Conditions: Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of continued administration of paclitaxel given weekly in subjects considered to need to continue treatment after completion of the preceding "Phase II Clinical Study of Weekly Paclitaxel (BMS-181339) with Advanced Breast Cancer (Protocol No. CA139-371)"

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Paclitaxel
Intervention descriptions: intervention 1: Solution, I.V., 100 mg/m2, Weekly for 6 of 7 weeks, Until disease progression or unacceptable toxicity became apparent

Protocol document:
Prot_000.pdf: 
 
 
Page: 1 
Protocol Number: CA139387 
 
Date: 25-May-2005 
 
  
 
  
 
Clinical Protocol CA139387 
Rollover Study of weekly Paclitaxel (BMS-181339) in Patients with Breast Cancer 
 
 
Study Director: 
 
Taku Seriu, M.D. PhD., Director 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
24-hr Emergency Telephone Number 
 
 
 
 
 
 
 
 
 
 
This protocol contains information that is confidential and proprietary to 
Bristol-Myers Squibb (BMS)/Bristol-Myers K.K. (BMKK). 
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SYNOPSIS 
Clinical Protocol CA139387 
Title of Study: Protocol CA139387: Rollover Study of Weekly Paclitaxel (BMS-181339) in Patients with 
Advanced Breast Cancer. 
Estimated Number of Study Centers and Countries/Regions: 5 sites/Japan 
Study Phase: II 
 
 
 
Primary Objective: The primary objective is to provide an access to Paclitaxel therapy to all subjects who 
have completed previous 
 and are deemed to be benefiting from this 
treatment (and should continue on this therapy) as assessed by the treating investigator(s). Cond study 
(CA 139-387) will also evaluate the frequency and the severity of observed adverse events in treated study 
subjects. 
Study Design: This study is a rollover study designed to provide an access to Paclitaxel therapy to breast 
cancer subjects who have completed previous 
 and are 
believed to be benefiting from this treatment as assessed by the treating investigator(s). Only breast cancer 
patients who have participated in a previous 
 can enroll in this 
rollover weekly Paclitaxel trial (CA139387) provided that they meet all eligibility criteria. Study subjects 
will receive weekly Paclitaxel at the dose consistent with their last dose in the previous Phase II weekly 
Paclitaxel trial. Paclitaxel will be given as a one hour intravenous (iv) infusion on Days 1, 8 15,22, 29, 36 
followed by 2 weeks of no treatment (observation). One treatment course will consist of 49 days. Safety 
assessment required in the protocol should be done at each of these weekly visits. Tumor response will be 
assessed at the completion of at least every 7 weeks. 
Number of Subjects per Group: Approximately 10 subjects. 
Study Population: Patients with advanced breast cancer that have completed therapy in a previous 
 and are proven to be benefiting from it with recommendation 
of continuation of this treatment, as assessed by the treating investigator(s).  
Test Product, Dose and Mode of Administration, Duration of Treatment: Paclitaxel will be 
administered intravenously by a 1-hour infusion for the first week of each treatment course. All patients 
will receive premedication with Paclitaxel given at the last dose that each individual patient was receiving 
on the  previous 
 The day of the initial drug dose administration on 
the given course is defined as Day 1 of the treatment course. Subsequent Paclitaxel administrations will be 
given on Days 8, 15, 22, 29 and 36 followed by two weeks of rest (i.e. until Day 49). One treatment course 
consists of 49 days total. 
Reference Therapy, Dose and Mode of Administration, Duration of Treatment: Not applicable. 
Criteria for Evaluation: Every adverse event shall be evaluated and its severity be graded according to 
the NCI- Common Toxicity Criteria (NCI-CTC) Ver.2.0 (see Appendix 10; It also includes Japanese-
language version translated by the JCOG.). 
Responses will be assessed according to the “Evaluation Criteria on the Therapeutic Effects in Patients 
with Advanced or Recurrent Breast Cancer “(Extract) and RECIST criteria (See Appendix 7).   
Statistical Methods: Demographic data and safety will be summarized using descriptive statistics. 
 
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TABLE OF CONTENTS
TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   1
SYNOPSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   2
TABLE OF CONTENTS. . . . . . . . . . . . . . . . . . . . . . . . . . .   3
    
    
2 STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . .  11
2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . .  11
2.2 Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . .  12
3 STUDY DESIGN AND EVALUATION. . . . . . . . . . . . . . .  12
3.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  12
3.2 Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . .  12
3.3 Criteria for Evaluation . . . . . . . . . . . . . . . . . . . . . . .  12
3.4 Sample Size Determination . . . . . . . . . . . . . . . . . . .  13
3.5 Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . .  13
4 STATISTICAL METHODOLOGY . . . . . . . . . . . . . . . . . .   13
4.1 Data Set Descriptions . . . . . . . . . . . . . . . . . . . . . . .  13
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4.2 Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  13
4.2.1 Demographics and Baseline Characteristics. . . . . . . . .   13
4.2.2 Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   14
4.2.3 Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   14
4.2.5 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   14
5 SUBJECT SELECTION CRITERIA . . . . . . . . . . . . . . . .  14
5.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . .  14
5.2 Exclusion Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . .  16
6 STUDY CONDUCT. . . . . . . . . . . . . . . . . . . . . . . . . . . . .  17
6.1 Ethics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  17
6.2 Study Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  19
6.2.2 Treatment Group Assignment . . . . . . . . . . . . . . . . . . . .   19
6.2.3 Treatment Administration . . . . . . . . . . . . . . . . . . . . . . .   20
6.2.3.1 Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   20
6.2.3.2 Criteria for re-treatment within the course of
therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   21
6.2.3.3 Re-treatment Criteria for Course 2 and thereafter.   22
6.2.4 Dose Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . .   23
6.2.5 Discontinuation of Therapy . . . . . . . . . . . . . . . . . . . . . .   23
6.2.6 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . .   24
6.2.7 Other Guidance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   24
6.3 Blinding/Unblinding . . . . . . . . . . . . . . . . . . . . . . . . .  24
6.3.1 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   25
6.3.2 Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   25
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6.5 Non-therapy Precautions and Restrictions . . . . . . .  26
6.5.1 Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   26
6.5.2 Restrictions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   27
6.6 Withdrawal of Subjects from Study . . . . . . . . . . . . .  28
7 STUDY PROCEDURES AND OBSERVATIONS . . . . . .  28
7.1 Flow Chart/Time and Events Schedule . . . . . . . . . .  28
7.2 Procedures by Visit . . . . . . . . . . . . . . . . . . . . . . . . .  30
7.2.1 Screening evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . .   30
7.2.2 Day 1 of  the first therapy course (before infusion) . . . .   30
7.2.3 Evaluations during each therapy course (on Days 8,
15, 22, 29, 36, 43 of each course). . . . . . . . . . . . . . . . . . .   31
7.2.4 Evaluations on Day 1 of Course 2 and thereafter
(excluding the first course) . . . . . . . . . . . . . . . . . . . . . . . .   31
7.2.5 Discharge evaluations. . . . . . . . . . . . . . . . . . . . . . . . . .   32
7.3 Details of Procedures . . . . . . . . . . . . . . . . . . . . . . .  32
7.3.1 Study Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   32
7.3.2 Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . .   32
7.3.2.1 Subjective/objective findings . . . . . . . . . . . . . . . . .   32
7.3.2.2 Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . .   33
7.3.2.3 Chest X-ray and PaO2 . . . . . . . . . . . . . . . . . . . . .   33
7.3.3 Laboratory Test Assessments. . . . . . . . . . . . . . . . . . . .   33
7.3.4 Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . .   34
7.3.4.1 Primary Efficacy Assessments . . . . . . . . . . . . . . .   34
7.3.4.2 Secondary Efficacy Assessments . . . . . . . . . . . . .   34
8 INVESTIGATIONAL PRODUCT . . . . . . . . . . . . . . . . . . .  34
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8.1 Investigational Product Identification . . . . . . . . . . . .  34
8.2 Packaging and Labeling . . . . . . . . . . . . . . . . . . . . .  35
8.3 Handling and Dispensing of Investigational
Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  35
8.4 Investigational Product Records at Investigational
Site(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  36
8.5 Return and Destruction of Investigational Product .  36
8.5.1 Return of Investigational Product . . . . . . . . . . . . . . . . .   36
8.5.2 Destruction of Investigational Product. . . . . . . . . . . . . .   37
8.6 Retained Samples for
Bioavailability/Bioequivalence Studies . . . . . . . . . . .  37
9 ADVERSE EVENT REPORTING IN CLINICAL TRIALS  37
9.1 Importance of Adverse Event Reporting . . . . . . . . .  37
9.2 Collection of Safety Information. . . . . . . . . . . . . . . .  37
9.3 Adverse Events Related to Study Conditions . . . . .  40
9.4 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  40
9.5 AE Follow up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  40
9.6 Reporting of AE Information Following Study
Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  40
9.7 Handling of Serious Adverse Events (SAEs). . . . . .  41
9.8 Laboratory Test Abnormalities. . . . . . . . . . . . . . . . .  44
9.9 Other Safety Considerations . . . . . . . . . . . . . . . . . .  44
9.10 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  44
10 ADMINISTRATIVE SECTION. . . . . . . . . . . . . . . . . . . .  46
10.1 Compliance with the Protocol and Protocol
Revisions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  46
10.2 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . .  47
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10.2.1 Informed Consent Procedures . . . . . . . . . . . . . . . . . .   47
10.2.2 Subjects Unable to Give Informed Consent . . . . . . . .   47
10.2.2.1 Miscellaneous Circumstances. . . . . . . . . . . . . . .   47
10.2.3 Illiterate Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . .   48
10.2.4 Update of Informed Consent . . . . . . . . . . . . . . . . . . . .   48
10.3 Monitoring for Protocol Compliance. . . . . . . . . . . .  48
10.4 Records and Reports. . . . . . . . . . . . . . . . . . . . . . .  49
10.5 Institutional Review Board/Independent Ethics
Committee (IRB/IEC). . . . . . . . . . . . . . . . . . . . . . . . .  50
10.6 Records Retention. . . . . . . . . . . . . . . . . . . . . . . . .  50
10.7 Study Completion, Termination and Suspension
Study Completion . . . . . . . . . . . . . . . . . . . . . . . . . . .  50
10.7.1 Study Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . .   50
10.7.2 Termination or Suspension of an Entire Study . . . . . .   51
10.7.3 Termination or Suspension of the Study at the
Medical Institution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   51
11 GLOSSARY OF TERMS AND LIST OF
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  52
11.1 Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . .  52
11.2 List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . .  52
APPENDIX 1 INFORMED CONSENT ELEMENT . . . . . . .  56
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APPENDIX 4 ROLES AND RESPONSIBILITIES OF
STUDY RELATED PERSONNEL AND STUDY
PERIODD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  63
APPENDIX 5 DEFINITION OF ABNORMAL CHANGES
AND OUTCOME OF LABORATORY TESTS . . . . . . . .  66
APPENDIX 6 DIRECT ACCESS TO SOURCE
DOCUMENTS AND DEFINITION THEREOF . . . . . . . .  68
APPENDIX 7 CRITERIA FOR RESPONSEE . . . . . . . . . .  69
APPENDIX 8 PERFORMANCE STATUS . . . . . . . . . . . . .  77
APPENDIX 9 THERAPEUTIC ACTIONS FOR ACUTE
ALLERGIC SYMPTOMS, ARRHYTHMIA,
HYPOTENSION OR INTERSTITIAL PNEUMONIAA . .  78
APPENDIX 10 COMMON TOXICITY CRITERIA. . . . . . . .  82
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary study objectives are as follow: 
1) 
To provide the access to Paclitaxel therapy to breast cancer subjects who have 
completed at least 2 course on the previous 
 
 conducted in Japan and are believed to be benefiting from this treatment, 
as assessed by the treating investigator(s). 
2) 
To evaluate the frequency and the severity of observed adverse reactions in 
treated subjects. 
 
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2.2 
Secondary Objectives 
The secondary objective is to obtain additional data on the response rate and duration 
of responses to complement information collected on the previous 
 
. 
3 
STUDY DESIGN AND EVALUATION 
3.1 
Study Design  
Only subjects who participated in the previous Phase II study may enroll in this 
rollover study provided that they meet all specified in this protocol inclusion and 
exclusion criteria. Subjects will receive weekly Paclitaxel at the dose that was their 
last dose on the previous 
 delivered as a one hour iv 
infusion on Days 1,8,15,22,29,36 followed by 2 weeks of rest (no therapy). One 
course of therapy  consists of 49 days.  The range of doses on this study are expected 
to be decided based on dose reductions seen in 
.  Safety assessment 
required in the protocol should be done at each of these weekly visits. Response to 
therapy will be assessed at least every 7 weeks, if clinically indicated. 
3.2 
Study Population 
Patients with advanced breast cancer who have completed weekly Paclitaxel dosing in 
previous 
 and are believed to benefit from this treatment 
with recommendation to continue this regimen, as assessed by the treating 
investigator(s). 
3.3 
Criteria for Evaluation 
Observed responses should be evaluated according to the “Evaluation Criteria on the 
Therapeutic Effects in Patients with Advanced or Recurrent Breast Cancer “(Extracts) 
and the “RECIST” criteria (See Appendix 7). 
Every observed adverse event shall be evaluated according to the NCI Common 
Toxicity Criteria (NCI-CTC) Ver.2.0 (see Appendix 10, translated by the JCOG 
Japanese language version will also be available).  For any toxicity not defined by the 
NCI-CTC criteria, it must be classified into the category of “Other toxicity” with 
detailed description on the toxicity observed and be graded according to the following 
criteria: 
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Grade 0: Normal, normal/within normal range, no toxicity 
Grade 1: Minor/Mild toxicity 
Grade 2: Medium/Moderate toxicity 
Grade 3: Severe/High-grade toxicity 
Grade 4: Life-threatening toxicity 
Grade 5: Death due to toxicity  
 
3.4 
Sample Size Determination 
Sample size will be determined by the number of appropriate subjects who have 
completed previous 
 and are eligible to 
participate in this rollover (CA139387) study.  At the present time 9 patients remain 
on 
.  It is estimated that less than 10 patients will be rolled over to 
this study from 
. 
3.5 
Interim Analyses 
There are no planned interim analyses. If requested by Japanese regulatory agencies, 
an interim analysis of this trial may be performed to support the Japanese regulatory 
filing. 
4 
STATISTICAL METHODOLOGY 
4.1 
Data Set Descriptions 
Subjects who receive at least one dose of weekly Paclitaxel treatment will be included 
in the baseline, dosing and safety summaries. Data from the previous 
 
 will be utilized for the demographic data and baseline 
values in enrolled patients for this rollover trial. To obtain an additional data on a 
response rate and duration of responses, efficacy data will be collected in this rollover 
CA139387 study. 
4.2 
Analyses 
4.2.1 
Demographics and Baseline Characteristics 
Demographic data, performance status, diagnosis, stage, disease locations, prior 
treatment(s), and selected baseline laboratory results will be summarized using 
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descriptive statistics for all patients who received at least one dose of study 
medication. 
Baseline laboratory measurements will be collected from the data obtained for the 
participation in a previous 
 
4.2.2 
Efficacy Analyses 
Duration of response will be summarized using descriptive statistics for all responders 
among response-evaluable patients.  
4.2.3 
Safety Analyses 
All patients who received at least one dose of study medication will be included in the 
safety analysis. Worst toxicity grades per patient will be tabulated for adverse events 
and laboratory measurements. 
 
 
. 
4.2.5 
Other Analyses 
Not applicable. 
5 
SUBJECT SELECTION CRITERIA 
For entry into the study, the following criteria MUST be met. 
5.1 
Inclusion Criteria 
Only patients enrolled in the previous 
 
who have completed 
 dosing and are believed to be benefiting from this 
treatment with advice to continue this regimen, as assessed by the treating 
investigator(s), may be considered for this rollover study after meeting study 
eligibility criteria as listed below.   
Signed written informed consent 
1) 
Give written and voluntary informed consent. 
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Target population 
2) Patients should receive at least 2 courses, or more, of 
 in the 
previous study (
)and the efficacy evaluation should be completed and 
confirmed by the treating investigator(s).  
3) Patients who maintain bone marrow function and meet the following standards at 
the time of laboratory test obtained prior to the 1st Paclitaxel administration in this 
rollover study; 
• WBC count of 3,000/µL or higher, or absolute neutrophile count (ANC) of 
1,500/µL or above. 
• Platelet count of 75,000/µL or above.  
 
4) Performance Status (PS) of 0 - 2 (according to Classification Criteria of 
Performance Status by the Eastern Cooperative Oncology Group-ECOG. (See 
Appendix 8). 
 
Age and Sex 
5)  Women, ages 20 or older. 
Women of childbearing potential (WOCBP) must be using an adequate method of 
contraception to avoid pregnancy throughout the study and for up to 2 weeks after the 
study in such a manner that the risk of pregnancy is minimized.  
WOCBP include any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or 
bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea 
≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with 
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL]. Even 
women who are using oral, implanted or injectable contraceptive hormones or 
mechanical products such as an intrauterine device or barrier methods (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner 
is sterile (e.g., vasectomy), should be considered to be of child bearing potential. 
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study 
medication. 
 
 
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5.2 
Exclusion Criteria 
Sex and Reproductive Status  
1) WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and for up to 2 weeks after the study. 
2) WOCBP using a prohibited contraceptive method (however, prohibited 
contraceptive methods are not specified in this protocol). 
3) Women who are pregnant or breastfeeding 
4) Women with a positive pregnancy test on enrollment or prior to study drug 
administration.  
Target Disease Exceptions  
5) Patients with cerebral metastasis that are associated with clinical symptoms, 
and/or are associated with surrounding edema, or that require ongoing therapy 
with steroids or anti-convulsants. 
Medical History and Concurrent Diseases 
6) Patients with serious uncontrolled medical illness despite optimal therapy i.e. 
uncontrolled cardiac disease, unstable angina, cerebrovascular disorder, diabetes 
mellitus etc; active infection, active gastric ulcer etc. 
Allergies and Adverse Drug Reactions 
7) Patients with previous history of serious hypersensitivity reaction to Paclitaxel. 
Prohibited Therapies and/or Medications  
8) Patients who following their last dose of 
 given on the previous 
 
 study received chemotherapy other than 
, surgical procedure, 
hormonal therapy, immunotherapy, radiotherapy, physiotherapy and/or other 
therapies against their cancer that may prohibit appropriate evaluation of the 
efficacy and safety of Paclitaxel on this rollover study. 
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Other Exclusion Criteria 
9) Subjects who are compulsorily detained for legal reasons or treatment of either a 
psychiatric or physical (e.g., infectious disease) illness must not be enrolled into 
this study. 
10) Patients whose final efficacy evaluation is judged as Progressive Disease (PD) by 
the treating investigator(s) based on the CT or any other images taken within 
4 weeks prior to the enrollment in this study. 
11) Patients with grade 2 or higher peripheral neuropathy and/or grade 2 or higher 
arthralgia/myalgia despite optimal medical therapy that, in the opinion of treating 
investigator(s), will make unsafe to continue further Paclitaxel therapy. 
12) Any serious, clinically unmanageable by standard medical therapy (i.e. G-CSF for 
neutropenia, 
blood 
transfusion 
for 
anemia, 
etc.) 
adverse 
event(s), 
subjective/objective findings, abnormal laboratory values etc. that occur prior to 
initiation of Paclitxel therapy on this rollover study that, in the opinion of treating 
investigator(s), will make unsafe to continue further Paclitaxel therapy. 
 
 
 
 
 
 
 
6 
STUDY CONDUCT 
6.1 
Ethics 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and will be consistent with International 
Conference on Harmonization Good Clinical Practice (ICH GCP), Japan GCP and 
regulatory requirements. 
The study will be conducted in compliance with the protocol. The protocol and any 
Amendments and the subject informed consent will receive Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) approval/favorable opinion prior to 
initiation of the study. 
Freely given written informed consent must be obtained from every subject prior to 
clinical trial participation, including informed consent for any screening procedures 
conducted to establish subject eligibility for the trial.  
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Subjects unable to give their written consent (e.g., stroke patients, or subjects with 
severe dementia) may only be enrolled in the study with the consent of their legally 
acceptable representatives. The subject must also be informed about the nature of the 
study to the extent compatible with the subject’s understanding, and should they 
become capable, personally sign and date the consent form as soon as possible.  
For further details on informed consent, see Section 10.2. 
The rights, safety and well-being of the trial subjects are the most important 
considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, 
training, and experience to perform their respective task(s). 
This trial will not use the services of study personnel where sanctions have been 
invoked or where there has been scientific misconduct or fraud (e.g., loss of medical 
licensure, debarment). 
Systems with procedures that assure the quality of every aspect of the study will be 
implemented. 
Study site personnel involved in this study must bear in mind that study subjects are at 
a risk of experiencing adverse events as a result of administration of the 
investigational product and study-related procedures. Anticipated benefits of the 
investigational products and anticipated disadvantages to the subjects must be 
described in the informed consent form and explained to subjects prior to enrollment 
in this study. During and following a subject’s participation in the trial, the head of 
the medical institution or the investigator should ensure that adequate medical care is 
provided to a subject for any adverse events, including clinically significant 
laboratory values, related to the clinical trial. 
When serious unexpected events occur in a subject during the course of this study, the 
investigators should promptly evaluate whether the study should be discontinued, in 
collaboration with the Sponsor. 
All study site and sponsor personnel involved in this study must take the necessary 
actions to ensure that all information collected about study subjects throughout the 
study appropriately protects subjects’ privacy according to the requirements specified 
in the criminal law and the pharmaceutical affairs law. This applies, but is not limited 
to, information collected on the written informed consent, CRFs, source documents, 
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and publication of study results. Consequently, study subjects should, wherever 
possible, be identified by subject number. 
A detailed summary of the applicable regulatory requirements is provided in 
Appendix 2. 
6.2 
Study Therapy 
 
 
 
 
 
 
 
 
6.2.2 
Treatment Group Assignment 
Every potential study patient shall, when she/he fully meets all the eligibility criteria 
and submits a signed freely given informed consent, be eligible for this study 
registration. For each study participant, an Investigator/Sub-investigator is required to 
fill in all necessary items on a case registration form and send it to the Case 
Registration Center via facsimile as specified below. The Case Registration Center 
shall confirm that the data described in a registration card sent by an 
Investigator/Sub-investigator fulfills all inclusion criteria and does not meet any of the 
exclusion criteria before a case registration. The Case Registration Center shall inform 
an Investigator/Sub-investigator of the registration number for a registered case by 
telephone or facsimile. If the data described in a registration card does not fulfill the 
inclusion criteria or does meet any of the exclusion criteria, the Case Registration 
Center shall confirm the data in question by discussing it with an 
Investigator/Sub-investigator and, if the case is ineligible for the study, inform an 
Investigator/Sub-investigator of this decision by telephone and facsimile.  
 
 
 
 
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6.2.3 
Treatment Administration 
6.2.3.1 
Method 
The firs Paclitaxel dose on a given course is defined as Day 1 of therapy with 
subsequent drug administrations being given on Days 8, 15, 22, 29 and 36 followed 
by 2 weeks of rest (no drug given). One course of treatment will therfore consist of 
total of 49 days. 
1) 
Pre-medications (also see Section 6.5.1) 
The following premedications must be given before each paclitaxel infusion 
• Dexamethasone 8 mg i.v.(*: Dose can be reduced to 4mg → 2mg → 1mg) 
administered 1 hour before and completed 30 minutes prior to the initiation of the 
paclitaxel infusion 
• Ranitidine 50 mg i.v.- administered 1 hour before and completed 30 minutes prior 
to the initiation of the paclitaxel infusion 
• Diphenhydramine 50 mg p.o. 
 
(*): Dexamethasone: 
Dexamethasone dose at the initial administration day (Day 1) shall be the same as the 
last dose in the previous 
. If any hypersensitivity reaction 
was observed at the last dose in the previous Phase II study, a dosage of 
dexamethasone shall be double of the last dose. During the observation period 
(Days 1 – 7), if there are no specific clinical problems, dexamethasone dose for the 
subsequent week (Day 8) would be allowed to be decreased by half the dose from the 
previous week (i.e.4mg), if necessary. Consequently, if no clinically significant 
hypersensitivity reaction is observed in a week following the drug administration, it 
would be possible to use again a half of the previous dexamethasone dose (i.e. 2mg), 
if necessary. The minimum dexamethasone dosage however, can not be less then 
1 mg). If clinically significant hypersensitivity reaction develops, and it is judged that 
further continuation of weekly Paclitaxel is in the best patient’s interest, 
dexamethasone dose shall be double the previous dose (e.g. if 8 mg was given and 
there was an event observed then, the next dexamethasone should be 16 mg) for the 
subsequent Paclitaxel administrations. 
 
2) 
Paclitaxel (Day1, 8, 15, 22, 29, 36) ( see Section 6.5.1) 
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After administration of the pre-medications, the patient should receive Paclitaxel dose 
that is consistent with the last dose(*) of Paclitaxel that the given patient has received 
in the previous study 
). This Paclitaxel dose shall be mixed with 250 mL 
of a saline solution or 5% glucose solution for intravenous infusion given over 1-hour. 
(*) weekly Paclitaxel dose should be reduced, if appropriate, according to the severity 
of adverse effect(s) observed  at the last Paclitaxel treatment in the previous Phase II 
study according to the “Dose Modification” criteria  (See Section 6.2.3)”. 
Administration of weekly Paclitaxel dose should be given on the expected date of 
treatment + one day. 
 
course 1 
course 2 
Days 
Day1 
Day8 
Day15 
Day22 
Day29 
Day36 
Day43 
Day50 
+++ 
Paclitaxel 
O 
O 
O 
O 
O 
O 
˜ 
O 
+++ 
 
6.2.3.2 
Criteria for re-treatment within the course of therapy 
(Days: 8, 15, 22, 29, 36 of a therapy course)  
An in-course repeated dosing could be allowed only when the laboratory test values 
and clinical assessments in the previous week or immediately before Paclitaxel 
administration meet the following requirements; 
• WBC count of 2,000/µL or above, or absolute neutrophile count (ANC) of 
1,000/µL or above.  
• Platelet count of 75,000/µL or above. 
• No Grade 2 or higher peripheral neuropathy and/or Grade 2 arthralgia/myalgia 
despite optimal medical therapy which, in the opinion of treating investigator(s), 
will make further Paclitaxel therapy unsafe. 
• Any serious, clinically unmanageable by standard medical therapy (i.e. G-CSF for 
neutropenia, 
blood 
transfusion 
for 
anemia, 
etc.) 
adverse 
event(s), 
subjective/objective findings, abnormal laboratory values etc. occur that, in the 
opinion of treating investigator(s), will make unsafe to continue further Paclitaxel 
therapy. 
If the patient does not meet above requirements or if the investigator/sub-investigator 
judges that, it is in the best patient’s interest to delay Paclitaxel dosing, the drug 
administration shall be postponed by one week. Reasons for this decision should be 
described in a case report form. A dose modification, if appropriate, should be 
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performed for a successive in-course dosing. (See Section 6.2.3 “Dose 
Modification"). 
The study should be discontinued if more than two consecutive Paclitaxel 
administrations or more than three out of six doses total within the given treatment 
course are not delivered. However, in patients with evidence of Paclitaxel anti-tumor 
effects, as judged by the treating investigator(s), subsequent Paclitaxel therapy 
following longer than allowed suspension of treatment may be allowed. The reasons 
for this decision shall be described in a case report form and all safety precautions 
should be observed. 
6.2.3.3 
Re-treatment Criteria for Course 2 and thereafter 
The second and consequent courses of therapy should be started after confirmation 
that the following criteria are all met prior to the drug administration.   
• WBC count of 3,000/µL or above, or ANC of 1,500/µL or above.  
• Platelet count of 75,000/µL or above. 
• No Grade 2 or higher peripheral neuropathy and/or Grade 2 arthralgia/myalgia 
despite optimal medical therapy which, in the opinion of treating investigator(s), 
will make further Paclitaxel therapy unsafe. 
• Any serious, clinically unmanageable by standard medical therapy (i.e. G-CSF for 
neutropenia, 
blood 
transfusion 
for 
anemia, 
etc.) 
adverse 
event(s), 
subjective/objective findings, abnormal laboratory values etc. occur that, in the 
opinion of the treating investigator(s), will make unsafe to continue further 
Paclitaxel therapy. 
• No Grade 3 or higher non-hematological toxicity despite optimal medical therapy. 
 
When any one of the criteria is not met, administration should not be started (a dose 
modification should be performed for a successive in-course repeated dosing. See 
Section 6.2.3 “Dose Modification").  Paclitaxel therapy should be started as soon as 
the laboratory test values and the symptoms are recovered to the acceptable level. 
However, if the re-treatment criteria are not met following 2 weeks after the 
scheduled initiation date of the given treatment course, the study therapy shall be 
discontinued in a given patient. When the initiation of the treatment course is delayed, 
the delayed initiation date shall be set as Day 1 of the given course with the 
subsequent treatment schedule adjusted accordingly. 
However, in the given patient (i.e. in case of electrolytes abnormalities, etc.), if in the 
opinion of the treating investigator(s) it is still safe and in the best patient’s interest to 
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continue Paclitaxel therapy (with dose adjustment, if clinically indicated), the 
treatment may continue but the reasons for this decision must be described in the case 
report form. 
6.2.4 
Dose Modifications 
Paclitaxel dose shall be reduced according to the severity of an adverse event using 
criteria listed below. Paclitaxel dose should be decreased by the increment of 
20mg/m2 /dose. Patients who require a decrease below the total of 60mg/m2 /dose will 
be discontinued from treatment.. 
• WBC count: less than 1000/µL (*1) 
• Grade 3 neutropenia (neutrophils count <1000/µL but ≥ 500//µL) or higher, 
neutropenia associated with fever (≥38°C) or infection   
• Grade 3 or higher non-hematological toxicity (*2) 
• Development of Grade 2 or higher peripheral neuropathy and/or Grade 2 
arthralgia/myalgia despite optimal medical therapy which, in the opinion of 
treating investigator(s), will make further Paclitaxel therapy clinically difficult. 
• When an investigator/sub-investigator judges to be clinically appropriate to skip a 
scheduled drug administration and/or to require a dose reduction. 
• In the opinion of the treating investigator/sub-investigator there is a need for dose 
modification. Reasons for this decision should be described in a case report form. 
 
(*1) Dose reduction based on the WBC count being less than 1,000/µL shall  depend 
on a decision of treating investigator/sub-investigator (taking into consideration the 
time of bone marrow recovery, clinical scenario for a given patient, etc.). 
(*2): For the given patient, if in the opinion of the treating investigator/sub-
investigator it is not clinically necessary to reduce the Paclitaxel dose (including 
Grade 3 or higher electrolyte abnormality, etc.) the dose may stay the same however, 
the reason for this decision must be described in a case report form. 
6.2.5 
Discontinuation of Therapy 
Study therapy MUST be immediately discontinued for the following reasons: 
• If the clinical efficacy evaluation reveals progressive disease (PD). 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued treatment with study 
therapy is not in the best interest of the subject. 
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• Pregnancy. 
• Termination of the study by BPKK. 
• The compulsory detention for legal reasons or for treatment of either a psychiatric 
or physical (e.g., infectious disease) illness.  
• If a patient becomes ineligible after registration for the study. 
 
Also, the study subject should be discontinued from the study therapy for the 
following reasons: 
• A treatment delay of > 2-weeks because of paclitaxel related toxicity  
• If in the opinion of the treating investigator(s) further continuation of Paclitaxel 
therapy is judged to be unsafe or clinically inappropriate based on the 
development of new or worsening of previous symptoms. 
• If any clinical findings consistent with the Grade 1 or higher interstitial 
pneumonia, pneumonia, pulmonary fibrosis or severe infection develops. 
• If there is a need for dose reduction below the total of 60mg/m2/dose which 
violates the dose-reduction criteria. 
• If an alternative systemic or local anti-cancer therapy is initiated. 
• If the patient has moved away from the area during the study participation that 
makes the continuation of the study therapy no longer feasible. 
• If the treating investigator/sub-investigator judges that the discontinuation of 
study therapy is in the best patient’s interest.. 
 
For discontinuation of the study see Section 6.6. 
6.2.6 
Treatment Compliance 
Each study drug administration must be conducted under the supervision of an 
investigator/sub-investigator and the following data must be described in the case 
report form (CRF); date of paclitaxel administration, dosage, infusion time, body 
weight, and the pre-medications given. 
6.2.7 
Other Guidance 
Not applicable. 
6.3 
Blinding/Unblinding  
Not applicable. 
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6.3.1 
Blinding  
Not applicable. 
6.3.2 
Unblinding  
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
. 
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6.5 
Non-therapy Precautions and Restrictions 
6.5.1 
Precautions 
1) Pre-medication drugs:  
Based on the foreign literature, prolonged use of dexamethasone as pre-medication for 
the weekly Paclitaxel regimen appears is utilized. Compared with the dosing method 
for every 3 weeks Paclitaxel schedule, the total volume of steroids administered with 
the weekly regimen(s) appears to be fairly large. Therefore, it is considered highly 
likely that this may cause suppression of the adrenocortical function hence, lower 
doses of dexamethasone are permitted  based on tolerance of the individual patient. 
A clinical study reported by 
  using decreasing doses of dexamethasone 
demonstrated that the dose of 20mg of dexamethasone (administered twice: 12 hours 
and 6 hours before Paclitaxel infusion) was gradually decreased to 2mg and only 
1/22 patients developed skin rash but others tolerated Paclitaxel therapy well. Another 
report by 
 revealed following results: 16mg of dexamethasone was 
administered as pre-medication to 43 patients. There was one patient with apnea that 
resolved without treatment but other 42 patients had no evidence of any  
hypersensitivity reaction. 
Based on these reports, in the Japanese Phase I weekly Paclitaxel study, 
dexamethasone was initially administered at the 16mg dose, which was lower than the 
approved 20 mg dose, with subsequent decrease to a total of 2 mg. During this study 
dexamethasone dosing was further changed to the initial dose of 8 mg with 
subsequent dose decrease to a total of 1mg.  With this last dexamethasone 
pre-medication regimen there were no hypersensitivity reaction observed. 
Based on these data, the pre-medication regimen shall be used as described in the 
Section 6.2.2.1 (1). 
2) 
Paclitaxel 
2-1) Preparation and i.v. infusion time  
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Immediately prior to the infusion, Paclitaxel shall be mixed with 250 ml of a saline 
solution or 5% glucose solution and administered as a 1-hour IV infusion.   
Containers for the solution MUST be made of glass, polyethylene or polypropylene.  
Paclitaxel is known to dissolve the container if it is made of polyvinyl chloride (PVC) 
and the plasticizer, DEHP[di-(2-ethylhexyl)phthalate], in the container may cause 
leaching.   
2-2) Injection kit 
An injection kit made of PVC should NOT be used because of a possible leaching 
caused by plasticizer (DEHP). For the Paclitaxel injection, an in-line filter must be 
used. 
2-3) Other Caution Items 
Paclitaxel is reconstituted with ethanol as a solvent.  For any patient with alcoholic 
sensitivity, administration shall be made with full care.  Upon administration, a 
patient’s subjective and objective symptoms shall be carefully monitored and a patient 
should be carefully monitored during the time-points specified below;  
a) First-at 30 minutes following initiation of IV infusion for possible development of 
immediate allergy-like symptom or arrhythmia 
b) Subsequently- during and immediately after completion of IV infusion for 
possible hypotension.   
For treatment of immediate allergy-like symptoms, arrhythmia or hypotension, 
refer to Appendix 9. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.6 
Withdrawal of Subjects from Study 
Subjects MUST be discontinued from the study therapy AND withdrawn from the 
study participation for the reasons described in Section 6.2.5. 
 
7 
STUDY PROCEDURES AND OBSERVATIONS 
7.1 
Flow Chart/Time and Events Schedule 
Clinical laboratory testing and monitoring during the study period shall be conducted 
at every appropriate time-point as detailed in Table 1.  For those tests conducted after 
the final course of treatment on a previous
 please follow 
instructions shown in Table 1.   
Any adverse event that does not recover to a baseline level by the 14th day of 
observation a follow-up shall be done, as much as possible, until the recovery to 
baseline or symptoms stabilization. 
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Table.7.1: 
X: required measurement point,  XX: Conduct, if possible, 
at the time of clinic visit. 
 
Rollover study (CA139387) 
As needed after 
2nd course 
1st course 
2nd- course
1st week (Day1) 
Procedure 
Last 
dose 
Obser-
vation Pre-dosea Infusion
Post- 
infusion
Day8, 
15,22, 
29,36 
7w 
Day43 
(off) 
1w 
Day1 
Patient background 
X 
 
 
 
 
 
 
Body weight (BW), 
Height, and BSA 
 
 
X 
 
 
 
 
X 
Subjective/objective 
findings and P.S. 
X 
X 
X 
X 
X 
X 
Blood Test (clinical 
laboratory) 
X 
X 
X 
 
 
X 
X 
X 
Cab 
 
 
X 
 
 
 
 
Xb  
Chest CT-scanc 
Conduct when acute lung disorder or interstitial pneumonia were suspected 
Chest X-rayd 
Conduct if necessary 
PaO2
e 
Conduct if necessary 
ECGf 
Conduct if necessary 
Blood pressureg 
 
 
X 
 
X 
X  
 
X  
Urine test h 
 
 
X 
 
 
 
 
Xh 
Pregnancy testi 
 
 
X 
 
 
 
 
XX  
 
Observation of 
lesion for efficacy 
evaluationj 
Conduct at least every 7 weeksj 
*  A day that a study drug is administered is Day 1. 
*  Each laboratory test  (except for tumor marker test) must be completed prior to administration of 
each weekly drug administration. 
*  Administration of weekly Paclitaxel doses and initiation of successive treatment courses must be 
done within an expected date of treatment + one day. 
a Each required examination before the administration of a 1st course shall be conducted within 
2 days before the first dose. Tumor status evaluation (tumor measurements, tumor markers) could be 
conducted within one month prior to the scheduled 1st Paclitaxel dose. 
b Once a course evaluation is required. 
c Conduct when acute lung disorder or interstitial pneumonia is suspected. 
d Can be done for evaluation of clinical symptoms such as fever, cough, shortness of breath or 
dyspnea. Can be repeated as clinically indicated. 
e Conduct if clinically indicated i.e. if any respiratory symptoms such as cough or shortness of breath 
develops. 
f Done for patients with  suspected  cardiac-related toxicity.  ECG monitoring during subsequent  
treatments shall be done when clinically indicated. with strong consideration given to safety of 
further Paclitaxel therapy. 
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g Frequent monitoring shall be performed. Patients should be closely monitored  during and after the 
study drug infusion. Patients who will be going home following completion of Paclitaxel infusion 
(outpatient clinic practice) should be thoroughly evaluated for any side effects including vital signs 
and performance status. 
h Should be done once prior to each treatment course. If the drug safety can be adequately judged from 
other evaluation(s) i.e. serum creatinine, etc., this test may not have to be done routinely. 
i A pregnancy  test  shall  be  conducted  within  72  hours  prior  to  Day 1 of a 1st course  for a  
WOCBP (WOCBP must have a negative serum or urine pregnancy test which has minimum 
sensitivity 25 IU/L or equivalent units of HCG). For successive treatment courses, it will be 
conducted prior to a Day 1 of each treatment course(as much as possible). 
j To objectively evaluate the anti-tumor effect , an identical imaging diagnostic method shall be 
utilized  for the individual patient  More than one diagnostic method could be applied, if clinically 
indicated.  In addition, lesion(s) that can be evaluated only clinically i.e. skin or chest wall lesions , 
should be, as much as possible, photographed and  lesion measurements should be documented. 
* A day that a study drug is administered is Day 1. 
* Each laboratory test  (except for tumor marker test) must be completed prior to administration of 
each weekly drug administration. 
* Administration of weekly Paclitaxel doses and initiation of successive treatment courses must be 
done within an expected date of treatment + one day. 
 
7.2 
Procedures by Visit 
7.2.1 
Screening evaluation 
The following tests should be performed within 14 days prior to a first dose of study 
drug administration.  If data (i.e. laboratory test values, etc.) from the time prior to 
obtaining the informed consent is used for study enrollment, the study subject shall 
agree to this herself/himself. 
• Subjective/objective findings(including Performance Status-PS) 
• Clinical efficacy from 
 
• ECG (see Table 1) 
• Blood test (Hb, WBC, ANC, Plt, T-Bil, AST(GOT), ALT(GPT), BUN, S-Cr, Ca) 
• Serum or Urine pregnancy test: in case of WOCBP(minimum sensitivity 25IU/L 
or equivalent units of HCG) 
 
7.2.2 
Day 1 of  the first therapy course (before infusion) 
The following evaluation shall be conducted on Day1 of the 1st treatment course prior 
to a study drug administration; 
• Body weight and height. Body Surface Area (BSA) 
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• Subjective/objective findings(including PS) 
• Blood test and urine test (see Section 7.3.3for details) 
• Blood pressure (pre-dose and post- infusion) 
• Serum or Urine pregnancy test: in case of WOCBP (minimum sensitivity 25IU/L 
or equivalent units of HCG within 72 hours prior to the start of study medication.  
However, if a pregnancy test is already conducted within 72 hours prior to the 
study drug administration during the enrollment period the repeated test is not 
needed. 
 
7.2.3 
Evaluations during each therapy course (on Days 8, 15, 22, 29, 
36, 43 of each course) 
The following items shall be examined; 
• Subjective/objective findings (including PS) 
• Blood test and urine test (see Section 7.3.3 for details) 
• Blood pressure (pre-dose and post- infusion) 
 
See Table 1 for details of evaluation on day 43 (7th week of each course of treatment)  
7.2.4 
Evaluations on Day 1 of Course 2 and thereafter (excluding 
the first course) 
Following evaluation should be done on Day1 of the second therapy course and each 
subsequent treatment course(excluding the first course). 
• Body weight, BSA. 
 
Serum calcium and urine test shall be conducted at least once a course. When safety 
of further Paclitaxel therapy is adequately judged from i.e. serum creatinine values, 
etc., the urine test may not to be done routinely. 
Tumor status evaluation should be done after completion of each treatment course 
(i.e. every 4~ 7 weeks or sooner, if clinically indicated)  
• Measurements of lesion(s) for efficacy evaluation should be done using the same 
imagining method for each tumor status evaluation i.e. CT and/or MRI and/or 
bone scan etc. Lesions that can be evaluated only clinically i.e. skin and/or chest 
wall lesions should be photographed and measurement(s) of such lesions should 
be  documented (as much as possible) 
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• Tumor marker (at least one type regardless of marker type) 
 
7.2.5 
Discharge evaluations  
When the patient is discontinued from the study therapy (taken off the study) either 
due to a progressive disease or toxicity, or other (please see Section 6.2.5 for details), 
the following evaluation shall be done at the 14th day from the last dose (it may also 
be done on the 15th day or later, if necessary i.e. subject’s personal matters or 
unexpected inconvenience at a study site,etc). 
• Subjective/objective findings (including PS) 
• Blood test, urine test (see Section 7.3.3) 
 
7.3 
Details of Procedures 
7.3.1 
Study Materials 
The Sponsor will provide the Paclitaxel(BMS-181339) Investigator Brochure, any 
relevant safety addendum, protocol and any amendments to the protocol, Case Report 
Forms(CRF), instructions for completing CRFs, case registration forms and Severe 
Adverse Reaction (SAE) forms etc. 
7.3.2 
Safety Assessments 
7.3.2.1 
Subjective/objective findings 
It shall be conducted weekly on a day of the drug administration and, if possible, 
during the week when therapy is suspended (during the patient visit at the clinic or in 
the hospital).  Instruct all patients to inform the investigator immediately if the patient 
develops  fever, dry cough, shortness of breath for early detection and diagnosis of 
acute lung disorder or interstitial pneumonia. Investigator must evaluate carefully 
each study patient (i.e.auscultation, etc) even without clinical symptoms. Conduct 
chest CT-scan immediately, if clinically indicated, for proper diagnosis and 
treatment.. Conduct A-aDO2 or DLCO, if necessary.  
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7.3.2.2 
Blood Pressure 
It should be measured pre-dose and post-dose on every drug administrations. Frequent 
monitoring should be performed, fully observing the patients during and after the 
study drug IV infusion. If the patient is treated in the outpatient clinic settings, she/he 
should be thoroughly evaluated ( i.e. for any side effects, performance status, vital 
signs, etc)  prior to discharge to home. 
7.3.2.3 
Chest X-ray and PaO2 
Monitor carefully for the clinical symptoms such as fever, cough, shortness of breath 
or dyspnea, and if any of these symptoms develop, chest x-ray and/or PaO2 may be 
conducted, if clinically indicated. If acute lung disorder or interstitial pneumonia is 
suspected, a chest CT-scan and, if necessary, additional A-aDO2 or DLCO can be done 
(cf. 6.2.4 and Appendix 9). Consider consult with experts on respiratory diseases, if 
needed. 
7.3.3 
Laboratory Test Assessments  
The following laboratory tests shall be conducted at the time of registration and prior 
to the scheduled Paclitaxel administration at each study site (corrected Ca test shall be 
conducted at least once a course); 
1) Hematology 
 
RBC count, hemoglobin, WBC count, neutrophil count, and platelet count. 
2) Serum Chemistry 
 
Total protein, albumin, total bilirubin, ALP, AST, ALT, LDH, BUN, S-Cr, Na, K, 
Cl and Ca. 
3) Others 
 
CRP (C-reactive protein) 
 
The following tests will be done at least once for each course prior to Paclitaxel 
administration. 
4) Urine test: urine protein, urine sugar, urobilinogen 
 
The following obligatory evaluation should be done prior to the administration of 
a first drug dose on the first treatment course and subsequently, every ~ 7 weeks. 
5) Tumor marker 
 
Appropriate type (at least one type regardless of marker type)  
 
For WOCBP, a pregnancy test must be conducted within 72 hours prior to an 
initial study drug administration on a 1st course and prior to the1st dose on 
subsequent treatment courses (as much as possible). 
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6) Pregnancy test 
 
Appropriate test (Serum or Urine pregnancy test [minimum sensitivity 25 IU/L or 
equivalent units of HCG]).  
 
 
Results of all laboratory tests required by this protocol must be recorded on the 
laboratory pages of the CRF or by another method as agreed upon between the 
Investigator/Sub-investigator and this, too must be recorded in the CRF (see Section 
9.8 Laboratory Test Abnormalities). 
The following evaluation should be conducted if any respiratory symptoms such as 
cough or shortness of breath develop. 
7) 
PaO2 
 
7.3.4 
Efficacy Assessments 
7.3.4.1 
Primary Efficacy Assessments 
The primary efficacy endpoint will not be set in this study. 
7.3.4.2 
Secondary Efficacy Assessments 
Not applicable. 
8 
INVESTIGATIONAL PRODUCT 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
8.1 
Investigational Product Identification 
The sponsor will provide Paclitaxel and pre-medication drugs as study drugs. 
# Study Drug: 
Code name: BMS-181339 
Generic name: Paclitaxel 
Dosage form/content: Each vial (16.7 mL) contains 100 mg of paclitaxel. 
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# Premedications: 
Drug Name 
Formulation 
Contents 
Packaging 
Dexamethasone 
vial 
One vial (2 mL) contains 8 mg  
dexamethasone sodium phosphate (6.6 mg 
as dexamethasone) 
50 vials/box 
Diphenhydramine 
tablet 
One tablet contains 10 mg  
diphenhydramine hydrochloride 
500 tablets/bottle 
Ranitidine 
ampule 
One ampule contains 50 mg ranitidine 
10 ampules/box 
 
8.2 
Packaging and Labeling  
A label bearing the following information will be placed on the container or the 
package of the investigational product (see Appendix 3): 
• The fact that the drug is for clinical study use 
• Name of the investigational product (code name) 
• Lot number 
• Dosage form and content 
• Storage condition 
• Name and address of the sponsor 
• Use date, if necessary 
 
8.3 
Handling and Dispensing of Investigational Product 
After study contract between the sponsor and the medical institution is finalized, the 
sponsor will supply the investigational drug to the investigational product storage 
manager designated by the head of the medical institution. The investigational product 
storage manager will store and manage the investigational product appropriately, 
according to the written procedures prepared and provided by the sponsor, and follow 
up the status of dispensing by keeping the record of the investigational product 
management sheet. 
Investigational product should be stored in a secure area according to local 
regulations. It is the responsibility of the Investigator to ensure that investigational 
product is only dispensed to study subjects. The investigational product must be 
dispensed only from official study sites by authorized personnel according to local 
regulations. 
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8.4 
Investigational Product Records at Investigational 
Site(s) 
It is the responsibility of the investigational product storage manager designated by 
the head of the medical institution 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. 
• Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
• Amount dispensed to and returned by each subject, including unique subject 
identifiers. 
• Amount transferred to another area for dispensing or storage. 
• Non-study disposition (e.g., lost, wasted, broken). 
• Amount returned to Sponsor. 
 
Sponsor will provide forms to facilitate inventory control if the staff at the 
investigational site does not have an established system that meets these requirements. 
Sponsor should also provide procedures stipulating instructions for the handling, 
storage and management of investigational products and recording thereof. 
8.5 
Return and Destruction of Investigational Product 
8.5.1 
Return of Investigational Product 
Upon completion or termination of the study, all unused and/or partially used 
investigational product must be returned to BMKK, if not authorized by BMKK to be 
destroyed at the site. 
All investigational products returned to BMKK must be accompanied by the 
appropriate documentation and be clearly identified by protocol number and study site 
name. Empty containers should not be returned to BMKK. It is the responsibility of 
the medical institution to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable local 
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and institutional guidelines and procedures. The return of unused investigational 
product(s) should be arranged by the responsible Study Monitor.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product must be returned to BMKK, if not authorized by BMKK to be 
destroyed at the site. 
All investigational products and empty containers returned to BMKK must be 
accompanied by the appropriate documentation and be clearly identified by protocol 
number and study site name. The return of unused investigational product(s) should 
be arranged by the responsible Study Monitor. 
8.5.2 
Destruction of Investigational Product 
All unused investigational products must be returned to BMKK and therefore, the 
product can not be destroyed at the site without appropriate reasons. The 
investigational product storage manager must provide a detailed explanation to 
BMKK if the drug is destroyed at the site. BMKK will ensure appropriate destruction 
of investigational product. 
8.6 
Retained Samples for Bioavailability/Bioequivalence 
Studies 
Not Applicable. 
9 
ADVERSE EVENT REPORTING IN CLINICAL TRIALS 
9.1 
Importance of Adverse Event Reporting  
Timely and complete reporting of safety information assists BMS/BMKK in 
identifying any untoward medical occurrence, thereby allowing:  (1) protection of 
safety of study subjects; (2) a greater understanding of the overall safety profile of the 
investigational product; (3) recognition of dose-related investigational product 
toxicity; (4) appropriate modification of study protocols; (5) improvements in study 
design or procedures; and (6) adherence to worldwide regulatory requirements. 
9.2 
Collection of Safety Information 
In BMS/BMKK clinical trials, an Adverse Event (AE) is defined as any new 
untoward medical occurrence or worsening of a pre-existing medical condition in a 
patient or clinical investigation subject administered a medicinal product and which 
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does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal (investigational or marketed) product, whether or not considered related to 
the medicinal (investigational or marketed) product.   
During clinical trials, adverse events can be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, patients should not be questioned regarding the specific occurrence of 
one or more adverse events.) 
Following the subject’s written consent to participate in the study, all serious AEs 
should be collected. The collection of non-serious AE information should begin at 
initiation of investigational product. Non-serious AE information should also be 
collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the patient. 
All identified AEs must be recorded and described on the appropriate Non-serious or 
Serious AE page of the CRF. If known, the diagnosis of the underlying illness or 
disorder should be recorded, rather than its individual symptoms.  The following 
information should be captured for all AEs: date (and time) of onset and resolution, 
severity of the event (see definitions), investigator’s opinion of the relationship to 
investigational product (see definitions), treatment required for the AE (see 
categories), cause of the event (if known), and information regarding 
resolution/outcome (see definitions).   
Severity will be graded according to the... NCI-CTC 
The following categories and definitions of severity should be used for AEs in this 
clinical trial:   
• Mild (Grade I) - Awareness of event but easily tolerated 
• Moderate (Grade II) - Discomfort enough to cause some interference with usual 
activity 
• Severe (Grade III) - Inability to carry out usual activity 
• Very Severe (Grade IV) - Debilitating, significantly incapacitates subject despite 
symptomatic therapy 
 
The following categories and definitions of causal relationship to study drug should 
be used for all BMS/BMKK clinical trial AEs: 
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• Certain:  There is a reasonable causal relationship between the study drug and the 
AE.  The event responds to withdrawal of study drug (dechallenge), and recurs 
with rechallenge when clinically feasible. 
• Probable:  There is a reasonable causal relationship between the study drug and 
the AE.  The event responds to dechallenge.  Rechallenge is not required. 
• Possible:  There is reasonable causal relationship between the study drug and the 
AE.  Dechallenge information is lacking or unclear. 
• Not likely: There is a temporal relationship to study drug administration, but there 
is not a reasonable causal relationship between the study drug and the AE.   
• Unrelated:  There is not a temporal relationship to study drug administration (too 
early, or late, or study drug not taken), or there is a reasonable causal relationship 
between another drug, concurrent disease, or circumstance and the AE. 
 
The adverse event will be regarded as related to study drug if the causal relationship is 
assessed as either "1. Certain ","2. Probable" or "3. Possible”. 
If a causal relation of an adverse event is assessed as “4. Not likely” or "5. Unrelated," 
reasons for the evaluation are to be described.  
The following categories and definitions of outcome /resolution should be used for all 
BMS/BMKK clinical trial AEs  
1) Did not resolve (Persisted or Aggravated) 
2) Resolved (Recovered) 
3) Resolved, but residual effects(s) persist (Relieved) 
4) Unknown 
5) Subject Died* 
 
* “Subject Died” category applies to reporting of Serious AEs only. 
The following categories and definitions on action taken with respect to 
investigational product administration should be used for all BMS/BMKK clinical 
trial AEs  
1) 
None 
2) 
Dose reduced* 
3) 
Interrupted 
4) 
Discontinued 
5) 
Dose Increased* 
 
* “Dose reduced” and “dose increased” should be deleted if not applicable 
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The following categories on treatment required should be used for all BMS/BMKK 
clinical trial AEs  
1) 
No 
2) 
Yes (If Yes, comment on the treatment.) 
 
A detailed explanation of the categories and definitions applicable to AEs due to 
laboratory abnormalities is provided in Appendix 5. 
9.3 
Adverse Events Related to Study Conditions 
If the investigator believes that an SAE is not related to the investigational product, 
but is potentially related to the conditions of the study, (such as withdrawal of 
previous therapy, or complication of a diagnostic procedure), the relationship should 
be specified in the narrative section of the SAE page of the CRF. 
9.4 
Overdose 
An overdose is defined as the accidental or intentional ingestion of any dose of a 
product that is considered both excessive and medically important.  For reporting 
purposes, BMS considers an overdose, regardless of adverse outcome, as an important 
medical event (see Serious Adverse Events). 
9.5 
AE Follow-up 
AEs should be followed to resolution or stabilization, and reported as SAEs if they 
become serious.  This also applies to subjects experiencing AEs that cause 
interruption or discontinuation of investigational product, or those experiencing AEs 
that are present at the end of their participation in the study; such subjects should 
receive post-treatment follow-up as appropriate. If an ongoing AE changes in its 
severity or in its perceived relationship to study drug, a new AE entry for the event 
should be completed. 
9.6 
Reporting of AE Information Following Study 
Completion 
Collection of safety information following the end of investigational product 
administration is important in assisting in the identification of possible delayed 
toxicities or withdrawal effects. In BMS/BMKK trials, all SAEs must be collected 
which occur within 30 days of discontinuation of dosing or completion of the 
patient’s participation in the study if the last scheduled visit occurs at a later time. In 
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addition, the investigator should notify BMS/BMKK of any SAE which may occur 
after this time period which they believe to be certainly, probably or possibly related 
to investigational product. 
9.7 
Handling of Serious Adverse Events (SAEs) 
A serious AE is any untoward medical occurrence that at any dose:  
• results in death,  
• is life-threatening (defined as an event in which the subject or patient was at risk 
of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe),  
• requires 
inpatient 
hospitalization 
or 
causes 
prolongation 
of 
existing 
hospitalization,  
• results in persistent or significant disability/incapacity,  
• is a cancer, 
• is a congenital anomaly/birth defect,  
• results in the development of drug dependency or drug abuse,  
• is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient/subject or 
may require intervention (e.g., medical, surgical) to prevent one of the other 
serious outcomes listed in the definition above.)  Examples of such events include, 
but are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  For reporting purposes, BMS/BMKK also considers the 
occurrences of pregnancy or overdose (regardless of adverse outcome) as events 
which must be reported as important medical events. 
 
Adverse events classified as "serious" must be recorded on the SERIOUS AE (SAE) 
page of the CRF and require expeditious handling and reporting to BMKK as well as 
to the head of the medical institutions to comply with regulatory requirements.  
All serious AEs whether related or unrelated to investigational product, must be 
immediately reported to BMKK as well as to the head of the medical institution (or 
designee) by confirmed facsimile transmission. A documented telephone call may be 
used in lieu of a facsimile. If only limited information is initially available, follow-up 
reports are required. The original BMKK SAE form must be kept on file at the 
sponsor.  In selected circumstances, the protocol may specify conditions which 
require additional telephone reporting. 
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Cases of pregnancy must be reported on Pregnancy Surveillance Forms in lieu of SAE 
pages (see Section 9.10). 
Collection of complete information concerning SAEs is extremely important. Thus, 
follow-up information which becomes available as the SAE evolves, as well as 
supporting documentation (e.g., hospital discharge summaries and autopsy reports), 
should be collected subsequently, if not available at the time of the initial report, and 
immediately sent using the same procedure as the initial SAE report. 
 
 
 
 
 
 
 
 
  
 
 
 
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
As required, BMKK will notify Investigators and the heads of the medical institutions 
of all AEs that are serious, unexpected, and certainly, probably, or possibly related to 
the investigational product. This notification will be in the form of a Safety Update.  
Upon receiving such notices, the Investigator must review and retain the notice with 
the Investigator Brochure. At the same time sponsor will immediately submit a copy 
of this information to the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) according to local regulations, via the head of the medical 
institution. The Investigator and IRB/IEC will determine if the informed consent 
requires revision. The Investigator should also comply with the IRB/IEC procedures 
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for reporting any other safety information. Where required, submission of Safety 
Updates by the Investigator to Health Authorities, should be handled according to 
local regulations. 
Serious adverse events whose causal relationship to the investigational product cannot 
be ruled out (adverse drug reactions) and that meet the criteria as specified in Article 
273 of the Enforcement Regulations of the Pharmaceutical Affairs Law are to be 
reported on an expedited basis. The sponsor will report the adverse drug reactions to 
the regulatory authority. The time limit of reporting varies according to whether the 
reported adverse drug reactions are expected or unexpected. 
i. 
Unexpected “Death” or “cases which might result in death”:  within 7 days 
ii. 
Unexpected events other than those listed above:  within 15 days 
iii. 
Expected “Death” or “Cases which might result in death”:  within 15 days 
 
When necessary, the sponsor will consult with the medical expert on the actions to be 
taken regarding the conduct of the study, including whether this study is to be 
continued or not. Procedures for termination or suspension of this study are described 
in Section 10.7. 
 
 
 
 
 
 
 
Reporting of Serious Adverse Events Seen in the Other Studies 
When serious adverse events possibly related to the investigational product (adverse 
drug reactions) are reported in other studies, the sponsor will take the following 
actions. 
For an unexpected serious adverse drug reaction, the sponsor will consult with the 
medical expert, if necessary, and the sponsor will notify Investigator and the head of 
the medical institution promptly. Any serious adverse drug reactions specified in 
Section 9.7 Serious Adverse events (SAEs) will be reported to the regulatory 
authority on an expedited basis within the specified time limits. 
Periodically, according to the Investigator Brochure SOP, the Investigator Brochure 
will be updated to include new and relevant safety information.  Until such time that 
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an AE becomes identified in the Investigator Brochure, it will continue to be reported 
to Investigators and to health authorities in line with local regulations.   
9.8 
Laboratory Test Abnormalities 
All laboratory test values captured as part of the study should be recorded on the 
appropriate laboratory test results pages of the CRF, or be submitted electronically 
from a central lab.  In addition, in order for BMKK to collect additional information 
about clinically important laboratory abnormalities, at a minimum, the following 
laboratory abnormalities should be captured on the non-serious or serious AE pages of 
the CRF as appropriate:  
• Any laboratory test result that meets the criteria for a Serious Adverse Event  
• Any laboratory abnormality that required the patient to have investigational 
product discontinued or interrupted 
• Any laboratory abnormality that required the patient to receive specific corrective 
therapy. 
 
It is expected that wherever possible, the clinical, rather than the laboratory term 
would be used by the reporting investigator (e.g., anemia versus low hemoglobin 
value). 
A detailed definition of abnormal laboratory changes and outcome is provided in 
Appendix 5. 
9.9 
Other Safety Considerations 
Any clinically significant changes noted during interim or final physical 
examinations, electrocardiograms, x-rays, and any other potential safety assessments, 
whether or not these procedures are required by the protocol, should also be recorded 
on the appropriate AE page of the CRF (i.e., NON-SERIOUS or SERIOUS). 
9.10 
Pregnancy 
Sexually active women of childbearing potential must use an effective method of birth 
control during the course of the study, in a manner such that risk of failure is 
minimized.  (See Section 5.1 for definition of WOCBP). 
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Before enrolling women of childbearing potential (WOCBP) in this clinical trial, 
Investigators must review the guideline about study participation for WOCBP which 
can be found in the GCP Manual for Investigators.  The topics include the following: 
• General Information 
• Informed Consent Form 
• Pregnancy Prevention Information Sheet 
• Drug Interactions with Hormonal Contraceptives 
• Contraceptives in Current Use 
• Guidelines for the Follow-up of a Reported Pregnancy 
 
Prior to study enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. The subject must sign an informed consent form documenting this 
discussion.  
All WOCBP MUST have a negative pregnancy test within 72 hours prior to 
receiving investigational product. The minimum sensitivity of the pregnancy test must 
be 25 IU/L or equivalent units of HCG. If the pregnancy test is positive, the subject 
must not receive investigational product and must not be enrolled in the study. 
Pregnancy testing must also be performed throughout the study as specified in 
Section 7.3.3 and the results of all pregnancy tests (positive or negative) recorded on 
the case report form. 
In addition, all WOCBP should be instructed to contact the Investigator 
immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. 
If following initiation of study treatment, it is subsequently discovered that a trial 
subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for subject safety). Exceptions to investigational 
product discontinuation may be considered for life-threatening conditions only after 
consultation with the BMKK Medical Monitor or as otherwise specified in this 
protocol. The Investigator must immediately notify the BMKK Medical Monitor of 
this event and record the pregnancy on the Pregnancy Surveillance Form. Pregnancy 
Surveillance Forms are forwarded to BMKK as described in Section 9.7 (SAEs). 
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Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies).  
Other appropriate pregnancy follow-up procedures should be considered if indicated.  
In addition, the Investigator must report to BMKK, on the appropriate BMKK 
pregnancy surveillance forms(s), follow-up information regarding the course of the 
pregnancy, including perinatal and neonatal outcome.  Infants should be followed for 
a minimum of eight weeks. 
10 
ADMINISTRATIVE SECTION 
10.1 
Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol. All revisions to 
the protocol must be discussed with, and be prepared by, BMKK. The Investigator 
should not implement any deviation or change to the protocol without prior review 
and documented approval/favorable opinion from the IRB/IEC of an Amendment, 
except where necessary to eliminate an immediate hazard(s) to study subjects. Any 
significant deviation must be documented in the CRF or in the specific sheet provided 
to record these deviations. 
If a deviation or change to a protocol is implemented to eliminate an immediate 
hazard(s) prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible 
the deviation or change will be submitted to: 
• IRB/IEC, via the head of the medical institution, for review and 
approval/favorable opinion; 
• Bristol-Myers K.K.; 
• The head of the medical institution; 
• Regulatory Authority(ies), if required by local regulations. 
 
Documentation of approval signed by the chairperson or designee of the 
IRB(s)/IEC(s) must be sent to BMKK. 
If the revision is an Administrative Letter, the Sponsor must inform their 
IRB(s)/IEC(s) via the head of the medical institution.  
If an Amendment substantially alters the study design or increases the potential risk to 
the subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) 
for review and approval/favorable opinion; (2) the revised form must be used to 
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obtain consent from subjects currently enrolled in the study if they are affected by the 
Amendment; and (3) the new form must be used to obtain consent from new subjects 
prior to enrollment. 
10.2 
Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the 
purpose, potential risks and other critical issues regarding clinical trials in which they 
volunteer to participate. 
10.2.1 
Informed Consent Procedures 
Preparation of the consent form is the responsibility of the Investigator and must 
include all elements required by ICH, GCP and applicable regulatory requirements, 
and must adhere to GCP and to the ethical principles that have their origin in the 
Declaration of Helsinki. The consent form must also include a statement that BMKK 
and regulatory authorities have direct access to subject records. Prior to the beginning 
of the study, the Investigator must have the IRB/IEC’s written approval/favorable 
opinion of the written informed consent form and any other information to be 
provided to the subjects. 
The Investigator must provide the subject with a copy of the consent form and written 
information about the study in the language in which the subject is most proficient. 
The language must be non-technical and easily understood. The Investigator should 
allow time necessary for subject to inquire about the details of the study, then 
informed consent must be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion. The subject should receive a 
copy of the signed informed consent and any other written information provided to 
study subjects prior to subject's participation in the trial. 
10.2.2 
Subjects Unable to Give Informed Consent 
10.2.2.1 
Miscellaneous Circumstances  
Subjects who are compulsorily detained for legal reasons or treatment of either a 
psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this 
study. 
In circumstances where a subject’s only access to treatment is through enrollment in a 
clinical trial, e.g., for subjects in developing countries with limited resources or for 
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subjects with no marketed treatment options, the investigator must take special care to 
explain the potential risks and benefits associated with the trial and ensure that the 
subject is giving informed consent. 
When a subject may be in a dependent relationship with the investigator, a 
subinvestigator who is completely independent of the relationship between the subject 
and investigator should obtain the subject’s informed consent. 
10.2.3 
Illiterate Subjects 
If the subject is unable to read, a reliable and independent witness should be present 
during the entire informed consent discussion. The choice of the witness must not 
breach the subject’s rights to confidentiality. A reliable independent witness is defined 
as one not affiliated with the institution or engaged in the investigation. A family 
member or acquaintance are appropriate independent witnesses. After the subject 
orally consents and has signed, if capable, the witness should sign and personally date 
the consent form attesting that the information is accurate and that the subject has 
fully understood the content of the informed consent agreement and is giving true 
informed consent.   
10.2.4 
Update of Informed Consent 
The informed consent and any other information provided to subjects, should be 
revised whenever important new information becomes available that is relevant to the 
subject's consent, and should receive IRB/IEC approval/favorable opinion prior to 
use. The Investigator, or a person designated by the head of the medical institution, 
should fully inform the subject of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented.  
During a subject's participation in the trial, any updates to the consent form and any 
updates to the written information will be provided to the subject. 
10.3 
Monitoring for Protocol Compliance 
Representatives of BMKK/BMS must be allowed to visit all study site locations 
periodically to assess the data, quality and study integrity. On site they will review 
study records and directly compare them with source documents and discuss the 
conduct of the study with the Investigator, and verify that the facilities remain 
acceptable. 
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In addition, the study may be evaluated by BMS/BMKK internal auditors and 
government inspectors who must be allowed access to CRFs, source documents and 
other study files. BMS/BMKK audit reports will be kept confidential. 
THE HEAD OF THE MEDICAL INSTITUTION MUST NOTIFY BMKK 
PROMPTLY OF ANY INSPECTIONS SCHEDULED BY REGULATORY 
AUTHORITIES, AND PROMPTLY FORWARD COPIES OF INSPECTION 
REPORTS TO BMKK. 
10.4 
Records and Reports 
An Investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
investigation on each individual treated with the investigational product or entered as 
a control in the investigation. Data reported on the CRF, that are derived from source 
documents, must be consistent with the source documents or the discrepancies must 
be explained.  
The CRF must be completed legibly in ink.  Subjects are to be identified by birth date 
and subject number, if applicable. All requested information must be entered on the 
CRF in the spaces provided. If an item is not available or is not applicable, it must be 
documented as such; do not leave a space blank. 
The confidentiality of records that could identify subjects must be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable 
regulatory requirement(s). 
The Investigator will maintain a copy of the Signature Sheet to document signatures 
and seals of all persons authorized to make entries and/or corrections on CRFs. The 
original of this sheet will be kept by the sponsor. A correction must be made by 
striking through the incorrect entry with a single or double line and entering the 
correct information adjacent to the incorrect entry. The correction must be dated, 
signed or sealed and explained (if necessary) by the person making the correction and 
must not obscure the original entry. 
The completed CRF must be promptly reviewed, signed or sealed, and dated by a 
qualified physician who is an Investigator or Subinvestigator. The Investigator must 
retain a copy of the CRFs including records of the changes and corrections. 
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10.5 
Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) 
Before study initiation, the Sponsor must have written and dated approval/favorable 
opinion from the IRB/IEC, via the head of the medical institution, for the protocol, 
consent form, subject recruitment materials/process (e.g., advertisements), and any 
other written information to be provided to subjects. The Sponsor should also provide 
the IRB/IEC, via the head of the medical institution, with a copy of the Investigator 
Brochure or product labeling, information to be provided to subjects and any updates. 
The Investigator and Sponsor should provide the IRB/IEC, via the head of the medical 
institution, with reports, updates, and other information (e.g., Safety Updates, 
Amendments, Administrative Letters) according to regulatory requirements or 
Institution procedures. 
10.6 
Records Retention 
The head of the medical institution must retain investigational product disposition 
records, copies of CRFs (or electronic files), and source documents for the maximum 
period required by applicable regulations and guidelines, or Institution procedures, or 
for the period specified by the Sponsor, whichever is longer. The head of the medical 
institution must contact BMKK prior to destroying any records associated with the 
study. 
BMKK will notify the head of the medical institution when the trial records are no 
longer needed. 
10.7 
Study Completion, Termination and Suspension 
Study Completion 
10.7.1 
Study Completion 
When this study is completed, the investigator will notify the head of the medical 
institution in writing of the completion and provide a written overview of the study 
results. 
The head of the medical institution will in turn notify the Sponsor and the IRB in 
writing of the completion and send a copy of the written overview of the study results. 
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10.7.2 
Termination or Suspension of an Entire Study 
For an event that may require termination of this study, the sponsor will consult with 
the medical expert before deciding on the termination or suspension of this study. The 
sponsor will provide to the medical expert any relevant safety, efficacy or other 
available information that may justify the need for terminating or suspending the 
study. The termination or suspension of this study will be decided by the sponsor, 
taking in consideration the advice given by the medical expert. 
When the termination of this study is decided, the sponsor will promptly notify the 
investigator and the head of the medical institution in writing of the decision and 
reasons for the termination. 
10.7.3 
Termination or Suspension of the Study at the Medical 
Institution 
When the investigator considers it necessary to terminate or suspend this study, the 
investigator will promptly report the fact and reasons in writing to the head of the 
medical institution to which the investigator belongs. 
The head of the medical institution will in turn promptly notify the Sponsor and the 
IRB in writing of the fact and explain in detail the events and rationale which required 
the termination or suspension of the study. 
 
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11 
GLOSSARY OF TERMS AND LIST OF 
ABBREVIATIONS 
11.1 
Glossary of Terms 
Not applicable. 
11.2 
List of Abbreviations 
Term 
Definition 
d.i.v.  
drip infusion in vein 
3w1q  
3 weeks administration, 1week quit 
6w1q 
6 weeks administration, 1week quit 
6w2q  
6 weeks administration, 2week quit 
°C 
degrees centigrade 
µL 
microliters 
µm 
micrometers 
A-aDO2 
Alveolar to arterial oxygen gradient 
ADM 
doxorubicin 
AE(s) 
adverse event(s) 
Alb 
Albumin 
ALP 
alkaline phosphatase 
ALT 
(GOT) 
alanine aminotransferase 
(Glutamic Oxaloacetic Transaminase) 
ANC 
Absolute Neutrophil Count 
AST 
(GPT) 
aspartate aminotransferase 
(Glutamin Pyruvic Transaminase) 
A-V 
atrioventricular 
BMKK 
Bristol Myers K.K. 
BRM 
biological response modifiers 
BUN 
blood urea nitrogen 
Ca 
Calcium 
CAP 
cyclophosphamide, doxorubicin, cisplatin 
CHF 
congestive heart failure 
Cl 
Chloride 
cm3 
centimeters cubed 
CPA 
cyclophosphamide 
CR 
complete response 
CRF 
case report form 
CRP 
C-reactive protein 
CT 
computed tomography 
DLCO  
Diffusing capacity of the lung for carbon monoxide 
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Term 
Definition 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ER 
estrogen receptor 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
IC50 
50% inhibitory concentration 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
K 
potassium 
LDH 
lactosedehydrogenase 
mg/m2 
milligrams per square meter 
mL 
mililiters 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
Na 
sodium 
NCI 
National Cancer Institute 
ng/mL 
nanograms per milliliter 
NSCLC 
Non-small cell lung cancer 
PaO2 
Partial pressure oxygen 
PD 
progressive disease 
PgR 
Progesterone receptor 
Plt 
Platelet 
PO, p.o. 
orally 
PR 
partial response 
PS 
performance status 
PVC 
polyvinyl chloride 
RBC 
red blood cells 
SAE(s) 
serious adverse event(s) 
S-Cr 
Serum Creatinine 
SD 
stable disease 
T-Bil 
Total Bilirubin 
TP 
Total Protein 
WBC 
white blood cells 
 
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APPENDIX 1 
INFORMED CONSENT ELEMENT 
The informed consent discussion and the written informed consent form and any other 
written information to be provided to subjects should include explanations of the 
following mandatory topics: 
1 
That the study involves research. 
 
 
2 
The purpose of the study. 
 
 
3 
The expected duration of the subject’s participation in the study. 
 
 
4 
The study treatment(s) and the probability for random assignment to each 
treatment. 
 
 
5 
The study procedures to be followed, including all invasive procedures. 
 
 
6 
Those aspects of the study that are experimental. 
 
 
7 
The reasonably foreseeable risks or inconveniences to the subject, and 
when applicable, to an embryo, fetus, or nursing infant. 
 
 
8 
The reasonably expected benefits. When there is no intended clinical 
benefit to the subject, the subject should be made aware of this. 
 
 
9 
The alternative procedure(s) or course(s) of treatment that may be available 
to the subject, and their important potential benefits and risks. 
 
 
10 
That records identifying the subject will be kept confidential and, to the 
extent permitted by the applicable laws and/or regulations, will not be 
made publicly available. If the results of the study are published, the 
subject's identity will remain confidential. 
 
 
11 
That the BPKK/BMS  monitor and/or BPKK/BMS representative, 
IRB/IEC, and regulatory authority(ies) will be granted direct access to the 
subject's original medical records for verification of clinical study 
procedures and/or data, without violating the confidentiality of the subject, 
to the extent permitted by the applicable laws and regulations and that, by 
signing and dating a written informed consent form, the subject or the 
subject's legally acceptable representative is authorizing such access. 
 
 
12 
The subject’s responsibilities. 
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13 
The compensation and/or treatment available to the subject in the event of 
study-related injury. 
 
 
14 
The anticipated prorated payment, if any, to the subject for participating in 
the study. 
 
 
15 
The person(s) to contact for further information regarding the study and the 
rights of study subject's, and whom to contact in the event of study-related 
injury. 
 
 
16 
That the subject's participation in the trial is voluntary and that the subject 
may refuse to participate or withdraw from the study, at any time, without 
penalty or loss of benefits to which the subject is otherwise entitled. 
 
 
17 
The foreseeable circumstances and/or reasons under which the subject's 
participation in the study may be terminated. 
 
 
18 
The anticipated expenses, if any, to the subject for participating in the 
study. 
 
 
19 
The consequences of a subject's decision to withdraw from the research 
and procedures for orderly termination of participation by the subject. 
 
 
20 
That the subject or the subject's legally acceptable representative will be 
informed in a timely manner if information becomes available that may be 
relevant to the subject's willingness to continue participation in the study. 
 
 
21 
The approximate number of subjects involved in the study. 
 
 
22 
The name, title and address of the Investigator or the subinvestigator to 
contact. 
Additional mandatory topics for inclusion in the informed consent of studies enrolling 
Women of Child Bearing Potential (WOCBP): 
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1 
General Statement 
 
The subject must not be, and should not become pregnant during exposure 
to the investigational product. Subjects should be instructed to contact the 
Investigator if they plan to change their pregnancy avoidance method or if 
they need to take any prescription drug or other medication not prescribed 
by Investigator. Sexually active subjects must use an effective method of 
pregnancy avoidance during the course of the study, in a manner such that 
risk of failure is minimized. The informed consent must indicate that 
information on pregnancy prevention for women of child-bearing potential 
has been reviewed with the subject by the Investigator or study designee. 
 
 
2 
Laboratory & Animal Reproductive Toxicology 
 
A statement addressing what is known about the investigational product 
from laboratory and animal reproductive toxicity studies concerning 
possible mutagenic and/or teratogenic effects should be included in the 
consent. The consent should indicate that this information has limited 
predictive value for humans. 
 
 
3 
Unforeseeable Risks 
 
The consent must indicate that exposure to the investigational product may 
involve currently unforeseeable risks to the subject (or embryo or fetus, if 
the subject is or may become pregnant). 
 
 
4 
Occurrence of Pregnancy or Suspected Pregnancy 
 
The informed consent must include study contact name(s) and telephone 
number(s) for the subject to call if she becomes pregnant or suspects 
pregnancy, has missed her period or it is late, or she has a change in her 
usual menstrual cycle (e.g., heavier bleeding during her period or bleeding 
between periods). 
 
 
5 
Discontinuation from the Study 
 
Any subject who becomes pregnant during the course of the study will be 
immediately withdrawn (unless allowed or stated differently in the protocol) 
and referred for obstetrical care. All financial aspects of obstetrical, child or 
related care are the responsibility of the subject. 
 
 
6 
Pregnancy Follow-up 
 
If a subject becomes pregnant, BMS will seek access to the subject's and/or 
infant's clinic/hospital records through the pregnancy, and for a minimum of 
8 weeks following delivery. 
 
 
7 
Use of a Study-prohibited Contraceptive Method 
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When applicable, the informed consent should clearly indicate if a 
contraceptive method is prohibited (e.g., when hormonal contraceptive 
interaction with the investigational product(s) is known or suspected). In 
this situation, a study participant should be instructed to notify the 
Investigator or study designee if a prohibited contraceptive method is 
initiated during the course of the study so that additional precautions can be 
taken or the subject discontinued from the study. 
 
 
8 
Non-investigational product Interactions with Hormonal Contraceptives 
 
Women using a hormonal method of contraception (oral contraceptives, 
implantable or injectable agents) must be instructed to notify the 
Investigator or study designee of the need to take any prescription drug or 
other medication not prescribed by the Investigator. The purpose of this 
statement is to identify any potential non-investigational product interaction 
with the contraceptive which might reduce the effectiveness of the 
contraceptive method. 
 
 
 
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ku, Tokyo 
Contact: 03-5323-8366 
 
 
 
 
 
 
 
 
 
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APPENDIX 4 
ROLES AND RESPONSIBILITIES OF STUDY 
RELATED PERSONNEL AND STUDY PERIOD 
The study system is described below. 
4.1 
SPONSOR 
4.1.1 
Sponsor 
 
 
 
 
4.1.2 
Study Director 
Taku Seriu, M.D., Director 
 
 
 
 
4.1.3 
Medical Expert and Roles Thereof 
 
 
 
 
Roles 
The medical expert will, as occasion demands, advise about the following matters etc. 
from a medical point of view: 
• Examination of the Protocol 
• Preparation for and participation, if necessary, at KIKO Consultations 
• Examination of the Case Report Form (CRF) 
• Examination of the informed consent form and explanatory document 
• Examination of investigator’s brochure 
• Examination of handling for adverse events (AEs) and safety information 
• Examination of continuation, change, termination and suspension of the study 
• Review of the clinical study report 
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4.1.4 
Monitor 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
4.1.5 
Auditor 
 
 
 
 
 
4.1.6 Biostatistics Analyst 
 
 
 
 
 
 
 
4.2 
PK/PD ANALYST 
Not applicable. 
 
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4.3 COORDINATING INVESTIGATOR AND ROLES THEREOF 
 
   
 
 
[Roles] 
• Coordinate the details of the protocol between the study sites. 
• Coordinate troubles on interpretations of the protocol occurring during the study. 
• Opinion co-adjustment between the study coordinating investigators and 
investigators at Evaluation Committee Meeting and other occasions. 
• Advise about the preparation and revision of the protocol and others. 
 
4.4 
COORDINATION COMMITTEE AND ROLES THEREOF 
Not applicable 
 
4.5 
EFFICACY AND SAFETY COMMISSIONER 
 
 [Roles] 
1) The efficacy/safety evaluation commissioner shall evaluate the progress of the 
study, safety information and others, when appropriate, and advise the sponsor about 
continuation, change and termination or suspension of the study. The efficacy/safety 
evaluation committee consists of members independent of the sponsor and the 
investigator. 
2) At the request of the sponsor, the efficacy/safety evaluation committee shall 
conduct the following tasks; 
• The committee shall advise the sponsor about the appropriateness of study plan 
concerning safety assurance and others. The committee shall examine whether the 
protocol is to be revised or not and, if required, advise the sponsor about the 
revision. 
• When a serious adverse event possibly affecting the conduct of the entire study is 
reported by the sponsor (see 8.2), the committee shall hold a meeting (or handed-
round decision-making system*) and advise about continuation of the study, 
changes of the study plan and termination or suspension of the study. 
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• Each committee member shall review the minutes of the meeting (if a handed- 
round decision-making system is used, replies from each committee member are 
handled as the minutes) and affix his or her signature or seal. 
 
Supplemental information on the handed-round decision-making system. The 
chairman shall decide whether handed-round decision-making is to be required or not. 
When it is considered necessary to use a handed-round decision-making system from 
the standpoint of the items of discussion or because of expedited nature of discussion, 
the chairman shall ask each member to deliberate the matters in writing, and each 
member shall report the results of deliberation to the chairman in writing. The sponsor 
shall receive the report of each member from the chairman and retain the report as the 
minutes of the committee meeting. 
 
4.6 
INVESTIGATORS 
Refer to an Attachment, “List of Clinical Trial Sites and Investigators” 
 
4.7 
ASSIGNMENT MANAGER AND ROLES THEREOF 
Not applicable. 
 
4. 8 
STUDY PERIOD 
June/2005- Approval  
APPENDIX 5 
DEFINITION OF ABNORMAL CHANGES AND 
OUTCOME OF LABORATORY TESTS  
Laboratory values will be monitored, and their significance will be evaluated by the 
investigator/subinvestigator taking in consideration how they evolve throughout the 
study. Any abnormal change observed, per the definition below, shall be recorded in 
the appropriate form as an “Adverse Event”, together with its severity, actions taken 
and causal relationship to study drug, to be evaluated as described Section 9 in this 
protocol For details on the follow-up of AEs please refer to Section 9 in this protocol.  
On laboratory test values: The abnormal values shall be evaluated according to the 
NCI Common Toxicity Criteria (NCI-CTC) ver.2.0 (Translated version into Japanese 
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by the JCOG will also be available in Appendix 10) . For the item that is not listed in 
the NCI-CTC, a normal value at each study site shall be applied). 
 
1) Definition of abnormal changes 
For laboratory test parameters, an "abnormal value" is defined as a value deviated 
from the normal range specified at the medical institution. When a laboratory 
value is initially "normal" and becomes "abnormal" during the treatment period or 
is initially "abnormal" and further "aggravates," such a change in laboratory 
values, if it is clinically significant (adverse event), is considered to be an 
"abnormal change." 
If the investigator/subinvestigator did not assess such a change in laboratory 
values as an "abnormal change," the investigator/subinvestigator must provide 
details of and reasons for the assessment in column "Comment" on the laboratory 
pages of the CRF. 
2) Outcome 
The outcome of an abnormal change will be recorded according to the following 
criteria: 
1) Did not resolve: The value remained outside the normal range and continued to be 
clinically significant (or worsened with a consequent increase in severity) 
2) Resolved: The value was reversed to the pretreatment level or returned to a 
normal range 
3) Resolved, but residual effect(s) persist: The value was not reversed to a normal 
range but improved to a clinically insignificant level 
4) Unknown: Use of an alternative therapeutic method or failure of following-up (the 
reasons should be described) 
 
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APPENDIX 6 
DIRECT ACCESS TO SOURCE DOCUMENTS 
AND DEFINITION THEREOF 
The head of the medical institution and the investigator must permit monitoring and 
auditing to be performed by the sponsor, reviews by the IRB, and inspection by the 
regulatory authorities. Direct access to all the study-related records such as source 
documents should be provided upon request by the monitors and the auditors of the 
sponsor, the IRB, or the regulatory authorities. In this particular study, source 
documents, and the CRF data deemed as source data are defined as follows:  
1) Source documents 
• Subject identification code sheet 
• Medical records 
• Written consent 
• Study drug management sheet 
• Laboratory examination data 
• Electrocardiography (ECG) charts 
• Image that can identify the lesion (MRI, CT, etc.). 
 
2) CRF data deemed as source data 
Of the data directly recorded in the CRFs, the following data are deemed as 
source data: various comments described in the CRFs, study drug relation to 
abnormal laboratory test finding, comments of adverse events (event, severity, 
date of onset, actions taken regarding study drug, treatment required for event, 
outcome, causal relationship to study drug, comments), comments of 
discontinuation or drop-outs due to any safety problem, comments of protocol 
compliance status). The data directly described in the margin area of CRF, they 
are also deemed as source data. 
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APPENDIX 7 
CRITERIA FOR RESPONSE 
7.1 
Evaluation Criteria on Therapeutic Effects in Patients with 
Advanced or Recurrent Breast Cancer(Extracts) 
7.1.1 Measurement of a Lesion 
1-1 Tumor lesion sites are divided into 13, as shown in Table 1, and individually 
measured site-by-site.  These lesions include the 3 categories; 1) bi-
directional measurable lesions, 2) one-directional measurable lesions and 3) 
immeasurable (evaluable) lesions.  However, if two or more categories of 
lesions co-exist in one identical lesion site, these lesions shall independently 
be measured for records.  The measurement shall in principle be made every 
4 weeks.   
1-2 A bi-directional lesion represents a product multiplying the largest diameter 
by its vertical counterpart diameter. (cm2)  If a plural number of lesions exist 
in one identical lesion site, a product for each lesion must separately be 
figured out.  In case only one directional measurement could be available in a 
front view image by X-ray, etc., a measured value of lateral view that is 
assumed to be vertical to the front view could be allowable for use.   
1-3 One directional lesion measurement must always be done on one identical 
site. (cm)  If a plural number of lesions exist in one identical lesion site, a 
product for each lesion must separately be figured out. 
1-4 In an immeasurable (evaluable) lesion, an evaluation must be made as much 
as possible on a dose-response reaction using various parameters 
(radiography, diagnostic imaging methods and other useful means to trace 
the post-dose progresses) before and during the therapeutic period. 
1-5 An efficacy evaluation on radiotherapy shall be applied only to the limited 
area of irradiated lesion.   
7.1.2 Definition of Objective Effects 
2-1 CR(Complete Response): A disappearance of all tumor lesions confirmed 
lasts at lest 4 weeks or longer. 
2-1-1  For each skeletal (osseous) lesion, a definition shall be made as follows; 
1) In osteolytic lesions prior to this study drug therapy, it shall be defined 
as a fluoroscopically completely hardened or a recovered back-to-
normal. 
2) In osteogenic lesions prior to this study drug therapy, it shall be defined 
as a fluoroscopically significant decrease in concentration level.   
Note 1:Bone scintigraphy findings could be available for use as an 
auxiliary tool for diagnostics. 
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Note 2:For the spinal bones, a diagnosis by CT or MRI is better.   
2-2 Partial Response(PR): defined as a decrease by 50% or more in a total 
product of measurable lesions.  In an immeasurable (evaluable) lesion, 
defined as a clear improvement.  As for any bone metastasis, defined as a 
calcification of bone-soluble lesion or a decrease in concentration of an 
osteogenic lesion.  These phenomena must last at least 4 weeks or longer.  
During the course, either one of the lesions (secondary lesions included) shall 
not be increased by 25% or more and not bear any new lesion. 
2-3 No Change (NC):  defined as a decrease by 50% or  less or as an increase by 
25% or more in a total product of measurable lesions.  In immeasurable 
(evaluable) and secondary lesions, neither clear improvement nor clear 
increase is shown and no new lesion appears in either case.  These 
phenomena must last at least 4 weeks or longer, and for a bone lesion 8 
weeks or more. 
2-4 Progressive Disease(PD): defined as an increase by 25% or more in a total 
product of measurable lesions; a significant increase of measurable 
(evaluable) and secondary lesions, or a development of new lesion.  
However, in case of bone metastasis, a pathological fracture or necrosis (or 
weakness) will not always be interpreted as an evidence for progressive 
disease.   
2-4-1  Though an improvement seen in some lesions and a total product of 
lesions reveals a shrinkage, if any one of the lesions that shows an 
increase by 25% or more at the time of the most shrunken compared 
with the baseline value, it shall be defined as PD.  However, even if any 
one of the lesions that shows an increase by 25% or more at the time of 
the most shrinkage compared with the baseline value in patients with 
PR, it shall be interpreted as PR as long as thr shrinkage rate stays at 
50% or lower compared with the baseline values. (Actual cases seen 
below)                       
Figure 1. the case of CR 
 
 
 
 
 
0 
 
 
 
 
 
 
 
CR period 
 
 
25 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
 
 
 
75 
 
 
 
 
 
Tumor Shrinkage rate 
 
 
 
 
 
 
100 
Trerapeutic Period 
 
A: Day of study therapy initiation 
B: Day that CR is first confirmed 
C: Day that CR is last confirmed 
D: Day that PD is confirmed 
B-C: CR period 
 
Note: Though Point D shows a shrinkage of 50% or 
more, compared with Point A, but since it shows 25% 
or more increase in the value at start of study therapy 
compared with Point C, it shall be interpreted as PD. 
D
B 
C
A 
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Figure 2. the case of PR 
 
 
 
 
 
0 
 
 
 
 
 
 
 
PR period 
 
 
25 
 
 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
 
 
 
75 
 
 
 
 
 
Tumor Shrinkage rate 
 
 
 
 
 
 
100 
Therapeutic Period 
 
A: Day of study therapy initiation 
B: Day that PR is first confirmed 
C: Day that PR is last confirmed 
D: Day that PD is confirmed 
B-C: PR period 
 
Note: Points C & D show 25% or more increase in the 
value at start of study therapy compared with Point B.  
However, since Point C shows 50% or more in 
shrinkage compared with Point A, it will be PR; in the 
same manner, Point D 50% or less in shrinkage 
compared with Point D, be interpreted as PD. 
 
Figure 3. the case of NC 
 
 
 
 
 
0 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
 
50 
NC period 
 
 
 
 
 
 
 
75 
 
 
 
 
 
Tumor Shrinkage rate 
 
 
 
 
 
 
100 
Therapeutic Period 
 
A: Day of study therapy initiation 
B: Day that the most tumor shrinkage is first 
confirmed 
C: Day that NC is last confirmed 
D: Day that PD is confirmed 
A-C: NC period 
Note: Point D shows an increase of 25% or less 
compared with Point A, but  
it shows 25% or more increase in baseline values 
compared with Point B, be interpreted as PD. 
 
Note 1: CR: Complete Response(Complete or significant response), PR: Partial 
Response(partial or responsed), NC: No Change (Not any changed), PD: 
Progressive Disease 
Note 2: A total product of lesions means a total product of the largest diameter and 
its vertical largest diameter multiplied (cm2) for bi-directional lesions and a 
product of measured values for one-directional lesions in plural number of 
lesions of one identical site.   
Note 3:  When a progressive disease stays as NC for long (24 weeks or longer) by the 
study drug therapy, it will be recorded separately as long NC in efficacy. 
However, it will not be added to “9. Calculation of Response Rate”. 
Note 4: Cases that a decrease of 50% or more in a total product of measurable 
lesions lasts for 4 weeks or less and those that a decrease of 25% or more to 
50% or less lasts for 4 weeks or longer could be recorded separately as 
D
B 
C
A 
D
B 
C
A 
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MR(Minor Response).  However, it will not be added to “9. Calculation of 
Response Rate” 
Note 5: Upon evaluating the effects in a therapeutic plan that a minimum dosage or 
a minimum dosing period is specified, it requires a regulated observation 
period of 4 weeks or more and that of 8 weeks or more for bone lesions.  
However, for a clarified PD, it will not be applied. 
Note 6: Evaluations for radiotherapy, they will be recorded immediately after, 4 
weeks and 12 weeks after radiotherapy. 
Note 7: For successively planned surgery, etc., an evaluation of objective effects in 
case of not enough observation period given after study therapy(topical 
arterial injection therapy, etc.) could well be made by only changes of 
concerned lesions according to the specifications, regardless of duration.  
However, it must be described separately to other treatment methods. 
 
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Clinical Protocol 
 
 
Table 1: Total Evaluation of Objective Effects for Lesions 
bi-directionally 
measurable 
one-directionally 
measurable 
Cate- 
gory 
Sites 
Disease Type 
measured
values 
Judg- 
ments 
measured
values 
Judg- 
ments 
immea- 
surable 
Total 
Evaluation
a. tumor 
 
 
 
 
 
 
1 
Primary breast 
and opposite 
side of breast b. diffuse infiltration 
 
 
 
 
 
 
a. node 
 
 
 
 
 
 
b. disperse 
 
 
 
 
 
 
topical 
c. diffuse infiltration 
 
 
 
 
 
 
2 
Dermal(Skin) 
and 
Subcutaneous 
d. distal 
 
 
 
 
 
 
a. topical/local 
 
 
 
 
 
 
3 lymphatic 
node 
b. distal 
 
 
 
 
 
 
Soft tissues 
4 mediastinal hilar tumor 
 
 
 
 
 
 
a. bone 
 
 
 
 
 
 
bone 
5 bone 
b. bone marrow 
 
 
 
 
 
 
a. node type 
 
 
 
 
 
 
b. disperse type 
 
 
 
 
 
 
6 lung 
c. funicular type 
 
 
 
 
 
 
a. node/thickness 
 
 
 
 
 
 
7 pleura 
b. pleural effusion 
 
 
 
 
 
 
8 pericardial humor 
 
 
 
 
 
 
9 hepatic 
 
 
 
 
 
 
10 intra-abdominal tumor 
 
 
 
 
 
 
11 ascites 
 
 
 
 
 
 
Viscera 
12 central nervous system(CNS, brain, eyes, 
etc.) 
 
 
 
 
 
 
 13 Others (                        ) 
 
 
 
 
 
 
Note 1: Topical area for skin and subcutaneous tissue means an anterior ipsilateral 
thorax and others distal. 
Note 2: A topical/local area of lymphatic node includes ipsilateral axilla, supra- and 
sub-clavicular and parasternal, and others distal. 
Note 3: For pleural effusion, pericardial humor and ascites, it requires to be 
sytologically diagnosed as positive.  A cytological negativity without use of 
diuretics and complete disappearance of lesion with no humoral retention; this 
is the only one case for PR. 
Note 4: For hepatic and cerebral tests, lesions must be identified by angiography, 
scintigraphy, echography and CT, etc.  Measurement for hepatic hypertrophy 
shall be made vertically from the costal end in identical site. 
Note 5: See Text 2-1,2 and 4. 
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Note 6: No CR evaluation will be made in these lesions. 
 
7.2 
Response Evaluation Criteria in Solid Tumors 
(RECIST;Outlines) 
7.2.1 
Measurability of Tumor Lesions at Baseline 
At baseline, tumor lesions will be categorized as: 
 
measurable lesions: lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as 20 mm 
with conventional techniques or as 10 mm with spiral CT 
scan. 
non- measurable lesions: all other lesions, including small lesions (longest 
diameter 20 mm with conventional techniques or 10 mm 
with spiral CT scan) and truly non-measurable lesions. 
 
All measurements should be recorded in metric notation, using a ruler or calipers. 
All baseline evaluations should be performed as close as possible to the treatment 
start and never more than 4 weeks before the beginning of the treatment. 
Lesions that are considered as truly non-measurable include the following: 
• bone lesions; 
• leptomeningeal disease; 
• ascites; 
• pleural/pericardial effusion; 
• inflammatory breast disease; 
• lymphangitis cutis/pulmonis; 
• abdominal masses that are not confirmed and followed by imaging techniques; 
• cystic lesions; 
 
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7.2.2 
Tumor response evaluation 
7.2.2.1 
Baseline Documentation of "Target" and "Non-Target" 
Lesions 
All measurable lesions up to a maximum of 10 lesions representative of all involved 
organs should be identified as target lesions and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repetitive measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target 
lesions will be calculated and reported as the baseline sum LD. The baseline sum LD 
will be used as reference to further characterize the objective tumor response of the 
measurable dimension of the disease. 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required and these lesions 
should be followed as “Present” or “Absent”. 
 
7.2.2.2 
Response Criteria 
7.2.2.2.1 
Evaluation of Target Lesions 
Complete Response CR  
disappearance of all target lesions. 
Partial response PR  
at least a 30% decrease in the sum of LD of target 
lesions taking as reference the baseline sum LD. 
Progression PD  
at least a 20% increase in the sum of LD of target 
lesions taking as references the smallest sum LD 
recorded since the treatment started or the appearance of 
one and more new lesions. 
Stable Disease SD  
neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as references 
the smallest sum LD since the treatment started. 
 
7.2.2.2.2 
Evaluation of non target lesions 
Complete Response CR  
disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level. 
Non-Complete Response CR/ 
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Non-Progression(non-PD): 
persistence of one and more non-target lesion 
or/and maintenance of tumor marker level 
above the normal limits. 
 
Progression PD  
 
appearance of one and more new lesions. 
Unequivocal progression of existing non-target lesions. 
 
7.2.2.2.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence. The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria (see 
Section 9.2.3)  
 
Target lesions Non-Target lesions 
New Lesions 
Overall response 
CR 
 
 
CR 
 
 
No 
 
CR 
CR 
 
 
Non-CR/Non-PD  
No  
 
PR 
PR  
 
 
Non-PD  
 
No  
 
PR 
SD  
 
 
Non-PD  
 
No  
 
SD 
PD  
 
 
Any  
 
 
Yes or No  
PD 
Any   
 
PD  
 
 
Yes or No  
PD 
Any   
 
Any   
 
Yes  
 
PD 
 
7.2.3 
Confirmation Criteria 
To be assigned a status of PR or CR, the size changes in tumor measurements must be 
confirmed by repeat studies that should be performed no less than 4 weeks after the 
criteria for response are first met. 
In the case of SD, the follow-up measurements conducted at least 6 weeks and longer 
after registration must have met the SD criteria at least once. 
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Clinical Protocol 
 
 
APPENDIX 8 
PERFORMANCE STATUS  
CLASSIFICATION OF PERFORMANCE STATUS (GENERAL CONDITIONS) 
SPECIFIED BY THE EASTERN COOPERATIVE ONCOLOGY GROUP 
Grade 
Performance Status 
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 selfcare but unable to carry out any work
activities. Up and about more than 50% of walking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of
walking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or
chair 
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Clinical Protocol 
 
 
APPENDIX 9 
THERAPEUTIC ACTIONS FOR ACUTE 
ALLERGIC SYMPTOMS, ARRHYTHMIA, 
HYPOTENSION OR INTERSTITIAL 
PNEUMONIA 
Careful monitoring should be made, especially during the first 30 minutes after 
initiation of infusion when hypersensitivity reactions (immediate type allergy-like 
symptoms) or arrhythmia possibly appear, during, and after, the infusion when 
hypotension may appear.  
[Hypersensitivity Reactions (Immediate type Allergy-like Symptoms)] 
In the U.S. clinical studies, the reported hypersensitivity reactions (immediate type 
allergy-like symptoms) attributed to paclitaxel administration included dyspnea, 
bronchospasm, decreased blood pressure, increased blood pressure, angioedema 
(laryngeal stridor, epiglottic swelling, periorbital edema, etc.), urticaria, flushing, 
erythematous rash, abdominal pain, pain of extremities, vomiting, fever, and rigidity. 
In the event of clear evidence of hypersensitivity reaction (immediate type 
allergy-like reactions), paclitaxel should immediately be discontinued, and the 
following actions should be taken while close cardiopulmonary monitoring: 
1) 
Diphenhydramine-calcium 
bromide 
(5 
ml; 
containing 
20 
mg 
of 
diphenhydramine) should be intravenously administered (the dose should be 
adjusted appropriately according to the patient™s status). 
2) Epinephrine (not greater than 0.25 mg) should be diluted with saline or other 
solvents and administered intravenously as slowly as possible. This course 
should be repeated at 5- to 15-minute intervals at its need (alternatives are 
dobutamine and dopamine preparations). 
a) Hypotension not responding to epinephrine: Central venous pressure and 
other cardiovascular parameters should be monitored, and intravenous fluid 
should be given, if necessary. 
b) Stridor not responding to epinephrine: bronchodilators such as salbutamol 
sulfate (1.5 - 2.5 mg of salbutamol or equivalent doses of other drugs) 
should be given by inhalation, using a nebulizer. 
3) It is known that corticosteroids are effective in blocking allergic reactions of 
delayed type due to various antigens. Sodium methylprednisolone succinate 
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Clinical Protocol 
 
 
125 mg may be administered intravenously for prevention of recurrence or 
allergic symptoms. 
 
[Arrhythmia] 
The following therapeutic actions may be taken for arrhythmia: 
1) Asymptomatic bradycardia: paclitaxel may be continued. 
2) Symptomatic bradycardia: paclitaxel should be discontinued. 
3) Marked sinus bradycardia: paclitaxel should be discontinued, and atropine 
should be administered intravenously at 5-minute intervals (0.5 mg per 
administration) until the total dose reaches 2.0 mg. 
4) Atrioventricular block: paclitaxel should be discontinued. Class I block and 
block of Mobitz Type I will usually disappear spontaneously. Atropine produces 
transient improvement of atrioventricular conduction. For severe bradycardia and 
others (block of Mobitz Type II or complete atrioventricular block), pacing 
therapy should be used. 
5) Marked ventricular ectopy (PVC, non-sustained VT, etc.) and marked 
tachycardia: paclitaxel should be discontinued, and lidocaine should be used. 
Intravenous lidocaine therapy should be started with 1 - 2 mg/kg/min and, if 
effective, followed by drip infusion of 1 - 2 mg/min. 
 
[Hypotension] 
The following therapeutic actions may be taken for hypotension: 
1) Mild: Fluid therapy should be used, if necessary, for keeping blood pressure. 
2) Moderate or severe: Persistent intravenous infusion of dopamine should 
immediately be started. Doses (5 - 15 ∝g/kg/min) should be adjusted according 
to the severity. The infusion should be continued until blood pressure is 
stabilized. If necessary, norepinephrine should be administered. After confirming 
that blood pressure remains stable, the dose of dopamine should be reduced, or 
the use of this drug should be discontinued. 
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Clinical Protocol 
 
 
[Interstitial pneumonia] 
The following therapeutic measures may be taken for interstitial pneumonia 
diagnosed with clinical symptoms and diagnostic imaging after failure of 
antibiotics treatment: 
 
It is reported that following treatment is effective: Discontinue the drug therapy, 
and apply corticosteroid pulse therapy (methylprednisolone 1000mg in 5% glucose 
solution or saline solution 200mL for intravenous over 1-hour for consecutive three 
days (1 course).  Repeat 3 courses at maximum with an interval of 1 to 2 week.  
Following prednisolon 40-60 mg/day p.o. with dose reduction every 1 to 2 weeks). 
Consult with doctors who are expert in respiratory disease in time of need. 
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Clinical Protocol 
 
 
APPENDIX 10 
NATIONAL CANCER INSTITUTE CTC 
VERSION 2 
PDF file can be found at 
 
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CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
1
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
COMMON TOXICITY CRITERIA (CTC)
Grade
Adverse Event
0
1
2
3
4
ALLERGY/IMMUNOLOGY
Allergic reaction/
hypersensitivity
(including drug fever)
none
transient rash, drug
fever <38°C (<100.4°F)
urticaria, drug fever
≥38°C (≥100.4°F),
and/or asymptomatic
bronchospasm
symptomatic
bronchospasm,
requiring parenteral
medication(s), with or
without urticaria;
allergy-related
edema/angioedema
anaphylaxis
Note: Isolated urticaria, in the absence of other manifestations of an allergic or hypersensitivity reaction, is graded in the DERMATOLOGY/SKIN category.
Allergic rhinitis
(including sneezing, nasal
stuffiness, postnasal drip)
none
mild, not requiring
treatment
moderate, requiring
treatment
-
-
Autoimmune reaction
none
serologic or other
evidence of
autoimmune reaction
but patient is
asymptomatic (e.g.,
vitiligo), all organ
function is normal and
no treatment is required
evidence of
autoimmune reaction
involving a non-
essential organ or
function (e.g.,
hypothyroidism),
requiring treatment
other than
immunosuppressive
drugs
reversible autoimmune
reaction involving
function of a major
organ or other adverse
event (e.g., transient
colitis or anemia),
requiring short-term
immunosuppressive
treatment
autoimmune reaction
causing major grade 4
organ dysfunction;
progressive and
irreversible reaction;
long-term
administration of high-
dose immuno-
suppressive therapy
required
Also consider Hypothyroidism, Colitis, Hemoglobin, Hemolysis.
Serum sickness
none
-
-
present
-
Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom. If it occurs with other manifestations of allergic or
hypersensitivity reaction, grade as Allergic reaction/hypersensitivity above.
Vasculitis
none
mild, not requiring
treatment
symptomatic, requiring
medication
requiring steroids
ischemic changes or
requiring amputation
Allergy/Immunology - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
AUDITORY/HEARING
Conductive hearing loss is graded as Middle ear/hearing in the AUDITORY/HEARING category.
Earache is graded in the PAIN category.
External auditory canal
normal
external otitis with
erythema or dry
desquamation
external otitis with
moist desquamation
external otitis with
discharge, mastoiditis
necrosis of the canal
soft tissue or bone
Note: Changes associated with radiation to external ear (pinnae) are graded under Radiation dermatitis in the DERMATOLOGY/SKIN category.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
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CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
2
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Inner ear/hearing
normal
hearing loss on
audiometry only
tinnitus or hearing loss,
not requiring hearing
aid or treatment
tinnitus or hearing loss,
correctable with hearing
aid or treatment
severe unilateral or
bilateral hearing loss
(deafness), not
correctable
Middle ear/hearing
normal
serous otitis without
subjective decrease in
hearing
serous otitis or infection
requiring medical
intervention; subjective
decrease in hearing;
rupture of tympanic
membrane with
discharge
otitis with discharge,
mastoiditis or
conductive hearing loss
necrosis of the canal
soft tissue or bone
Auditory/Hearing - Other
(Specify, __________)
normal
mild
moderate
severe
life-threatening or
disabling
BLOOD/BONE MARROW
Bone marrow cellularity
normal for age
mildly hypocellular or
≤25% reduction from
normal cellularity for
age
moderately hypocellular
or >25 - ≤50%
reduction from normal
cellularity for age or >2
but <4 weeks to
recovery of normal
bone marrow cellularity
severely hypocellular or
>50 - ≤75% reduction
in cellularity for age or
4 - 6 weeks to recovery
of normal bone marrow
cellularity
aplasia or >6 weeks to
recovery of normal
bone marrow cellularity
Normal ranges:
children (≤18 years)
90% cellularity
average
younger adults (19-59)
60 - 70%
cellularity average
older adults (≥60 years)
50% cellularity
average
Note: Grade Bone marrow cellularity only for changes related to treatment not disease.
CD4 count
WNL
<LLN - 500/mm3
200 - <500/mm3
50 - <200/mm3
<50/mm3
Haptoglobin
normal
decreased
-
absent
-
Hemoglobin (Hgb)
WNL
<LLN - 10.0 g/dL
<LLN - 100 g/L
<LLN - 6.2 mmol/L
8.0 - <10.0 g/dL
80 - <100 g/L
4.9 - <6.2 mmol/L
6.5 - <8.0 g/dL
65 - <80 g/L
4.0 - <4.9 mmol/L
<6.5 g/dL
<65 g/L
<4.0 mmol/L
For leukemia studies or bone
marrow infiltrative/
myelophthisic processes, if
specified in the protocol.
WNL
10 - <25% decrease
from pretreatment
25 - <50% decrease
from pretreatment
50 - <75% decrease
from pretreatment
≥75% decrease from
pretreatment
Hemolysis (e.g., immune
hemolytic anemia, drug-
related hemolysis, other)
none
only laboratory
evidence of hemolysis
[e.g., direct antiglobulin
test (DAT, Coombs’)
schistocytes]
evidence of red cell
destruction and ≥2gm
decrease in hemoglobin,
no transfusion
requiring transfusion
and/or medical
intervention (e.g.,
steroids)
catastrophic
consequences of
hemolysis (e.g., renal
failure, hypotension,
bronchospasm,
emergency
splenectomy)
Also consider Haptoglobin, Hemoglobin.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
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CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
3
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Leukocytes (total WBC)
WNL
<LLN - 3.0 x 109 /L
<LLN - 3000/mm3
≥2.0 - <3.0 x 109 /L
≥2000 - <3000/mm3
≥1.0 - <2.0 x 109 /L
≥1000 - <2000/mm3
<1.0 x 109 /L
<1000/mm3
For BMT studies, if
specified in the protocol.
WNL
≥2.0 - <3.0 X 109/L
≥2000 - <3000/mm3
≥1.0 - <2.0 x 109 /L
≥1000 - <2000/mm3
≥0.5 - <1.0 x 109 /L
≥500 - <1000/mm3
<0.5 x 109 /L
<500/mm3
For pediatric BMT studies
(using age, race and sex
normal values), if specified
in the protocol.
≥75 - <100% LLN
≥50 - <75% LLN
≥25 - 50% LLN
<25% LLN
Lymphopenia
WNL
<LLN - 1.0 x 109 /L
<LLN - 1000/mm3
≥0.5 - <1.0 x 109 /L
≥500 - <1000/mm3
<0.5 x 109 /L
<500/mm3
-
For pediatric BMT studies
(using age, race and sex
normal values), if specified
in the protocol.
≥75 - <100%LLN
≥50 - <75%LLN
≥25 - <50%LLN
<25%LLN
Neutrophils/granulocytes
(ANC/AGC)
WNL
≥1.5 - <2.0 x 109 /L
≥1500 - <2000/mm3
≥1.0 - <1.5 x 109 /L
≥1000 - <1500/mm3
≥0.5 - <1.0 x 109 /L
≥500 - <1000/mm3
<0.5 x 109 /L
<500/mm3
For BMT studies, if
specified in the protocol.
WNL
≥1.0 - <1.5 x 109 /L
≥1000 - <1500/mm3
≥0.5 - <1.0 x 109 /L
≥500 - <1000/mm3
≥0.1 - <0.5 x 109 /L
≥100 - <500/mm3
<0.1 x 109 /L
<100/mm3
For leukemia studies or bone
marrow infiltrative/
myelophthisic process, if
specified in the protocol.
WNL
10 - <25% decrease
from baseline
25 - <50% decrease
from baseline
50 - <75% decrease
from baseline
≥75% decrease from
baseline
Platelets
WNL
<LLN - 75.0 x 109 /L
<LLN - 75,000/mm3
≥50.0 - <75.0 x 109 /L
≥50,000 - <75,000/mm3
≥10.0 - <50.0 x 109 /L
≥10,000 - <50,000/mm3
<10.0 x 109 /L
<10,000/mm3
For BMT studies, if
specified in the protocol.
WNL
≥50.0 - <75.0 x 109 /L
≥50,000 - <75,000/mm3
≥20.0 - <50.0 x 109 /L
≥20,000 - <50,000/mm3
≥10.0 - <20.0 x 109 /L
≥10,000 - <20,000/mm3
<10.0 x 109 /L
<10,000/mm3
For leukemia studies or bone
marrow infiltrative/
myelophthisic process, if
specified in the protocol.
WNL
10 - <25% decrease
from baseline
25 - <50% decrease
from baseline
50 - <75% decrease
from baseline
≥75% decrease from
baseline
Transfusion: Platelets
none
-
-
yes
platelet transfusions and
other measures required
to improve platelet
increment; platelet
transfusion
refractoriness associated
with life-threatening
bleeding. (e.g., HLA or
cross matched platelet
transfusions)
For BMT studies, if
specified in the protocol.
none
1 platelet transfusion in
24 hours
2 platelet transfusions in
24 hours
≥3 platelet transfusions
in 24 hours
platelet transfusions and
other measures required
to improve platelet
increment; platelet
transfusion
refractoriness associated
with life-threatening
bleeding. (e.g., HLA or
cross matched platelet
transfusions)
Also consider Platelets.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
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CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
4
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Transfusion: pRBCs
none
-
-
yes
-
For BMT studies, if
specified in the protocol.
none
≤2 u pRBC in 24 hours
elective or planned
3 u pRBC in 24 hours
elective or planned
≥4 u pRBC in 24 hours
hemorrhage or
hemolysis associated
with life-threatening
anemia; medical
intervention required to
improve hemoglobin
For pediatric BMT studies, if
specified in the protocol.
none
≤15mL/kg in 24 hours
elective or planned
>15 - ≤30mL/kg in 24
hours elective or
planned
>30mL/kg in 24 hours
hemorrhage or
hemolysis associated
with life-threatening
anemia; medical
intervention required to
improve hemoglobin
Also consider Hemoglobin.
Blood/Bone Marrow - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
CARDIOVASCULAR (ARRHYTHMIA)
Conduction abnormality/
Atrioventricular heart block
none
asymptomatic, not
requiring treatment
(e.g., Mobitz type I
second-degree AV
block, Wenckebach)
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment
(e.g., Mobitz type II
second-degree AV
block, third-degree AV
block)
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
Nodal/junctional
arrhythmia/dysrhythmia
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
Palpitations
none
present
-
-
-
Note: Grade palpitations only in the absence of a documented arrhythmia.
Prolonged QTc interval
(QTc >0.48 seconds)
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
Sinus bradycardia
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
Sinus tachycardia
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment of
underlying cause
-
Supraventricular arrhythmias
(SVT/atrial fibrillation/
flutter)
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
Syncope (fainting) is graded in the NEUROLOGY category.
Vasovagal episode
none
-
present without loss of
consciousness
present with loss of
consciousness
-
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
85 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
5
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Ventricular arrhythmia
(PVCs/bigeminy/trigeminy/
ventricular tachycardia)
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic and
requiring treatment
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
Cardiovascular/
Arrhythmia - Other
(Specify, ___________)
none
asymptomatic, not
requiring treatment
symptomatic, but not
requiring treatment
symptomatic, and
requiring treatment of
underlying cause
life-threatening (e.g.,
arrhythmia associated
with CHF, hypotension,
syncope, shock)
CARDIOVASCULAR (GENERAL)
Acute vascular leak
syndrome
absent
-
symptomatic, but not
requiring fluid support
respiratory compromise
or requiring fluids
life-threatening;
requiring pressor
support and/or
ventilatory support
Cardiac-ischemia/infarction
none
non-specific T - wave
flattening or changes
asymptomatic, ST - and
T - wave changes
suggesting ischemia
angina without evidence
of infarction
acute myocardial
infarction
Cardiac left ventricular
function
normal
asymptomatic decline
of resting ejection
fraction of ≥10% but
<20% of baseline value;
shortening fraction
≥24% but <30%
asymptomatic but
resting ejection fraction
below LLN for
laboratory or decline of
resting ejection fraction
≥20% of baseline value;
<24% shortening
fraction
CHF responsive to
treatment
severe or refractory
CHF or requiring
intubation
CNS cerebrovascular ischemia is graded in the NEUROLOGY category.
Cardiac troponin I (cTnI)
normal
-
-
levels consistent with
unstable angina as
defined by the
manufacturer
levels consistent with
myocardial infarction as
defined by the
manufacturer
Cardiac troponin T (cTnT)
normal
≥0.03 - <0.05 ng/mL
≥0.05 - <0.1 ng/mL
≥0.1 - <0.2 ng/mL
≥0.2 ng/mL
Edema
none
asymptomatic, not
requiring therapy
symptomatic, requiring
therapy
symptomatic edema
limiting function and
unresponsive to therapy
or requiring drug
discontinuation
anasarca (severe
generalized edema)
Hypertension
none
asymptomatic, transient
increase by >20 mmHg
(diastolic) or to
>150/100* if previously
WNL; not requiring
treatment
recurrent or persistent
or symptomatic increase
by >20 mmHg
(diastolic) or to
>150/100* if previously
WNL; not requiring
treatment
requiring therapy or
more intensive therapy
than previously
hypertensive crisis
*Note: For pediatric patients, use age and sex appropriate normal values >95th percentile ULN.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
86 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
6
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Hypotension
none
changes, but not
requiring therapy
(including transient
orthostatic hypotension)
requiring brief fluid
replacement or other
therapy but not
hospitalization; no
physiologic
consequences
requiring therapy and
sustained medical
attention, but resolves
without persisting
physiologic
consequences
shock (associated with
acidemia and impairing
vital organ function due
to tissue hypoperfusion)
Also consider Syncope (fainting).
Notes: Angina or MI is graded as Cardiac-ischemia/infarction in the CARDIOVASCULAR (GENERAL) category.
For pediatric patients, systolic BP 65 mmHg or less in infants up to 1 year old and 70 mmHg or less in children older than 1 year of age, use two successive
or three measurements in 24 hours.
Myocarditis
none
-
-
CHF responsive to
treatment
severe or refractory
CHF
Operative injury of
vein/artery
none
primary suture repair
for injury, but not
requiring transfusion
primary suture repair
for injury, requiring
transfusion
vascular occlusion
requiring surgery or
bypass for injury
myocardial infarction;
resection of organ (e.g.,
bowel, limb)
Pericardial effusion/
pericarditis
none
asymptomatic effusion,
not requiring treatment
pericarditis (rub, ECG
changes, and/or chest
pain)
with physiologic
consequences
tamponade (drainage or
pericardial window
required)
Peripheral arterial ischemia
none
-
brief episode of
ischemia managed non-
surgically and without
permanent deficit
requiring surgical
intervention
life-threatening or with
permanent functional
deficit (e.g.,
amputation)
Phlebitis (superficial)
none
-
present
-
-
Notes: Injection site reaction is graded in the DERMATOLOGY/SKIN category.
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category.
Syncope (fainting) is graded in the NEUROLOGY category.
Thrombosis/embolism
none
-
deep vein thrombosis,
not requiring
anticoagulant
deep vein thrombosis,
requiring anticoagulant
therapy
embolic event including
pulmonary embolism
Vein/artery operative injury is graded as Operative injury of vein/artery in the CARDIOVASCULAR (GENERAL) category.
Visceral arterial ischemia
(non-myocardial)
none
-
brief episode of
ischemia managed non-
surgically and without
permanent deficit
requiring surgical
intervention
life-threatening or with
permanent functional
deficit (e.g., resection of
ileum)
Cardiovascular/
General - Other
(Specify, ______________)
none
mild
moderate
severe
life-threatening or
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
87 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
7
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
COAGULATION
Note: See the HEMORRHAGE category for grading the severity of bleeding events.
DIC
(disseminated intravascular
coagulation)
absent
-
-
laboratory findings
present with no
bleeding
laboratory findings and
bleeding
Also consider Platelets.
Note: Must have increased fibrin split products or D-dimer in order to grade as DIC.
Fibrinogen
WNL
≥0.75 - <1.0 x LLN
≥0.5 - <0.75 x LLN
≥0.25 - <0.5 x LLN
<0.25 x LLN
For leukemia studies or bone
marrow infiltrative/
myelophthisic process, if
specified in the protocol.
WNL
<20% decrease from
pretreatment value or
LLN
≥20 - <40% decrease
from pretreatment value
or LLN
≥40 - <70% decrease
from pretreatment value
or LLN
<50 mg
Partial thromboplastin time
(PTT)
WNL
>ULN - ≤1.5 x ULN
>1.5 - ≤2 x ULN
>2 x ULN
-
Phlebitis is graded in the CARDIOVASCULAR (GENERAL) category.
Prothrombin time (PT)
WNL
>ULN - ≤1.5 x ULN
>1.5 - ≤2 x ULN
>2 x ULN
-
Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category.
Thrombotic
microangiopathy (e.g.,
thrombotic
thrombocytopenic
purpura/TTP or hemolytic
uremic syndrome/HUS)
absent
-
-
laboratory findings
present without clinical
consequences
laboratory findings and
clinical consequences,
(e.g., CNS hemorrhage/
bleeding or thrombosis/
embolism or renal
failure) requiring
therapeutic intervention
For BMT studies, if
specified in the protocol.
-
evidence of RBC
destruction
(schistocytosis) without
clinical consequences
evidence of RBC
destruction with
elevated creatinine (≤3
x ULN)
evidence of RBC
destruction with
creatinine (>3 x ULN)
not requiring dialysis
evidence of RBC
destruction with renal
failure requiring
dialysis and/or
encephalopathy
Also consider Hemoglobin, Platelets, Creatinine.
Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments).
Coagulation - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
CONSTITUTIONAL SYMPTOMS
Fatigue
(lethargy, malaise, asthenia)
none
increased fatigue over
baseline, but not
altering normal
activities
moderate (e.g., decrease
in performance status
by 1 ECOG level or
20% Karnofsky or
Lansky) or causing
difficulty performing
some activities
severe (e.g., decrease in
performance status by
≥2 ECOG levels or 40%
Karnofsky or Lansky) or
loss of ability to
perform some activities
bedridden or disabling
Note: See Appendix III for performance status scales.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
88 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
8
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Fever (in the absence of
neutropenia, where
neutropenia is defined as
AGC <1.0 x 109/L)
none
38.0 - 39.0°C (100.4 -
102.2°F)
39.1 - 40.0°C (102.3 -
104.0°F )
>40.0°C (>104.0°F ) for
<24hrs
>40.0°C (>104.0°F ) for
>24hrs
Also consider Allergic reaction/hypersensitivity.
Note: The temperature measurements listed above are oral or tympanic.
Hot flashes/flushes are graded in the ENDOCRINE category.
Rigors, chills
none
mild, requiring
symptomatic treatment
(e.g., blanket) or non-
narcotic medication
severe and/or
prolonged, requiring
narcotic medication
not responsive to
narcotic medication
-
Sweating
(diaphoresis)
normal
mild and occasional
frequent or drenching
-
-
Weight gain
<5%
5 - <10%
10 - <20%
≥20%
-
Also consider Ascites, Edema, Pleural effusion (non-malignant).
Weight gain associated with
Veno-Occlusive Disease
(VOD) for BMT studies, if
specified in the protocol.
<2%
≥2 - <5%
≥5 - <10%
≥10% or as ascites
≥10% or fluid retention
resulting in pulmonary
failure
Also consider Ascites, Edema, Pleural effusion (non-malignant).
Weight loss
<5%
5 - <10%
10 - <20%
≥20%
-
Also consider Vomiting, Dehydration, Diarrhea.
Constitutional Symptoms -
Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
DERMATOLOGY/SKIN
Alopecia
normal
mild hair loss
pronounced hair loss
-
-
Bruising
(in absence of grade 3 or 4
thrombocytopenia)
none
localized or in
dependent area
generalized
-
-
Note: Bruising resulting from grade 3 or 4 thrombocytopenia is graded as Petechiae/purpura and Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia in the
HEMORRHAGE category, not in the DERMATOLOGY/SKIN category.
Dry skin
normal
controlled with
emollients
not controlled with
emollients
-
-
Erythema multiforme (e.g.,
Stevens-Johnson syndrome,
toxic epidermal necrolysis)
absent
-
scattered, but not
generalized eruption
severe or requiring IV
fluids (e.g., generalized
rash or painful
stomatitis)
life-threatening (e.g.,
exfoliative or ulcerating
dermatitis or requiring
enteral or parenteral
nutritional support)
Flushing
absent
present
-
-
-
Hand-foot skin reaction
none
skin changes or
dermatitis without pain
(e.g., erythema, peeling)
skin changes with pain,
not interfering with
function
skin changes with pain,
interfering with
function
-
Injection site reaction
none
pain or itching or
erythema
pain or swelling, with
inflammation or
phlebitis
ulceration or necrosis
that is severe or
prolonged, or requiring
surgery
-
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
89 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
9
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Nail changes
normal
discoloration or ridging
(koilonychia) or pitting
partial or complete loss
of nail(s) or pain in
nailbeds
-
-
Petechiae is graded in the HEMORRHAGE category.
Photosensitivity
none
painless erythema
painful erythema
erythema with
desquamation
-
Pigmentation changes (e.g.,
vitiligo)
none
localized pigmentation
changes
generalized
pigmentation changes
-
-
Pruritus
none
mild or localized,
relieved spontaneously
or by local measures
intense or widespread,
relieved spontaneously
or by systemic measures
intense or widespread
and poorly controlled
despite treatment
-
Purpura is graded in the HEMORRHAGE category.
Radiation dermatitis
none
faint erythema or dry
desquamation
moderate to brisk
erythema or a patchy
moist desquamation,
mostly confined to skin
folds and creases;
moderate edema
confluent moist
desquamation ≥1.5 cm
diameter and not
confined to skin folds;
pitting edema
skin necrosis or
ulceration of full
thickness dermis; may
include bleeding not
induced by minor
trauma or abrasion
Note: Pain associated with radiation dermatitis is graded separately in the PAIN category as Pain due to radiation.
Radiation recall reaction
(reaction following
chemotherapy in the absence
of additional radiation
therapy that occurs in a
previous radiation port)
none
faint erythema or dry
desquamation
moderate to brisk
erythema or a patchy
moist desquamation,
mostly confined to skin
folds and creases;
moderate edema
confluent moist
desquamation ≥1.5 cm
diameter and not
confined to skin folds;
pitting edema
skin necrosis or
ulceration of full
thickness dermis; may
include bleeding not
induced by minor
trauma or abrasion
Rash/desquamation
none
macular or papular
eruption or erythema
without associated
symptoms
macular or papular
eruption or erythema
with pruritus or other
associated symptoms
covering <50% of body
surface or localized
desquamation or other
lesions covering <50%
of body surface area
symptomatic
generalized
erythroderma or
macular, papular or
vesicular eruption or
desquamation covering
≥50% of body surface
area
generalized exfoliative
dermatitis or ulcerative
dermatitis
Also consider Allergic reaction/hypersensitivity.
Note:  Stevens-Johnson syndrome is graded separately as Erythema multiforme in the DERMATOLOGY/SKIN category.
Rash/dermatitis associated
with high-dose
chemotherapy or BMT
studies.
none
faint erythema or dry
desquamation
moderate to brisk
erythema or a patchy
moist desquamation,
mostly confined to skin
folds and creases;
moderate edema
confluent moist
desquamation ≥1.5 cm
diameter and not
confined to skin folds;
pitting edema
skin necrosis or ulcera-
tion of full thickness
dermis; may include
spontaneous bleeding
not induced by minor
trauma or abrasion
Rash/desquamation
associated with graft versus
host disease (GVHD) for
BMT studies, if specified in
the protocol.
None
macular or papular
eruption or erythema
covering <25% of body
surface area without
associated symptoms
macular or papular
eruption or erythema
with pruritus or other
associated symptoms
covering ≥25 - <50% of
body surface or
localized desquamation
or other lesions
covering ≥25 - <50% of
body surface area
symptomatic
generalized
erythroderma or
symptomatic macular,
papular or vesicular
eruption, with bullous
formation, or
desquamation covering
≥50% of body surface
area
generalized exfoliative
dermatitis or ulcerative
dermatitis or bullous
formation
Also consider Allergic reaction/hypersensitivity.
Note:  Stevens-Johnson syndrome is graded separately as Erythema multiforme in the DERMATOLOGY/SKIN category.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
90 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
10
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Urticaria
(hives, welts, wheals)
none
requiring no medication
requiring PO or topical
treatment or IV
medication or steroids
for <24 hours
requiring IV medication
or steroids for ≥24
hours
-
Wound-infectious
none
cellulitis
superficial infection
infection requiring IV
antibiotics
necrotizing fasciitis
Wound-non-infectious
none
incisional separation
incisional hernia
fascial disruption
without evisceration
fascial disruption with
evisceration
Dermatology/Skin - Other
(Specify, ________)
none
mild
moderate
severe
life-threatening or
disabling
ENDOCRINE
Cushingoid appearance (e.g.,
moon face, buffalo hump,
centripetal obesity,
cutaneous striae)
absent
-
present
-
-
Also consider Hyperglycemia, Hypokalemia.
Feminization of male
absent
-
-
present
-
Gynecomastia
none
mild
pronounced or painful
pronounced or painful
and requiring surgery
-
Hot flashes/flushes
none
mild or no more than 1
per day
moderate and greater
than 1 per day
-
-
Hypothyroidism
absent
asymptomatic,TSH
elevated, no therapy
given
symptomatic or thyroid
replacement treatment
given
patient hospitalized for
manifestations of
hypothyroidism
myxedema coma
Masculinization of female
absent
-
-
present
-
SIADH (syndrome of
inappropriate antidiuretic
hormone)
absent
-
-
present
-
Endocrine - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
GASTROINTESTINAL
Amylase is graded in the METABOLIC/LABORATORY category.
Anorexia
none
loss of appetite
oral intake significantly
decreased
requiring IV fluids
requiring feeding tube
or parenteral nutrition
Ascites (non-malignant)
none
asymptomatic
symptomatic, requiring
diuretics
symptomatic, requiring
therapeutic paracentesis
life-threatening
physiologic
consequences
Colitis
none
-
abdominal pain with
mucus and/or blood in
stool
abdominal pain, fever,
change in bowel habits
with ileus or peritoneal
signs, and radiographic
or biopsy
documentation
perforation or requiring
surgery or toxic
megacolon
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Melena/GI bleeding,
Rectal bleeding/hematochezia, Hypotension.
Constipation
none
requiring stool softener
or dietary modification
requiring laxatives
obstipation requiring
manual evacuation or
enema
obstruction or toxic
megacolon
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
91 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
11
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Dehydration
none
dry mucous membranes
and/or diminished skin
turgor
requiring IV fluid
replacement (brief)
requiring IV fluid
replacement (sustained)
physiologic
consequences requiring
intensive care;
hemodynamic collapse
Also consider Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis), Hypotension.
Diarrhea
patients without colostomy:
none
increase of <4
stools/day over pre-
treatment
increase of 4-6
stools/day, or nocturnal
stools
increase of ≥7
stools/day or
incontinence; or need
for parenteral support
for dehydration
physiologic
consequences requiring
intensive care; or
hemodynamic collapse
patients with a colostomy:
none
mild increase in loose,
watery colostomy
output compared with
pretreatment
moderate increase in
loose, watery colostomy
output compared with
pretreatment, but not
interfering with normal
activity
severe increase in loose,
watery colostomy
output compared with
pretreatment, interfering
with normal activity
physiologic
consequences, requiring
intensive care; or
hemodynamic collapse
Diarrhea associated with
graft versus host disease
(GVHD) for BMT studies, if
specified in the protocol.
None
>500 - ≤1000mL of
diarrhea/day
>1000 - ≤1500mL of
diarrhea/day
>1500mL of
diarrhea/day
severe abdominal pain
with or without ileus
For pediatric BMT studies, if
specified in the protocol.
>5 - ≤10 mL/kg of
diarrhea/day
>10 - ≤15 mL/kg of
diarrhea/day
>15 mL/kg of
diarrhea/day
-
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Pain, Dehydration,
Hypotension.
Duodenal ulcer (requires
radiographic or endoscopic
documentation)
none
-
requiring medical
management or non-
surgical treatment
uncontrolled by
outpatient medical
management; requiring
hospitalization
perforation or bleeding,
requiring emergency
surgery
Dyspepsia/heartburn
none
mild
moderate
severe
-
Dysphagia, esophagitis,
odynophagia (painful
swallowing)
none
mild dysphagia, but can
eat regular diet
dysphagia, requiring
predominantly pureed,
soft, or liquid diet
dysphagia, requiring IV
hydration
complete obstruction
(cannot swallow saliva)
requiring enteral or
parenteral nutritional
support, or perforation
Note: If the adverse event is radiation-related, grade either under Dysphagia-esophageal related to radiation or Dysphagia-pharyngeal related to radiation.
Dysphagia-esophageal
related to radiation
none
mild dysphagia, but can
eat regular diet
dysphagia, requiring
predominantly pureed,
soft, or liquid diet
Dysphagia, requiring
feeding tube, IV
hydration or
hyperalimentation
complete obstruction
(cannot swallow saliva);
ulceration with bleeding
not induced by minor
trauma or abrasion or
perforation
Also consider Pain due to radiation, Mucositis due to radiation.
Note: Fistula is graded separately as Fistula-esophageal.
Dysphagia-pharyngeal
related to radiation
none
mild dysphagia, but can
eat regular diet
dysphagia, requiring
predominantly pureed,
soft, or liquid diet
dysphagia, requiring
feeding tube, IV
hydration or
hyperalimentation
complete obstruction
(cannot swallow saliva);
ulceration with bleeding
not induced by minor
trauma or abrasion or
perforation
Also consider Pain due to radiation, Mucositis due to radiation.
Note: Fistula is graded separately as Fistula-pharyngeal.
Fistula-esophageal
none
-
-
present
requiring surgery
Fistula-intestinal
none
-
-
present
requiring surgery
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
92 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
12
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Fistula-pharyngeal
none
-
-
present
requiring surgery
Fistula-rectal/anal
none
-
-
present
requiring surgery
Flatulence
none
mild
moderate
-
-
Gastric ulcer
(requires radiographic or
endoscopic documentation)
none
-
requiring medical
management or non-
surgical treatment
bleeding without
perforation, uncon-
trolled by outpatient
medical management;
requiring hospitalization
or surgery
perforation or bleeding,
requiring emergency
surgery
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia.
Gastritis
none
-
requiring medical
management or non-
surgical treatment
uncontrolled by out-
patient medical
management; requiring
hospitalization or
surgery
life-threatening
bleeding, requiring
emergency surgery
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia.
Hematemesis is graded in the HEMORRHAGE category.
Hematochezia is graded in the HEMORRHAGE category as Rectal bleeding/hematochezia.
Ileus (or neuroconstipation)
none
-
intermittent, not
requiring intervention
requiring non-surgical
intervention
requiring surgery
Mouth dryness
normal
mild
moderate
-
-
Mucositis
Notes: Mucositis not due to radiation is graded in the GASTROINTESTINAL category for specific sites: Colitis, Esophagitis, Gastritis, Stomatitis/pharyngitis
(oral/pharyngeal mucositis), and Typhlitis; or the RENAL/GENITOURINARY category for Vaginitis.
Radiation-related mucositis is graded as Mucositis due to radiation.
Mucositis due to radiation
none
erythema of the mucosa
patchy pseudomembra-
nous reaction (patches
generally ≤1.5 cm in
diameter and non-
contiguous)
confluent pseudomem-
branous reaction
(contiguous patches
generally >1.5 cm in
diameter)
necrosis or deep
ulceration; may include
bleeding not induced by
minor trauma or
abrasion
Also consider Pain due to radiation.
Notes: Grade radiation mucositis of the larynx here.
Dysphagia related to radiation is also graded as either Dysphagia-esophageal related to radiation or Dysphagia-pharyngeal related to radiation, depending on
the site of treatment.
Nausea
none
able to eat
oral intake significantly
decreased
no significant intake,
requiring IV fluids
-
Pancreatitis
none
-
-
abdominal pain with
pancreatic enzyme
elevation
complicated by shock
(acute circulatory
failure)
Also consider Hypotension.
Note: Amylase is graded in the METABOLIC/LABORATORY category.
Pharyngitis is graded in the GASTROINTESTINAL category as Stomatitis/pharyngitis (oral/pharyngeal mucositis).
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
93 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
13
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Proctitis
none
increased stool
frequency, occasional
blood-streaked stools or
rectal discomfort
(including hemorrhoids)
not requiring
medication
increased stool
frequency, bleeding,
mucus discharge, or
rectal discomfort
requiring medication;
anal fissure
increased stool fre-
quency/diarrhea requir-
ing parenteral support;
rectal bleeding requir-
ing transfusion; or per-
sistent mucus discharge,
necessitating pads
perforation, bleeding or
necrosis or other life-
threatening
complication requiring
surgical intervention
(e.g., colostomy)
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Pain due to radiation.
Notes: Fistula is graded separately as Fistula-rectal/anal.
Proctitis occurring more than 90 days after the start of radiation therapy is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme. (See
Appendix IV)
Salivary gland changes
none
slightly thickened
saliva; may have
slightly altered taste
(e.g., metallic);
additional fluids may be
required
thick, ropy, sticky
saliva; markedly altered
taste; alteration in diet
required
-
acute salivary gland
necrosis
Sense of smell
normal
slightly altered
markedly altered
-
-
Stomatitis/pharyngitis
(oral/pharyngeal mucositis)
none
painless ulcers,
erythema, or mild
soreness in the absence
of lesions
painful erythema,
edema, or ulcers, but
can eat or swallow
painful erythema,
edema, or ulcers
requiring IV hydration
severe ulceration or
requires parenteral or
enteral nutritional
support or prophylactic
intubation
For BMT studies, if
specified in the protocol.
none
painless ulcers,
erythema, or mild
soreness in the absence
of lesions
painful erythema,
edema or ulcers but can
swallow
painful erythema,
edema, or ulcers
preventing swallowing
or requiring hydration
or parenteral (or enteral)
nutritional support
severe ulceration
requiring prophylactic
intubation or resulting
in documented
aspiration pneumonia
Note: Radiation-related mucositis is graded as Mucositis due to radiation.
Taste disturbance
(dysgeusia)
normal
slightly altered
markedly altered
-
-
Typhlitis
(inflammation of the cecum)
none
-
-
abdominal pain,
diarrhea, fever, and
radiographic or biopsy
documentation
perforation, bleeding or
necrosis or other life-
threatening
complication requiring
surgical intervention
(e.g., colostomy)
Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hypotension, Febrile
neutropenia.
Vomiting
none
1 episode in 24 hours
over pretreatment
2-5 episodes in 24 hours
over pretreatment
≥6 episodes in 24 hours
over pretreatment; or
need for IV fluids
requiring parenteral
nutrition; or physiologic
consequences requiring
intensive care;
hemodynamic collapse
Also consider Dehydration.
Weight gain is graded in the CONSTITUTIONAL SYMPTOMS category.
Weight loss is graded in the CONSTITUTIONAL SYMPTOMS category.
Gastrointestinal - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
94 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
14
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
HEMORRHAGE
Notes: Transfusion in this section refers to pRBC infusion.
For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia. Also consider Platelets,
Transfusion: pRBCs, and Transfusion: platelets in addition to grading severity by grading  the site or type of bleeding.
If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: CNS Hemorrhage/bleeding, Hematuria,
Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal
bleeding/hematochezia, Vaginal bleeding.
If the platelet count is ≥50,000 and the site or type of bleeding is listed, grade the specific site. If the site or type is not listed and the platelet count is
≥50,000, grade Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia and specify the site or type in the OTHER category.
Hemorrhage/bleeding with
grade 3 or 4
thrombocytopenia
none
mild without
transfusion
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, site or type of bleeding.  If the site is not listed, grade as Hemorrhage-Other
(Specify site, ___________).
Note: This adverse event must be graded for any bleeding with grade 3 or 4 thrombocytopenia.
Hemorrhage/bleeding
without grade 3 or 4
thrombocytopenia
none
mild without
transfusion
requiring transfusion
catastrophic bleeding
requiring major non-
elective intervention
Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, Hemorrhage - Other (Specify site, ___________).
Note: Bleeding in the absence of grade 3 or 4 thrombocytopenia is graded here only if the specific site or type of bleeding is not listed elsewhere in the
HEMORRHAGE category. Also grade as Other in the HEMORRHAGE category.
CNS hemorrhage/bleeding
none
-
-
bleeding noted on CT or
other scan with no
clinical consequences
hemorrhagic stroke or
hemorrhagic vascular
event (CVA) with
neurologic signs and
symptoms
Epistaxis
none
mild without
transfusion
-
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Hematemesis
none
mild without
transfusion
-
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Hematuria
(in the absence of vaginal
bleeding)
none
microscopic only
intermittent gross
bleeding, no clots
persistent gross
bleeding or clots; may
require catheterization
or instrumentation, or
transfusion
open surgery or necrosis
or deep bladder
ulceration
Hemoptysis
none
mild without
transfusion
-
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Hemorrhage/bleeding
associated with surgery
none
mild without
transfusion
-
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Note: Expected blood loss at the time of surgery is not graded as an adverse event.
Melena/GI bleeding
none
mild without
transfusion
-
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
95 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
15
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Petechiae/purpura
(hemorrhage/bleeding into
skin or mucosa)
none
rare petechiae of skin
petechiae or purpura in
dependent areas of skin
generalized petechiae or
purpura of skin or
petechiae of any
mucosal site
-
Rectal bleeding/
hematochezia
none
mild without
transfusion or
medication
persistent, requiring
medication (e.g., steroid
suppositories) and/or
break from radiation
treatment
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Vaginal bleeding
none
spotting, requiring <2
pads per day
requiring ≥2 pads per
day, but not requiring
transfusion
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
Hemorrhage - Other
(Specify site, ___________)
none
mild without
transfusion
-
requiring transfusion
catastrophic bleeding,
requiring major non-
elective intervention
HEPATIC
Alkaline phosphatase
WNL
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Bilirubin
WNL
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
Bilirubin associated with
graft versus host disease
(GVHD) for BMT studies, if
specified in the protocol.
normal
≥2 - <3 mg/100 mL
≥3 - <6 mg/100 mL
≥6 - <15 mg/100 mL
≥15 mg/100 mL
GGT
(γ - Glutamyl transpeptidase)
WNL
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Hepatic enlargement
absent
-
-
present
-
Note: Grade Hepatic enlargement only for treatment related adverse event including Veno-Occlusive Disease.
Hypoalbuminemia
WNL
<LLN - 3 g/dL
≥2 - <3 g/dL
<2 g/dL
-
Liver dysfunction/ failure
(clinical)
normal
-
-
asterixis
encephalopathy or coma
Portal vein flow
normal
-
decreased portal vein
flow
reversal/retrograde
portal vein flow
-
SGOT (AST)
(serum glutamic oxaloacetic
transaminase)
WNL
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
SGPT (ALT)
(serum glutamic pyruvic
transaminase)
WNL
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Hepatic - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
INFECTION/FEBRILE NEUTROPENIA
Catheter-related infection
none
mild, no active
treatment
moderate, localized
infection, requiring
local or oral treatment
severe, systemic
infection, requiring IV
antibiotic or antifungal
treatment or
hospitalization
life-threatening sepsis
(e.g., septic shock)
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
96 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
16
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Febrile neutropenia
(fever of unknown origin
without clinically or
microbiologically
documented infection)
none
-
-
Present
Life-threatening sepsis
(e.g., septic shock)
(ANC <1.0 x 109/L, fever
≥38.5°C)
Also consider Neutrophils.
Note: Hypothermia instead of fever may be associated with neutropenia and is graded here.
Infection (documented
clinically or
microbiologically) with
grade 3 or 4 neutropenia
none
-
-
present
life-threatening sepsis
(e.g., septic shock)
(ANC <1.0 x 109/L)
Also consider Neutrophils.
Notes: Hypothermia instead of fever may be associated with neutropenia and is graded here.
In the absence of documented infection grade 3 or 4 neutropenia with fever is graded as Febrile neutropenia.
Infection with unknown
ANC
none
-
-
present
life-threatening sepsis
(e.g., septic shock)
Note: This adverse event criterion is used in the rare case when ANC is unknown.
Infection without
neutropenia
none
mild, no active
treatment
moderate, localized
infection, requiring
local or oral treatment
severe, systemic
infection, requiring IV
antibiotic or antifungal
treatment, or
hospitalization
life-threatening sepsis
(e.g., septic shock)
Also consider Neutrophils.
Wound-infectious is graded in the DERMATOLOGY/SKIN category.
Infection/Febrile
Neutropenia - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
LYMPHATICS
Lymphatics
normal
mild lymphedema
moderate lymphedema
requiring compression;
lymphocyst
severe lymphedema
limiting function;
lymphocyst requiring
surgery
severe lymphedema
limiting function with
ulceration
Lymphatics - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
METABOLIC/LABORATORY
Acidosis
(metabolic or respiratory)
normal
pH <normal, but ≥7.3
-
pH <7.3
pH <7.3 with life-
threatening physiologic
consequences
Alkalosis
(metabolic or respiratory)
normal
pH >normal, but ≤7.5
-
pH >7.5
pH >7.5 with life-
threatening physiologic
consequences
Amylase
WNL
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
Bicarbonate
WNL
<LLN - 16 mEq/dL
11 - 15 mEq/dL
8 - 10 mEq/dL
<8 mEq/dL
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
97 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
17
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
CPK
(creatine phosphokinase)
WNL
>ULN - 2.5 x ULN
>2.5 - 5 x ULN
>5 - 10 x ULN
>10 x ULN
Hypercalcemia
WNL
>ULN - 11.5 mg/dL
>ULN - 2.9 mmol/L
>11.5 - 12.5 mg/dL
>2.9 - 3.1 mmol/L
>12.5 - 13.5 mg/dL
>3.1 - 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Hypercholesterolemia
WNL
>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
Hyperglycemia
WNL
>ULN - 160 mg/dL
>ULN - 8.9 mmol/L
>160 - 250 mg/dL
>8.9 - 13.9 mmol/L
>250 - 500 mg/dL
>13.9 - 27.8 mmol/L
>500 mg/dL
>27.8 mmol/L or
acidosis
Hyperkalemia
WNL
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L
>7.0 mmol/L
Hypermagnesemia
WNL
>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
Hypernatremia
WNL
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L
>160 mmol/L
Hypertriglyceridemia
WNL
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 10 x ULN
>10 x ULN
Hyperuricemia
WNL
>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
Also consider Tumor lysis syndrome, Renal failure, Creatinine, Hyperkalemia.
Hypocalcemia
WNL
<LLN - 8.0 mg/dL
<LLN - 2.0 mmol/L
7.0 - <8.0 mg/dL
1.75 - <2.0 mmol/L
6.0 - <7.0 mg/dL
1.5 - <1.75 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Hypoglycemia
WNL
<LLN - 55 mg/dL
<LLN - 3.0 mmol/L
40 - <55 mg/dL
2.2 - <3.0 mmol/L
30 - <40 mg/dL
1.7 - <2.2 mmol/L
<30 mg/dL
<1.7 mmol/L
Hypokalemia
WNL
<LLN - 3.0 mmol/L
-
2.5 - <3.0 mmol/L
<2.5 mmol/L
Hypomagnesemia
WNL
<LLN - 1.2 mg/dL
<LLN - 0.5 mmol/L
0.9 - <1.2 mg/dL
0.4 - <0.5 mmol/L
0.7 - <0.9 mg/dL
0.3 - <0.4 mmol/L
<0.7 mg/dL
<0.3 mmol/L
Hyponatremia
WNL
<LLN - 130 mmol/L
-
120 - <130 mmol/L
<120 mmol/L
Hypophosphatemia
WNL
<LLN -2.5 mg/dL
<LLN - 0.8 mmol/L
≥2.0 - <2.5 mg/dL
≥0.6 - <0.8 mmol/L
≥1.0 - <2.0 mg/dL
≥0.3 - <0.6 mmol/L
<1.0 mg/dL
<0.3 mmol/L
Hypothyroidism is graded in the ENDOCRINE category.
Lipase
WNL
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
Metabolic/Laboratory -
Other (Specify,
__________)
none
mild
moderate
severe
life-threatening or
disabling
MUSCULOSKELETAL
Arthralgia is graded in the PAIN category.
Arthritis
none
mild pain with
inflammation, erythema
or joint swelling but not
interfering with
function
moderate pain with
inflammation,
erythema, or joint
swelling interfering
with function, but not
interfering with
activities of daily living
severe pain with
inflammation,
erythema, or joint
swelling and interfering
with activities of daily
living
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
98 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
18
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Muscle weakness
(not due to neuropathy)
normal
asymptomatic with
weakness on physical
exam
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
bedridden or disabling
Myalgia [tenderness or pain in muscles] is graded in the PAIN category.
Myositis
(inflammation/damage of
muscle)
none
mild pain, not
interfering with
function
pain interfering with
function, but not
interfering with
activities of daily living
pain interfering with
function and interfering
with activities of daily
living
bedridden or disabling
Also consider CPK.
Note: Myositis implies muscle damage (i.e., elevated CPK).
Osteonecrosis
(avascular necrosis)
none
asymptomatic and
detected by imaging
only
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
symptomatic; or
disabling
Musculoskeletal - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
NEUROLOGY
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category.
Arachnoiditis/meningismus/
radiculitis
absent
mild pain not interfering
with function
moderate pain
interfering with
function, but not
interfering with
activities of daily living
severe pain interfering
with activities of daily
living
unable to function or
perform activities of
daily living; bedridden;
paraplegia
Also consider Headache, Vomiting, Fever.
Ataxia (incoordination)
normal
asymptomatic but
abnormal on physical
exam, and not
interfering with
function
mild symptoms
interfering with
function, but not
interfering with
activities of daily living
moderate symptoms
interfering with
activities of daily living
bedridden or disabling
CNS cerebrovascular
ischemia
none
-
-
transient ischemic event
or attack (TIA)
permanent event (e.g.,
cerebral vascular
accident)
CNS hemorrhage/bleeding is graded in the HEMORRHAGE category.
Cognitive disturbance/
learning problems
none
cognitive disability; not
interfering with
work/school
performance;
preservation of
intelligence
cognitive disability;
interfering with
work/school
performance; decline of
1 SD (Standard
Deviation) or loss of
developmental
milestones
cognitive disability;
resulting in significant
impairment of
work/school
performance; cognitive
decline >2 SD
inability to work/frank
mental retardation
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
99 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
19
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Confusion
normal
confusion or
disorientation or
attention deficit of brief
duration; resolves
spontaneously with no
sequelae
confusion or
disorientation or
attention deficit
interfering with
function, but not
interfering with
activities of daily living
confusion or delirium
interfering with
activities of daily living
harmful to others or
self; requiring
hospitalization
Cranial neuropathy is graded in the NEUROLOGY category as Neuropathy-cranial.
Delusions
normal
-
-
present
toxic psychosis
Depressed level of
consciousness
normal
somnolence or sedation
not interfering with
function
somnolence or sedation
interfering with
function, but not
interfering with
activities of daily living
obtundation or stupor;
difficult to arouse;
interfering with
activities of daily living
coma
Note: Syncope (fainting) is graded in the NEUROLOGY category.
Dizziness/lightheadedness
none
not interfering with
function
interfering with
function, but not
interfering with
activities of daily living
interfering with
activities of daily living
bedridden or disabling
Dysphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category.
Extrapyramidal/
involuntary movement/
restlessness
none
mild involuntary
movements not
interfering with
function
moderate involuntary
movements interfering
with function, but not
interfering with
activities of daily living
severe involuntary
movements or torticollis
interfering with
activities of daily living
bedridden or disabling
Hallucinations
normal
-
-
present
toxic psychosis
Headache is graded in the PAIN category.
Insomnia
normal
occasional difficulty
sleeping not interfering
with function
difficulty sleeping
interfering with
function, but not
interfering with
activities of daily living
frequent difficulty
sleeping, interfering
with activities of daily
living
-
Note: This adverse event is graded when insomnia is related to treatment. If pain or other symptoms interfere with sleep do NOT grade as insomnia.
Irritability
(children <3 years of age)
normal
mild; easily consolable
moderate; requiring
increased attention
severe; inconsolable
-
Leukoencephalopathy
associated radiological
findings
none
mild increase in SAS
(subarachnoid space)
and/or mild
ventriculomegaly;
and/or small (+/-
multiple) focal T2
hyperintensities,
involving
periventricular white
matter or <1/3 of
susceptible areas of
cerebrum
moderate increase in
SAS; and/or moderate
ventriculomegaly;
and/or focal T2
hyperintensities
extending into centrum
ovale; or involving 1/3
to 2/3 of susceptible
areas of cerebrum
severe increase in SAS;
severe
ventriculomegaly; near
total white matter T2
hyperintensities or
diffuse low attenuation
(CT); focal white matter
necrosis (cystic)
severe increase in SAS;
severe
ventriculomegaly;
diffuse low attenuation
with calcification (CT);
diffuse white matter
necrosis (MRI)
Memory loss
normal
memory loss not
interfering with
function
memory loss interfering
with function, but not
interfering with
activities of daily living
memory loss interfering
with activities of daily
living
amnesia
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
100 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
20
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Mood alteration-anxiety,
agitation
normal
mild mood alteration
not interfering with
function
moderate mood
alteration interfering
with function, but not
interfering with
activities of daily living
severe mood alteration
interfering with
activities of daily living
suicidal ideation or
danger to self
Mood alteration-depression
normal
mild mood alteration
not interfering with
function
moderate mood
alteration interfering
with function, but not
interfering with
activities of daily living
severe mood alteration
interfering with
activities of daily living
suicidal ideation or
danger to self
Mood alteration-euphoria
normal
mild mood alteration
not interfering with
function
moderate mood
alteration interfering
with function, but not
interfering with
activities of daily living
severe mood alteration
interfering with
activities of daily living
danger to self
Neuropathic pain is graded in the PAIN category.
Neuropathy-cranial
absent
-
present, not interfering
with activities of daily
living
present, interfering with
activities of daily living
life-threatening,
disabling
Neuropathy-motor
normal
subjective weakness but
no objective findings
mild objective
weakness interfering
with function, but not
interfering with
activities of daily living
objective weakness
interfering with
activities of daily living
paralysis
Neuropathy-sensory
normal
loss of deep tendon
reflexes or paresthesia
(including tingling) but
not interfering with
function
objective sensory loss
or paresthesia
(including tingling),
interfering with
function, but not
interfering with
activities of daily living
sensory loss or
paresthesia interfering
with activities of daily
living
permanent sensory loss
that interferes with
function
Nystagmus
absent
present
-
-
-
Also consider Vision-double vision.
Personality/behavioral
normal
change, but not
disruptive to patient or
family
disruptive to patient or
family
disruptive to patient and
family; requiring mental
health intervention
harmful to others or
self; requiring
hospitalization
Pyramidal tract dysfunction
(e.g., ↑ tone, hyperreflexia,
positive Babinski, ↓ fine
motor coordination)
normal
asymptomatic with
abnormality on physical
examination
symptomatic or
interfering with
function but not
interfering with
activities of daily living
interfering with
activities of daily living
bedridden or disabling;
paralysis
Seizure(s)
none
-
seizure(s) self-limited
and consciousness is
preserved
seizure(s) in which
consciousness is altered
seizures of any type
which are prolonged,
repetitive, or difficult to
control (e.g., status
epilepticus, intractable
epilepsy)
Speech impairment
(e.g., dysphasia or aphasia)
normal
-
awareness of receptive
or expressive dysphasia,
not impairing ability to
communicate
receptive or expressive
dysphasia, impairing
ability to communicate
inability to
communicate
Syncope (fainting)
absent
-
-
present
-
Also consider CARDIOVASCULAR (ARRHYTHMIA), Vasovagal episode, CNS cerebrovascular ischemia.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
101 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
21
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Tremor
none
mild and brief or
intermittent but not
interfering with
function
moderate tremor
interfering with
function, but not
interfering with
activities of daily living
severe tremor
interfering with
activities of daily living
-
Vertigo
none
not interfering with
function
interfering with
function, but not
interfering with
activities of daily living
interfering with
activities of daily living
bedridden or disabling
Neurology - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
OCULAR/VISUAL
Cataract
none
asymptomatic
symptomatic, partial
visual loss
symptomatic, visual
loss requiring treatment
or interfering with
function
-
Conjunctivitis
none
abnormal
ophthalmologic
changes, but
asymptomatic or
symptomatic without
visual impairment (i.e.,
pain and irritation)
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
-
Dry eye
normal
mild, not requiring
treatment
moderate or requiring
artificial tears
-
-
Glaucoma
none
increase in intraocular
pressure but no visual
loss
increase in intraocular
pressure with retinal
changes
visual impairment
unilateral or bilateral
loss of vision
(blindness)
Keratitis
(corneal inflammation/
corneal ulceration)
none
abnormal
ophthalmologic changes
but asymptomatic or
symptomatic without
visual impairment (i.e.,
pain and irritation)
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
unilateral or bilateral
loss of vision
(blindness)
Tearing (watery eyes)
none
mild: not interfering
with function
moderate: interfering
with function, but not
interfering with
activities of daily living
interfering with
activities of daily living
-
Vision-blurred vision
normal
-
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
-
Vision-double vision
(diplopia)
normal
-
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
-
Vision-flashing
lights/floaters
normal
mild, not interfering
with function
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
-
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
102 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
22
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Vision-night blindness
(nyctalopia)
normal
abnormal electro-
retinography but
asymptomatic
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
-
Vision-photophobia
normal
-
symptomatic and
interfering with
function, but not
interfering with
activities of daily living
symptomatic and
interfering with
activities of daily living
-
Ocular/Visual - Other
(Specify, __________)
normal
mild
moderate
severe
unilateral or bilateral
loss of vision
(blindness)
PAIN
Abdominal pain or cramping
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Arthralgia
(joint pain)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Arthritis (joint pain with clinical signs of inflammation) is graded in the MUSCULOSKELETAL category.
Bone pain
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Chest pain
(non-cardiac and non-
pleuritic)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Dysmenorrhea
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Dyspareunia
none
mild pain not interfering
with function
moderate pain
interfering with sexual
activity
severe pain preventing
sexual activity
-
Dysuria is graded in the RENAL/GENITOURINARY category.
Earache (otalgia)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Headache
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
103 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
23
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Hepatic pain
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Myalgia
(muscle pain)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Neuropathic pain
(e.g., jaw pain, neurologic
pain, phantom limb pain,
post-infectious neuralgia, or
painful neuropathies)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Pain due to radiation
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Pelvic pain
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Pleuritic pain
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Rectal or perirectal pain
(proctalgia)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Tumor pain
(onset or exacerbation of
tumor pain due to treatment)
none
mild pain not interfering
with function
moderate pain: pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain: pain or
analgesics severely
interfering with
activities of daily living
disabling
Tumor flare is graded in the SYNDROME category.
Pain - Other
(Specify, __________)
none
mild
moderate
severe
disabling
PULMONARY
Adult Respiratory Distress
Syndrome (ARDS)
absent
-
-
-
present
Apnea
none
-
-
present
requiring intubation
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
104 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
24
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Carbon monoxide diffusion
capacity (DLCO)
≥90% of
pretreatment or
normal value
≥75 - <90% of
pretreatment or normal
value
≥50 - <75% of
pretreatment or normal
value
≥25 - <50% of
pretreatment or normal
value
<25% of pretreatment
or normal value
Cough
absent
mild, relieved by non-
prescription medication
requiring narcotic
antitussive
severe cough or
coughing spasms,
poorly controlled or
unresponsive to
treatment
-
Dyspnea
(shortness of breath)
normal
-
dyspnea on exertion
dyspnea at normal level
of activity
dyspnea at rest or
requiring ventilator
support
FEV1
≥90% of
pretreatment or
normal value
≥75 - <90% of
pretreatment or normal
value
≥50 - <75% of
pretreatment or normal
value
≥25 - <50% of
pretreatment or normal
value
<25% of pretreatment
or normal value
Hiccoughs (hiccups,
singultus)
none
mild, not requiring
treatment
moderate, requiring
treatment
severe, prolonged, and
refractory to treatment
-
Hypoxia
normal
-
decreased O2 saturation
with exercise
decreased O2 saturation
at rest, requiring
supplemental oxygen
decreased O2 saturation,
requiring pressure
support (CPAP) or
assisted ventilation
Pleural effusion
(non-malignant)
none
asymptomatic and not
requiring treatment
symptomatic, requiring
diuretics
symptomatic, requiring
O2 or therapeutic
thoracentesis
life-threatening (e.g.,
requiring intubation)
Pleuritic pain is graded in the PAIN category.
Pneumonitis/pulmonary
infiltrates
none
radiographic changes
but asymptomatic or
symptoms not requiring
steroids
radiographic changes
and requiring steroids or
diuretics
radiographic changes
and requiring oxygen
radiographic changes
and requiring assisted
ventilation
Pneumothorax
none
no intervention required
chest tube required
sclerosis or surgery
required
life-threatening
Pulmonary embolism is graded as Thrombosis/embolism in the CARDIOVASCULAR (GENERAL) category.
Pulmonary fibrosis
none
radiographic changes,
but asymptomatic or
symptoms not requiring
steroids
requiring steroids or
diuretics
requiring oxygen
requiring assisted
ventilation
Note: Radiation-related pulmonary fibrosis is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme-Lung. (See Appendix IV)
Voice changes/stridor/larynx
(e.g., hoarseness, loss of
voice, laryngitis)
normal
mild or intermittent
hoarseness
persistent hoarseness,
but able to vocalize;
may have mild to
moderate edema
whispered speech, not
able to vocalize; may
have marked edema
marked dyspnea/stridor
requiring tracheostomy
or intubation
Notes: Cough from radiation is graded as cough in the PULMONARY category.
Radiation-related hemoptysis from larynx/pharynx is graded as Grade 4  Mucositis due to radiation in the GASTROINTESTINAL category.  Radiation-
related hemoptysis from the thoracic cavity is graded as Grade 4  Hemoptysis in the HEMORRHAGE category.
Pulmonary - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
105 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
25
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
RENAL/GENITOURINARY
Bladder spasms
absent
mild symptoms, not
requiring intervention
symptoms requiring
antispasmodic
severe symptoms
requiring narcotic
-
Creatinine
WNL
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 6.0 x ULN
>6.0 x ULN
Note: Adjust to age-appropriate levels for pediatric patients.
Dysuria
(painful urination)
none
mild symptoms
requiring no
intervention
symptoms relieved with
therapy
symptoms not relieved
despite therapy
-
Fistula or GU fistula
(e.g., vaginal, vesicovaginal)
none
-
-
requiring intervention
requiring surgery
Hemoglobinuria
-
present
-
-
-
Hematuria (in the absence of vaginal bleeding) is graded in the HEMORRHAGE category.
Incontinence
none
with coughing,
sneezing, etc.
spontaneous, some
control
no control (in the
absence of fistula)
-
Operative injury to bladder
and/or ureter
none
-
injury of bladder with
primary repair
sepsis, fistula, or
obstruction requiring
secondary surgery; loss
of one kidney; injury
requiring anastomosis
or re-implantation
septic obstruction of
both kidneys or
vesicovaginal fistula
requiring diversion
Proteinuria
normal or <0.15
g/24 hours
1+ or 0.15 - 1.0 g/24
hours
2+ to 3+ or 1.0 - 3.5
g/24 hours
4+ or >3.5 g/24 hours
nephrotic syndrome
Note: If there is an inconsistency between absolute value and dip stick reading, use the absolute value for grading.
Renal failure
none
-
-
requiring dialysis, but
reversible
requiring dialysis and
irreversible
Ureteral obstruction
none
unilateral, not requiring
surgery
-
bilateral, not requiring
surgery
stent, nephrostomy
tube, or surgery
Urinary electrolyte wasting
(e.g., Fanconi’s syndrome,
renal tubular acidosis)
none
asymptomatic, not
requiring treatment
mild, reversible and
manageable with oral
replacement
reversible but requiring
IV replacement
irreversible, requiring
continued replacement
Also consider Acidosis, Bicarbonate, Hypocalcemia, Hypophosphatemia.
Urinary frequency/urgency
normal
increase in frequency or
nocturia up to 2 x
normal
increase >2 x normal
but <hourly
hourly or more with
urgency, or requiring
catheter
-
Urinary retention
normal
hesitancy or dribbling,
but no significant
residual urine; retention
occurring during the
immediate
postoperative period
hesitancy requiring
medication or
occasional in/out
catheterization (<4 x per
week), or operative
bladder atony requiring
indwelling catheter
beyond immediate
postoperative period but
for <6 weeks
requiring frequent
in/out catheterization
(≥4 x per week) or
urological intervention
(e.g., TURP, suprapubic
tube, urethrotomy)
bladder rupture
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
106 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
26
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Urine color change
(not related to other dietary
or physiologic cause e.g.,
bilirubin, concentrated urine,
hematuria)
normal
asymptomatic, change
in urine color
-
-
-
Vaginal bleeding is graded in the HEMORRHAGE category.
Vaginitis
(not due to infection)
none
mild, not requiring
treatment
moderate, relieved with
treatment
severe, not relieved
with treatment, or
ulceration not requiring
surgery
ulceration requiring
surgery
Renal/Genitourinary - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
SECONDARY MALIGNANCY
Secondary Malignancy -
Other
(Specify type, __________)
excludes metastasis from
initial primary
none
-
-
-
present
SEXUAL/REPRODUCTIVE FUNCTION
Dyspareunia is graded in the PAIN category.
Dysmenorrhea is graded in the PAIN category.
Erectile impotence
normal
mild (erections
impaired but
satisfactory)
moderate (erections
impaired, unsatisfactory
for intercourse)
no erections
-
Female sterility
normal
-
-
sterile
-
Feminization of male is graded in the ENDOCRINE category.
Irregular menses
(change from baseline)
normal
occasionally irregular or
lengthened interval, but
continuing menstrual
cycles
very irregular, but
continuing menstrual
cycles
persistent amenorrhea
-
Libido
normal
decrease in interest
severe loss of interest
-
-
Male infertility
-
-
oligospermia
(low sperm count)
azoospermia
(no sperm)
-
Masculinization of female is graded in the ENDOCRINE category.
Vaginal dryness
normal
mild
requiring treatment
and/or interfering with
sexual function,
dyspareunia
-
-
Sexual/Reproductive
Function - Other
(Specify, __________)
none
mild
moderate
severe
disabling
SYNDROMES (not included in previous categories)
Acute vascular leak syndrome is graded in the CARDIOVASCULAR (GENERAL) category.
ARDS (Adult Respiratory Distress Syndrome) is graded in the PULMONARY category.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
107 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
27
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Grade
Adverse Event
0
1
2
3
4
Autoimmune reactions are graded in the ALLERGY/IMMUNOLOGY category.
DIC (disseminated intravascular coagulation) is graded in the COAGULATION category.
Fanconi’s syndrome is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category.
Renal tubular acidosis is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category.
Stevens-Johnson syndrome (erythema multiforme) is graded in the DERMATOLOGY/SKIN category.
SIADH (syndrome of inappropriate antidiuretic hormone) is graded in the ENDOCRINE category.
Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) is graded in the COAGULATION category.
Tumor flare
none
mild pain not interfering
with function
moderate pain; pain or
analgesics interfering
with function, but not
interfering with
activities of daily living
severe pain; pain or
analgesics interfering
with function and
interfering with
activities of daily living
Disabling
Also consider Hypercalcemia.
Note: Tumor flare is characterized by a constellation of symptoms and signs in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional
hormones). The symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.
Tumor lysis syndrome
absent
-
-
present
-
Also consider Hyperkalemia, Creatinine.
Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) is graded in the RENAL/GENITOURINARY category.
Syndromes - Other
(Specify, __________)
none
mild
moderate
severe
life-threatening or
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
108 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
28
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix I
Adverse Event Module
To be implemented at the request of the study sponsor or principal investigator in the protocol or by protocol
amendment when more detailed information is considered pertinent.
Adverse Event:
Date of Treatment:
Course Number:
Date of onset:
Grade at onset:
Date of first change in grade:
Grade:
Date of next change in grade:
Grade:
Date of next change in grade:
Grade:
Date of next change in grade:
Grade:
Date of next change in grade:
Grade:
Date of next change in grade:
Grade:
Did adverse event resolve?
Yes______
No______
If so, date of resolution of adverse event:
Date of last observation (if prior to
recovery):
Reason(s) observations stopped (if prior
to recovery):
Was patient retreated?
Yes______
No______
If yes, was treatment delayed for
recovery?
Yes______
No______
Date of next treatment?
Dose reduced for next treatment?
Yes______
No______
Additional Comments:
________________________________________________________________________________________________________
________________________________________________________________________________________________________
If module is being activated for new adverse event not currently in CTC, please provide definitions for adverse event grading:
Grade 0 = ____________________________________________________________________
Grade 1 = ____________________________________________________________________
Grade 2 = ____________________________________________________________________
Grade 3 = ____________________________________________________________________
Grade 4 = ____________________________________________________________________
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
109 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
29
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix II
Infection Module
To be implemented at the request of the study sponsor or principal investigator in the protocol or by protocol
amendment when more detailed information is considered pertinent.
1. Use the Common Toxicity Criteria definitions to grade the severity of the infection.
2. Specify type of infection from the following (CHOOSE ONE):
BACTERIAL
FUNGAL
PROTOZOAL
VIRAL
UNKNOWN
3. Specify site of infection from the following (CHOOSE ALL THAT APPLY):
BLOOD CULTURE POSITIVE
BONE INFECTION
CATHETER (intravenous)
CATHETER (intravenous), tunnel infection
CENTRAL NERVOUS SYSTEM INFECTION
EAR INFECTION
EYE INFECTION
GASTROINTESTINAL INFECTION
ORAL INFECTION
PNEUMONIA
SKIN INFECTION
UPPER RESPIRATORY INFECTION
URINARY TRACT INFECTION
VAGINAL INFECTION
INFECTION, not otherwise specified (Specify site, __________)
4. Specify organism, if known: _______________.
5. Prophylactic antibiotic, antifungal, or antiviral therapy administration
Yes_______
No_______
If prophylaxis was given prior to infection, please specify below:
Antibiotic prophylaxis _____________________________________________________
Antifungal prophylaxis ____________________________________________________
Antiviral prophylaxis ______________________________________________________
Other prophylaxis ________________________________________________________
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
110 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
30
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix III
Performance Status Scales/Scores
PERFORMANCE STATUS CRITERIA
Karnofsky and Lansky performance scores are intended to be multiples of 10.
ECOG (Zubrod)
Karnofsky
Lansky*
Score
Description
Score
Description
Score
Description
100
Normal, no complaints, no
evidence of disease.
100
Fully active, normal.
0
Fully active, able to carry on
all pre-disease performance
without restriction.
90
Able to carry on normal
activity; minor signs or
symptoms of disease.
90
Minor restrictions in physically
strenuous activity.
80
Normal activity with effort;
some signs or symptoms of
disease.
80
Active, but tires more quickly
1
Restricted in physically
strenuous activity but
ambulatory and able to carry
out work of a light or
sedentary nature, e.g., light
housework, office work.
70
Cares for self, unable to carry
on normal activity or do active
work.
70
Both greater restriction of and less time
spent in play activity.
60
Requires occasional
assistance, but is able to care
for most of his/her needs.
60
Up and around, but minimal active play;
keeps busy with quieter activities.
2
Ambulatory and capable of all
selfcare but unable to carry
out any work activities.  Up
and about more than 50% of
waking hours.
50
Requires considerable
assistance and frequent
medical care.
50
Gets dressed, but lies around much of
the day; no active play; able to
participate in all quiet play and
activities.
40
Disabled, requires special care
and assistance.
40
Mostly in bed; participates in quiet
activities.
3
Capable of only limited
selfcare, confined to bed or
chair more than 50% of
waking hours.
30
Severely disabled,
hospitalization indicated.
Death not imminent.
30
In bed; needs assistance even for quiet
play.
20
Very sick, hospitalization
indicated.  Death not imminent.
20
Often sleeping; play entirely limited to
very passive activities.
4
Completely disabled.  Cannot
carry on any selfcare.  Totally
confined to bed or chair.
10
Moribund, fatal processes
progressing rapidly.
10
No play; does not get out of bed.
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
111 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
31
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix IV
RTOG/EORTC Late Radiation Morbidity Scoring Scheme
Use for adverse event occurring greater than 90 days after radiation therapy.
Grade
Adverse Event
0
1
2
3
4
Bladder-
Late RT Morbidity Scoring
No change from
baseline
Slight epithelial
atrophy/minor
telangiectasia
(microscopic hematuria)
Moderate frequency/
generalized
telangiectasia/
intermittent
macroscopic hematuria
Severe frequency and
dysuria/severe
generalized
telangiectasia (often
with petechiae);
frequent hematuria;
reduction in bladder
capacity (<150 mL)
Necrosis/contracted
bladder (capacity <100
mL)/severe
hemorrhagic cystitis
Bone-
Late RT Morbidity Scoring
No change from
baseline
Asymptomatic; no
growth retardation;
reduced bone density
Moderate pain or
tenderness; growth
retardation; irregular
bone sclerosis
Severe pain or
tenderness; complete
arrest of bone growth;
dense bone sclerosis
Necrosis/
spontaneous fracture
Brain-
Late RT Morbidity Scoring
No change from
baseline
Mild headache; slight
lethargy
Moderate headache;
great lethargy
Severe headaches;
severe CNS dysfunction
(partial loss of power or
dyskinesia)
Seizures or paralysis;
coma
Esophagus-
Late RT Morbidity Scoring
No change from
baseline
Mild fibrosis; slight
difficulty in swallowing
solids; no pain on
swallowing
Unable to take solid
food normally;
swallowing semi-solid
food; dilation may be
indicated
Severe fibrosis; able to
swallow only liquids;
may have pain on
swallowing; dilation
required
Necrosis/
perforation; fistula
Eye-
Late RT Morbidity Scoring
No change from
baseline
Asymptomatic cataract;
minor corneal
ulceration or keratitis
Symptomatic cataract;
moderate corneal
ulceration; minor
retinopathy or glaucoma
Severe keratitis; severe
retinopathy or
detachment; severe
glaucoma
Panophthalmitis;
blindness
Heart-
Late RT Morbidity Scoring
No change from
baseline
Asymptomatic or mild
symptoms; transient T
wave inversion and ST
changes; sinus
tachycardia >110 (at
rest)
Moderate angina on
effort; mild pericarditis;
normal heart size;
persistent abnormal T
wave and ST changes;
low QRS
Severe angina;
pericardial effusion;
constrictive pericarditis;
moderate heart failure;
cardiac enlargement;
EKG abnormalities
Tamponade/severe heart
failure/severe
constrictive pericarditis
Joint-
Late RT Morbidity Scoring
No change from
baseline
Mild joint stiffness;
slight limitation of
movement
Moderate stiffness;
intermittent or moderate
joint pain; moderate
limitation of movement
Severe joint stiffness;
pain with severe
limitation of movement
Necrosis/complete
fixation
Kidney-
Late RT Morbidity Scoring
No change from
baseline
Transient albuminuria;
no hypertension; mild
impairment of renal
function; urea 25 - 35
mg%; creatinine 1.5 -
2.0 mg%; creatinine
clearance >75%
Persistent moderate
albuminuria (2+); mild
hypertension; no related
anemia; moderate
impairment of renal
function; urea >36 - 60
mg%; creatinine
clearance >50 - 74%
Severe albuminuria;
severe hypertension;
persistent anemia (<10
g%); severe renal
failure; urea >60 mg%;
creatinine >4 mg%;
creatinine clearance
<50%
Malignant hypertension;
uremic coma/urea
>100%
Larynx-
Late RT Morbidity Scoring
No change from
baseline
Hoarseness; slight
arytenoid edema
Moderate arytenoid
edema; chondritis
Severe edema; severe
chondritis
Necrosis
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
112 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
32
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix IV (continued)
RTOG/EORTC Late Radiation Morbidity Scoring Scheme
Use for adverse event occurring greater than 90 days after radiation therapy.
Grade
Adverse Event
0
1
2
3
4
Liver-
Late RT Morbidity Scoring
No change from
baseline
Mild lassitude; nausea;
dyspepsia; slightly
abnormal liver function
Moderate symptoms;
some abnormal liver
function tests; serum
albumin normal
Disabling hepatic
insufficiency; liver
function tests grossly
abnormal; low albumin;
edema or ascites
Necrosis/hepatic coma
or encephalopathy
Lung-
Late RT Morbidity Scoring
No change from
baseline
Asymptomatic or mild
symptoms (dry cough);
slight radiographic
appearances
Moderate symptomatic
fibrosis or pneumonitis
(severe cough); low
grade fever; patchy
radiographic
appearances
Severe symptomatic
fibrosis or pneumonitis;
dense radiographic
changes
Severe respiratory
insufficiency/
continuous O2/assisted
ventilation
Mucous membrane-
Late RT Morbidity Scoring
No change from
baseline
Slight atrophy and
dryness
Moderate atrophy and
telangiectasia; little
mucus
Marked atrophy with
complete dryness;
severe telangiectasia
Ulceration
Salivary glands-
Late RT Morbidity Scoring
No change from
baseline
Slight dryness of
mouth; good response
on stimulation
Moderate dryness of
mouth; poor response
on stimulation
Complete dryness of
mouth; no response on
stimulation
Fibrosis
Skin-
Late RT Morbidity Scoring
No change from
baseline
Slight atrophy;
pigmentation change;
some hair loss
Patchy atrophy;
moderate telangiectasia;
total hair loss
Marked atrophy; gross
telangiectasia
Ulceration
Small/Large intestine-
Late RT Morbidity Scoring
No change from
baseline
Mild diarrhea; mild
cramping; bowel
movement 5 x daily;
slight rectal discharge
or bleeding
Moderate diarrhea and
colic; bowel movement
>5 x daily; excessive
rectal mucus or
intermittent bleeding
Obstruction or bleeding,
requiring surgery
Necrosis/perforation
fistula
Spinal cord-
Late RT Morbidity Scoring
No change from
baseline
Mild Lhermitte’s
syndrome
Severe Lhermitte’s
syndrome
Objective neurological
findings at or below
cord level treatment
Mono-, para-,
quadriplegia
Subcutaneous tissue-
Late RT Morbidity Scoring
No change from
baseline
Slight induration
(fibrosis) and loss of
subcutaneous fat
Moderate fibrosis but
asymptomatic; slight
field contracture; <10%
linear reduction
Severe induration and
loss of subcutaneous
tissue; field contracture
>10% linear
measurement
Necrosis
Radiation - Other
(Specify, __________)
None
Mild
Moderate
Severe
Life-threatening or
disabling
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
113 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
33
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix V
BMT-Specific Adverse Events
Summary of BMT-Specific Adverse Events that may be used if specified by the protocol.  These differ
from the standard CTC and may be more relevant to the transplant setting.  They are listed here for the
convenience of investigators writing transplant protocols.  They are also included in the CTC document.
Grade
Adverse Event
0
1
2
3
4
Bilirubin associated with
graft versus host disease for
BMT studies .
normal
≥2 - <3 mg/100 mL
≥3 - <6 mg/100 mL
≥6 - <15 mg/100 mL
≥15 mg/100 mL
Diarrhea associated with
graft versus host disease
(GVHD) for BMT studies.
none
>500 - ≤1000mL of
diarrhea/day
>1000 - ≤1500mL of
diarrhea/day
>1500mL of
diarrhea/day
severe abdominal pain
with or without ileus
Diarrhea for pediatric BMT
studies.
>5 - ≤10 mL/kg of
diarrhea/day
>10 - ≤15 mL/kg of
diarrhea/day
>15 mL/kg of
diarrhea/day
-
Hepatic enlargement
absent
-
-
present
-
Leukocytes (total WBC) for
BMT studies.
WNL
≥2.0 - <3.0 X 109 /L
≥2000 - <3000/mm3
≥1.0 - <2.0 x 109 /L
≥1000 - <2000/mm3
≥0.5 - <1.0 x 109 /L
≥500 - <1000/mm3
<0.5 x 109 /L
<500/mm3
Leukocytes (total WBC) for
pediatric BMT studies (using
age, race and sex normal
values).
≥75 - <100% LLN
≥50 - <75% LLN
≥25 - 50% LLN
<25% LLN
Lymphopenia for pediatric
BMT studies (using age,
race and sex normal values).
mm3
≥75-<100%LLN
≥50-<75%LLN
≥25-<50%LLN
<25%LLN
Neutrophils/granulocytes
(ANC/AGC) for BMT
studies.
WNL
≥1.0 - <1.5 x 109 /L
≥1000 - <1500/mm3
≥0.5 - <1.0 x 109 /L
≥500 - <1000/mm3
≥0.1 - <0.5 x 109 /L
≥100 - <500/mm3
<0.1 x 109 /L
<100/mm3
Platelets for BMT studies.
WNL
≥50.0 - <75.0 x 109 /L
≥50,000 - <75,000/mm3
≥20.0 - <50.0 x 109 /L
≥20,000 - <50,000/mm3
≥10.0 - <20.0 x 109 /L
≥10,000 - <20,000/mm3
<10.0 x 109 /L
<10,000/mm3
Rash/dermatitis associated
with high-dose
chemotherapy or BMT
studies.
none
faint erythema or dry
desquamation
moderate to brisk
erythema or a patchy
moist desquamation,
mostly confined to skin
folds and creases;
moderate edema
confluent moist
desquamation, ≥1.5 cm
diameter, not confined
to skin folds; pitting
edema
skin necrosis or
ulceration of full
thickness dermis; may
include spontaneous
bleeding not induced by
minor trauma or
abrasion
Rash/desquamation
associated with graft versus
host disease (GVHD) for
BMT studies.
none
macular or papular
eruption or erythema
covering <25% of body
surface area without
associated symptoms
macular or papular
eruption or erythema
with pruritus or other
associated symptoms
covering ≥25 - <50% of
body surface or
localized desquamation
or other lesions
covering ≥25 - <50% of
body surface area
symptomatic
generalized
erythroderma or
symptomatic macular,
papular or vesicular
eruption, with bullous
formation, or
desquamation covering
≥50% of body surface
area
generalized exfoliative
dermatitis or ulcerative
dermatitis or bullous
formation
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
114 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
34
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix V (Continued)
BMT-Specific Adverse Events
Summary of BMT-Specific Adverse Events that may be used if specified by the protocol.  These differ
from the standard CTC and may be more relevant to the transplant setting.  They are listed here for the
convenience of investigators writing transplant protocols.  They are also included in the CTC document.
Grade
Adverse Event
0
1
2
3
4
Stomatitis/pharyngitis
(oral/pharyngeal mucositis)
for BMT studies.
none
painless ulcers,
erythema, or mild
soreness in the absence
of lesions
painful erythema,
edema or ulcers but can
swallow
painful erythema,
edema, or ulcers
preventing swallowing
or requiring hydration
or parenteral (or enteral)
nutritional support
severe ulceration
requiring prophylactic
intubation or resulting
in documented
aspiration pneumonia
Transfusion: Platelets for
BMT studies.
none
1 platelet transfusion in
24 hours
2 platelet transfusions in
24 hours
≥3 platelet transfusions
in 24 hours
platelet transfusions and
other measures required
to improve platelet
increment; platelet
transfusion
refractoriness associated
with life-threatening
bleeding. (e.g., HLA or
cross matched platelet
transfusions)
Transfusion: pRBCs for
BMT studies.
none
≤2 u pRBC in 24 hours
elective or planned
3 u pRBC in 24 hours
elective or planned
≥4 u pRBC in 24 hours
hemorrhage or
hemolysis associated
with life-threatening
anemia; medical
intervention required to
improve hemoglobin
Transfusion: pRBCs for
pediatric BMT studies.
none
≤15mL/kg in 24 hours
elective or planned
>15 - ≤30mL/kg in 24
hours elective or
planned
>30mL/kg in 24 hours
hemorrhage or
hemolysis associated
with life-threatening
anemia; medical
intervention required to
improve hemoglobin
Thrombotic
microangiopathy (e.g.,
thrombotic
thrombocytopenic
purpura/TTP or hemolytic
uremic syndrome/HUS) for
BMT studies.
-
evidence of RBC
destruction
(schistocytosis) without
clinical consequences
evidence of RBC
destruction with
elevated creatinine (≤3
x ULN)
evidence of RBC
destruction with
creatinine (>3 x ULN)
not requiring dialysis
evidence of RBC
destruction with renal
failure requiring
dialysis and/or
encephalopathy
Weight gain associated with
Veno-Occlusive Disease
(VOD) for BMT studies.
<2%
≥2 - <5%
≥5 - <10%
≥10% or as ascites
≥10% or fluid retention
resulting in pulmonary
failure
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
115 
1.0
Approved
930010978
2.0
v


CTC Version 2.0
Publish Date: April 30, 1999
Cancer Therapy Evaluation Program
35
Revised March 23, 1998
Common Toxicity Criteria, Version 2.0
DCTD, NCI, NIH, DHHS   March 1998
Appendix VI
BMT Complex/Multicomponent Events
Grade
Adverse Event
0
1
2
3
4
Note: The grading of Complex/Multicomponent Events in bone marrow transplant will be defined in the protocol. The grading scale must use the CTC criteria for
grading the specific component events (adverse events).
Failure to engraft
absent
mild
moderate
severe
life-threatening
Also consider Hemoglobin, Neutrophils/granulocytes (ANC/AGC), Neutrophils/granulocytes (ANC/AGC) for BMT studies, if specified in the protocol, Platelets,
Platelets for BMT studies, if specified in the protocol
Graft versus host disease
absent
mild
moderate
severe
life-threatening
Also consider Fatigue, Rash/desquamation, Rash/desquamation associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol,
Diarrhea for patients without colostomy, Diarrhea for patients with colostomy, Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if
specified in the protocol, Diarrhea for pediatric BMT studies, if specified in the protocol, Bilirubin, Bilirubin associated with graft versus host disease (GVHD) for
BMT studies, if specified in the protocol
Stem cell infusion
complications
absent
mild
moderate
severe
life-threatening
Also consider Allergic reaction/hypersensitivity, Conduction abnormality/Atrioventricular heart block, Nodal/junctional arrhythmia/dysrhythmia, Prolonged QTc
interval (QTc >0.48 seconds), Sinus bradycardia, Sinus tachycardia, Supraventricular arrhythmias (SVT/atrial fibrillation/flutter), Vasovagal episode, Ventricular
arrhythmia (PVCs/bigeminy/trigeminy/ventricular tachycardia), Cardiovascular/Arrhythmia - Other (Specify, ___________), Hypertension, Hypotension, Fever (in
the absence of neutropenia, where neutropenia is defined as AGC <1.0 x 109/L), Rigors/chills, Sweating (diaphoresis), Rash/desquamation, Rash/desquamation
associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Urticaria (hives, welts, wheals), Diarrhea for patients without
colostomy, Diarrhea for patients with colostomy, Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Diarrhea
for pediatric BMT studies, if specified in the protocol, Nausea, Vomiting, Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without
grade 3 or 4 thrombocytopenia, Hemoptysis, Alkaline phosphatase, Bilirubin, Bilirubin associated with graft versus host disease (GVHD) for BMT studies, if
specified in the protocol, GGT, SGOT (AST), SGPT (ALT), Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC <1.0 x
109/L), Infection without neutropenia, Hyperkalemia, Hypernatremia, Hypokalemia, Depressed level of consciousness, Seizures, Abdominal pain, Headache,
Creatinine, Hemoglobinuria
Veno-Occlusive Disease
(VOD)
absent
mild
moderate
severe
life-threatening
Also consider  Weight gain associated with Veno-Occlusive Disease (VOD) for BMT studies, if specified in the protocol, Bilirubin, Bilirubin associated with graft
versus host disease (GVHD) for BMT studies, if specified in the protocol, Depressed level of consciousness, Hepatic pain, Renal failure, Hepatic enlargement
Paclitaxel
CA139387
BMS-181339
Clinical Protocol 
Date: 25-May-2005
116 
1.0
Approved
930010978
2.0
v

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
ROLLOVER STUDY OF WEEKLY PACLITAXEL (BMS-181339) IN PATIENTS WITH ADVANCED BREAST 
CANCER 
 
 
Protocol: CA139-387 
 
NCT Number: NCT00971945 
 
 
 
 
 
October 16, 2007 (Ver. 1.00) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
1
Table of Contents 
 
 
 
Table of Contents 
1 
Introduction .................................................................................................................................................................................... 2 
 
...........................................................................................................................................................................  
3 
Study Objectives ............................................................................................................................................................................ 2 
3.1 
Primary Endpoint ................................................................................................................................................................. 2 
3.2 
Secondary Endpoint .............................................................................................................................................................. 2 
4 
Study Overview .............................................................................................................................................................................. 2 
4.1 
Study Design ........................................................................................................................................................................ 2 
4.2 
Study Population .................................................................................................................................................................. 2 
4.3 
Dose, Route, and Duration of Study Drug ............................................................................................................................ 2 
4.4 
Blinding and Unblinding ...................................................................................................................................................... 2 
5 
Criteria for Evaluation .................................................................................................................................................................... 2 
5.1 
Efficacy Evaluations ............................................................................................................................................................. 2 
5.2 
Safety Assessments ............................................................................................................................................................... 2 
6 
Sample Size Determination ............................................................................................................................................................ 3 
7 
Interim Review ............................................................................................................................................................................... 3 
8 
Data Sets Analyzed ........................................................................................................................................................................ 3 
8.1 
Enrolled Subjects .................................................................................................................................................................. 3 
8.2 
Treated subjects .................................................................................................................................................................... 3 
9 
Statistical Analysis ......................................................................................................................................................................... 3 
9.1 
Analysis Consideration ......................................................................................................................................................... 3 
9.1.1 
Subjects and Data Handling ............................................................................................................................................. 3 
9.1.2 
Data conversion ............................................................................................................................................................... 3 
9.1.3 
Adverse Event Coding ..................................................................................................................................................... 3 
9.1.4 
Review of Subgroup ........................................................................................................................................................ 3 
9.1.5 
Covariate Alignment ........................................................................................................................................................ 3 
9.1.6 
Multicenter Test ............................................................................................................................................................... 3 
9.1.7 
Multiplicity ...................................................................................................................................................................... 3 
9.1.8 
Significance Level ........................................................................................................................................................... 3 
9.2 
General Methods .................................................................................................................................................................. 4 
9.3 
Changes made to Statistical Analysis described in the Protocol ........................................................................................... 4 
9.3.1 
Additional points ............................................................................................................................................................. 4 
9.3.2 
Change ............................................................................................................................................................................. 4 
9.4 
Subject Disposition ............................................................................................................................................................... 4 
9.4.1 
Subject Disposition .......................................................................................................................................................... 4 
9.4.2 
Protocol Deviations ......................................................................................................................................................... 4 
9.4.3 
Baseline Subject Characteristics ...................................................................................................................................... 4 
9.5 
Drug Administration ............................................................................................................................................................. 4 
9.5.1 
Study Drug Administration .............................................................................................................................................. 4 
9.6 
Efficacy ................................................................................................................................................................................ 5 
9.6.1 
Response, Duration of Response ..................................................................................................................................... 5 
9.7 
Safety.................................................................................................................................................................................... 5 
9.7.1 
Subjective and objective adverse events .......................................................................................................................... 5 
9.7.2 
Peripheral neuropathies ................................................................................................................................................... 5 
9.7.3 
Nail Disorders .................................................................................................................................................................. 5 
9.7.4 
Allergic Reactions ........................................................................................................................................................... 5 
9.7.5 
Laboratory (Test) Abnormalities ...................................................................................................................................... 5 
9.7.6 
Laboratory Evaluations .................................................................................................................................................... 6 
9.7.6.1 
Myelosuppression ....................................................................................................................................................... 6 
10 ............................................................................................................................................................................................................. 6 
 
 ......................................................................................................................................................................................  
 
 
 
 
 
 
 


 
2
1 
Introduction 
 The purpose of this document is to provide a detailed plan for the final analysis of rollover study of weekly Paclitaxel (BMS-181339) 
in patients with advanced breast cancer (Identification number: CA139-387). 
 Attached materials show the table format to be used in the statistical analysis report. These tables and figures are referenced in the 
analysis section. Each figures and tables show the dataset (Analysis Sets) used for the analysis. 
 
 
 
 
 
3 
Study Objectives 
3.1 
Primary Endpoint 
The primary endpoint is the frequency and severity of adverse events (Subjective and objective findings and changes in laboratory 
(test) abnormalities) for the subjects in the study. 
3.2 
Secondary Endpoint 
Tumor response and duration of response. 
4 
Study Overview 
4.1 
Study Design 
This study is an extension study of weekly paclitaxel in subjects participating in the 
 who require continued weekly paclitaxel 
due to lack of alternative treatment, and is an open-label clinical study by enrollment using the central multicenter method. 
The primary endpoint in this study will determine the frequency and severity of adverse events (Subjective and objective findings and 
changes in laboratory (test) abnormalities) in study subjects to evaluate the safety of continued paclitaxel treatment. In addition, the 
Safety Monitoring Board will be established as an advisory body to sponsor and the coordinating investigator to deliberate and report 
the preparation and revision of protocol, actions in the event of serious adverse event, and actions for situations requiring consideration 
of discontinuation of the entire study. 
4.2 
Study Population 
Among patients with advanced/recurrent breast cancer who meet the inclusion criteria and participated in the 
 
, those who are judged 
by the investigator (
) to require continued administration of paclitaxel because there is no appropriate alternative therapy.  
4.3 
Dose, Route, and Duration of Study Drug 
Paclitaxel 100 mg / m2 is intravenously infused for 1 hour after premedication,. The first dose date of paclitaxel is Day 1, and the 
drug is administered at Day 8, 15, 22, 29, 36 (7-day intervals (± 1 day)), and then the drug is withdrawn until Day 49. One course is 49 
days, and in principle, one or more courses are administered. For subjects who do not meet the discontinuation criteria, administration 
should be continued as much as possible within the study period at the discretion of the investigator. 
4.4 
Blinding and Unblinding 
Not applicable. 
5 
Criteria for Evaluation 
5.1 
Efficacy Evaluations 
Tumor response will be assessed using the Breast Cancer Treatment Code (Edited by the Japan Breast Cancer Society). Response 
Evaluation Criteria in Solid Tumors (RECIST) will be evaluated for reference. 
5.2 
Safety Assessments 
The safety endpoint will be adverse events (Subjective and objective findings and laboratory (test) abnormality), which will be graded 
according to the NCI Common Toxicity Criteria version 2 (JCOG Version). Final assessment of adverse events will be made by the 
Adjudication Committee for review outside the study site. 
Toxicities not included in CTC will be graded in accordance with the following criteria as "Other" toxicity of the applicable category, 
with specific descriptions. 
 
Grade 0: Normal, normal/within normal limits (WNL), none 
Grade 1: Mild/mild toxicity 
Grade 2: Moderate/moderate toxicity 


 
3
Grade 3: Severe/severe toxicity 
Grade 4: Life-threatening or toxicity leading to inactivity 
Grade 5: Death due to toxicity 
6 
Sample Size Determination 
The number of subjects with this study will be determined by the number of subjects continuing from the preceding 
 
 Currently, in 
Study
, 9 subjects are continuing treatment, and therefore, it is expected that no more than 10 subjects will be enrolled in 
this study. 
7 
Interim Review 
No interim analysis will be performed in this study; however, an interim analysis will be performed if necessary to support the 
application for approval. 
8 
Data Sets Analyzed 
8.1 
Enrolled Subjects 
All subjects who are enroll to the study. 
8.2 
Treated subjects 
Subjects who entered the study and received at least one dose of investigational product. Safety and efficacy analyses will be 
performed. 
9 
Statistical Analysis 
 This chapter is organized as follows. 
9.1: Analysis Consideration 
9.2: General methods 
9.3 : Changes made to Statistical Analysis Described in the Protocol 
9.4-9.7 : Detailed analysis method for analysis items. 
(Presentation formats for each analysis is provided in the attachment.) 
 All analyses will be performed using SAS release 8.02. 
9.1 
Analysis Consideration 
9.1.1 
Subjects and Data Handling 
Handling of subjects and data will be specified separately before data lock as needed. 
9.1.2 
Data conversion 
No variables will be analyzed using converted values. However, this is not applicable to the case where an exploratory post-hoc 
analysis is performed. 
9.1.3 
Adverse Event Coding 
Adverse event terms/names of diseases described in case report form were coded to MedDRA terms to be used for reporting of 
analysis results. The most recent or one previous MedDRA version at the time of analysis will be used. 
9.1.4 
Review of Subgroup 
Subgroup will not be evaluated. 
9.1.5 
Covariate Alignment 
Analyses that would require adjustment by covariate will not be performed. 
9.1.6 
Multicenter Test 
Since the number of subjects per site is expected to be small, no investigation of inter-site differences will be conducted. 
9.1.7 
Multiplicity 
Multiplicity is not applicable because no statistical test will be performed. 
9.1.8 
Significance Level 
Significance level is not defined because no statistical test will be performed. 


 
4
9.2 
General Methods 
Baseline should be the most recent measurement or finding up to the start of the first dose in the parent study. 
Descriptive statistics will be used to summarize demographic factors, treatment status, and laboratory data. Categorical variables will 
be summarized using frequency tabulations.  
Adverse events for which the causal relationship is "related", "Probably related" or "possibly related" are defined as events for which 
the relationship with investigational product cannot be ruled out (adverse drug reaction). Events assessed as "not likely relarted" or "not 
related" to the study drug should be assessed as not related to investigational product. The same adverse event may occur more than 
once within a subject's scope as a MedDRA SOC, HLGT, or PT, and will be counted only once in the adverse event summary table. If 
the same adverse event is regarded as a single event, the most abnormal grade among them will be used for summary. Similarly, if 
multiple same adverse events are counted as 1 event, the most abnormal grade among the related events will be used for summary. The 
same handling as above will be applied to the total number of subjects with adverse events. 
For the outcome of adverse events, the final outcome by LLT in MedDRA is adopted as the outcome by PT in the order of priority of 
death > persistent > unknown > recovering > recovering, and the outcome in adverse drug reaction is handled in the same manner among 
related events. 
When frequency tabulations are prepared for adverse events and laboratory (test) abnormalities changes by symptom name, they 
should be presented in ascending order of SOC (HLGT) codes and in descending order of the number of applicable subjects. If the 
number of subjects in the same, display them in ascending order of PT code. 
The target of demographic analysis is data from the preceding study. 
Dosing and efficacy analyses will be summarized, including data from the subject's previous study. 
For the number of display digits to be used in the report, an appropriate number of digits should be selected according to the parameters, 
but rounding should be done as a rounded method unless otherwise specified. Proportion shows the first decimal places. 
9.3 
Changes made to Statistical Analysis described in the Protocol 
9.3.1 
Additional points 
Tabulation of exposure was added. 
9.3.2 
Change 
 There were no changes. 
9.4 
Subject Disposition 
9.4.1 
Subject Disposition 
Subject composition (Table 1.1) 
– 
Study Drug administration 
– 
Primary reason for discontinuation 
One primary reason for discontinuation will be identified for each subject. 
Reasons for discontinuation by discontinuation course (Table 1.2)  
The discontinuation course is the sum of the administration courses in the preceding study. 
 
9.4.2 
 Protocol Deviations 
Protocol deviations (Table 1.3) 
9.4.3 
Baseline Subject Characteristics 
Demographic characteristics (Table 2.1) 
– 
Age (years) 
– 
Body surface area (m 2) 
– 
P.S. (ECOG) 
The age should be accurately calculated from the date of informed consent and date of birth in years of age.  
9.5 
Drug Administration 
9.5.1 
Study Drug Administration 
In the following summaries, the number of courses plus the number of courses administered in the preceding study will be used. (For 
example, if a subject completed or discontinued 2 courses of the parent study and subsequently entered an extension study, the first 
course of the extension study will be counted as 3 courses.) 
Study Drug Administration (Table 3.1) 
– 
Number of administration courses 


 
5
– 
Number of dose 
– 
Course interval (days) 
・Course interval = first dose date in the course - last dose date in the previous course 
Dose delay (Table 3.2) 
Drug interruption (Table 3.3) 
Dose reduction (Table 3.4) 
9.6 
Efficacy 
9.6.1 
Response, Duration of Response 
In the following summary, the date will be specified based on the assessment by the attending physician and the data from the 
preceding study, and the period and cumulative dose will be calculated based on the date. 
Duration of response (Japan Breast Cancer Society) (Table 4.1) 
・Duration of CR response = date of progression - date of CR 
・Duration of PR response = date of progression - date of PR 
・Overall response duration= date of progression - date of first dose 
The date of progression is defined as the earliest date among the date of progression of a lesion, the date of appearance of a new 
lesion, the date of initiation of subsequent treatment, or the date of death based on the evaluation criteria in the General Rules for 
Clinical Practice for Breast Cancer, and the date of the last measurement of a lesion in patients without progression.  
Duration of response (RECIST) (Table 4.2) 
・Duration of complete response = date of progression - date of CR 
・Overall response duration  = date of progression - date of PR 
The date of progression is defined as the earliest date among the date of progression of lesion based on RECIST evaluation 
criteria, the date of appearance of new lesion, the date of initiation of subsequent treatment, or the date of death, and the date of the 
last measurement of lesion in patients without progression.  
9.7 
Safety 
The following summaries are based on events that are new or ongoing in the extension study. 
9.7.1 
Subjective and objective adverse events 
The number of subjects with subjective and objective adverse events will be summarized by SOC and PT. However, summaries by 
outcome will not be performed by SOC but only by PT. 
Subjective and objective adverse events: by worst grade 
 
 
 
(Table 5.1) 
Drug Related Subjective and objective adverse events: by worst grade  
 
(Table 5.2) 
Drug Related Subjective and objective adverse events by outcome 
 
 
(Table 5.3) 
9.7.2 
Peripheral neuropathies 
The number of subjects with peripheral neuropathy will be summarized by SOC and PT.  
Peripheral nerve disorders: by worst grade 
 
 
 
 
(Table 5.4) 
Peripheral nerve disorders- excluding "not related" and "not likely relarted" -: by worst grade 
(Table 5.5) 
9.7.3 
Nail Disorders 
The number of subjects with nail disorders will be summarized by SOC and PT.  
Nail disorders: by worst grade 
 
 
 
 
 
(Table 5.6) 
9.7.4 
Allergic Reactions 
The number of subjects with allergic reactions will be summarized by SOC and PT. In addition, the occurrence by dexamethasone 
dose will be summarized. 
Allergic reactions: by worst grade  
 
 
 
(Table 5.7) 
9.7.5 
Laboratory (Test) Abnormalities 
For laboratory (test) abnormalities changes, the number of subjects with each HLGT and each PT will be summarized. However, 
summaries by outcome will not be performed by HLGT but only by PT. 
Laboratory abnormalities: by worst grade 
 
 
 
(Table 6.1) 
Laboratory abnormalities (Drug Related): by worst grade  
 
(Table 6.2) 
Laboratory (test) abnormalities (Drug Related): Incidence by outcome  
(Table 6.3) 


 
6
9.7.6 
Laboratory Evaluations 
9.7.6.1 
Myelosuppression 
Worst grade, nadir, number of days to nadir, and number of days to recovery of white blood cell count decreased 
     
(Table 6.4 a) 
Worst grade of neutrophil count decreased, Nadir, number of days to Nadir, number of days to resolution  
     (Table 6.4 b) 
Nadir (lowest value), number of days to Nadir and number of days to resolution will only be calculated for subjects who achieve 
Grade ≥ 2 in each course. The calculation method is as follows:.  
 Number of days to Nadir: date Nadir was reached - first dose date in each course + 1 
 Recovery date: Between the day of achievement of Nadir and before the start of the next course (Last measurement time point 
including follow-up data in the last course), the first day when the grade has recovered to ≤ 1 and has not 
subsequently worsened to ≥ 2. 
 Number of days to recovery: Recovery date - date Nadir was reached 
10 
List of Tables 
 The following figures and tables will be included in the analysis report:. 
Table/table 
number 
Title 
Table 1.1 
Subject Disposition 
Table 1.2 
Reason for Discontinuation by Discontinuation Course 
Table 1.3 
Protocol Deviations 
Table 2.1 
Demographic Characteristics 
Table 3.1 
Study Drug Administration  - Including Prior Studies - 
Table 3.2 
Dose Delay - Including Prior Studies - 
Table 3.3 
Drug Interruption - Including Previous Studies - 
Table 3.4 
Dose Reduction - Including Previous Studies - 
Table 4.1 
Duration of Response (Japan Breast Cancer Society)  - Including Prior Studies - 
Table 4.2 
Duration of Response (RECIST)  - Including Prior Studies - 
Table 5.1 
Subjective and Objective Adverse Events 
Table 5.2 
Drug Related Subjective and Objective Events 
Table 5.3 
Drug Related Subjective and Objective Adverse Events by Outcome 
Table 5.4 
Peripheral Nerve Disorders 
Table 5.5 
Peripheral Neuropathies - excluding "not Related" "not Likely Related" - 
Table 5.6 
Nail Disorders 
Table 5.7 
Allergic Reactions 
Table 6.1 
Laboratory Test Abnormalities 
Table 6.2 
Laboratory Test Abnormalities (Drug Related) 
Table 6.3 
Laboratory Test Abnormalities (Drug Related) by Onset Status/Outcome 
Table 6.4 a 
White Blood Cell Count Decreased Recovered to ≤ Grade 1 
Table 6.4 b 
Neutrophil Count Decreased Recovered to ≤ Grade 1 
 
 
 
. 


 
7
Document History 
Date 
Edition 
Number 
Person who 
created/updated 
Remarks 
2007/01/10 
Draft 
 
Initiation of draft preparation 
2007/08/06 
0.00 
 
Completion of draft statistical analysis plan 
Submit to Reviewers 
2007/09/07 
0.50 
 
Reflected the review results. 
Resubmission to Reviewers 
2007/09/28 
0.60 
 
Reflected the results of the meeting with Clinical Strategy 
Department 
Resubmission to Reviewers 
2007/10/16 
1.00 
 
Reflected the review results, and prepared the approval document.