Instruments 
It is recommended that tandem and ovoids or tandem and ring be used for  
brachytherapy. A tandem and cylinder or interstitial system is also permissible. 
Determination of Normal Tissue Tolerance 
Maximum allowable cumulative doses (external beam + brachytherapy) to normal 
tissues are (in EQD2, α/β=3, T1/2 = 1.5 hours): bladder (ICRU reference point), 80 
Gy; rectum (ICRU reference point), 75 Gy. It is recommended that the rectum and 
bladder for each fraction receive less than or equal to 70% and 80% of the point A 

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dose, respectively, if feasible. If CT is used for planning it is recommended to keep 
the maximum bowel dose < 25% of the brachytherapy prescription dose. Every 
attempt should be made to deliver the full prescription dose, even if the late 
responding tissues receive a slightly higher dose.  
Intracavitary Radiotherapy Dosimetry 
The dose to points A and B, the rectal reference point dose, bladder reference point 
dose, and vaginal surface reference point dose, and central axis isodose curve should 
be calculated and documented.  
Point A: Measure 2 cm along the intrauterine tandem from the cervical os or flange of 
the tandem and 2 cm laterally in the plane of the intracavitary system.  
Point B: Measure 5 cm lateral from a point 2 cm vertically superior to the cervical os 
or flange of the central tandem along the patients’ midline. 
Bladder Dose: Calculated at the center (in the superior-inferior plane on AP view) of 
a contrast-filled balloon of a Foley catheter and closest to the applicator system on a 
lateral view, as defined by ICRU 38. 
Rectal dose: In accordance with ICRU 38, mark the point 0.5 cm posterior to the 
vaginal surface (as demarcated by the opaque packing) at the midpoint of the 
applicator system or at the level of the flange if no ovoids are used. 
Parametrial Boost to Involved Parametrium 
All patients with initial parametrial involvement should be considered for a 
parametrial boost. The radiation oncologist should choose the dose and beam and 
beam energy to be used to the involved parametrium based on bulk of parametrial 
disease at presentation, as well as the contribution from intracavitary brachytherapy to 
the external beam, in order to deliver a minimum cumulative (external beam and 
brachytherapy) dose to the mid-parametrium, or Point B dose, of 5500 cGy 
(maximum of 6000 cGy) when using LDR intracavitary brachytherapy or a minimum 
of 5000 cGy (maximum of 5500 cGy) when using HDR intracavitary brachytherapy. 
Patients with parametrial involvement at the time of brachytherapy implant should 
receive a cumulative dose to Point B of no less than 6000 cGy (maximum of 7000 
cGy) when using LDR brachytherapy or a minimum of 5500 cGy (maximum of 6500 
cGy) with HDR implant. 
Maximum parametrial boost shall be 1000 cGy at 180 cGy per fraction given AP/PA 
daily to mid-plane if unilateral or bilateral parametrial boost is used. The prescription 
point should be at the center of the unblocked portion of the field. The parametrial 
boost should be delivered if possible between implant 1 & 2 or immediately after 
implant 1 if only one implant is used. 
The total elapsed time for completion of external whole pelvis, intracavitary RT, and 
parametrial RT shall not exceed eight to ten weeks. 
l. Radiation Adverse Events 
Risks and side effects related to radiation therapy include:  
Likely (more than 10%)  
• Redness and skin irritation in the treatment area that may result in 
bleeding and/or infection, which may require hospitalization  

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• Loss of pubic hair in the treated area, usually temporary  
• Tiredness  
• Nausea and/or vomiting  
• Sterility (inability to bear children) in fertile women  
• Sterility (inability to produce children) in men  
Less Likely (3-9%)  
• Diarrhea  
• Sores and bleeding from the bowel (these side effects may occur well after 
treatment and be serious enough to require surgery)  
• Narrowing and dryness of the vagina (birth canal) and genital area with 
painful or difficult intercourse and possibly bleeding  
• Development of extra tissue (fibrosis) in the anal canal, which may result 
in decreased function  
• Long-term dryness of the skin  
• Inability to have or keep an erection (impotency)  
• Hip, pelvic, or sacral fracture  
• Build up of fluid in ankles, feet, and/or legs  
Rare, but serious (less than 2%)  
• Narrowing or blockage of the bowel (these side effects may occur well 
after treatment and be serious enough to require surgery)  
• Blockage of the urinary tubes  
• Development of an abnormal path or connection between organs (fistulae)  
• Skin damage (tissue death), which may result in surgery  
• Narrowing of or persistent bleeding in the vagina (birth canal), which may 
result in surgery 

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13.4 
Appendix 4:  Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03 dated June 14, 2010 
 

1. CTCAE 4.03
 
 
Common Terminology Criteria for
Adverse Events (CTCAE)
Version 4.0
Published: May 28, 2009 (v4.03: June 14, 2010)
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Cancer Institute

__________ 
† CTCAE v4.0 incorporates certain elements of the MedDRA terminology. For further details on MedDRA refer to the MedDRA MSSO Web site (http://www.meddramsso.com). 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
Publish Date: May 28, 2009
Quick Reference 
The NCI Common Terminology Criteria for 
Adverse Events is a descriptive terminology which 
can be utilized for Adverse Event (AE) reporting.  
A grading (severity) scale is provided for each AE 
term. 
Components and Organization 
SOC 
System Organ Class, the highest level of the 
MedDRA hierarchy, is identified by anatomical or 
physiological system, etiology, or purpose (e.g., 
SOC Investigations for laboratory test results).  
CTCAE terms are grouped by MedDRA Primary 
SOCs. Within each SOC, AEs are listed and 
accompanied by descriptions of severity (Grade). 
CTCAE Terms  
An Adverse Event (AE) is any unfavorable and 
unintended 
sign 
(including 
an 
abnormal 
laboratory 
finding), 
symptom, 
or 
disease 
temporally associated with the use of a medical 
treatment or procedure that may or may not be 
considered related to the medical treatment or 
procedure.  An AE is a term that is a unique 
representation of a specific event used for 
medical documentation and scientific analyses.  
Each CTCAE v4.0 term is a MedDRA LLT (Lowest 
Level Term). 
 
Definitions 
A brief definition is provided to clarify the 
meaning of each AE term. 
Grades 
Grade refers to the severity of the AE.  The CTCAE 
displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this 
general guideline: 
 
Grade 1 
Mild; 
asymptomatic 
or 
mild 
symptoms; clinical or diagnostic 
observations only; intervention not 
indicated. 
 
Grade 2 
Moderate; 
minimal, 
local 
or 
noninvasive intervention indicated; 
limiting 
age-appropriate 
instrumental ADL*. 
 
Grade 3 
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated; disabling; 
limiting self care ADL**. 
 
Grade 4 
Life-threatening 
consequences; 
urgent intervention indicated. 
 
Grade 5 
Death related to AE. 
A Semi-colon indicates ‘or’ within the description 
of the grade. 
A single dash (-) indicates a grade is not available. 
Not all Grades are appropriate for all AEs. 
Therefore, some AEs are listed with fewer than 
five options for Grade selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs 
and therefore is not an option. 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, 
shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self care ADL refer to bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 

CONTENTS
SOC
Page
Blood and lymphatic system disorders
3
Cardiac disorders
4
Congenital, familial and genetic disorders
7
Ear and labyrinth disorders
8
Endocrine disorders
9
Eye disorders
10
Gastrointestinal disorders
12
General disorders and administration site conditions
22
Hepatobiliary disorders
24
Immune system disorders
26
Infections and infestations
27
Injury, poisoning and procedural complications
34
Investigations
41
Metabolism and nutrition disorders
44
Musculoskeletal and connective tissue disorders
46
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
50
Nervous system disorders
51
Pregnancy, puerperium and perinatal conditions
56
Psychiatric disorders
57
Renal and urinary disorders
59
Reproductive system and breast disorders
61
Respiratory, thoracic and mediastinal disorders
65
Skin and subcutaneous tissue disorders
71
Social circumstances
75
Surgical and medical procedures
76
Vascular disorders
77

CTCAE 4.03 - June 14, 2010 : Blood and lymphatic system disorders 
3
2. Blood and lymphatic system disorders
Blood and lymphatic system disorders
Grade
Adverse Event
1
2
3
4
5
Anemia
Hemoglobin (Hgb) <LLN - 10.0
g/dL; <LLN - 6.2 mmol/L; <LLN -
100 g/L
Hgb <10.0 - 8.0 g/dL; <6.2 - 4.9
mmol/L;  <100 - 80g/L
Hgb <8.0 g/dL; <4.9 mmol/L;
<80 g/L; transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of anemia may include pallor of the skin and mucous
membranes, shortness of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability.
Bone marrow hypocellular
Mildly hypocellular or <=25%
reduction from normal cellularity
for age
Moderately hypocellular or >25 -
<50% reduction from normal
cellularity for age
Severely hypocellular or >50 -
<=75% reduction cellularity from
normal for age
Aplastic persistent for longer
than 2 weeks
Death
Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements.
Disseminated intravascular
coagulation
 -
Laboratory findings with no
bleeding
Laboratory findings and
bleeding
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in the
risk of hemorrhage as the body is depleted of platelets and coagulation factors.
Febrile neutropenia
 -
 -
ANC <1000/mm3 with a single
temperature of >38.3 degrees C
(101 degrees F) or a sustained
temperature of >=38 degrees C
(100.4 degrees F) for more than
one hour.
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4
degrees F) for more than one hour.
Hemolysis
Laboratory evidence of
hemolysis only (e.g., direct
antiglobulin test; DAT; Coombs';
schistocytes; decreased
haptoglobin)
Evidence of hemolysis and >=2
gm decrease in hemoglobin.
Transfusion or medical
intervention indicated (e.g.,
steroids)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction.
Hemolytic uremic syndrome
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia.
Leukocytosis
 -
 -
>100,000/mm3
Clinical manifestations of
leucostasis; urgent intervention
indicated
Death
Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood.
Lymph node pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a lymph node.
Spleen disorder
Incidental findings (e.g., Howell-
Jolly bodies); mild degree of
thrombocytosis and
leukocytosis
Prophylactic antibiotics
indicated
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder of the spleen.
Thrombotic thrombocytopenic
purpura
Evidence of RBC destruction
(schistocytosis) without clinical
consequences
 -
Laboratory findings with clinical
consequences (e.g., renal
insufficiency, petechiae)
Life-threatening consequences,
(e.g., CNS hemorrhage or
thrombosis/embolism or renal
failure)
Death
Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities such
as seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition.
Blood and lymphatic system
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
4
3. Cardiac disorders
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Acute coronary syndrome
 -
Symptomatic, progressive
angina; cardiac enzymes
normal; hemodynamically stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
stable
Symptomatic, unstable angina
and/or acute myocardial
infarction, cardiac enzymes
abnormal, hemodynamically
unstable
Death
Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers a
spectrum of heart diseases from unstable angina to myocardial infarction.
Aortic valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in aortic valve function or structure.
Asystole
Periods of asystole; non-urgent
medical management indicated
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart.
Atrial fibrillation
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbance
originates above the ventricles.
Atrial flutter
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker), or ablation
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in the
atria.
Atrioventricular block complete
 -
Non-urgent intervention
indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles.
Atrioventricular block first
degree
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
 -
 -
 -
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2
seconds; prolongation of the PR interval greater than 200 milliseconds.
Cardiac arrest
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by cessation of the pumping function of the heart.
Chest pain - cardiac
Mild pain
Moderate pain; limiting
instrumental ADL
Pain at rest; limiting self care
ADL
 -
 -
Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation.
Conduction disorder
Mild symptoms; intervention not
indicated
Moderate symptoms
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by pathological irregularities in the cardiac conduction system.
Constrictive pericarditis
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action.
Heart failure
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevation
in the filling pressure.

CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
5
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Left ventricular systolic
dysfunction
 -
 -
Symptomatic due to drop in
ejection fraction responsive to
intervention
Refractory or poorly controlled
heart failure due to drop in
ejection fraction; intervention
such as ventricular assist
device, intravenous vasopressor
support, or heart transplant
indicated
Death
Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinical
manifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema.
Mitral valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in mitral valve function or structure.
Mobitz (type) II atrioventricular
block
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical
impulse conduction through the atrioventricular (AV) node to the ventricles.
Mobitz type I
Asymptomatic, intervention not
indicated
Symptomatic; medical
intervention indicated
Symptomatic and incompletely
controlled medically, or
controlled with device (e.g.,
pacemaker)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of
atrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles.
Myocardial infarction
 -
Asymptomatic and cardiac
enzymes minimally abnormal
and no evidence of ischemic
ECG changes
Severe symptoms; cardiac
enzymes abnormal;
hemodynamically stable; ECG
changes consistent with
infarction
Life-threatening consequences;
hemodynamically unstable
Death
Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area.
Myocarditis
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe with symptoms at rest or
with minimal activity or exertion;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., continuous IV therapy or
mechanical hemodynamic
support)
Death
Definition: A disorder characterized by inflammation of the muscle tissue of the heart.
Palpitations
Mild symptoms; intervention not
indicated
Intervention indicated
 -
 -
 -
Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart.
Paroxysmal atrial tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; medical
management indicated
IV medication indicated
Life-threatening consequences;
incompletely controlled
medically; cardioversion
indicated
Death
Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbance
originates in the atria.
Pericardial effusion
 -
Asymptomatic effusion size
small to moderate
Effusion with physiologic
consequences
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation.
Pericardial tamponade
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium.
Pericarditis
Asymptomatic, ECG or physical
findings (e.g., rub) consistent
with pericarditis
Symptomatic pericarditis (e.g.,
chest pain)
Pericarditis with physiologic
consequences (e.g., pericardial
constriction)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).

CTCAE 4.03 - June 14, 2010 : Cardiac disorders 
6
Cardiac disorders
Grade
Adverse Event
1
2
3
4
5
Pulmonary valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis by imaging
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis by
imaging; symptoms controlled
with medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in pulmonary valve function or structure.
Restrictive cardiomyopathy
 -
 -
Symptomatic heart failure or
other cardiac symptoms,
responsive to intervention
Refractory heart failure or other
poorly controlled cardiac
symptoms
Death
Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility.
Right ventricular dysfunction
Asymptomatic with laboratory
(e.g., BNP [B-Natriuretic
Peptide ]) or cardiac imaging
abnormalities
Symptoms with mild to
moderate activity or exertion
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening consequences;
urgent intervention indicated
(e.g., ventricular assist device);
heart transplant indicated
Death
Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall.
Sick sinus syndrome
Asymptomatic, intervention not
indicated
Non-urgent intervention
indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness.
Sinus bradycardia
Asymptomatic, intervention not
indicated
Symptomatic, medical
intervention indicated
Severe, medically significant,
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node.
Sinus tachycardia
Asymptomatic, intervention not
indicated
Symptomatic; non-urgent
medical intervention indicated
Urgent medical intervention
indicated
 -
 -
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node.
Supraventricular tachycardia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles.
Tricuspid valve disease
Asymptomatic valvular
thickening with or without mild
valvular regurgitation or
stenosis
Asymptomatic; moderate
regurgitation or stenosis by
imaging
Symptomatic; severe
regurgitation or stenosis;
symptoms controlled with
medical intervention
Life-threatening consequences;
urgent intervention indicated
(e.g., valve replacement,
valvuloplasty)
Death
Definition: A disorder characterized by a defect in tricuspid valve function or structure.
Ventricular arrhythmia
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles.
Ventricular fibrillation
 -
 -
 -
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the
ventricles.
Ventricular tachycardia
 -
Non-urgent medical intervention
indicated
Medical intervention indicated
Life-threatening consequences;
hemodynamic compromise;
urgent intervention indicated
Death
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His.
Wolff-Parkinson-White
syndrome
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Symptomatic and incompletely
controlled medically or
controlled with procedure
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation.
Cardiac disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Congenital, familial and genetic disorders 
7
4. Congenital, familial and genetic disorders
Congenital, familial and genetic disorders
Grade
Adverse Event
1
2
3
4
5
Congenital, familial and genetic
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Ear and labyrinth disorders 
8
5. Ear and labyrinth disorders
Ear and labyrinth disorders
Grade
Adverse Event
1
2
3
4
5
Ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the ear.
External ear inflammation
External otitis with erythema or
dry desquamation
External otitis with moist
desquamation, edema,
enhanced cerumen or
discharge; tympanic membrane
perforation; tympanostomy
External otitis with mastoiditis;
stenosis or osteomyelitis;
necrosis of soft tissue or bone
Urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal.
External ear pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the external ear region.
Hearing impaired
Adults enrolled on a Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of 15 - 25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: subjective change in
hearing in the absence of
documented hearing loss.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 8 kHz in at least
one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz  audiogram):  Threshold
shift of >25 dB averaged at 2
contiguous test frequencies in at
least one ear.
Adults not enrolled in Monitoring
Program: hearing loss but
hearing aid or intervention not
indicated; limiting instrumental
ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift >20 dB at 4 kHz and above
in at least one ear.
Adults enrolled in Monitoring
Program (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): Threshold
shift of >25 dB averaged at 3
contiguous test frequencies in at
least one ear; therapeutic
intervention indicated.
Adults not enrolled in Monitoring
Program:  hearing loss with
hearing aid or intervention
indicated; limiting self care ADL.
Pediatric (on a 1, 2, 3, 4, 6 and
8 kHz audiogram): hearing loss
sufficient to indicate therapeutic
intervention, including hearing
aids; threshold shift >20 dB at 3
kHz and above in at least one
ear; additional speech-language
related services indicated.
Adults: Decrease in hearing to
profound bilateral loss (absolute
threshold >80 dB HL  at 2 kHz
and above); non-servicable
hearing.
Pediatric: Audiologic indication
for cochlear implant and
additional speech-language
related services indicated.
 -
Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures.
Middle ear inflammation
Serous otitis
Serous otitis, medical
intervention indicated
Mastoiditis; necrosis of canal
soft tissue or bone
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear.
Tinnitus
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking.
Vertigo
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjective
vertigo).
Vestibular disorder
 -
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems.
Ear and labyrinth disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Endocrine disorders 
9
6. Endocrine disorders
Endocrine disorders
Grade
Adverse Event
1
2
3
4
5
Adrenal insufficiency
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorder
of the adrenal cortex as in Addison's disease or primary adrenal insufficiency.
Cushingoid
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms, medical
intervention or hospitalization
indicated
 -
 -
Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, and
osteoporosis, usually due to exogenous corticosteroids.
Delayed puberty
 -
No breast development by age
13 yrs for females; testes
volume of <3 cc or no Tanner
Stage 2 development by age
14.5 yrs for males
No breast development by age
14 yrs for females; no increase
in testes volume or no Tanner
Stage 2 by age 16 yrs for
males; hormone replacement
indicated
 -
 -
Definition: A disorder characterized by unusually late sexual maturity.
Growth accelerated
 -
>= +2 SD (standard deviation)
above mid parental height or
target height
 -
 -
 -
Definition: A disorder characterized by greater growth than expected for age.
Hyperparathyroidism
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium in
the blood).
Hyperthyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
suppression therapy indicated;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose.
Hypoparathyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; medical
intervention or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.
Hypothyroidism
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thyroid
replacement indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland.
Precocious puberty
Physical signs of puberty with
no biochemical markers for
females <8 years and males <9
years
Physical signs and biochemical
markers of puberty for females
<8 years and males <9 years
 -
 -
 -
Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age
9 for boys.
Virilization
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male.
Endocrine disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Eye disorders 
10
7. Eye disorders
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Blurred vision
Intervention not indicated
Symptomatic; limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Cataract
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic with marked
decrease in visual acuity
(worse than 20/40 but better
than 20/200); operative
intervention indicated (e.g.,
cataract surgery)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness if
untreated.
Conjunctivitis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; topical
intervention indicated (e.g.,
antibiotics); limiting
instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye.
Corneal ulcer
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Limiting self care ADL;
declining vision (worse than
20/40 but better than 20/200)
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber.
Dry eye
Asymptomatic; clinical or
diagnostic observations only;
mild symptoms relieved by
lubricants
Symptomatic; multiple
agents indicated; limiting
instrumental ADL
Decrease in visual acuity
(<20/40); limiting self care
ADL
 -
 -
Definition: A disorder characterized by dryness of the cornea and conjunctiva.
Extraocular muscle paresis
Asymptomatic; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
disabling
 -
 -
Definition: A disorder characterized by incomplete paralysis of an extraocular muscle.
Eye pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the eye.
Eyelid function disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; nonoperative
intervention indicated;
limiting instrumental ADL
Limiting self care ADL;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by impaired eyelid function.
Flashing lights
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by a sudden or brief burst of light.
Floaters
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens.
Glaucoma
Elevated intraocular
pressure (EIOP) with single
topical agent for intervention;
no visual field deficit
EIOP causing early visual
field deficits; multiple topical
or oral agents indicated;
limiting instrumental ADL
EIOP causing marked visual
field deficits (e.g., involving
both superior and inferior
visual fields); operative
intervention indicated;
limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow.
Keratitis
 -
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Decline in vision (worse than
20/40 but better than
20/200); limiting self care
ADL
Perforation or blindness
(20/200 or worse) in the
affected eye
 -
Definition: A disorder characterized by inflammation to the cornea of the eye.
Night blindness
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by an inability to see clearly in dim light.

CTCAE 4.03 - June 14, 2010 : Eye disorders 
11
Eye disorders
Grade
Adverse Event
1
2
3
4
5
Optic nerve disorder
Asymptomatic; clinical or
diagnostic observations only
Limiting vision of the affected
eye (20/40 or better)
Limiting vision in the affected
eye (worse than 20/40 but
better than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve).
Papilledema
Asymptomatic; no visual field
defects
Symptomatic decline in
vision; visual field defect
present sparing the central
20 degrees
Marked visual field defect
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by swelling around the optic disc.
Photophobia
Symptomatic but not limiting
ADL
Limiting instrumental ADL
Limiting self care ADL
 -
 -
Definition: A disorder characterized by fear and avoidance of light.
Retinal detachment
Asymptomatic
Exudative and visual acuity
20/40 or better
Rhegmatogenous or
exudative detachment;
operative intervention
indicated; decline in vision
(worse than 20/40 but better
than 20/200)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium.
Retinal tear
 -
Laser therapy or
pneumopexy indicated
Vitroretinal surgical repair
indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters.
Retinal vascular disorder
 -
Topical medication indicated
Intravitreal medication;
operative intervention
indicated
 -
 -
Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision.
Retinopathy
Asymptomatic; clinical or
diagnostic observations only
Symptomatic with moderate
decrease in visual acuity
(20/40 or better); limiting
instrumental ADL
Symptomatic with marked
decrease in visual acuity
(worse than 20/40);
disabling; limiting self care
ADL
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder involving the retina.
Scleral disorder
Asymptomatic; clinical or
diagnostic observations only
Symptomatic, limiting
instrumental ADL; moderate
decrease in visual acuity
(20/40 or better)
Symptomatic, limiting self
care ADL; marked decrease
in visual acuity (worse than
20/40)
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by involvement of the sclera of the eye.
Uveitis
Asymptomatic; clinical or
diagnostic observations only
Anterior uveitis; medical
intervention indicated
Posterior or pan-uveitis
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by inflammation to the uvea of the eye.
Vitreous hemorrhage
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only
Symptomatic; limiting
instrumental ADL
Limiting self care ADL;
vitrectomy indicated
Blindness (20/200 or worse)
in the affected eye
 -
Definition: A disorder characterized by blood extravasation into the vitreous humor.
Watering eyes
Intervention not indicated
Intervention indicated
Operative intervention
indicated
 -
 -
Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct.
Eye disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or
diagnostic observations only;
intervention not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental
ADL
Severe or medically
significant but not
immediately sight-
threatening; hospitalization
or prolongation of existing
hospitalization indicated;
disabling;  limiting self care
ADL
Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse)
in the affected eye
 -

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
12
8. Gastrointestinal disorders
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal distension
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe discomfort; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling of the abdomen.
Abdominal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region.
Anal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin.
Anal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the anal region.
Anal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the anus.
Anal necrosis
 -
 -
TPN or hospitalization indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the anal region.
Anal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the anal region.
Anal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; non-
emergent operative intervention
indicated; TPN or hospitalization
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the anal canal.
Anal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal.
Ascites
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; invasive
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Bloating
No change in bowel function or
oral intake
Symptomatic, decreased oral
intake; change in bowel function
 -
 -
 -
Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen.
Cecal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cecum.
Cheilitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; intervention indicated
 -
 -
Definition: A disorder characterized by inflammation of the lip.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
13
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Colitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe abdominal pain; change
in bowel habits; medical
intervention indicated;
peritoneal signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the colon.
Colonic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site.
Colonic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the colon.
Colonic obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization indicated;
elective operative intervention
indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon.
Colonic perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the colonic wall.
Colonic stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the colon.
Colonic ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon.
Constipation
Occasional or intermittent
symptoms; occasional use of
stool softeners, laxatives,
dietary modification, or enema
Persistent symptoms with
regular use of laxatives or
enemas; limiting instrumental
ADL
Obstipation with manual
evacuation indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels.
Dental caries
One or more dental caries, not
involving the root
Dental caries involving the root
Dental caries resulting in pulpitis
or periapical abscess or
resulting in tooth loss
 -
 -
Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous.
Diarrhea
Increase of <4 stools per day
over baseline; mild increase in
ostomy output compared to
baseline
Increase of 4 - 6 stools per day
over baseline; moderate
increase in ostomy output
compared to baseline
Increase of >=7 stools per day
over baseline; incontinence;
hospitalization indicated; severe
increase in ostomy output
compared to baseline; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by frequent and watery bowel movements.
Dry mouth
Symptomatic (e.g., dry or thick
saliva) without significant dietary
alteration; unstimulated saliva
flow >0.2 ml/min
Moderate symptoms; oral intake
alterations (e.g., copious water,
other lubricants, diet limited to
purees and/or soft, moist foods);
unstimulated saliva 0.1 to 0.2
ml/min
Inability to adequately aliment
orally; tube feeding or TPN
indicated; unstimulated saliva
<0.1 ml/min
 -
 -
Definition: A disorder characterized by reduced salivary flow in the oral cavity.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
14
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Duodenal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site.
Duodenal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the duodenum.
Duodenal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Hospitalization or elective
operative intervention indicated;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum.
Duodenal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the duodenal wall.
Duodenal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the duodenum.
Duodenal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall.
Dyspepsia
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,
heartburn, nausea and vomiting.
Dysphagia
Symptomatic, able to eat
regular diet
Symptomatic and altered
eating/swallowing
Severely altered
eating/swallowing; tube feeding
or TPN or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by difficulty in swallowing.
Enterocolitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Abdominal pain; mucus or blood
in stool
Severe or persistent abdominal
pain; fever; ileus; peritoneal
signs
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the small and large intestines.
Enterovesical fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Severe, medically significant;
medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine.
Esophageal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site.
Esophageal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the esophagus.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
15
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Esophageal necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the esophageal wall.
Esophageal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus.
Esophageal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region.
Esophageal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the esophagus.
Esophageal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the esophagus.
Esophageal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall.
Esophageal varices
hemorrhage
 -
Self-limited; intervention not
indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from esophageal varices.
Esophagitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered
eating/swallowing;  oral
supplements indicated
Severely altered
eating/swallowing; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the esophageal wall.
Fecal incontinence
Occasional use of pads required Daily use of pads required
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by inability to control the escape of stool from the rectum.
Flatulence
Mild symptoms; intervention not
indicated
Moderate; persistent;
psychosocial sequelae
 -
 -
 -
Definition: A disorder characterized by a state of excessive gas in the alimentary canal.
Gastric fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
bowel rest; tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site.
Gastric hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the gastric wall.
Gastric necrosis
 -
 -
Inability to aliment adequately
by GI tract; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gastric wall.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
16
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Gastric perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the stomach wall.
Gastric stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding; hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the stomach.
Gastric ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach.
Gastritis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; medical intervention
indicated
Severely altered eating or
gastric function; TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the stomach.
Gastroesophageal reflux
disease
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Severe symptoms; surgical
intervention indicated
 -
 -
Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the lower
esophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion.
Gastrointestinal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site.
Gastrointestinal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region.
Gastroparesis
Mild nausea, early satiety and
bloating, able to maintain caloric
intake on regular diet
Moderate symptoms; able to
maintain nutrition with dietary
and lifestyle modifications; may
need pharmacologic
intervention
Weight loss; refractory to
medical intervention; unable to
maintain nutrition orally
 -
 -
Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine.
Gingival pain
Mild pain
Moderate pain interfering with
oral intake
Severe pain; inability to aliment
orally
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gingival region.
Hemorrhoidal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the hemorrhoids.
Hemorrhoids
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; banding or
medical intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area.
Ileal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site.
Ileal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the ileal wall.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
17
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Ileal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum.
Ileal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the ileal wall.
Ileal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the ileum.
Ileal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum.
Ileus
 -
Symptomatic; altered GI
function; bowel rest indicated
Severely altered GI function;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by failure of the ileum to transport intestinal contents.
Intra-abdominal hemorrhage
 -
Medical intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding in the abdominal cavity.
Jejunal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site.
Jejunal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the jejunal wall.
Jejunal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum.
Jejunal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the jejunal wall.
Jejunal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the jejunum.
Jejunal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum.
Lip pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort of the lip.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
18
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Lower gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus).
Malabsorption
 -
Altered diet; oral intervention
indicated
Inability to aliment adequately;
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea.
Mucositis oral
Asymptomatic or mild
symptoms; intervention not
indicated
Moderate pain; not interfering
with oral intake; modified diet
indicated
Severe pain; interfering with oral
intake
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the oral mucosal.
Nausea
Loss of appetite without
alteration in eating habits
Oral intake decreased without
significant weight loss,
dehydration or malnutrition
Inadequate oral caloric or fluid
intake; tube feeding, TPN, or
hospitalization indicated
 -
 -
Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
Obstruction gastric
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach.
Oral cavity fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site.
Oral dysesthesia
Mild discomfort; not interfering
with oral intake
Moderate pain; interfering with
oral intake
Disabling pain; tube feeding or
TPN indicated
 -
 -
Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth.
Oral hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mouth.
Oral pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips.
Pancreatic duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct.
Pancreatic fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site.
Pancreatic hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the pancreas.
Pancreatic necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the pancreas.
Pancreatitis
 -
Enzyme elevation or radiologic
findings only
Severe pain; vomiting; medical
intervention indicated (e.g.,
analgesia, nutritional support)
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
19
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by inflammation of the pancreas.
Periodontal disease
Gingival recession or gingivitis;
limited bleeding on probing; mild
local bone loss
Moderate gingival recession or
gingivitis; multiple sites of
bleeding on probing; moderate
bone loss
Spontaneous bleeding; severe
bone loss with or without tooth
loss; osteonecrosis of maxilla or
mandible
 -
 -
Definition: A disorder in the gingival tissue around the teeth.
Peritoneal necrosis
 -
 -
Tube feeding or TPN  indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the peritoneum.
Proctitis
Rectal discomfort, intervention
not indicated
Symptoms (e.g., rectal
discomfort, passing blood or
mucus); medical intervention
indicated; limiting instrumental
ADL
Severe symptoms; fecal
urgency or stool incontinence;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the rectum.
Rectal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
TPN or hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site.
Rectal hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus.
Rectal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the rectum.
Rectal necrosis
 -
 -
Tube feeding or TPN indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the rectal wall.
Rectal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum.
Rectal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the rectal region.
Rectal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the rectal wall.
Rectal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Severely altered GI function;
tube feeding or hospitalization
indicated; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the rectum.
Rectal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function (e.g. altered dietary
habits, vomiting, diarrhea)
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
20
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Retroperitoneal hemorrhage
 -
Self-limited; intervention
indicated
Transfusion, medical, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the retroperitoneal area.
Salivary duct inflammation
Slightly thickened saliva; slightly
altered taste (e.g., metallic)
Thick, ropy, sticky saliva;
markedly altered taste;
alteration in diet indicated;
secretion-induced symptoms;
limiting instrumental ADL
Acute salivary gland necrosis;
severe secretion-induced
symptoms (e.g., thick saliva/oral
secretions or gagging);  tube
feeding or TPN indicated;
limiting self care ADL; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the salivary duct.
Salivary gland fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; tube feeding indicated
Severely altered GI function;
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site.
Small intestinal mucositis
Asymptomatic or mild
symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe pain; interfering with oral
intake; tube feeding, TPN or
hospitalization indicated; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine.
Small intestinal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Hospitalization indicated;
elective operative intervention
indicated; limiting self care ADL;
disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the intestinal contents.
Small intestinal perforation
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the small intestine wall.
Small intestinal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the small intestine.
Small intestine ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; limiting instrumental
ADL
Severely altered GI function;
TPN indicated; elective
operative or endoscopic
intervention indicated; limiting
self care ADL; disabling
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine.
Stomach pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the stomach.
Tooth development disorder
Asymptomatic; hypoplasia of
tooth or enamel
Impairment correctable with oral
surgery
Maldevelopment with
impairment not surgically
correctable; disabling
 -
 -
Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development.
Tooth discoloration
Surface stains
 -
 -
 -
 -
Definition: A disorder characterized by a change in tooth hue or tint.
Toothache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the tooth.

CTCAE 4.03 - June 14, 2010 : Gastrointestinal disorders 
21
Gastrointestinal disorders
Grade
Adverse Event
1
2
3
4
5
Typhlitis
 -
 -
Symptomatic (e.g., abdominal
pain, fever, change in bowel
habits with ileus); peritoneal
signs
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation of the cecum.
Upper gastrointestinal
hemorrhage
Mild; intervention not indicated
Moderate symptoms; medical
intervention or minor
cauterization indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach).
Vomiting
1 - 2 episodes (separated by 5
minutes) in 24 hrs
3 - 5 episodes (separated by 5
minutes) in 24 hrs
>=6 episodes (separated by 5
minutes) in 24 hrs; tube feeding,
TPN or hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Gastrointestinal disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
22
9. General disorders and administration site conditions
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Chills
Mild sensation of cold;
shivering; chattering of teeth
Moderate tremor of the entire
body; narcotics indicated
Severe or prolonged, not
responsive to narcotics
 -
 -
Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever.
Death neonatal
 -
 -
 -
 -
Death
Definition: A disorder characterized by cessation of life occurring during the first 28 days of life.
Death NOS
 -
 -
 -
 -
Death
Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
Edema face
Localized facial edema
Moderate localized facial
edema; limiting instrumental
ADL
Severe swelling; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues.
Edema limbs
5 - 10% inter-limb discrepancy
in volume or circumference at
point of greatest visible
difference; swelling or
obscuration of anatomic
architecture on close inspection
>10 - 30% inter-limb
discrepancy in volume or
circumference at point of
greatest visible difference;
readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
>30% inter-limb discrepancy in
volume; gross deviation from
normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities.
Edema trunk
Swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour; limiting
instrumental ADL
Gross deviation from normal
anatomic contour; limiting self
care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area.
Facial pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the face.
Fatigue
Fatigue relieved by rest
Fatigue not relieved by rest;
limiting instrumental ADL
Fatigue not relieved by rest,
limiting self care ADL
 -
 -
Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.
Fever
38.0 - 39.0 degrees C  (100.4 -
102.2 degrees F)
>39.0 - 40.0 degrees C (102.3 -
104.0 degrees F)
>40.0 degrees C (>104.0
degrees F) for <=24 hrs
>40.0 degrees C (>104.0
degrees F) for >24 hrs
Death
Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.
Flu like symptoms
Mild flu-like symptoms present
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and dry
cough.
Gait disturbance
Mild change in gait (e.g., wide-
based, limping or hobbling)
Moderate change in gait (e.g.,
wide-based, limping or
hobbling); assistive device
indicated; limiting instrumental
ADL
Disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by walking difficulties.
Hypothermia
 -
35 - >32 degrees C;  95 - >89.6
degrees F
32 - >28 degrees C;  89.6 -
>82.4 degrees F
<=28 degrees C; 82.4 degrees
F; life-threatening
consequences (e.g., coma,
hypotension, pulmonary edema,
acidemia, ventricular fibrillation)
Death
Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.

CTCAE 4.03 - June 14, 2010 : General disorders and administration site conditions 
23
General disorders and administration site conditions
Grade
Adverse Event
1
2
3
4
5
Infusion related reaction
Mild transient reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances.
Infusion site extravasation
 -
Erythema with associated
symptoms (e.g., edema, pain,
induration, phlebitis)
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,
erythema, swelling, burning sensation and marked discomfort at the infusion site.
Injection site reaction
Tenderness with or without
associated symptoms (e.g.,
warmth, erythema, itching)
Pain; lipodystrophy; edema;
phlebitis
Ulceration or necrosis; severe
tissue damage; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection.
Irritability
Mild; easily consolable
Moderate; limiting instrumental
ADL; increased attention
indicated
Severe abnormal or excessive
response; limiting self care ADL;
inconsolable
 -
 -
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical
condition.
Localized edema
Localized to dependent areas,
no disability or functional
impairment
Moderate localized edema and
intervention indicated; limiting
instrumental ADL
Severe localized edema and
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site.
Malaise
Uneasiness or lack of well being Uneasiness or lack of well
being; limiting instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling.
Multi-organ failure
 -
 -
Shock with azotemia and acid-
base disturbances; significant
coagulation abnormalities
Life-threatening consequences
(e.g., vasopressor dependent
and oliguric or anuric or
ischemic colitis or lactic
acidosis)
Death
Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms.
Neck edema
Asymptomatic localized neck
edema
Moderate neck edema; slight
obliteration of anatomic
landmarks; limiting instrumental
ADL
Generalized neck edema (e.g.,
difficulty in turning neck);
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck.
Non-cardiac chest pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder.
Pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony.
Sudden death NOS
 -
 -
 -
 -
Death
Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5.
General disorders and
administration site conditions -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
24
10. Hepatobiliary disorders
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Bile duct stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated <24
hrs
Severely altered GI function;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the lumen of the bile duct.
Biliary fistula
 -
Symptomatic and intervention
not indicated
Severely altered GI function;
TPN indicated; endoscopic
intervention indicated; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site.
Cholecystitis
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones.
Gallbladder fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Symptomatic or severely altered
GI function; TPN indicated;
radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site.
Gallbladder necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the gallbladder.
Gallbladder obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; altered GI
function; IV fluids indicated  <24
hrs
Symptomatic and severely
altered GI function; tube
feeding, TPN or hospitalization
indicated; non-emergent
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder.
Gallbladder pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region.
Gallbladder perforation
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the gallbladder wall.
Hepatic failure
 -
 -
Asterixis; mild encephalopathy;
limiting self care ADL
Moderate to severe
encephalopathy; coma; life-
threatening consequences
Death
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic
dehydrogenase, and alkaline phosphatase.
Hepatic hemorrhage
Mild; intervention not indicated
Symptomatic; medical
intervention indicated
Transfusion indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the liver.
Hepatic necrosis
 -
 -
 -
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma.
Hepatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the liver region.
Perforation bile duct
 -
 -
Radiologic, endoscopic or
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.

CTCAE 4.03 - June 14, 2010 : Hepatobiliary disorders 
25
Hepatobiliary disorders
Grade
Adverse Event
1
2
3
4
5
Portal hypertension
 -
Decreased portal vein flow
Reversal/retrograde portal vein
flow; associated with varices
and/or ascites
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in blood pressure in the portal venous system.
Portal vein thrombosis
 -
Intervention not indicated
Medical intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein.
Hepatobiliary disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Immune system disorders 
26
11. Immune system disorders
Immune system disorders
Grade
Adverse Event
1
2
3
4
5
Allergic reaction
Transient flushing or rash, drug
fever <38 degrees C (<100.4
degrees F); intervention not
indicated
Intervention or infusion
interruption indicated; responds
promptly to symptomatic
treatment (e.g., antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for <=24 hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen.
Anaphylaxis
 -
 -
Symptomatic bronchospasm,
with or without urticaria;
parenteral intervention
indicated; allergy-related
edema/angioedema;
hypotension
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Autoimmune disorder
Asymptomatic; serologic or
other evidence of autoimmune
reaction, with normal organ
function;  intervention not
indicated
Evidence of autoimmune
reaction involving a non-
essential organ or function (e.g.,
hypothyroidism)
Autoimmune reactions involving
major organ (e.g., colitis,
anemia, myocarditis, kidney)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his own
tissue constituents.
Cytokine release syndrome
Mild reaction; infusion
interruption not indicated;
intervention not indicated
Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.,
antihistamines, NSAIDS,
narcotics, IV fluids); prophylactic
medications indicated for <=24
hrs
Prolonged (e.g., not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);
recurrence of symptoms
following initial improvement;
hospitalization indicated for
clinical sequelae (e.g., renal
impairment, pulmonary
infiltrates)
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells.
Serum sickness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate arthralgia; fever, rash,
urticaria, antihistamines
indicated
Severe arthralgia or arthritis;
extensive rash; steroids or IV
fluids indicated
Life-threatening consequences;
pressor or ventilatory support
indicated
Death
Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one days
following the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea.
Immune system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
27
12. Infections and infestations
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Abdominal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the abdominal cavity.
Anorectal infection
Localized; local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the anal area and the rectum.
Appendicitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent.
Appendicitis perforated
 -
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of the
appendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity.
Arteritis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving an artery.
Biliary tract infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the biliary tract.
Bladder infection
 -
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bladder.
Bone infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bones.
Breast infection
 -
Local infection with moderate
symptoms; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
Severe infection; axillary
adenitis;  IV antibacterial,
antifungal, or antiviral
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the breast.
Bronchial infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the bronchi.
Catheter related infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process that arises secondary to catheter use.
Cecal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
28
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the cecum.
Cervicitis infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the uterine cervix.
Conjunctivitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes.
Corneal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the cornea.
Cranial nerve infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a cranial nerve.
Device related infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the use of a medical device.
Duodenal infection
 -
Moderate symptoms; medical
intervention indicated (e.g., oral
antibiotics)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the duodenum.
Encephalitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
severe changes in mental
status; self-limited seizure
activity; focal neurologic
abnormalities
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain tissue.
Encephalomyelitis infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues.
Endocarditis infective
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart.
Endophthalmitis
 -
Local intervention indicated
Systemic intervention or
hospitalization indicated
Blindness (20/200 or worse)
 -
Definition: A disorder characterized by an infectious process involving the internal structures of the eye.

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
29
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Enterocolitis infectious
 -
Passage of >3 unformed stools
per 24 hrs or duration of illness
>48 hrs; moderate abdominal
pain
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated;
profuse watery diarrhea with
signs of hypovolemia;  bloody
diarrhea; fever; severe
abdominal pain; hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small and large intestines.
Esophageal infection
 -
Local intervention indicated
(e.g., oral antibiotic, antifungal,
antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the esophagus.
Eye infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated;
enucleation
Death
Definition: A disorder characterized by an infectious process involving the eye.
Gallbladder infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gallbladder.
Gum infection
Local therapy indicated (swish
and swallow)
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the gums.
Hepatic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the liver.
Hepatitis viral
Asymptomatic, treatment not
indicated
 -
Symptomatic liver dysfunction;
fibrosis by biopsy; compensated
cirrhosis; reactivation of chronic
hepatitis
Decompensated liver function
(e.g., ascites, coagulopathy,
encephalopathy, coma)
Death
Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma.
Infective myositis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skeletal muscles.
Joint infection
 -
Localized; local intervention
indicated; oral intervention
indicated (e.g., antibiotic,
antifungal, antiviral); needle
aspiration indicated (single or
multiple)
Arthroscopic intervention
indicated (e.g., drainage) or
arthrotomy (e.g., open surgical
drainage)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a joint.
Kidney infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the kidney.

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
30
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Laryngitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammatory process involving the larynx.
Lip infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the lips.
Lung infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lungs.
Lymph gland infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the lymph nodes.
Mediastinal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mediastinum.
Meningitis
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated; focal
neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord.
Mucosal infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a mucosal surface.
Nail infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by an infectious process involving the nail.
Otitis externa
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)
and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage.
Otitis media
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the middle ear.
Ovarian infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the ovary.

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
31
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Pancreas infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pancreas.
Papulopustular rash
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10-30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self-care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering  any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upper
chest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions.
Paronychia
Nail fold edema or erythema;
disruption of the cuticle
Localized intervention indicated;
oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral);
nail fold edema or erythema
with pain; associated with
discharge or nail plate
separation; limiting instrumental
ADL
Surgical intervention or IV
antibiotics indicated; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an infectious process involving the soft tissues around the nail.
Pelvic infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pelvic cavity.
Penile infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the penis.
Periorbital infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the orbit of the eye.
Peripheral nerve infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peripheral nerves.
Peritoneal infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the peritoneum.
Pharyngitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the throat.
Phlebitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
32
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the course
of the infected vein.
Pleural infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the pleura.
Prostate infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the prostate gland.
Rash pustular
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus.
Rhinitis infective
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
 -
 -
 -
Definition: A disorder characterized by an infectious process involving the nasal mucosal.
Salivary gland infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the salivary gland.
Scrotal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the scrotum.
Sepsis
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock.
Sinusitis
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses.
Skin infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the skin.
Small intestine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the small intestine.
Soft tissue infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving soft tissues.
Splenic infection
 -
 -
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Infections and infestations 
33
Infections and infestations
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an infectious process involving the spleen.
Stoma site infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body).
Tooth infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving a tooth.
Tracheitis
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the trachea.
Upper respiratory infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea).
Urethral infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic, endoscopic, or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urethra.
Urinary tract infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra.
Uterine infection
 -
Moderate symptoms; oral
intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues.
Vaginal infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vagina.
Vulval infection
Localized, local intervention
indicated
Oral intervention indicated (e.g.,
antibiotic, antifungal, antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the vulva.
Wound infection
 -
Localized; local intervention
indicated (e.g., topical antibiotic,
antifungal, or antiviral)
IV antibiotic, antifungal, or
antiviral intervention indicated;
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an infectious process involving the wound.
Infections and infestations -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
34
13. Injury, poisoning and procedural complications
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Ankle fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving the
affected leg and foot.
Aortic injury
 -
 -
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the aorta.
Arterial injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to an artery.
Biliary anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures).
Bladder anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures).
Bruising
Localized or in a dependent
area
Generalized
 -
 -
 -
Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues.
Burn
Minimal symptoms; intervention
not indicated
Medical intervention; minimal
debridement indicated
Moderate to major debridement
or reconstruction indicated
Life-threatening consequences
Death
Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames and
radiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment.
Dermatitis radiation
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation.
Esophageal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures).
Fall
Minor with no resultant injuries;
intervention not indicated
Symptomatic; noninvasive
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding of sudden movement downward, usually resulting in injury.
Fallopian tube anastomotic leak
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures).
Fallopian tube perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A finding of rupture of the fallopian tube wall.
Fracture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but non-displaced;
immobilization indicated
Severe symptoms; displaced or
open wound with bone
exposure; disabling; operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
35
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Gastric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures).
Gastrointestinal stoma necrosis
 -
Superficial necrosis;
intervention not indicated
Severe symptoms;
hospitalization or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma.
Hip fracture
 -
Hairline fracture; mild pain;
limiting instrumental ADL; non-
surgical intervention indicated
Severe pain; hospitalization or
intervention indicated for pain
control (e.g., traction); operative
intervention indicated
Life-threatening consequences;
symptoms associated with
neurovascular compromise
 -
Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken.
Injury to carotid artery
 -
 -
Severe symptoms; limiting self
care ADL (e.g., transient
cerebral ischemia); repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the carotid artery.
Injury to inferior vena cava
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the inferior vena cava.
Injury to jugular vein
 -
 -
Symptomatic limiting self care
ADL; disabling; repair or
revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the jugular vein.
Injury to superior vena cava
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic; repair or revision
not indicated
Severe symptoms; limiting self
care ADL; disabling; repair or
revision indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to the superior vena cava.
Intestinal stoma leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body).
Intestinal stoma obstruction
 -
Self-limited; intervention not
indicated
Severe symptoms; IV fluids,
tube feeding, or TPN indicated
>=24 hrs; elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma.
Intestinal stoma site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the intestinal stoma.
Intraoperative arterial injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to an artery during a surgical procedure.
Intraoperative breast injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
36
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the breast parenchyma during a surgical procedure.
Intraoperative cardiac injury
 -
 -
Primary repair of injured
organ/structure indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the heart during a surgical procedure.
Intraoperative ear injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection of injured
organ/structure indicated;
disabling (e.g., impaired
hearing; impaired balance)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the ear during a surgical procedure.
Intraoperative endocrine injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the endocrine gland during a surgical procedure.
Intraoperative gastrointestinal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the gastrointestinal system during a surgical procedure.
Intraoperative head and neck
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the head and neck during a surgical procedure.
Intraoperative hemorrhage
 -
 -
Postoperative radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of uncontrolled bleeding during a surgical procedure.
Intraoperative hepatobiliary
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure.
Intraoperative musculoskeletal
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the musculoskeletal system during a surgical procedure.
Intraoperative neurological
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the nervous system during a surgical procedure.
Intraoperative ocular injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the eye during a surgical procedure.
Intraoperative renal injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the kidney during a surgical procedure.
Intraoperative reproductive tract
injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
37
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of damage to the reproductive organs during a surgical procedure.
Intraoperative respiratory injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the respiratory system during a surgical procedure.
Intraoperative skin injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the skin during a surgical procedure.
Intraoperative splenic injury
 -
Primary repair of injured
organ/structure indicated
Resection or reconstruction of
injured organ/structure
indicated; disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the spleen during a surgical procedure.
Intraoperative urinary injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to the urinary system during a surgical procedure.
Intraoperative venous injury
Primary repair of injured
organ/structure indicated
Partial resection of injured
organ/structure indicated
Complete resection or
reconstruction of injured
organ/structure indicated;
disabling
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of damage to a vein during a surgical procedure.
Kidney anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures).
Large intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine.
Pancreatic anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures).
Pharyngeal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures).
Postoperative hemorrhage
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; radiologic,
endoscopic, or operative
intervention indicated
Transfusion indicated of >=2
units (10 cc/kg for pediatrics)
pRBCs beyond protocol
specification; urgent radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding occurring after a surgical procedure.
Postoperative thoracic
procedure complication
 -
Extubated within 24 - 72 hrs
postoperatively
Extubated >72 hrs
postoperatively, but before
tracheostomy indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure.
Prolapse of intestinal stoma
Asymptomatic; reducible
Recurrent after manual
reduction; local irritation or stool
leakage; difficulty to fit
appliance; limiting instrumental
ADL
Severe symptoms; elective
operative intervention indicated;
limiting self care ADL
Life-threatening consequences;
urgent operative intervention
indicated
Death

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
38
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface.
Prolapse of urostomy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Local care or maintenance;
minor revision indicated
Dysfunctional stoma; elective
operative intervention or major
stomal revision indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of displacement of the urostomy.
Radiation recall reaction
(dermatologic)
Faint erythema or dry
desquamation
Moderate to brisk erythema;
patchy moist desquamation,
mostly confined to skin folds
and creases; moderate edema
Moist desquamation in areas
other than skin folds and
creases; bleeding induced by
minor trauma or abrasion
Life-threatening consequences;
skin necrosis or ulceration of full
thickness dermis; spontaneous
bleeding from involved site; skin
graft indicated
Death
Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reaction
is confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent.
Rectal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures).
Seroma
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; simple aspiration
indicated
Symptomatic, elective radiologic
or operative intervention
indicated
 -
 -
Definition: A finding of tumor-like collection of serum in the tissues.
Small intestinal anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel.
Spermatic cord anastomotic
leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures).
Spinal fracture
Mild back pain; nonprescription
analgesics indicated
Moderate back pain;
prescription analgesics
indicated; limiting instrumental
ADL
Severe back pain;
hospitalization or intervention
indicated for pain control (e.g.,
vertebroplasty); limiting self care
ADL; disability
Life-threatening consequences;
symptoms associated with
neurovascular compromise
Death
Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken.
Stenosis of gastrointestinal
stoma
 -
Symptomatic; IV fluids indicated
<24 hrs; manual dilation at
bedside
Severely altered GI function;
tube feeding, TPN or
hospitalization indicated;
elective operative intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body).
Stomal ulcer
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following a
gastroenterostomy procedure.
Tracheal hemorrhage
Minimal bleeding identified on
clinical or diagnostic exam;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the trachea.
Tracheal obstruction
Partial asymptomatic
obstruction on examination
(e.g., visual, radiologic or
endoscopic)
Symptomatic (e.g., noisy airway
breathing), no respiratory
distress; medical intervention
indicated (e.g., steroids); limiting
instrumental ADL
Stridor; radiologic or endoscopic
intervention indicated (e.g.,
stent, laser); limiting self care
ADL
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A finding of blockage of the lumen of the trachea.

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
39
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Tracheostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of blood leakage from the tracheostomy site.
Ureteric anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures).
Urethral anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures).
Urostomy leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage of contents from a urostomy.
Urostomy obstruction
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; dilation or
endoscopic repair or stent
placement indicated
Altered organ function (e.g.,
sepsis or hydronephrosis, or
renal dysfunction); elective
operative intervention indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A finding of blockage of the urostomy.
Urostomy site bleeding
Minimal bleeding identified on
clinical exam; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A finding of bleeding from the urostomy site.
Urostomy stenosis
 -
Symptomatic but no
hydronephrosis, no sepsis or no
renal dysfunction; dilation or
endoscopic repair or stent
placement indicated
Symptomatic (e.g.,
hydronephrosis, or renal
dysfunction); elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of narrowing of the opening of a urostomy.
Uterine anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures).
Uterine perforation
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the uterine wall.
Vaginal anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures).
Vas deferens anastomotic leak
Asymptomatic diagnostic
observations only; intervention
not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures).
Vascular access complication
 -
Device dislodgement, blockage,
leak, or malposition; device
replacement indicated
Deep vein or cardiac
thrombosis; intervention
indicated (e.g., anticoagulation,
lysis, filter, invasive procedure)
Embolic event including
pulmonary embolism or life-
threatening thrombus
Death
Definition: A finding of a previously undocumented problem related to the vascular access site.

CTCAE 4.03 - June 14, 2010 : Injury, poisoning and procedural complications 
40
Injury, poisoning and procedural complications
Grade
Adverse Event
1
2
3
4
5
Venous injury
Asymptomatic diagnostic
finding; intervention not
indicated
Symptomatic (e.g.,
claudication); repair or revision
not indicated
Severe symptoms; limiting self
care ADL; repair or revision
indicated; disabling
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A finding of damage to a vein.
Wound complication
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound; local care indicated
Hernia without evidence of
strangulation; fascial
disruption/dehiscence; primary
wound closure or revision by
operative intervention indicated
Hernia with evidence of
strangulation; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of development of a new problem at the site of an existing wound.
Wound dehiscence
Incisional separation of <=25%
of wound, no deeper than
superficial fascia
Incisional separation >25% of
wound with local care;
asymptomatic hernia or
symptomatic hernia without
evidence of strangulation
Fascial disruption or dehiscence
without evisceration; primary
wound closure or revision by
operative intervention indicated
Life-threatening consequences;
symptomatic hernia with
evidence of strangulation;
fascial disruption with
evisceration; major
reconstruction flap, grafting,
resection, or amputation
indicated
Death
Definition: A finding of separation of the approximated margins of a surgical wound.
Wrist fracture
Mild; non-surgical intervention
indicated
Limiting instrumental ADL;
operative intervention indicated
Limiting self care ADL; elective
surgery indicated
 -
 -
Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken.
Injury, poisoning and procedural
complications - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Investigations 
41
14. Investigations
Investigations
Grade
Adverse Event
1
2
3
4
5
Activated partial thromboplastin
time prolonged
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN; hemorrhage
 -
 -
Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged
partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Alanine aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen.
Alkaline phosphatase increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen.
Aspartate aminotransferase
increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen.
Blood antidiuretic hormone
abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen.
Blood bilirubin increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice.
Blood corticotrophin decreased
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Hospitalization indicated
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen.
Blood gonadotrophin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen.
Blood prolactin abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen.
Carbon monoxide diffusing
capacity decreased
3 - 5 units below LLN; for follow-
up, a decrease of 3 - 5 units
(ml/min/mm Hg) below the
baseline value
6 - 8 units below LLN; for follow-
up, an asymptomatic decrease
of >5 - 8 units (ml/min/mm Hg)
below the baseline value
Asymptomatic decrease  of >8
units drop;  >5 units drop along
with the presence of pulmonary
symptoms (e.g. , >Grade 2
hypoxia or >Grade 2 or higher
dyspnea)
 -
 -
Definition: A finding based on lung function test results that indicate  a decrease in the lung capacity to absorb carbon monoxide.
Cardiac troponin I increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen.
Cardiac troponin T increased
Levels above the upper limit of
normal and below the level of
myocardial infarction as defined
by the manufacturer
 -
Levels consistent with
myocardial infarction as defined
by the manufacturer
 -
 -
Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen.
CD4 lymphocytes decreased
<LLN - 500/mm3;  <LLN - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200 - 50/mm3; <0.2 x 0.05 -
10e9 /L
<50/mm3; <0.05 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of CD4 lymphocytes in a blood specimen.
Cholesterol high
>ULN - 300 mg/dL; >ULN - 7.75
mmol/L
>300 - 400 mg/dL; >7.75 - 10.34
mmol/L
>400 - 500 mg/dL; >10.34 -
12.92 mmol/L
>500 mg/dL; >12.92 mmol/L
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen.
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.

CTCAE 4.03 - June 14, 2010 : Investigations 
42
Investigations
Grade
Adverse Event
1
2
3
4
5
Creatinine increased
>1 - 1.5 x baseline; >ULN - 1.5
x ULN
>1.5 - 3.0 x baseline; >1.5 - 3.0
x ULN
>3.0 baseline; >3.0 - 6.0 x ULN
>6.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen.
Ejection fraction decreased
 -
Resting ejection fraction (EF) 50
- 40%; 10 - 19% drop from
baseline
Resting ejection fraction (EF) 39
- 20%; >20% drop from baseline
Resting ejection fraction (EF)
<20%
 -
Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to the
contraction.
Electrocardiogram QT corrected
interval prolonged
QTc 450 - 480 ms
QTc 481 - 500 ms
QTc >= 501 ms on at least two
separate ECGs
QTc >= 501 or >60 ms change
from baseline and Torsade de
pointes or polymorphic
ventricular tachycardia or
signs/symptoms of serious
arrhythmia
 -
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval.
Fibrinogen decreased
<1.0 - 0.75 x LLN  or <25%
decrease from baseline
<0.75 - 0.5 x LLN or 25 - <50%
decrease from baseline
<0.5 - 0.25 x LLN or 50 - <75%
decrease from baseline
<0.25 x LLN  or 75% decrease
from baseline or absolute value
<50 mg/dL
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen.
Forced expiratory volume
decreased
FEV1% (percentages of
observed FEV1 and FVC
related to their respective
predicted values)  99 - 70%
predicted
FEV1 60 - 69%
50 - 59%
<= 49%
 -
Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds.
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-
glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water.
Growth hormone abnormal
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
 -
 -
 -
Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen.
Haptoglobin decreased
<LLN
 -
 -
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of haptoglobin in a blood specimen.
Hemoglobin increased
Increase in >0 - 2 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >2 - 4 gm/dL above
ULN or above baseline if
baseline is above ULN
Increase in >4 gm/dL above
ULN or above baseline if
baseline is above ULN
 -
 -
Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen.
INR increased
>1 - 1.5 x ULN; >1 - 1.5 times
above baseline if on
anticoagulation
>1.5 - 2.5 x ULN; >1.5 - 2.5
times above baseline if on
anticoagulation
>2.5 x ULN; >2.5 times above
baseline if on anticoagulation
 -
 -
Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood.
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen.
Lymphocyte count decreased
 <LLN - 800/mm3; <LLN - 0.8 x
10e9 /L
<800 - 500/mm3; <0.8 - 0.5 x
10e9 /L
<500 - 200/mm3; <0.5 - 0.2 x
10e9 /L
<200/mm3; <0.2 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of lymphocytes in a blood specimen.
Lymphocyte count increased
 -
>4000/mm3 - 20,000/mm3
>20,000/mm3
 -
 -
Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow.
Neutrophil count decreased
<LLN - 1500/mm3; <LLN - 1.5 x
10e9 /L
<1500 - 1000/mm3; <1.5 - 1.0 x
10e9 /L
<1000 - 500/mm3; <1.0 - 0.5 x
10e9 /L
<500/mm3; <0.5 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of neutrophils in a blood specimen.
Pancreatic enzymes decreased
<LLN and asymptomatic
Increase in stool frequency,
bulk, or odor; steatorrhea
Sequelae of absorption
deficiency
 -
 -
Definition: A finding based on laboratory test results that indicate an decrease in levels of pancreatic enzymes in a biological specimen.

CTCAE 4.03 - June 14, 2010 : Investigations 
43
Investigations
Grade
Adverse Event
1
2
3
4
5
Platelet count decreased
<LLN - 75,000/mm3; <LLN -
75.0 x 10e9 /L
<75,000 - 50,000/mm3; <75.0 -
50.0 x 10e9 /L
<50,000 - 25,000/mm3; <50.0 -
25.0 x 10e9 /L
<25,000/mm3; <25.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Serum amylase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
 -
Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen.
Urine output decreased
 -
 -
Oliguria (<80 ml in 8 hr)
Anuria (<240 ml in 24 hr)
 -
Definition: A finding based on test results that indicate urine production is less relative to previous output.
Vital capacity abnormal
90 - 75% of predicted value
<75 - 50% of predicted value;
limiting instrumental ADL
<50% of predicted value;
limiting self care ADL
 -
 -
Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predicted
value.
Weight gain
5 - <10% from baseline
10 - <20% from baseline
>=20% from baseline
 -
 -
Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve.
Weight loss
5 to <10% from baseline;
intervention not indicated
10 - <20% from baseline;
nutritional support indicated
>=20% from baseline; tube
feeding or TPN indicated
 -
 -
Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve.
White blood cell decreased
<LLN - 3000/mm3; <LLN - 3.0 x
10e9 /L
<3000 - 2000/mm3; <3.0 - 2.0 x
10e9 /L
<2000 - 1000/mm3; <2.0 - 1.0 x
10e9 /L
<1000/mm3; <1.0 x 10e9 /L
 -
Definition: A finding based on laboratory test results that indicate an decrease in number of white blood cells in a blood specimen.
Investigations - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
44
15. Metabolism and nutrition disorders
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Acidosis
pH <normal, but >=7.3
 -
pH <7.3
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues.
Alcohol intolerance
 -
Present
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,
vomiting, indigestion and headaches.
Alkalosis
pH >normal, but <=7.5
 -
pH >7.5
Life-threatening consequences
Death
Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues.
Anorexia
Loss of appetite without
alteration in eating habits
Oral intake altered without
significant weight loss or
malnutrition; oral nutritional
supplements indicated
Associated with significant
weight loss or malnutrition (e.g.,
inadequate oral caloric and/or
fluid intake); tube feeding or
TPN indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a loss of appetite.
Dehydration
Increased oral fluids indicated;
dry mucous membranes;
diminished skin turgor
IV fluids indicated <24 hrs
IV fluids or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Glucose intolerance
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; dietary
modification or oral agent
indicated
Severe symptoms; insulin
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inability to properly metabolize glucose.
Hypercalcemia
Corrected serum calcium of
>ULN - 11.5 mg/dL; >ULN - 2.9
mmol/L;  Ionized calcium  >ULN
- 1.5 mmol/L
Corrected serum calcium of
>11.5 - 12.5 mg/dL; >2.9 - 3.1
mmol/L;  Ionized calcium >1.5 -
1.6 mmol/L; symptomatic
Corrected serum calcium of
>12.5 - 13.5 mg/dL; >3.1 - 3.4
mmol/L;  Ionized calcium  >1.6 -
1.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
>13.5 mg/dL; >3.4 mmol/L;
Ionized calcium  >1.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood.
Hyperglycemia
Fasting glucose value >ULN -
160 mg/dL; Fasting glucose
value >ULN - 8.9 mmol/L
Fasting glucose value >160 -
250 mg/dL; Fasting glucose
value >8.9 - 13.9 mmol/L
>250 - 500 mg/dL; >13.9 - 27.8
mmol/L; hospitalization
indicated
>500 mg/dL; >27.8 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucose
intolerance.
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
hospitalization indicated
>7.0 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes with
the use of diuretic drugs.
Hypermagnesemia
>ULN - 3.0 mg/dL; >ULN - 1.23
mmol/L
 -
>3.0 - 8.0 mg/dL; >1.23 - 3.30
mmol/L
>8.0 mg/dL; >3.30 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the  blood.
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
hospitalization indicated
>160 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the  blood.
Hypertriglyceridemia
150 mg/dL - 300 mg/dL; 1.71
mmol/L - 3.42 mmol/L
>300 mg/dL - 500 mg/dL;  >3.42
mmol/L - 5.7 mmol/L
>500 mg/dL - 1000 mg/dL;  >5.7
mmol/L - 11.4 mmol/L
>1000 mg/dL; >11.4 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood.
Hyperuricemia
>ULN - 10 mg/dL (0.59 mmol/L)
without physiologic
consequences
 -
>ULN - 10 mg/dL (0.59 mmol/L)
with physiologic consequences
>10 mg/dL; >0.59 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid.
Hypoalbuminemia
<LLN - 3 g/dL; <LLN - 30 g/L
<3 - 2 g/dL; <30 - 20 g/L
<2 g/dL; <20 g/L
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of albumin in the blood.

CTCAE 4.03 - June 14, 2010 : Metabolism and nutrition disorders 
45
Metabolism and nutrition disorders
Grade
Adverse Event
1
2
3
4
5
Hypocalcemia
Corrected serum calcium of
<LLN - 8.0 mg/dL; <LLN - 2.0
mmol/L; Ionized calcium  <LLN -
1.0 mmol/L
Corrected serum calcium of
<8.0 - 7.0 mg/dL; <2.0 - 1.75
mmol/L; Ionized calcium  <1.0 -
0.9 mmol/L; symptomatic
Corrected serum calcium of
<7.0 - 6.0 mg/dL; <1.75 - 1.5
mmol/L;  Ionized calcium  <0.9 -
0.8 mmol/L; hospitalization
indicated
Corrected serum calcium of
<6.0 mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8 mmol/L;
life-threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of calcium (corrected for albumin) in the  blood.
Hypoglycemia
<LLN - 55 mg/dL; <LLN - 3.0
mmol/L
<55 - 40 mg/dL; <3.0 - 2.2
mmol/L
<40 - 30 mg/dL; <2.2 - 1.7
mmol/L
<30 mg/dL; <1.7 mmol/L; life-
threatening consequences;
seizures
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of glucose in the blood.
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
symptomatic; intervention
indicated
<3.0 - 2.5 mmol/L;
hospitalization indicated
<2.5 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of potassium in the  blood.
Hypomagnesemia
<LLN - 1.2 mg/dL; <LLN - 0.5
mmol/L
<1.2 - 0.9 mg/dL; <0.5 - 0.4
mmol/L
<0.9 - 0.7 mg/dL; <0.4 - 0.3
mmol/L
<0.7 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of magnesium in the  blood.
Hyponatremia
<LLN - 130 mmol/L
 -
<130 - 120 mmol/L
<120 mmol/L; life-threatening
consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of sodium in the blood.
Hypophosphatemia
<LLN - 2.5 mg/dL; <LLN - 0.8
mmol/L
<2.5 - 2.0 mg/dL; <0.8 - 0.6
mmol/L
<2.0 - 1.0 mg/dL; <0.6 - 0.3
mmol/L
<1.0 mg/dL; <0.3 mmol/L; life-
threatening consequences
Death
Definition: A disorder characterized by laboratory test results that indicate a low concentration of phosphates in the  blood.
Iron overload
 -
Moderate symptoms;
intervention not indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by accumulation of iron in the tissues.
Obesity
 -
BMI 25 - 29.9 kg/m2
BMI 30 - 39.9 kg/m2
BMI >=40 kg/m2
 -
Definition: A disorder characterized by having a high amount of body fat.
Tumor lysis syndrome
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells.
Metabolism and nutrition
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
46
16. Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Abdominal soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g. tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall.
Arthralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in a joint.
Arthritis
Mild pain with inflammation,
erythema, or joint swelling
Moderate pain associated with
signs of inflammation,
erythema, or joint swelling;
limiting instrumental ADL
Severe pain associated with
signs of inflammation,
erythema, or joint swelling;
irreversible joint damage;
disabling; limiting self care ADL
 -
 -
Definition: A disorder characterized by inflammation involving a joint.
Avascular necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necrotic
changes result in the collapse and the destruction of the bone structure.
Back pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the back region.
Bone pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the bones.
Buttock pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the buttocks.
Chest wall pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the chest wall region.
Exostosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by non-neoplastic overgrowth of bone.
Fibrosis deep connective tissue
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues.
Flank pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip.
Generalized muscle weakness
Symptomatic; weakness
perceived by patient but not
evident on physical exam
Symptomatic; weakness evident
on physical exam; weakness
limiting instrumental ADL
Weakness limiting self care
ADL; disabling
 -
 -
Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites.
Growth suppression
Reduction in growth velocity by
10 - 29% ideally measured over
the period of a year
Reduction in growth velocity by
30 - 49% ideally measured over
the period of a year or 0 - 49%
reduction in growth from the
baseline growth curve
Reduction in growth velocity of
>=50% ideally measured over
the period of a year
 -
 -
Definition: A disorder characterized by of stature that is smaller than normal as expected for age.

CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
47
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Head soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head.
Joint effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated; disabling
 -
 -
Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation.
Joint range of motion decreased <=25% loss of ROM (range of
motion); decreased ROM
limiting athletic activity
>25 - 50% decrease in ROM;
limiting instrumental ADL
>50% decrease in ROM; limiting
self care ADL; disabling
 -
 -
Definition: A disorder characterized by a decrease in joint flexibility of any joint.
Joint range of motion decreased
cervical spine
Mild restriction of rotation or
flexion between 60 - 70 degrees
Rotation <60 degrees to right or
left; <60 degrees of flexion
Ankylosed/fused over multiple
segments with no C-spine
rotation
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint.
Joint range of motion decreased
lumbar spine
Stiffness; difficulty bending to
the floor to pick up a very light
object but able to do athletic
activity
Pain with range of motion
(ROM) in lumbar spine; requires
a reaching aid to pick up a very
light object from the floor
<50% lumbar spine flexion;
associated with symptoms of
ankylosis or fused over multiple
segments with no L-spine
flexion (e.g., unable to reach to
floor to pick up a very light
object)
 -
 -
Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint.
Kyphosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine.
Lordosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate accentuation; limiting
instrumental ADL
Severe accentuation; operative
intervention indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine.
Muscle weakness left-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body.
Muscle weakness lower limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the lower limb muscles.
Muscle weakness right-sided
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body.
Muscle weakness trunk
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the trunk muscles.
Muscle weakness upper limb
Symptomatic; perceived by
patient but not evident on
physical exam
Symptomatic; evident on
physical exam; limiting
instrumental ADL
Limiting self care ADL; disabling  -
 -
Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.

CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
48
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Musculoskeletal deformity
Cosmetically and functionally
insignificant hypoplasia
Deformity, hypoplasia, or
asymmetry able to be
remediated by prosthesis (e.g.,
shoe insert) or covered by
clothing
Significant deformity,
hypoplasia, or asymmetry,
unable to be remediated by
prosthesis or covered by
clothing; disabling
 -
 -
Definition: A disorder characterized by of a malformation of the musculoskeletal system.
Myalgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles.
Myositis
Mild pain
Moderate pain associated with
weakness; pain limiting
instrumental ADL
Pain associated with severe
weakness; limiting self care
ADL
 -
 -
Definition: A disorder characterized by inflammation involving the skeletal muscles.
Neck pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the neck area.
Neck soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck.
Osteonecrosis of jaw
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
topical agents); limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible.
Osteoporosis
Radiologic evidence of
osteoporosis or Bone Mineral
Density (BMD) t-score -1 to -2.5
(osteopenia); no loss of height
or intervention indicated
BMD t-score <-2.5; loss of
height <2 cm; anti-osteoporotic
therapy indicated; limiting
instrumental ADL
Loss of height >=2 cm;
hospitalization indicated; limiting
self care ADL
 -
 -
Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemical
composition), resulting in increased fracture incidence.
Pain in extremity
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities.
Pelvic soft tissue necrosis
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis.
Scoliosis
<20 degrees; clinically
undetectable
>20 - 45 degrees; visible by
forward flexion; limiting
instrumental ADL
>45 degrees; scapular
prominence in forward flexion;
operative intervention indicated;
limiting self care ADL; disabling
 -
 -
Definition: A disorder characterized by a malformed, lateral curvature of the spine.
Soft tissue necrosis lower limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity.
Soft tissue necrosis upper limb
 -
Local wound care; medical
intervention indicated (e.g.,
dressings or topical
medications)
Operative debridement or other
invasive intervention indicated
(e.g., tissue reconstruction, flap
or grafting)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.

CTCAE 4.03 - June 14, 2010 : Musculoskeletal and connective tissue disorders 
49
Musculoskeletal and connective tissue disorders
Grade
Adverse Event
1
2
3
4
5
Superficial soft tissue fibrosis
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration; unable to
slide or pinch skin; limiting joint
or orifice movement (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues.
Trismus
Decreased ROM (range of
motion) without impaired eating
Decreased ROM requiring small
bites, soft foods or purees
Decreased ROM with inability to
adequately aliment or hydrate
orally
 -
 -
Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication.
Unequal limb length
Mild length discrepancy <2 cm
Moderate length discrepancy 2 -
5 cm; shoe lift indicated; limiting
instrumental ADL
Severe length discrepancy >5
cm; limiting self care ADL;
disabling; operative intervention
indicated
 -
 -
Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities.
Musculoskeletal and connective
tissue disorder -  Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
50
17. Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Grade
Adverse Event
1
2
3
4
5
Leukemia secondary to
oncology chemotherapy
 -
 -
 -
Present
Death
Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents.
Myelodysplastic syndrome
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow.
Treatment related secondary
malignancy
 -
 -
Non life-threatening secondary
malignancy
Acute life-threatening secondary
malignancy; blast crisis in
leukemia
Death
Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy.
Tumor pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis.
Neoplasms benign, malignant
and unspecified (incl cysts and
polyps) - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
51
18. Nervous system disorders
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Abducens nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve).
Accessory nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve).
Acoustic nerve disorder NOS
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or increased
motor activity
Moderate restlessness or
increased motor activity; limiting
instrumental ADL
Severe restlessness or
increased motor activity; limiting
self care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs.
Amnesia
Mild; transient memory loss
Moderate; short term memory
loss; limiting instrumental ADL
Severe; long term memory loss;
limiting self care ADL
 -
 -
Definition: A disorder characterized by systematic and extensive loss of memory.
Aphonia
 -
 -
Voicelessness; unable to speak
 -
 -
Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space.
Ataxia
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; mechanical
assistance indicated
 -
 -
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand.
Central nervous system
necrosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
corticosteroids indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord.
Cerebrospinal fluid leakage
Post-craniotomy: asymptomatic;
Post-lumbar puncture: transient
headache; postural care
indicated
Post-craniotomy: moderate
symptoms; medical intervention
indicated; Post-lumbar
puncture: persistent moderate
symptoms; blood patch
indicated
Severe symptoms; medical
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues.
Cognitive disturbance
Mild cognitive disability; not
interfering with work/school/life
performance; specialized
educational services/devices
not indicated
Moderate cognitive disability;
interfering with work/school/life
performance but capable of
independent living; specialized
resources on part time basis
indicated
Severe cognitive disability;
significant impairment of
work/school/life performance
 -
 -
Definition: A disorder characterized by a conspicuous change in cognitive function.
Concentration impairment
Mild inattention or decreased
level of concentration
Moderate impairment in
attention or decreased level of
concentration; limiting
instrumental ADL
Severe impairment in attention
or decreased level of
concentration; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a deterioration in the ability to concentrate.

CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
52
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Depressed level of
consciousness
Decreased level of alertness
Sedation; slow response to
stimuli; limiting instrumental
ADL
Difficult to arouse
Life-threatening consequences
Death
Definition: A disorder characterized by a decrease in ability to perceive and respond.
Dizziness
Mild unsteadiness or sensation
of movement
Moderate unsteadiness or
sensation of movement; limiting
instrumental ADL
Severe unsteadiness or
sensation of movement; limiting
self care ADL
 -
 -
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Dysarthria
Mild slurred speech
Moderate impairment of
articulation or slurred speech
Severe impairment of
articulation or slurred speech
 -
 -
Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory alteration;
limiting instrumental ADL
Severe sensory alteration;
limiting self care ADL
 -
 -
Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no change in
diet
Altered taste with change in diet
(e.g., oral supplements);
noxious or unpleasant taste;
loss of taste
 -
 -
 -
Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell.
Dysphasia
Awareness of receptive or
expressive characteristics; not
impairing ability to communicate
Moderate receptive or
expressive characteristics;
impairing ability to communicate
spontaneously
Severe receptive or expressive
characteristics; impairing ability
to read, write or communicate
intelligibly
 -
 -
Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage.
Edema cerebral
 -
 -
 -
Life-threatening consequences;
urgent intervention indicated
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain.
Encephalopathy
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a pathologic process involving the brain.
Extrapyramidal disorder
Mild involuntary movements
Moderate involuntary
movements; limiting
instrumental ADL
Severe involuntary movements
or torticollis; limiting self care
ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by a reduction in the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve
disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve).
Headache
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms;
intervention not indicated
Severe symptoms or
neurological deficit; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain.
Hypersomnia
Mild increased need for sleep
Moderate increased need for
sleep
Severe increased need for
sleep
 -
 -
Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.

CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
53
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Hypoglossal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve).
Intracranial hemorrhage
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated
Ventriculostomy, ICP
monitoring, intraventricular
thrombolysis, or operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the cranium.
Ischemia cerebrovascular
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
 -
 -
 -
Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological
damage.
IVth nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced
alertness and awareness
Moderate symptoms; limiting
instrumental ADL
 -
 -
 -
Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness.
Leukoencephalopathy
Asymptomatic; small focal
T2/FLAIR hyperintensities;
involving periventricular white
matter or <1/3 of susceptible
areas of cerebrum +/- mild
increase in subarachnoid space
(SAS) and/or mild
ventriculomegaly
Moderate symptoms; focal
T2/FLAIR hyperintensities,
involving periventricular white
matter extending into centrum
semiovale or involving 1/3 to 2/3
of susceptible areas of
cerebrum +/- moderate increase
in SAS and/or moderate
ventriculomegaly
Severe symptoms; extensive
T2/FLAIR hyperintensities,
involving periventricular white
matter involving 2/3 or more of
susceptible areas of cerebrum
+/- moderate to severe increase
in SAS and/or moderate to
severe ventriculomegaly
Life-threatening consequences;
extensive T2/FLAIR
hyperintensities, involving
periventricular white matter
involving most of susceptible
areas of cerebrum +/- moderate
to severe increase in SAS
and/or moderate to severe
ventriculomegaly
Death
Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory impairment;
limiting instrumental ADL
Severe memory impairment;
limiting self care ADL
 -
 -
Definition: A disorder characterized by a deterioration in memory function.
Meningismus
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by uncontrolled and purposeless movements.
Myelitis
Asymptomatic; mild signs (e.g.,
Babinski's reflex or Lhermitte's
sign)
Moderate weakness or sensory
loss; limiting instrumental ADL
Severe weakness or sensory
loss; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves.
Nystagmus
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involuntary movements of the eyeballs.
Oculomotor nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
 -
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).

CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
54
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Paresthesia
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth that
are experienced in the absence of a stimulus.
Peripheral motor neuropathy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; assistive device
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves.
Peripheral sensory neuropathy
Asymptomatic; loss of deep
tendon reflexes or paresthesia
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves.
Phantom pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body.
Presyncope
 -
Present (e.g., near fainting)
 -
 -
 -
Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope.
Pyramidal tract syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include  an increase in the muscle tone in the lower extremities,
hyperreflexia, positive Babinski and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; limiting
instrumental ADL; medical
intervention indicated
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on the
connecting nerve root.
Recurrent laryngeal nerve palsy
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms
Severe symptoms; medical
intervention indicated (e.g.,
thyroplasty, vocal cord injection)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve.
Reversible posterior
leukoencephalopathy syndrome
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; abnormal
imaging studies; limiting
instrumental ADL
Severe symptoms; very
abnormal imaging studies;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It has
been observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition.
Seizure
Brief partial seizure; no loss of
consciousness
Brief generalized seizure
Multiple seizures despite
medical intervention
Life-threatening; prolonged
repetitive seizures
Death
Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual
drowsiness or sleepiness
Moderate sedation; limiting
instrumental ADL
Obtundation or stupor
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in muscle
tone
Moderate increase in muscle
tone and increase in resistance
through range of motion
Severe increase in muscle tone
and increase in resistance
through range of motion
Life-threatening; unable to move
active or passive range of
motion
Death
Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speech
disturbances.
Stroke
Asymptomatic or mild
neurologic deficit; radiographic
findings only
Moderate neurologic deficit
Severe neurologic deficit
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event.
Syncope
 -
 -
Fainting; orthostatic collapse
 -
 -
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.

CTCAE 4.03 - June 14, 2010 : Nervous system disorders 
55
Nervous system disorders
Grade
Adverse Event
1
2
3
4
5
Transient ischemic attacks
Mild neurologic deficit with or
without imaging confirmation
Moderate neurologic deficit with
or without imaging confirmation
 -
 -
 -
Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts.
Trigeminal nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve).
Vasovagal reaction
 -
 -
Present
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from an
increase in the stimulation of the vagus nerve.
Nervous system disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Pregnancy, puerperium and perinatal conditions 
56
19. Pregnancy, puerperium and perinatal conditions
Pregnancy, puerperium and perinatal conditions
Grade
Adverse Event
1
2
3
4
5
Fetal death
 -
 -
 -
 -
Fetal loss at
any
gestational
age
Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle after
expulsion from the uterus, without possibility of resuscitation.
Fetal growth retardation
 -
<10% percentile of weight for
gestational age
<5% percentile of weight for
gestational age
<1% percentile of weight for
gestational age
 -
Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight.
Premature delivery
Delivery of a liveborn infant at
>34 to 37 weeks gestation
Delivery of a liveborn infant at
>28 to 34 weeks gestation
Delivery of a liveborn infant at
24 to 28 weeks gestation
Delivery of a liveborn infant at
24 weeks of gestation or less
 -
Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week of
gestation.
Unintended pregnancy
 -
 -
Unintended pregnancy
 -
 -
Definition: A disorder characterized by an unexpected pregnancy at the time of conception.
Pregnancy, puerperium and
perinatal conditions - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
57
20. Psychiatric disorders
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Agitation
Mild mood alteration
Moderate mood alteration
Severe agitation; hospitalization
not indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension.
Anorgasmia
Inability to achieve orgasm not
adversely affecting relationship
Inability to achieve orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by an inability to achieve orgasm.
Anxiety
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; hospitalization not
indicated
Life-threatening; hospitalization
indicated
Death
Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable
stimulus.
Confusion
Mild disorientation
Moderate disorientation; limiting
instrumental ADL
Severe disorientation; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a lack of clear and orderly thought and behavior.
Delayed orgasm
Delay in achieving orgasm not
adversely affecting relationship
Delay in achieving orgasm
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax.
Delirium
Mild acute confusional state
Moderate and acute confusional
state; limiting instrumental ADL
Severe and acute confusional
state; limiting self care ADL;
hospitalization indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is a
reversible condition.
Delusions
 -
Moderate delusional symptoms
Severe delusional symptoms;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense.
Depression
Mild depressive symptoms
Moderate depressive
symptoms; limiting instrumental
ADL
Severe depressive symptoms;
limiting self care ADL;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by melancholic feelings of grief or unhappiness.
Euphoria
Mild mood elevation
Moderate mood elevation
Severe mood elevation (e.g.,
hypomania)
 -
 -
Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli.
Hallucinations
Mild hallucinations (e.g.,
perceptual distortions)
Moderate hallucinations
Severe hallucinations;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus.
Insomnia
Mild difficulty falling asleep,
staying asleep or waking up
early
Moderate difficulty falling
asleep, staying asleep or
waking up early
Severe difficulty in falling
asleep, staying asleep or
waking up early
 -
 -
Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep.
Libido decreased
Decrease in sexual interest not
adversely affecting relationship
Decrease in sexual interest
adversely affecting relationship
 -
 -
 -
Definition: A disorder characterized by a decrease in sexual desire.
Libido increased
Mild increase in sexual interest
not adversely affecting
relationship
Moderate increase in sexual
interest adversely affecting
relationship
Severe increase in sexual
interest leading to dangerous
behavior
 -
 -
Definition: A disorder characterized by an increase in sexual desire.
Mania
Mild manic symptoms (e.g.,
elevated mood, rapid thoughts,
rapid speech, decreased need
for sleep)
Moderate manic symptoms
(e.g., relationship and work
difficulties; poor hygiene)
Severe manic symptoms (e.g.,
hypomania; major sexual or
financial indiscretions);
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood.
Personality change
Mild personality change
Moderate personality change
Severe personality change;
hospitalization not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death

CTCAE 4.03 - June 14, 2010 : Psychiatric disorders 
58
Psychiatric disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking.
Psychosis
Mild psychotic symptoms
Moderate psychotic symptoms
(e.g., disorganized speech;
impaired reality testing)
Severe psychotic symptoms
(e.g., paranoid; extreme
disorganization); hospitalization
not indicated
Life-threatening consequences,
threats of harm to self or others;
hospitalization indicated
Death
Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or brain
tumor.
Restlessness
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an inability to rest, relax or be still.
Suicidal ideation
Increased thoughts of death but
no wish to kill oneself
Suicidal ideation with no specific
plan or intent
Specific plan to commit suicide
without serious intent to die
which may not require
hospitalization
Specific plan to commit suicide
with serious intent to die which
requires hospitalization
 -
Definition: A disorder characterized by thoughts of taking one's own life.
Suicide attempt
 -
 -
Suicide attempt or gesture
without intent to die which may
not require hospitalization
Suicide attempt with intent to
die which requires
hospitalization
Death
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life.
Psychiatric disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; disabling;  limiting
self care ADL
Life-threatening consequences;
hospitalization or urgent
intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
59
21. Renal and urinary disorders
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Acute kidney injury
Creatinine level increase of >0.3
mg/dL; creatinine 1.5 - 2.0 x
above baseline
Creatinine 2 - 3 x above
baseline
Creatinine >3 x baseline or >4.0
mg/dL; hospitalization indicated
Life-threatening consequences;
dialysis indicated
Death
Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renal
causes (ureteral or bladder outflow obstruction).
Bladder perforation
 -
Extraperitoneal perforation,
indwelling catheter indicated
Intraperitoneal perforation;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by a rupture in the bladder wall.
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall.
Chronic kidney disease
eGFR (estimated Glomerular
Filtration Rate) or CrCl
(creatinine clearance) <LLN - 60
ml/min/1.73 m2 or proteinuria
2+ present; urine
protein/creatinine >0.5
eGFR or CrCl 59 - 30
ml/min/1.73 m2
eGFR or CrCl 29 - 15
ml/min/1.73 m2
eGFR or CrCl <15 ml/min/1.73
m2; dialysis or renal transplant
indicated
Death
Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure.
Cystitis noninfective
Microscopic hematuria; minimal
increase in frequency, urgency,
dysuria, or nocturia; new onset
of incontinence
Moderate hematuria; moderate
increase in frequency, urgency,
dysuria, nocturia or
incontinence; urinary catheter
placement or bladder irrigation
indicated; limiting instrumental
ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract.
Hematuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; urinary catheter
or bladder irrigation indicated;
limiting instrumental ADL
Gross hematuria; transfusion, IV
medications or hospitalization
indicated; elective endoscopic,
radiologic or operative
intervention indicated; limiting
self care ADL
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by laboratory test results that indicate blood in the urine.
Hemoglobinuria
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine.
Proteinuria
1+ proteinuria; urinary protein
<1.0 g/24 hrs
Adults: 2+ proteinuria; urinary
protein 1.0 - 3.4 g/24 hrs;
Pediatric: urine P/C
(Protein/Creatinine) ratio 0.5 -
1.9
Adults: urinary protein >=3.5
g/24 hrs;
Pediatric: urine P/C >1.9
 -
 -
Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin.
Renal calculi
Asymptomatic or mild
symptoms; occasional use of
nonprescription analgesics
indicated
Symptomatic; oral antiemetics
indicated; around the clock
nonprescription analgesics or
any oral narcotic analgesics
indicated
Hospitalization indicated; IV
intervention (e.g., analgesics,
antiemetics); elective
endoscopic or radiologic
intervention indicated
Life-threatening consequences;
urgent radiologic, endoscopic or
operative intervention indicated
Death
Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney.
Renal colic
Mild pain not interfering with
activity; nonprescription
medication indicated
Moderate pain; limiting
instrumental ADL; prescription
medication indicated
Hospitalization indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.

CTCAE 4.03 - June 14, 2010 : Renal and urinary disorders 
60
Renal and urinary disorders
Grade
Adverse Event
1
2
3
4
5
Renal hemorrhage
Mild symptoms; intervention not
indicated
Analgesics and hematocrit
monitoring indicated
Transfusion, radiation, or
hospitalization indicated;
elective radiologic, endoscopic
or operative intervention
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by bleeding from the kidney.
Urinary fistula
 -
Noninvasive intervention
indicated; urinary or suprapubic
catheter placement indicated
Limiting self care ADL; elective
radiologic, endoscopic or
operative intervention indicated;
permanent urinary diversion
indicated
Life-threatening consequences;
urgent radiologic or operative
intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site.
Urinary frequency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by urination at short intervals.
Urinary incontinence
Occasional (e.g., with coughing,
sneezing, etc.), pads not
indicated
Spontaneous; pads indicated;
limiting instrumental ADL
Intervention indicated (e.g.,
clamp, collagen injections);
operative intervention indicated;
limiting self care ADL
 -
 -
Definition: A disorder characterized by inability to control the flow of urine from the bladder.
Urinary retention
Urinary, suprapubic or
intermittent catheter placement
not indicated; able to void with
some residual
Placement of urinary,
suprapubic or intermittent
catheter placement indicated;
medication indicated
Elective operative or radiologic
intervention indicated;
substantial loss of affected
kidney function or mass
Life-threatening consequences;
organ failure; urgent operative
intervention indicated
Death
Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate.
Urinary tract obstruction
Asymptomatic; clinical or
diagnostic observations only
Symptomatic but no
hydronephrosis, sepsis or renal
dysfunction; urethral dilation,
urinary or suprapubic catheter
indicated
Symptomatic and altered organ
function (e.g., hydronephrosis,
or renal dysfunction); elective
radiologic, endoscopic or
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract.
Urinary tract pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract.
Urinary urgency
Present
Limiting instrumental ADL;
medical management indicated
 -
 -
 -
Definition: A disorder characterized by a sudden compelling urge to urinate.
Urine discoloration
Present
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the urine.
Renal and urinary disorders -
Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate, local or noninvasive
intervention indicated; limiting
instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
61
22. Reproductive system and breast disorders
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Azoospermia
 -
 -
Absence of sperm in ejaculate
 -
 -
Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen.
Breast atrophy
Minimal asymmetry; minimal
atrophy
Moderate asymmetry; moderate
atrophy
Asymmetry >1/3 of breast
volume; severe atrophy
 -
 -
Definition: A disorder characterized by underdevelopment of the breast.
Breast pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the breast region.
Dysmenorrhea
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by abnormally painful abdominal cramps during menses.
Dyspareunia
Mild discomfort or pain
associated with vaginal
penetration; discomfort relieved
with use of vaginal lubricants or
estrogen
Moderate discomfort or pain
associated with vaginal
penetration; discomfort or pain
partially relieved with use of
vaginal lubricants or estrogen
Severe discomfort or pain
associated with vaginal
penetration; discomfort or pain
unrelieved by vaginal lubricants
or estrogen
 -
 -
Definition: A disorder characterized by painful or difficult coitus.
Ejaculation disorder
Diminished ejaculation
Anejaculation or retrograde
ejaculation
 -
 -
 -
Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation.
Erectile dysfunction
Decrease in erectile function
(frequency or rigidity of
erections) but intervention not
indicated (e.g., medication or
use of mechanical device,
penile pump)
Decrease in erectile function
(frequency/rigidity of erections),
erectile intervention indicated,
(e.g., medication or mechanical
devices such as penile pump)
Decrease in erectile function
(frequency/rigidity of erections)
but erectile intervention not
helpful (e.g., medication or
mechanical devices such as
penile pump); placement of a
permanent penile prosthesis
indicated (not previously
present)
 -
 -
Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity.
Fallopian tube obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube.
Fallopian tube stenosis
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated (e.g., organ resection)
Death
Definition: A disorder characterized by a narrowing of the fallopian tube lumen.
Female genital tract fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site.
Feminization acquired
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors.
Genital edema
Mild swelling or obscuration of
anatomic architecture on close
inspection
Readily apparent obscuration of
anatomic architecture;
obliteration of skin folds; readily
apparent deviation from normal
anatomic contour
Lymphorrhea; gross deviation
from normal anatomic contour;
limiting self care ADL
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals.
Gynecomastia
Asymptomatic breast
enlargement
Symptomatic (e.g., pain or
psychosocial impact)
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by excessive development of the breasts in males.
Hematosalpinx
Minimal bleeding identified on
imaging study or laparoscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death

CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
62
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by the presence of blood in a fallopian tube.
Irregular menstruation
Intermittent menses with
skipped menses for no more
than 1 to 3 months
Intermittent menses with
skipped menses for more than 4
to 6 months
Persistent amenorrhea for more
than 6 months
 -
 -
Definition: A disorder characterized by irregular cycle or duration of menses.
Lactation disorder
Mild changes in lactation, not
significantly affecting production
or expression of breast milk
Changes in lactation,
significantly affecting breast
production or expression of
breast milk
 -
 -
 -
Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males.
Menorrhagia
Mild; iron supplements indicated Moderate symptoms; medical
intervention indicated (e.g.,
hormones)
Severe; transfusion indicated;
surgical intervention indicated
(e.g., hysterectomy)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses.
Nipple deformity
Asymptomatic; asymmetry with
slight retraction and/or
thickening of the nipple areolar
complex
Symptomatic; asymmetry of
nipple areolar complex with
moderate retraction and/or
thickening of the nipple areolar
complex
 -
 -
 -
Definition: A disorder characterized by a malformation of the nipple.
Oligospermia
Sperm concentration >48
million/mL or motility >68%
Sperm concentration 13 - 48
million/mL or motility 32 - 68%
Sperm concentration <13
million/mL or motility <32%
 -
 -
Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen.
Ovarian hemorrhage
Minimal bleeding identified on
imaging study or laproscopy;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic  intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the ovary.
Ovarian rupture
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by tearing or disruption of the ovarian tissue.
Ovulation pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from the
ovarian follicle.
Pelvic floor muscle weakness
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic, not interfering
with bladder, bowel, or vaginal
function; limiting instrumental
ADL
Severe symptoms; limiting self
care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor.
Pelvic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pelvis.
Penile pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the penis.
Perineal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus.
Premature menopause
 -
 -
Present
 -
 -
Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive.
Prostatic hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death

CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
63
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by bleeding from the prostate gland.
Prostatic obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urine
stream, and incomplete emptying of the bladder).
Prostatic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland.
Scrotal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the scrotal area.
Spermatic cord hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the spermatic cord.
Spermatic cord obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord.
Testicular disorder
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic but not interfering
with urination or sexual
activities; intervention not
indicated; limiting instrumental
ADL
Severe symptoms; interfering
with urination or sexual function;
limiting self care ADL;
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by involvement of the testis.
Testicular hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the testis.
Testicular pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the testis.
Uterine fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site.
Uterine hemorrhage
Minimal bleeding identified on
imaging study; intervention not
indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the uterus.
Uterine obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of the uterine outlet.
Uterine pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the uterus.
Vaginal discharge
Mild vaginal discharge (greater
than baseline for patient)
Moderate to heavy vaginal
discharge; use of perineal pad
or tampon indicated
 -
 -
 -
Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years.
Vaginal dryness
Mild vaginal dryness not
interfering with sexual function
Moderate vaginal dryness
interfering with sexual function
or causing frequent discomfort
Severe vaginal dryness
resulting in dyspareunia or
severe discomfort
 -
 -
Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.

CTCAE 4.03 - June 14, 2010 : Reproductive system and breast disorders 
64
Reproductive system and breast disorders
Grade
Adverse Event
1
2
3
4
5
Vaginal fistula
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site.
Vaginal hemorrhage
Minimal bleeding identified on
clinical exam or imaging study;
intervention not indicated
Moderate bleeding; medical
intervention indicated
Severe bleeding; transfusion
indicated; radiologic or
endoscopic intervention
indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by bleeding from the vagina.
Vaginal inflammation
Mild discomfort or pain, edema,
or redness
Moderate discomfort or pain,
edema, or redness; limiting
instrumental ADL
Severe discomfort or pain,
edema, or redness; limiting self
care ADL; small areas of
mucosal ulceration
Widespread areas of mucosal
ulceration; life-threatening
consequences; urgent
intervention indicated
Death
Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge.
Vaginal obstruction
Diagnostic observations only;
intervention not indicated
Mild symptoms; elective
intervention indicated
Severe symptoms; elective
operative intervention indicated
 -
 -
Definition: A disorder characterized by blockage of vaginal canal.
Vaginal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by a sensation of marked discomfort in the vagina.
Vaginal perforation
Asymptomatic clinical or
diagnostic observations only;
intervention not indicated
Symptomatic and intervention
not indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a rupture in the vaginal wall.
Vaginal stricture
Asymptomatic; mild vaginal
shortening or narrowing
Vaginal narrowing and/or
shortening not interfering with
physical examination
Vaginal narrowing and/or
shortening interfering with the
use of tampons, sexual activity
or physical examination
 -
Death
Definition: A disorder characterized by a narrowing of the vaginal canal.
Vaginismus
Mild discomfort or pain
associated with vaginal
spasm/tightening; no impact
upon sexual function or physical
examination
Moderate discomfort or pain
associated with vaginal
spasm/tightening; disruption in
sexual function and physical
examination
Severe discomfort or pain
associated with vaginal
spasm/tightening; unable to
tolerate vaginal penetration or
physical examination
 -
 -
Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexual
intercourse.
Reproductive system and breast
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
65
23. Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Adult respiratory distress
syndrome
 -
 -
Present with radiologic findings;
intubation not indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma or
surgery.
Allergic rhinitis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may also
involve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching.
Apnea
 -
 -
Present; medical intervention
indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing.
Aspiration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Altered eating habits; coughing
or choking episodes after eating
or swallowing; medical
intervention indicated (e.g.,
suction or oxygen)
Dyspnea and pneumonia
symptoms (e.g., aspiration
pneumonia); hospitalization
indicated; unable to aliment
orally
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by inhalation of solids or liquids into the lungs.
Atelectasis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., dyspnea,
cough); medical intervention
indicated (e.g., chest
physiotherapy, suctioning);
bronchoscopic suctioning
Oxygen indicated;
hospitalization or elective
operative intervention indicated
(e.g., stent, laser)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by the collapse of part or the entire lung.
Bronchial fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site.
Bronchial obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., mild
wheezing); endoscopic
evaluation indicated;
radiographic evidence of
atelectasis/lobar collapse;
medical management indicated
(e.g., steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates.
Bronchial stricture
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., rhonchi or
wheezing) but without
respiratory distress; medical
intervention indicated (e.g.,
steroids, bronchodilators)
Shortness of breath with stridor;
endoscopic intervention
indicated (e.g., laser, stent
placement)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a narrowing of the bronchial tube.
Bronchopleural fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
with thoracoplasty, chronic open
drainage or multiple
thoracotomies indicated
Death
Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity.
Bronchopulmonary hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.

CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
66
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Bronchospasm
Mild symptoms; intervention not
indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Limiting self care ADL; oxygen
saturation decreased
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall.
Chylothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; thoracentesis or
tube drainage indicated
Severe symptoms; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity.
Cough
Mild symptoms; nonprescription
intervention indicated
Moderate symptoms, medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompanied
by a distinctive sound.
Dyspnea
Shortness of breath with
moderate exertion
Shortness of breath with
minimal exertion; limiting
instrumental ADL
Shortness of breath at rest;
limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Epistaxis
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated (e.g.,
nasal packing, cauterization;
topical vasoconstrictors)
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the nose.
Hiccups
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; interfering
with sleep; limiting self care
ADL
 -
 -
Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm.
Hoarseness
Mild or intermittent voice
change; fully understandable;
self-resolves
Moderate or persistent voice
changes; may require
occasional repetition but
understandable on telephone;
medical evaluation indicated
Severe voice changes including
predominantly whispered
speech
 -
 -
Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx.
Hypoxia
 -
Decreased oxygen saturation
with exercise (e.g., pulse
oximeter <88%); intermittent
supplemental oxygen
Decreased oxygen saturation at
rest (e.g., pulse oximeter <88%
or PaO2 <=55 mm Hg)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a decrease in the level of oxygen in the body.
Laryngeal edema
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated (e.g.,
dexamethasone, epinephrine,
antihistamines)
Stridor; respiratory distress;
hospitalization indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx.
Laryngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site.
Laryngeal hemorrhage
Mild cough or trace hemoptysis;
laryngoscopic findings
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by bleeding from the larynx.
Laryngeal inflammation
Mild sore throat; raspy voice
Moderate sore throat;
analgesics indicated
Severe throat pain; endoscopic
intervention indicated
 -
 -
Definition: A disorder characterized by an inflammation involving the larynx.

CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
67
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Laryngeal mucositis
Endoscopic findings only; mild
discomfort with normal intake
Moderate discomfort; altered
oral intake
Severe pain; severely altered
eating/swallowing; medical
intervention indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx.
Laryngeal obstruction
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by blockage of the laryngeal airway.
Laryngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a narrowing of the laryngeal airway.
Laryngopharyngeal dysesthesia
Mild symptoms; no anxiety;
intervention not indicated
Moderate symptoms; mild
anxiety, but no dyspnea; short
duration of observation and or
anxiolytic indicated; limiting
instrumental ADL
Severe symptoms; dyspnea and
swallowing difficulty; limiting self
care ADL
Life-threatening consequences
Death
Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx.
Laryngospasm
 -
Transient episode; intervention
not indicated
Recurrent episodes;
noninvasive intervention
indicated (e.g., breathing
technique, pressure point
massage)
Persistent or severe episodes
associated with syncope; urgent
intervention indicated (e.g.,
fiberoptic laryngoscopy,
intubation, botox injection)
Death
Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords.
Mediastinal hemorrhage
Radiologic evidence only;
minimal symptoms; intervention
not indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
(e.g., hemostasis of bleeding
site)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by bleeding from the mediastinum.
Nasal congestion
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Associated with bloody nasal
discharge or epistaxis
 -
 -
Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema.
Pharyngeal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site.
Pharyngeal hemorrhage
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
Transfusion, radiologic,
endoscopic, or operative
intervention indicated (e.g.,
hemostasis of bleeding site)
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pharynx.
Pharyngeal mucositis
Endoscopic findings only;
minimal symptoms with normal
oral intake; mild pain but
analgesics not indicated
Moderate pain and analgesics
indicated; altered oral intake;
limiting instrumental ADL
Severe pain; unable to
adequately aliment or hydrate
orally; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx.
Pharyngeal necrosis
 -
 -
Inability to aliment adequately
by GI tract; tube feeding or TPN
indicated; radiologic,
endoscopic, or operative
intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death

CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
68
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by a necrotic process occurring in the pharynx.
Pharyngeal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids); limiting instrumental
ADL
Limiting self care ADL; stridor;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the pharyngeal airway.
Pharyngolaryngeal pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region.
Pleural effusion
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., diuretics or
limited therapeutic
thoracentesis)
Symptomatic with respiratory
distress and hypoxia; surgical
intervention including chest tube
or pleurodesis indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort.
Pleural hemorrhage
Asymptomatic; mild hemorrhage
confirmed by thoracentesis
Symptomatic or associated with
pneumothorax; chest tube
drainage indicated
>1000 ml of blood evacuated;
persistent bleeding (150-200
ml/hr for 2 - 4 hr); persistent
transfusion indicated; elective
operative intervention indicated
Life-threatening respiratory or
hemodynamic compromise;
intubation or urgent intervention
indicated
Death
Definition: A disorder characterized by bleeding from the pleural cavity.
Pleuritic pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the pleura.
Pneumonitis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; oxygen indicated
Life-threatening respiratory
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma.
Pneumothorax
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; intervention
indicated (e.g., tube placement
without sclerosis)
Sclerosis and/or operative
intervention indicated;
hospitalization indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung.
Postnasal drip
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing.
Productive cough
Occasional/minimal production
of sputum with cough
Moderate sputum production;
limiting instrumental ADL
Persistent or copious production
of sputum; limiting self care ADL
 -
 -
Definition: A disorder characterized by expectorated secretions upon coughing.
Pulmonary edema
Radiologic findings only;
minimal dyspnea on exertion
Moderate dyspnea on exertion;
medical intervention indicated;
limiting instrumental ADL
Severe dyspnea or dyspnea at
rest; oxygen indicated; limiting
self care ADL
Life-threatening respiratory
compromise; urgent intervention
or intubation with ventilatory
support indicated
Death
Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure.
Pulmonary fibrosis
Mild hypoxemia; radiologic
pulmonary fibrosis <25% of lung
volume
Moderate hypoxemia; evidence
of pulmonary hypertension;
radiographic pulmonary fibrosis
25 - 50%
Severe hypoxemia; evidence of
right-sided heart failure;
radiographic pulmonary fibrosis
>50 - 75%
Life-threatening consequences
(e.g., hemodynamic/pulmonary
complications); intubation with
ventilatory support indicated;
radiographic pulmonary fibrosis
>75% with severe
honeycombing
Death
Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure.
Pulmonary fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
management indicated; limiting
instrumental ADL
Limiting self care ADL;
endoscopic stenting or
operative intervention indicated
Life-threatening consequences;
urgent operative intervention
indicated
Death

CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
69
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site.
Pulmonary hypertension
Minimal dyspnea; findings on
physical exam or other
evaluation
Moderate dyspnea, cough;
requiring evaluation by cardiac
catheterization and medical
intervention
Severe symptoms, associated
with hypoxemia, right heart
failure; oxygen indicated
Life-threatening airway
consequences; urgent
intervention indicated (e.g.,
tracheotomy or intubation)
Death
Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder.
Respiratory failure
 -
 -
 -
Life-threatening consequences;
urgent intervention, intubation,
or ventilatory support indicated
Death
Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associated
with an increase in arterial levels of carbon dioxide.
Retinoic acid syndrome
Fluid retention; <3 kg of weight
gain; intervention with fluid
restriction and/or diuretics
indicated
Moderate signs or symptoms;
steroids indicated
Severe symptoms;
hospitalization indicated
Life-threatening consequences;
ventilatory support indicated
Death
Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-trans
retinoic acid.
Sinus disorder
Asymptomatic mucosal crusting;
blood-tinged secretions
Symptomatic stenosis or
edema/narrowing interfering
with airflow; limiting instrumental
ADL
Stenosis with significant nasal
obstruction; limiting self care
ADL
Necrosis of soft tissue or bone;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by involvement of the paranasal sinuses.
Sleep apnea
Snoring and nocturnal sleep
arousal without apneic periods
Moderate apnea and oxygen
desaturation; excessive daytime
sleepiness; medical evaluation
indicated; limiting instrumental
ADL
Oxygen desaturation;
associated with hypertension;
medical intervention indicated;
limiting self care ADL
Cardiovascular or
neuropsychiatric symptoms;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by cessation of breathing for short periods during sleep.
Sneezing
Mild symptoms; intervention not
indicated
Moderate symptoms; medical
intervention indicated
 -
 -
 -
Definition: A disorder characterized by the involuntary expulsion of air from the nose.
Sore throat
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL; limiting ability to swallow
 -
 -
Definition: A disorder characterized by of marked discomfort in the throat
Stridor
 -
 -
Respiratory distress limiting self
care ADL; medical intervention
indicated
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction.
Tracheal fistula
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; tube
thoracostomy or medical
intervention indicated; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL; endoscopic or
operative intervention indicated
(e.g., stent or primary closure)
Life-threatening consequences;
urgent operative intervention
indicated (e.g., thoracoplasty,
chronic open drainage or
multiple thoracotomies)
Death
Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site.
Tracheal mucositis
Endoscopic findings only;
minimal hemoptysis, pain, or
respiratory symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe pain; hemorrhage or
respiratory symptoms; limiting
self care ADL
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea.
Tracheal stenosis
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic (e.g., noisy airway
breathing), but causing no
respiratory distress; medical
management indicated (e.g.,
steroids)
Stridor or respiratory distress
limiting self care ADL;
endoscopic intervention
indicated (e.g., stent, laser)
Life-threatening airway
compromise; urgent intervention
indicated (e.g., tracheotomy or
intubation)
Death
Definition: A disorder characterized by a narrowing of the trachea.

CTCAE 4.03 - June 14, 2010 : Respiratory, thoracic and mediastinal disorders 
70
Respiratory, thoracic and mediastinal disorders
Grade
Adverse Event
1
2
3
4
5
Voice alteration
Mild or intermittent change from
normal voice
Moderate or persistent change
from normal voice; still
understandable
Severe voice changes including
predominantly whispered
speech; may require frequent
repetition or face-to-face contact
for understandability; may
require assistive technology
 -
 -
Definition: A disorder characterized by a change in the sound and/or speed of the voice.
Wheezing
Detectable airway noise with
minimal symptoms
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Severe respiratory symptoms
limiting self care ADL; oxygen
therapy or hospitalization
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways.
Respiratory, thoracic and
mediastinal disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling; limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
71
24. Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Alopecia
Hair loss of <50% of normal for
that individual that is not
obvious from a distance but only
on close inspection; a different
hair style may be required to
cover the hair loss but it does
not require a wig or hair piece to
camouflage
Hair loss of >=50% normal for
that individual that is readily
apparent to others; a wig or hair
piece is necessary if the patient
desires to completely
camouflage the hair loss;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Body odor
Mild odor; physician intervention
not indicated; self care
interventions
Pronounced odor; psychosocial
impact; patient seeks medical
intervention
 -
 -
 -
Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body.
Bullous dermatitis
Asymptomatic; blisters covering
<10% BSA
Blisters covering 10 - 30% BSA;
painful blisters; limiting
instrumental ADL
Blisters covering >30% BSA;
limiting self care ADL
Blisters covering >30% BSA;
associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid.
Dry skin
Covering <10% BSA and no
associated erythema or pruritus
Covering 10 - 30% BSA and
associated with erythema or
pruritus; limiting instrumental
ADL
Covering >30% BSA and
associated with pruritus; limiting
self care ADL
 -
 -
Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture.
Erythema multiforme
Target lesions covering <10%
BSA and not associated with
skin tenderness
Target lesions covering 10 -
30% BSA and associated with
skin tenderness
Target lesions covering >30%
BSA and associated with oral or
genital erosions
Target lesions covering >30%
BSA; associated with fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by target lesions (a pink-red ring around a pale center).
Erythroderma
 -
Erythema covering >90% BSA
without associated symptoms;
limiting instrumental ADL
Erythema covering >90% BSA
with associated symptoms (e.g.,
pruritus or tenderness); limiting
self care ADL
Erythema covering >90% BSA
with associated fluid or
electrolyte abnormalities; ICU
care or burn unit indicated
Death
Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area.
Fat atrophy
Covering <10% BSA and
asymptomatic
Covering 10 - 30% BSA and
associated with erythema or
tenderness; limiting instrumental
ADL
Covering >30% BSA;
associated with erythema or
tenderness; limiting self-care
ADL
 -
 -
Definition: A disorder characterized by shrinking of adipose tissue.
Hirsutism
In women, increase in length,
thickness or density of hair in a
male distribution that the patient
is able to camouflage by
periodic shaving, bleaching, or
removal of hair
In women, increase in length,
thickness or density of hair in a
male distribution that requires
daily shaving or consistent
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and under
androgen control (beard, moustache, chest, abdomen)
Hyperhidrosis
Limited to one site (palms,
soles, or axillae); self care
interventions
Involving >1 site; patient seeks
medical intervention; associated
with psychosocial impact
Generalized involving sites
other than palms, soles, or
axillae; associated with
electrolyte/hemodynamic
imbalance
 -
 -
Definition: A disorder characterized by excessive perspiration.

CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
72
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Hypertrichosis
Increase in length, thickness or
density of hair that the patient is
either able to camouflage by
periodic shaving or removal of
hairs or is not concerned
enough about the overgrowth to
use any form of hair removal
Increase in length, thickness or
density of hair at least on the
usual exposed areas of the
body [face (not limited to
beard/moustache area)
plus/minus arms] that requires
frequent  shaving or use of
destructive means of hair
removal to camouflage;
associated with psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race.
Hypohidrosis
 -
Symptomatic; limiting
instrumental ADL
Increase in body temperature;
limiting self care ADL
Heat stroke
Death
Definition: A disorder characterized by reduced sweating.
Lipohypertrophy
Asymptomatic and covering
<10% BSA
Covering 10 - 30% BSA and
associated tenderness; limiting
instrumental ADL
Covering >30% BSA and
associated tenderness and
narcotics or NSAIDs indicated;
lipohypertrophy; limiting self
care ADL
 -
 -
Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin.
Nail discoloration
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by a change in the color of the nail plate.
Nail loss
Asymptomatic separation of the
nail bed from the nail plate or
nail loss
Symptomatic separation of the
nail bed from the nail plate or
nail loss; limiting instrumental
ADL
 -
 -
 -
Definition: A disorder characterized by loss of all or a portion of the nail.
Nail ridging
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
 -
 -
 -
 -
Definition: A disorder characterized by vertical or horizontal ridges on the nails.
Pain of skin
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin.
Palmar-plantar
erythrodysesthesia syndrome
Minimal skin changes or
dermatitis (e.g., erythema,
edema, or hyperkeratosis)
without pain
Skin changes (e.g., peeling,
blisters, bleeding, edema, or
hyperkeratosis) with pain;
limiting instrumental ADL
Severe skin changes (e.g.,
peeling, blisters, bleeding,
edema, or hyperkeratosis) with
pain; limiting self care ADL
 -
 -
Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet.
Periorbital edema
Soft or non-pitting
Indurated or pitting edema;
topical intervention indicated
Edema associated with visual
disturbance; increased
intraocular pressure, glaucoma
or retinal hemorrhage; optic
neuritis; diuretics indicated;
operative intervention indicated
 -
 -
Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face.
Photosensitivity
Painless erythema and
erythema covering <10% BSA
Tender erythema covering 10 -
30% BSA
Erythema covering >30% BSA
and erythema with blistering;
photosensitivity; oral
corticosteroid therapy indicated;
pain control indicated (e.g.,
narcotics or NSAIDs)
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by an increase in sensitivity of the skin to light.

CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
73
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical
intervention indicated
Intense or widespread;
intermittent; skin changes from
scratching (e.g., edema,
papulation, excoriations,
lichenification, oozing/crusts);
oral intervention indicated;
limiting instrumental ADL
Intense or widespread;
constant; limiting self care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated
 -
 -
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions
covering <10% BSA
Combined area of lesions
covering 10 - 30% BSA;
bleeding with trauma
Combined area of lesions
covering >30% BSA;
spontaneous bleeding
 -
 -
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple color
and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules
covering <10% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness
Papules and/or pustules
covering 10 - 30% BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness; associated with
psychosocial impact; limiting
instrumental ADL
Papules and/or pustules
covering >30% BSA, which may
or may not be associated with
symptoms of pruritus or
tenderness; limiting self care
ADL; associated with local
superinfection with oral
antibiotics indicated
Papules and/or pustules
covering any % BSA, which
may or may not be associated
with symptoms of pruritus or
tenderness and are associated
with extensive superinfection
with IV antibiotics indicated; life-
threatening consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Rash maculo-papular
Macules/papules covering
<10% BSA with or without
symptoms (e.g., pruritus,
burning, tightness)
Macules/papules covering 10 -
30% BSA with or without
symptoms (e.g., pruritus,
burning, tightness); limiting
instrumental ADL
Macules/papules covering
>30% BSA with or without
associated symptoms; limiting
self care ADL
 -
 -
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverse
events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Scalp pain
Mild pain
Moderate pain; limiting
instrumental ADL
Severe pain; limiting self care
ADL
 -
 -
Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head.
Skin atrophy
Covering <10% BSA;
associated with telangiectasias
or changes in skin color
Covering 10 - 30% BSA;
associated with striae or
adnexal structure loss
Covering >30% BSA;
associated with ulceration
 -
 -
Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis.
Skin hyperpigmentation
Hyperpigmentation covering
<10% BSA; no psychosocial
impact
Hyperpigmentation covering
>10% BSA; associated
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition.
Skin hypopigmentation
Hypopigmentation or
depigmentation covering <10%
BSA; no psychosocial impact
Hypopigmentation or
depigmentation covering >10%
BSA; associated psychosocial
impact
 -
 -
 -
Definition: A disorder characterized by loss of skin pigment.
Skin induration
Mild induration, able to move
skin parallel to plane (sliding)
and perpendicular to skin
(pinching up)
Moderate induration, able to
slide skin, unable to pinch skin;
limiting instrumental ADL
Severe induration, unable to
slide or pinch skin; limiting joint
movement or orifice (e.g.,
mouth, anus); limiting self care
ADL
Generalized; associated with
signs or symptoms of impaired
breathing or feeding
Death
Definition: A disorder characterized by an area of hardness in the skin.
Skin ulceration
Combined area of ulcers <1 cm;
nonblanchable erythema of
intact skin with associated
warmth or edema
Combined area of ulcers 1 - 2
cm; partial thickness skin loss
involving skin or subcutaneous
fat
Combined area of ulcers >2 cm;
full-thickness skin loss involving
damage to or necrosis of
subcutaneous tissue that may
extend down to fascia
Any size ulcer with extensive
destruction, tissue necrosis, or
damage to muscle, bone, or
supporting structures with or
without full thickness skin loss
Death
Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.

CTCAE 4.03 - June 14, 2010 : Skin and subcutaneous tissue disorders 
74
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Stevens-Johnson syndrome
 -
 -
Skin sloughing covering <10%
BSA with associated signs (e.g.,
erythema, purpura, epidermal
detachment and mucous
membrane detachment)
Skin sloughing covering 10 -
30% BSA with associated signs
(e.g., erythema, purpura,
epidermal detachment and
mucous membrane
detachment)
Death
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Telangiectasia
Telangiectasias covering <10%
BSA
Telangiectasias covering >10%
BSA; associated with
psychosocial impact
 -
 -
 -
Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Toxic epidermal necrolysis
 -
 -
 -
Skin sloughing covering >=30%
BSA with associated symptoms
(e.g., erythema, purpura, or
epidermal detachment)
Death
Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the
mucous membranes.
Urticaria
Urticarial lesions covering <10%
BSA; topical intervention
indicated
Urticarial lesions covering 10 -
30% BSA; oral intervention
indicated
Urticarial lesions covering >30%
BSA; IV intervention indicated
 -
 -
Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins.
Skin and subcutaneous tissue
disorders - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Social circumstances 
75
25. Social circumstances
Social circumstances
Grade
Adverse Event
1
2
3
4
5
Menopause
Menopause occurring at age 46
- 53 years of age
Menopause occurring at age 40
- 45 years of age
Menopause occurring before
age 40 years of age
 -
 -
Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age.
Social circumstances - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Surgical and medical procedures 
76
26. Surgical and medical procedures
Surgical and medical procedures
Grade
Adverse Event
1
2
3
4
5
Surgical and medical
procedures - Other, specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

CTCAE 4.03 - June 14, 2010 : Vascular disorders 
77
27. Vascular disorders
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Capillary leak syndrome
 -
Symptomatic; medical
intervention indicated
Severe symptoms; intervention
indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalized
leaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organ
failure.
Flushing
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Moderate symptoms; medical
intervention indicated; limiting
instrumental ADL
Symptomatic, associated with
hypotension and/or tachycardia;
limiting self care ADL
 -
 -
Definition: A disorder characterized by episodic reddening of the face.
Hematoma
Mild symptoms; intervention not
indicated
Minimally invasive evacuation or
aspiration indicated
Transfusion, radiologic,
endoscopic, or elective
operative intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel.
Hot flashes
Mild symptoms; intervention not
indicated
Moderate symptoms; limiting
instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling.
Hypertension
Prehypertension (systolic BP
120 - 139 mm Hg or diastolic
BP  80 - 89 mm Hg)
Stage 1 hypertension (systolic
BP 140 - 159 mm Hg or
diastolic BP 90 - 99 mm Hg);
medical intervention indicated;
recurrent or persistent (>=24
hrs); symptomatic increase by
>20 mm Hg (diastolic) or to
>140/90 mm Hg if previously
WNL; monotherapy indicated
Pediatric: recurrent or persistent
(>=24 hrs) BP >ULN;
monotherapy indicated
Stage 2 hypertension (systolic
BP >=160 mm Hg or diastolic
BP >=100 mm Hg); medical
intervention indicated; more
than one drug or more intensive
therapy than previously used
indicated
Pediatric: Same as adult
Life-threatening consequences
(e.g., malignant hypertension,
transient or permanent
neurologic deficit, hypertensive
crisis); urgent intervention
indicated
Pediatric: Same as adult
Death
Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg.
Hypotension
Asymptomatic, intervention not
indicated
Non-urgent medical intervention
indicated
Medical intervention or
hospitalization indicated
Life-threatening and urgent
intervention indicated
Death
Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment.
Lymph leakage
 -
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
Life-threatening consequences;
urgent intervention indicated
Death
Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity.
Lymphedema
Trace thickening or faint
discoloration
Marked discoloration; leathery
skin texture; papillary formation;
limiting instrumental ADL
Severe symptoms; limiting self
care ADL
 -
 -
Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling.
Lymphocele
Asymptomatic; clinical or
diagnostic observations only;
intervention not indicated
Symptomatic; medical
intervention indicated
Severe symptoms; radiologic,
endoscopic or elective operative
intervention indicated
 -
 -
Definition: A disorder characterized by a cystic lesion containing lymph.
Peripheral ischemia
 -
Brief (<24 hrs) episode of
ischemia managed non-
surgically and without
permanent deficit
Recurring or prolonged (>=24
hrs) and/or invasive intervention
indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by impaired circulation to an extremity.
Phlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by inflammation of the wall of a vein.
Superficial thrombophlebitis
 -
Present
 -
 -
 -
Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.

CTCAE 4.03 - June 14, 2010 : Vascular disorders 
78
Vascular disorders
Grade
Adverse Event
1
2
3
4
5
Superior vena cava syndrome
Asymptomatic; incidental finding
of SVC thrombosis
Symptomatic; medical
intervention indicated (e.g.,
anticoagulation, radiation or
chemotherapy)
Severe symptoms; multi-
modality intervention indicated
(e.g., anticoagulation,
chemotherapy, radiation,
stenting)
Life-threatening consequences;
urgent multi-modality
intervention indicated (e.g.,
lysis, thrombectomy, surgery)
Death
Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,
cough, orthopnea and headache.
Thromboembolic event
Venous thrombosis (e.g.,
superficial thrombosis)
Venous thrombosis (e.g.,
uncomplicated deep vein
thrombosis), medical
intervention indicated
Thrombosis (e.g.,
uncomplicated pulmonary
embolism [venous], non-embolic
cardiac mural [arterial]
thrombus), medical intervention
indicated
Life-threatening (e.g.,
pulmonary embolism,
cerebrovascular event, arterial
insufficiency); hemodynamic or
neurologic instability; urgent
intervention indicated
Death
Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream.
Vasculitis
Asymptomatic, intervention not
indicated
Moderate symptoms, medical
intervention indicated
Severe symptoms, medical
intervention indicated (e.g.,
steroids)
Life-threatening; evidence of
peripheral or visceral ischemia;
urgent intervention indicated
Death
Definition: A disorder characterized by inflammation involving the wall of a vessel.
Visceral arterial ischemia
 -
Brief (<24 hrs) episode of
ischemia managed medically
and without permanent deficit
Prolonged (>=24 hrs) or
recurring symptoms and/or
invasive intervention indicated
Life-threatening consequences;
evidence of end organ damage;
urgent operative intervention
indicated
Death
Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery.
Vascular disorders - Other,
specify
Asymptomatic or mild
symptoms; clinical or diagnostic
observations only; intervention
not indicated
Moderate; minimal, local or
noninvasive intervention
indicated; limiting age-
appropriate instrumental ADL
Severe or medically significant
but not immediately life-
threatening; hospitalization or
prolongation of existing
hospitalization indicated;
disabling;  limiting self care ADL
Life-threatening consequences;
urgent intervention indicated
Death

28. Publication Information
NIH Publication No. 09-5410
Revised June 2010
Reprinted June 2010

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Inovio Pharmaceuticals, Inc.  
 
 
 
        
  
 
 
 
 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
 
 
 
 
 
 
v 2.1 
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13.5 
Appendix 5:  Acute Radiation Morbidity Scoring Criteria (RTOG) 
[ 0 ] 
[ 1 ] 
[ 2 ] 
[ 3 ] 
[ 4 ] 
SKIN 
No change 
over baseline 
Follicular, faint or dull 
erythema/ epilation/dry 
desquamation/ decreased 
sweating 
Tender or bright 
erythema, patchy 
moist desquamation/ 
moderate edema 
Confluent, moist 
desquamation other than 
skin folds, pitting edema 
Ulceration, hemorrhage, 
necrosis 
UPPER G.I. 
No change 
Anorexia with <=5% 
weight loss from 
pretreatment baseline/ 
nausea not requiring 
antiemetics/ abdominal 
discomfort not requiring 
parasympatholytic drugs or 
analgesics 
Anorexia with 
<=15% weight loss 
from pretreatment 
baseline/nausea &/ or 
vomiting requiring 
antiemetics/ 
abdominal pain 
requiring analgesics 
Anorexia with >15% 
weight loss from 
pretreatment baseline or 
requiring N-G tube or 
parenteral support. Nausea 
&/or vomiting requiring 
tube or parenteral 
support/abdominal pain, 
severe despite 
medication/hematemesis 
or melena/ abdominal 
distention (flat plate 
radiograph demonstrates 
distended bowel loops 
Ileus, subacute or acute 
obstruction, perforation, 
GI bleeding requiring 
transfusion/abdominal 
pain requiring tube 
decompression or bowel 
diversion 
LOWER G.I. 
INCLUDING 
PELVIS 
No change 
Increased frequency or 
change in quality of bowel 
habits not requiring 
medication/ rectal 
discomfort not requiring 
analgesics 
Diarrhea requiring 
parasympatholytic 
drugs (e.g., Lomotil)/ 
mucous discharge not 
necessitating sanitary 
pads/ rectal or 
abdominal pain 
requiring analgesics 
Diarrhea requiring 
parenteral support/ severe 
mucous or blood 
discharge necessitating 
sanitary pads/abdominal 
distention (flat plate 
radiograph demonstrates 
distended bowel loops) 
Acute or subacute 
obstruction, fistula or 
perforation; GI bleeding 
requiring transfusion; 
abdominal pain or 
tenesmus requiring tube 
decompression or bowel 
diversion 

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Inovio Pharmaceuticals, Inc.  
 
 
 
        
  
 
 
 
 
 
Clinical Protocol 
 
Date: 27 April 2016 
 
 
 
 
 
 
 
v 2.1 
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[ 0 ] 
[ 1 ] 
[ 2 ] 
[ 3 ] 
[ 4 ] 
GENITOURINARY No change 
Frequency of urination or 
nocturia twice pretreatment 
habit/ dysuria, urgency not 
requiring medication 
Frequency of 
urination or nocturia 
which is less frequent 
than every hour. 
Dysuria, urgency, 
bladder spasm 
requiring local 
anesthetic (e.g., 
Pyridium) 
Frequency with urgency 
and nocturia hourly or 
more frequently/ dysuria, 
pelvis pain or bladder 
spasm requiring regular, 
frequent narcotic/gross 
hematuria with/ without 
clot passage 
Hematuria requiring 
transfusion/ acute 
bladder obstruction not 
secondary to clot 
passage, ulceration or 
necrosis 
HEMATOLOGIC 
WBC (X 1000) 
>=4.0 
3.0 - <4.0 
2.0 - <3.0 
1.0 - <2.0 
<1.0 
PLATELETS  
(X 1000) 
>=100 
75 - <100 
50 - <75 
25 - <50 
<25 or spontaneous 
bleeding 
NEUTROPHILS 
>=1.9 
1.5 - <1.9 
1.0 - <1.5 
0.5 - <1.0 
<0.5 or sepsis 
HEMOGLOBIN 
(GM %) 
>11 
11-9.5 
<9.5 - 7.5 
<7.5 - 5.0 
------- 
HEMATOCRIT (%) >=32 
28 - <32 
<28 
Packed RBC transfusion 
required 
------- 
GUIDELINES: The acute morbidity criteria are used to score/grade toxicity from radiation therapy. The criteria are relevant from day 
1, the commencement of therapy, through day 90. 
The evaluator must attempt to discriminate between disease- and treatment-related signs and symptoms. 
 An accurate baseline evaluation prior to commencement of therapy is necessary. 
 All toxicities Grade 3, 4 or 5* must be verified by the Principal Investigator. 
*ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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13.6 
Appendix 6:  Preparation of Investigational Products 
VGX-3100 and INO-9012 will be combined by the site pharmacist into a single syringe 
for subjects using the following procedure: 
 
0. Using aseptic technique, withdraw 1.2 mL from the vial SynConTM VGX-3100 
with a 3 mL syringe and inject into an empty sterile vial. Set this “mixing” vial 
which now contains 1.2 mL of VGX-3100 aside. 
1. Using a new 1 mL syringe, withdraw 0.12 mL from the vial SynConTM INO-9012 
and add the 0.12 mL to the “mixing” vial containing 1.2 mL of VGX-3100. The 
final volume of this vial should now be 1.32 mL of  INO-3112(VGX-3100 / INO-
9012). 
2. Using a 3 mL syringe, withdraw 1.1 mL of INO-3112 from the “mixing” vial. 
This syringe will be used for dosing of subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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13.7 
Appendix 7: CELLECTRA®-5P Error Reporting Form 
Please complete the form and fax to 
 or scan the form to 
   
 
Protocol#_________ 
Site# ______ 
Subject ID _________ 
Week#_______ 
Visit Date_______ 
DEVICE INFORMATION 
CELLECTRA®-5P Serial No:  
Located on label on the front cover 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CELLECTRA®-5P Applicator Serial No: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Located on label on the handle  
 
CELLECTRA®-5P Array Lot No:  
Located on label on the package 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time of Electroporation: __________ 
Location of Treatment/EP: ☐ Deltoid Right/Left __________ 
☐ Other Location, specify:_______________ 
IM-5P, was the EP Guide used? ☐ YES ☐ NO 
If EP Guide was used, please provide reason and include subject’s BMI. 
 
Was injection successful?  
☐ YES  
 
 ☐ NO 
If NO, please provide reason and include needle gauge and syringe volume used. 
 
Did the display on the device read EP successful? ☐ YES  
 
 ☐ NO 
If NO, please check all complications that led to failure and describe complication below 
☐ Impedance Test Error message displayed, fill out Impedance Test Error section below 
☐ Electroporation Error message displayed, fill out Electroporation Error section below 
☐ EP aborted by trigger or keypad error message displayed 
☐ Battery level too low for electroporation message displayed 
☐ Difficulty inserting array into muscle or skin 
☐ Other, please specify below 
 
Describe device complication below (continue on back if necessary): 
 
 
 
 
Total # of arrays used: _____________ 
 
Impedance Test Error 
 
Was the array inserted in subject’s arm? 
☐ YES 
 ☐ NO 
Total # of attempts: __________ 
Were all attempts performed on the same day?  
☐ YES 
 ☐ NO  
(provide other date(s):___________ 
Was a different location used for each attempt? 
☐ YES  
 ☐ NO 
Was a new array used for each attempt? 
☐ YES  
 ☐ NO 
Please provide any additional information below (continue on back if necessary): 
 
 
 
 
Electroporation Error 
 
Were there 3 (IM) or 4 (ID) involuntary muscle contractions? 
 ☐ YES 
 ☐ NO (how many__________ 
Was the array fully inserted in the subject’s arm? 
 ☐ YES 
 ☐ NO 
Was the array inserted perpendicular to the subject’s skin? 
 ☐ YES 
 ☐ NO 
Did the needles of the array appear damaged in any way?  
 ☐ YES 
 ☐ NO 
If you were provided a sharps shuttle, please eject the array into a shuttle and ship to Inovio. 
Please provide any additional information below (continue on back if necessary): 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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13.8 
Appendix 8: New York Heart Association (NYHA) Functional Classification 
 
The NYHA classifies heart failure into classes based on functional limitations and  
severity. 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or 
dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but 
less than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity 
is undertaken, discomfort is increased. 
 
*The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
 
 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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13.9 
Appendix 9: Participant Reminder Card 

HPV-004 Participant Reminder Card 
Version 1.0 
12/20/2013 
Appendix 10.  Participant Reminder Card
 
 
Participant ID: _______________________ Date of Study Treatment__________________________ 
 
Site of Injection:  
 
 Right Arm  
 Left Arm   
 Right Leg   
 Left Leg 
 
Instructions:  Please complete this reminder card in the evening after and for three days following your 
study treatment.  The “Evening of study treatment” column should include any side effects from the time 
you received the study treatment until 11:59pm of that day.  Days 1, 2 and 3 should include any side effects 
from  midnight  (12:00  am)  to  11:59  pm  of  that  day  (1  day,  2  days  or  3  days  after  receiving  the  study 
treatment). 
 
Take this card with you to your next study visit for review with the study team.   If you have any questions, 
or if you have any concerns or side effects that you’d like to discuss, please contact your study team.  
 
To  describe  the  size  of  any  area  that  is  red  or  swollen,  please  use  the  measuring  tool  provided  with  this 
reminder card to indicate the approximate size of a circle that could fully cover the area of redness or swelling. 
* OTC – Over the counter analgesics or painkillers such as paracetamol, acetaminophen (e.g. Tylenol®) or 
ibuprofen (e.g. Advil® or Motrin®). 
** After study treatment 
Possible side 
effects 
Evening of study 
treatment 
1 day after study 
treatment 
2 days after study 
treatment 
3 days after study 
treatment 
Date Resolved 
Redness or 
bruising at 
treatment 
site 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
 
If date 
unknown: 
□ 1 week** 
□ 2 weeks** 
□ 3 weeks** 
Pain at 
treatment 
site 
□ None 
□ A little, controlled 
with OTC* meds 
□ A lot, OTC meds 
didn’t work, 
prevented normal 
activity 
□ None 
□ A little, 
controlled with 
OTC* meds 
□ A lot, OTC meds 
didn’t work, 
prevented 
normal activity  
□ None 
□ A little, 
controlled with 
OTC* meds 
□ A lot, OTC meds 
didn’t work, 
prevented 
normal activity  
□ None 
□ A little, 
controlled with 
OTC* meds 
□ A lot, OTC meds 
didn’t work, 
prevented 
normal activity  
 
 
If date 
unknown: 
□ 1 week** 
□ 2 weeks** 
□ 3 weeks** 
Swelling/ 
Edema at 
treatment 
site 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
□ None 
□ Diameter (in cm) 
from measuring 
tool: 
_______________ 
□ Greater than 7cm 
 
If date 
unknown: 
□ 1 week** 
□ 2 weeks** 
□ 3 weeks** 
Oral 
Temperature 
Please record 
below: 
 
___________ 
 
Please record 
below: 
 
___________ 
 
Please record 
below: 
 
____________ 
Please record 
below: 
 
___________ 
 
□ oF 
□ oC 
□ oF 
□ oC 
□ oF 
□ oC 
□ oF 
□ oC 

HPV-004 Participant Reminder Card 
Version 1.0 
12/20/2013 
Did you have any other side effects?   
Other side 
effects 
(insert below) 
Evening of study 
treatment 
1 day after study 
treatment 
2 days after 
study treatment
3 days after 
study treatment 
Date Resolved 
 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
 
If date 
unknown: 
□ 1 week** 
□ 2 weeks** 
□ 3 weeks** 
 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
□ Mild, barely 
noticeable 
□ Moderate, 
slowed me 
down 
□ Severe 
 
If date 
unknown: 
□ 1 week** 
□ 2 weeks** 
□ 3 weeks** 
** After study treatment 
 
Did you contact the study team for any symptoms that were not listed here or the severity was worse 
than the available choices? 
 Yes   
 No 
 
About Injection Site Reaction 
The most common reactions to the study treatment are reactions at the injection site such as an area 
of  redness,  a  little  bruising,  possible  swelling,  and  temporary  pain.    For  most  people,  it  is  not 
bothersome at all and disappears in a day or two. However, it may last a week or more.   
 
If you have any concerns about your symptoms, have any ongoing injection site reactions or side 
effects that are still present more than 3 days after the study treatment, please contact your study 
team.   
 
 
Coordinator Name:    
 
 
 
 
 
 
 
 
 
Coordinator Telephone Number:  
 
 
 
 
 
 
 
  
 
Did you take any medications for your injection site reactions or other symptoms?  
 
 Yes (record below)  
  No 
 
 
 
 
 
 
Is there anything else that you would like to discuss with the study team?  
 
 Yes (record below) 
  No  
 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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13.10 Appendix 10: RECIST  
A. Response will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria: 
 
i. 
Definitions 
 
Evaluable for Target Disease response:  Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for 
target disease response.  These participants will have their response classified 
according to the definitions stated below.  (Note:  Participants who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response:  Participants who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  
 
ii. 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
≥ 20 mm by chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all considered non-measurable. 
 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are 
preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow up.  
 
iii. 
Response Criteria 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions is also considered 
progressions). 

INO-3112 
 
 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc.  
 
 
 
        
       Clinical Protocol
 
Date: 27 April 2016 
v 2.1 
 
 
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Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
iv. 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
v. 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in 
an anatomical location that was not scanned at baseline is considered new and 
will indicate PD. If a new lesion is equivocal (because of small size etc.), follow-
up evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the 
lesion was discovered. 
 
vi. 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 

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patient's best response assignment will depend on the achievement of both target 
and non-target disease. 

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Date: 27 April 2016 
v 2.1 
 
 
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Time point response: patients with target (+/- non-target disease) 
 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-
PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Time point response: patients with non-target disease only 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment 
of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised 
 
vii. 
Confirmation/Duration of Response 
 
Confirmation: Confirmation of PR and CR is required to ensure responses 
identified are not the results of measurement error. This will also permit 
appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation. 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
on study) 

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       Clinical Protocol
 
Date: 27 April 2016 
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Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest sum on study (if baseline sum is the smallest, this is the reference for 
calculation of PD).  
 
B. Progression Free Survival- any progression of disease as defined below will be 
recorded and summarized for subjects in the individual cohorts and overall 
 
Overall Survival: Overall Survival (OS) is defined as the time from randomization 
(or registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time 
from randomization (or registration) to the earlier of progression or death due to 
any cause. Participants alive without disease progression are censored at date of 
last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported