Clinical trial NCT02756013
Conditions: Gynecologic Malignancies
Keywords: chemotherapy dosing Body surface area BSA paclitaxel carboplatin dose dense
Sponsor: Case Comprehensive Cancer Center
Start date: 2016-04-20; Completion date: 2019-01-24
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the side effects and effectiveness of giving standard paclitaxel chemotherapy in doses based on actual body surface area in combination with standard dosed carboplatin chemotherapy for overweight women.

Detailed description:
Primary Objective The primary objective is to prospectively evaluate the Relative Dose Intensity (RDI) and toxicity of weight-based dose dense weekly paclitaxel and carboplatin in overweight patients with a BSA \> 2.0 compared to the Japanese Gynecologic Oncology Group trial (JGOG 2016) during 6 - 9 cycles of chemotherapy.

Secondary Objective(s) The secondary objective is to evaluate progression-free survival in this patient population.

Study Design This is a descriptive study to determine what the relative dose intensity of patients who are overweight with a BSA of greater than 2.0 can achieve.

Arms: arm 1: Paclitaxel dosed by actual body surface area and not maxed at BSA 2.0. The Carboplatin dose will be calculated according to the Calvert formula using as estimated glomerular filtration rate from the Cockcroft-Gault formula and will be subject to maximum allowed doses.
Interventions: intervention 1: Paclitaxel intervention 2: Carboplatin
Intervention descriptions: intervention 1: 80mg/m2 IV days 1,8, and 15 every 21 days x 6-9 cycles intervention 2: area under the curve (AUC) 6 IV day 1 every 21 days x 6-9 cycles

Protocol documents:
ICF_001.pdf: 
CASE13815 
April 20, 2016 
1 
CONSENT FOR CANCER RESEARCH  
Project Title: CASE 13815, A phase II trial of weight-based dosing for dense weekly 
paclitaxel and carboplatin in overweight patients with a BSA > 2.0. 
Principal Investigator: Peter Rose, MD, Cleveland Clinic 216-444-1712
Sponsor: None 
Cancer research studies are coordinated by physicians and scientists from Cleveland 
Clinic, University Hospitals and Case Western Reserve University (CWRU) through the 
NIH National Cancer Institute (NCI) designated Case Comprehensive Cancer Center 
(Case CCC).  The goal of this collaboration is to enhance cancer treatment and 
research in Northeast Ohio.  This study is being offered at Cleveland Clinic (CC)  
What is the usual approach to my gynecologic cancer? 
Standard chemotherapy dosing is based on body surface area (BSA) which is the total 
surface area of the human body. The BSA calculation involves the height and weight of 
a person- meaning that the taller you are and the more you weigh increases your BSA. 
The average body surface area for women is about 1.6. BSA is often used when 
calculating doses of medications, including chemotherapy.  
Many cancer studies limit the chemotherapy doses based on a BSA of 2.0. However, 
the number of overweight (or obese) people in the United States is increasing every 
year. In 2012 the American Society of Clinical Oncology (ASCO) recommended that 
chemotherapy dosing should be based on actual body weight for most chemotherapy 
drugs. Even though this recommendation was made it remains controversial. Doctors 
want to limit the amount and severity of side effects while at the same time giving 
treatment that has the most benefit in terms of survival (length of life). There has been 
very little research done prospectively (during the actual treatment time) that looks at 
this. In this study we want to look at side effects as they happen to determine if giving 
chemotherapy at a dose based on your actual BSA is both safe and effective.   
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices.  For example: 
• 
You may choose to have the usual approach as described above 
• 
You may choose to take part in a different study, if one is available 
• 
Or you may choose not to be treated for cancer.  For example: comfort/palliative 
care, which treats the symptoms of cancer, without necessarily giving chemotherapy, 
radiation therapy, or surgery. 
Why is this study being done?
The purpose of this study is to evaluate the side effects and effectiveness of giving 
standard chemotherapy in doses based on your actual body surface area and not 
limiting the dose to BSA 2.0.    
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
2 
About 28 -34 people will take part in this research study at Cleveland Clinic.   
What are the study groups? 
All study participants will get the same study intervention.  It will include chemotherapy 
(Paclitaxel and Carboplatin). Paclitaxel will be given at a dose based on your actual 
body surface area without limiting the amount given. The dose of carboplatin will be 
determined by a calculation that takes into account your kidney function, age, and 
weight. You will receive the same dose of carboplatin in this study that you would 
receive even if you were not in a study.   
How long will I be in this study? 
You will receive 6 -9 cycles of chemotherapy using Paclitaxel based on your actual body 
surface area plus Carboplatin at a standard dose. After completing the initial 6-9 cycles 
of chemotherapy, you will be asked to come back for follow up exams every 3 months 
for the first two years, then every 6 months for the next three years, then once yearly, 
depending on your clinical status.  
What extra tests and procedures will I have if I take part in this study?
The exams, tests and procedures you will have are part of the usual approach for your 
cancer. There are no extra tests or procedures.  
Before you begin the study: 
You will need to have the following screening procedures performed to find out if you 
can be in this study. These exams and tests are part of regular cancer care and may 
need to be done even if you are not in the study. If you have had some of them recently 
they may not need to be repeated. 
o History and physical examination including a measurement of your height and 
weight 
o A review of your general health and medications (including prescription, over 
the counter, vitamins, and herbal or nutritional supplements) as well as any 
baseline symptoms you may have 
o Routine blood tests (about 2 tablespoons) to check your blood counts, blood 
mineral levels, liver and kidney function, and a CA-125 (tumor marker that is 
sometimes elevated with your kind of cancer) 
o Computed Tomography (CT) scans and/or Chest X-Ray to measure the size 
of your cancer 
During the study the following will be additional procedures: 
If the exams and tests show that you can be part of the study and you choose to be in 
the study you will have the following done: 
Every cycle, Day 1 (one cycle equals 21 days) you will come to the clinic for: 
o History and physical examination including a measurement of your weight 
o A review of your general health and any side effects to the medication you 
may have 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
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o Routine blood tests (about 2 tablespoons) to check your blood counts, blood 
mineral levels, liver and kidney function, and a CA-125 (tumor marker that is 
sometimes elevated with your kind of cancer). 
o Receive chemotherapy treatment: Paclitaxel intravenously (IV) over 1 hour 
and carboplatin IV over 30 minutes. You will also receive medications through 
your IV for nausea and to help prevent an allergic reaction.  
Every week (Day 8 and Day 15) you will return to the clinic for: 
o Routine blood tests (about 1 teaspoon) to check your blood counts. 
o Receive chemotherapy treatment: Paclitaxel IV over 1 hour and medications 
for nausea and to help prevent an allergic reaction.  
Every 9 weeks (3 cycles) you will have a chest x-ray (or CT scan of the chest) and a CT 
scan of the abdomen and pelvis. 
Visit
What procedures/tests will be done at this visit
Within 28 days 
before starting 
treatment 
x Blood tests for CA-125 (about 1teaspoon) 
x History and physical examination including height and weight 
x Chest x-ray (or CT scan of the chest), CT scan of the abdomen and 
pelvis 
Within 14 days 
before starting 
treatment 
x Blood tests to measure blood counts, mineral blood levels, and 
check kidney and liver function (about 2 Tablespoons) 
x A review of your general health, medications as above, and any 
side effects to the medication you may have before starting 
treatment on this study.  
Day 1 
x History and physical examination including measurement of your 
weight 
x A review of your general health and any side effects to the 
medication you may have 
x  Routine blood tests (about 2 tablespoons) to check your blood 
counts, blood mineral levels, liver and kidney function, and a CA-
125 (tumor marker that is sometimes elevated with your kind of 
cancer).  
x IV Paclitaxel intravenously (IV) over 1 hour and carboplatin IV over 
30 minutes, along with medications for nausea and to prevent 
allergic reactions. 
Day 8 & 15 
x Routine blood tests 
x Paclitaxel IV over 1 hour and medications for nausea and to help 
prevent an allergic reaction. 
What possible risks can I expect from taking part in this study? 
You will have side effects while on the study. Everyone taking part in the study will be 
watched carefully for any side effects. However, doctors don’t know all the side effects 
that may happen. Because the dose of paclitaxel is based on your actual weight you 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
4 
may have additional side effects. Side effects may be mild or very serious. We will give 
you medicines to help lessen side effects. Many side effects go away soon after you 
stop taking the chemotherapy. In some cases, side effects can be serious because they 
can be long lasting, may never go away, may result in hospitalization, or may be life-
threatening. There also is a risk of death.   
The most common (more than 10%) adverse events associated with paclitaxel are: 
x Low white blood cell counts – this may make you more prone (open) to infection 
x Low platelet count – this may make you bruise more easily and bleed longer if 
injured  
x Low red blood cell count which may cause tiredness, shortness of breath and 
may cause the need for a blood transfusion 
x Bleeding 
x Mild to severe allergic reaction which may be life-threatening with hives, 
wheezing and a change in blood pressure (low or high) 
x Changes in the nerves that can cause numbness, tingling, or pain in the hands 
and feet.  This may lead to difficulty walking, buttoning clothes, etc. 
x Nausea and/or vomiting 
x Sores in the mouth or throat (that can lead to difficulty swallowing and 
dehydration)  
x Local swelling, redness, or skin tissue damage if some of the drug leaks from the 
vein while it is being given  
x Diarrhea 
x Hair loss 
x Muscle and joint aches 
x Low blood pressure that may cause lightheadedness 
Less common (less than and up to 10%) 
x A slowing of the heart rate (a slow pulse is not harmful; however if you should 
develop any other irregularities in heart rate during treatment, an EKG and other 
tests may be required) 
x Irregular heartbeats 
x Heart attack 
x Increase in liver function tests that indicate your liver may not be working 
properly; changes in liver function can sometimes be severe 
x Tiredness 
The most common (more than 10%) adverse events associated with carboplatin are: 
x Low white blood cell counts - this may make you more prone (open)  to infection  
x Low platelet count - this may make you bruise more easily and bleed longer if 
injured  
x Low red blood cell count which may cause tiredness, shortness of breath or 
fatigue and may cause the need for a blood transfusion. 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
5 
x Tiredness 
x Loss of appetite and weight loss 
x Diarrhea, constipation, nausea and vomiting, and abdominal pain 
x Complete hair loss 
x Skin rash 
x Changes in taste 
x Changes in electrolytes and minerals in the blood such as magnesium, 
potassium, sodium, and calcium 
Less common (less than and up to10%) 
x Changes in the nerves that can cause numbness, tingling, or pain in the hands 
and feet 
x Mild to severe allergic reaction which may be life-threatening with hives, 
wheezing and low blood pressure 
x Hair loss 
x Ringing in the ears and hearing loss 
x Other sensory side effects (for example: visual disturbances or changes in taste) 
x Abdominal pain, diarrhea, or constipation 
x Decrease in kidney (if severe, dialysis might be necessary) or liver function 
CT scans: 
If you take part in this research, you will have one or more medical imaging studies 
which use radiation.  The radiation dose we have discussed is what you will receive 
from this study only, and does not include any exposure you may have received or will 
receive from other tests. The CT scan that you will receive in this study will expose you 
to low amounts of radiation. Every day, people are naturally exposed to low levels of 
radiation that come from the sun and the environment. This type of radiation is called 
“background radiation.” No one knows for sure whether exposure to low amounts of 
radiation is harmful for your body. However, scientists believe that being exposed to too 
much radiation can cause harmful side effects, including causing a new cancer.   The 
amount of radiation that scientists think can cause harmful side effects equals more 
than 15 times the amount of extra radiation you would receive from being in this study. 
Also, scientists believe the number of people who would be at risk for developing a 
second cancer from being exposed to large amounts of radiation to be about 1 out of 
every 1,000.  
Blood Draws:  
The insertion of the needle to draw blood is painful; however, the discomfort is brief.  
For most people, needle punctures to get blood samples do not cause any serious 
problems; however, they may cause bleeding, bruising, discomfort, infections, dizziness, 
or fainting. 
Reproductive Health/Sexual Activity 
You should not get pregnant or breastfeed, a baby while in this study. The 
chemotherapy used in this study could be very damaging to an unborn baby. Check 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
6 
with the study doctor about what types of birth control, or pregnancy prevention, to use 
while in this study. 
What possible benefits can I expect from taking part in this study?
We cannot know if you will have any benefit as a result of your participation in the study; 
it is possible the study treatment may improve your cancer, which may give you relief 
from some symptoms, improve your quality of life or prolong your survival. However, it is 
possible that your condition could worsen. Your participation in this study will help to 
obtain information about treating subjects with gynecologic cancer in the future. 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is 
important to let the study doctor know as soon as possible so you can stop safely. If you 
stop, you can decide whether or not to let the study doctor continue to provide your 
medical information to the organization running the study. 
The study doctor will tell you about new information or changes in the study that may 
affect your health or your willingness to continue in the study. 
The study doctor may take you out of the study: 
 If your health changes and the study is no longer in your best interest 
 If new information becomes available 
 If you do not follow the study requirements 
 If the study is stopped by the doctors involved with the study, Institutional Review 
Board (IRB) or FDA. 
 If you get pregnant. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if 
your decision changes, there will be no penalty to you. You will not lose medical care or 
any legal rights.  
What are the costs of taking part in this study? 
Your involvement in this research study is voluntary and you will not be paid for your 
participation. 
You and/or your health plan/insurance company will need to pay for all of the costs of 
treating your cancer in this study (i.e., physical exams, routine blood tests, pregnancy 
test, x-rays and/or scans for tumor measurement, as well as the cost of any medicines 
to manage the side effects of treatment).  
The costs of the chemotherapy drugs paclitaxel and carboplatin as well as the costs of 
administering these treatments will be billed to your health plan or insurance company. 
If your insurance plan/company denies payment for the costs of and treatment with 
these chemotherapy drugs, you will be held responsible for covering these costs. 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
7 
Some health plans will not pay these costs for people taking part in studies. Before you 
decide to be in the study you should check with your health plan or insurance company 
to find out what they will pay for. You may also ask to speak with a financial counselor 
for specific insurance plan deductible/co-payment obligations. Taking part in this study 
will may or may not cost your insurance company more than the cost of getting regular 
cancer treatment. You will be responsible for paying any deductibles, coinsurance, and 
co-payments as required under the terms of your insurance plan(s). 
For more information on clinical trials and insurance coverage, you can visit the National 
Cancer Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout.
What happens if I am injured or hurt because I took part in this study? 
If you believe that you are injured as a result of the research procedures being 
performed, please immediately contact the study doctor. 
If injury occurs as a result of your involvement in this research, medical treatment is 
available from Cleveland Clinic or another medical facility but you/your medical 
insurance will be responsible for the cost of this treatment.  A research injury is an injury 
that happens as a result of taking part in this research study.  If you are injured by a 
medical treatment or procedure that you would have received even if you weren’t in the 
study that is not considered a “research injury”. There are no plans for payment of 
medical expenses or other payments, including lost wages, for any research related 
injury.  To help avoid injury, it is very important to follow all study directions. 
Further information about research-related injuries is available by contacting the 
Cleveland Clinic Institutional Review Board at (216) 444-2924. 
HIPAA AUTHORIZATION 
Authorization to Use or Disclose (Release) Health Information that Identifies You 
for a Research Study  
If you volunteer to participate in this research, your protected health information (PHI) 
that identifies you will be used or disclosed to Dr. Peter Rose and the research study 
staff at Cleveland Clinic for the purposes of this research and to Case Western Reserve 
University for administration. 
The PHI that we may use or disclose (release) for this research may include your name, 
address, phone number, date of birth, Social Security number, information from your 
medical record, lab tests, or certain information relating to your health or condition. 
Some of the tests and procedures done solely for this research study may also be 
placed in your medical record so other doctors know you are in this study.  Upon 
completion of the study, you may have access to the research information that is 
contained in your medical record.   
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
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In addition to the investigators and research staff listed above, your PHI may be looked 
at by other groups involved with the study such as the Cleveland Clinic Institutional 
Review Board, and the Case Comprehensive Cancer Center Protocol Review and 
Monitoring Committee.  Your PHI may also be used by and/or disclosed (released) to: 
 Case Comprehensive Cancer Center members and collaborators 
 The Food and Drug Administration;
 The Department of Health and Human Services;
 The National Cancer Institute (NCI);
Once your personal health information is released it may be re-disclosed and no longer 
protected by privacy laws. 
Your research information may be used and disclosed indefinitely, but you may stop 
these uses and disclosures at any time by writing to: 
Peter Rose, MD 
Case Comprehensive Cancer Center 
Cleveland Clinic 
9500 Euclid Avenue/A81 
Cleveland, OH 44195 
Your participation in the research will stop, but any information previously recorded 
about you cannot be removed from the records and will continue to be used as part of 
this research.  Also, information already disclosed outside the Cleveland Clinic cannot 
be retrieved.  This will not affect your rights to treatment or benefits outside the research 
study.    
The Cleveland Clinic will not use your information collected in this study for another 
research purpose without your written permission; unless the Cleveland Clinic 
Institutional Review Board (IRB) assures your privacy and confidentiality is protected.  
The IRB is a committee whose job it is to protect the safety and welfare of research 
subjects. 
By signing this informed consent form, you are authorizing such access to your research 
and medical record information.  If you choose not to sign this consent form, you will not 
be able to participate in this research study.  This Authorization does not have an 
expiration date. 
Voluntary Participation 
Your participation in this research study is voluntary. Choosing not to participate will not 
alter your usual health care or involve any penalty or loss of benefits to which you are 
otherwise entitled. If you decide to join the study, you may withdraw at any time and for 
any reason without penalty or loss of benefits. If information generated from this study is 
published or presented, your identity will not be revealed.   
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
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In the event new information becomes available that may affect the risks or benefits 
associated with this study or your willingness to participate in it, you will be notified so 
that you can decide whether or not to continue participating.   
Questions about the Research 
If you have any questions, you can ask the Principal Investigator and/or research staff 
at Cleveland Clinic (216) 444-1712).
Emergency or after-hours contact information  
Since you are a Cleveland Clinic Main Campus patient, you should contact the page 
operator at (216) 444-2200 or toll free at (800) 223-2273, and ask for the oncologist 
(cancer doctor) that is on call. 
If you are a Cleveland Clinic-Fairview patient, please call (216) 476-7540 
If you are a Cleveland Clinic-Hillcrest patient, please call (440) 312-5560. 
Where Can I Get More Information? 
If the researchers cannot be reached, or if you would like to talk to someone other than 
the researcher(s) about: concerns regarding the study, research participant’s rights; 
research-related injury; or other human subjects issues, you may contact the 
Institutional Review Board (IRB) at Cleveland Clinic IRB 216-444-2924  
You may call the National Cancer Institute's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237)  
You may also visit the NCI Web site at http://cancer.gov/ 

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form.  If you want more information about this study, ask your 
study doctor.   
US National Institutes of Health (NIH) Clinical Trial Database:
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, if 
applicable, as required by U.S. Law. This Web site will not include information that can 
identify you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time. 
12.  Signature 
Signing below indicates that you have been informed about the research study in which 
you voluntarily agree to participate; that you have asked any questions about the study 
that you may have; and that the information given to you has permitted you to make a 
fully informed and free decision about your participation in the study.  By signing this 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019


CASE13815 
April 20, 2016 
10 
consent form, you do not waive any legal rights, and the investigator(s) or sponsor(s) 
are not relieved of any liability they may have.  A copy of this consent form will be 
provided to you. 
Signature of Participant  
                     Date  
Printed Name of 
Participant 
I have discussed the information contained in this document with the participant and it is 
my opinion that the participant understands the risks, benefits, alternatives and 
procedures involved with this research study. 
Signature of Person Obtaining Consent 
Date  
 
 
Printed Name of Person Obtaining Consent 
CCF IRB #: 16-381
Approval Date: 4/1/2018
Expiration Date: 3/31/2019

Prot_SAP_002.pdf: 
CASE 13815 
Page 1 
Version date: 08MAR2016 
STUDY NUMBER:  CASE 13815 
Clinicaltrials.gov: NCT02756013 
Protocol Date: March 8, 2016 
STUDY TITLE:  A phase II trial of weight-based dosing for dense weekly paclitaxel 
and carboplatin in overweight patients with a BSA > 2.0. 
PRINCIPAL INVESTIGATOR: Peter Rose, MD 
Department of  Obstetrics and Gynecology 
Women’s Health Institute 
Cleveland Clinic 
9500 Euclid Avenue, A-81 
 
Cleveland, OH   44195 
 
 
CO- INVESTIGATOR: 
Mariam Al-Hilli, MD 
Department of  Obstetrics and Gynecology 
Women’s Health Institute 
Cleveland Clinic 
9500 Euclid Avenue, A-81 
 
Cleveland, OH   44195 
 
 
Robert Debernardo, MD 
Department of  Obstetrics and Gynecology 
Women’s Health Institute 
Cleveland Clinic 
9500 Euclid Avenue, A-81 
 
Cleveland, OH   44195 
 
 


CASE 13815  
 
 
 
Page 2  
 
Version date: 08MAR2016 
 
 
 
 
 
 
 
 
 
 
Haider Mahdi, MD 
 
 
 
 
Department of  Obstetrics and Gynecology  
 
 
 
 
Women’s Health Institute 
 
 
Cleveland Clinic 
 
 
 
9500 Euclid Avenue, A-81 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
 
 
 
 
 
 
Jason Knight, MD 
 
 
 
 
Department of  Obstetrics and Gynecology  
 
 
 
 
Women’s Health Institute 
 
 
Cleveland Clinic 
 
 
 
9500 Euclid Avenue, A-81 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chad Michener, MD 
 
 
 
 
Department of  Obstetrics and Gynecology  
 
 
 
 
Women’s Health Institute 
 
 
Cleveland Clinic 
 
 
 
9500 Euclid Avenue, A-81 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
 
 
 
 
 
 
 
Stephanie Ricci, MD 
 
 
 
 
Department of  Obstetrics and Gynecology  
 
 
 
 
Women’s Health Institute 
 
 
Cleveland Clinic 
 
 
 
9500 Euclid Avenue, A-81 
 
 
 
 
Cleveland, OH   44195 
 
 
 
 
  
 
 
 
 
 
STATISTICIAN:  
 
Xiaobo Liu, Sr Biostatistician 
 
 
 
 
Cleveland Clinic  
 
 
 
 
 
 
9500 Euclid Ave, JJN3-01 
 
Cleveland, OH 44195  
 
 
 
 
 
 
 
 
 


CASE 13815  
 
 
 
Page 3  
 
Version date: 08MAR2016 
 
 
STUDY COORDINATOR: 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
SPONSOR:  
 
 
None 
 
 
 
SUPPORT/FUNDING: 
 
None 
 
STUDY AGENT:  
 
Paclitaxel and Carboplatin both commercially available 
 
 
STUDY SCHEMA: 
 
Paclitaxel 80 mg/m2 IV over 1 hour Days 1, 8, and 15 plus  
Carboplatin (AUC=6) IV Day 1  
Every 21 days x 6 - 9cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CASE 13815  
 
 
 
Page 4  
 
Version date: 08MAR2016 
 
 
PROTOCOL SUMMARY 
 
Protocol Number/Title 
Case 13815 A phase II trial of weight-based dosing for dense 
weekly paclitaxel and carboplatin in overweight patients with a  
BSA (Body Surface Area) of 2.0.  
Study Phase 
II 
Brief Background/Rationale 
 
 
 
The percentage of patients who are overweight or obese (BMI > 
30) in the United States is increasing yearly.[1] Overweight and 
obese patients are at increased risk of certain cancers.[2]  
Gynecologic cancers that are increased in obese patients include 
endometrial, cervical and ovarian cancer.  Cancer patients who 
are overweight or obese have poorer survival across many tumor 
types.  Suboptimal chemotherapy dose delivery is a potential 
contributing 
factor 
in 
this 
poorer 
survival 
outcome.  
Retrospective studies in breast cancer demonstrate the relative 
dose intensity (RDI) of chemotherapy decreases with increasing 
body mass index.[3]  In breast cancer, survival is decreased as 
the RDI falls below 85% of prescribed dose.[4]  In 2012 the 
American Society of Clinical Oncology (ASCO) issued practice 
guidelines for chemotherapy dosing in the obese.[5]  These 
guidelines recommended weight-based dosing for all but a few 
agents (i.e. carboplatin and bleomycin).  Unfortunately there is a 
dearth of prospective studies supporting this approach.  This is in 
part due to the fact that the Gynecologic Oncology Group has 
always capped the maximum body surface area (BSA) at 2.0.  
Despite the ASCO guidelines weight-based dosing remains 
controversial.[6] 
 
Clinicians 
often 
avoid 
weight-based 
chemotherapy dosing because of concerns of increased toxicity 
with these very large doses.   
Primary Objective  
The primary objective is to prospectively evaluate the Relative 
Dose Intensity (RDI) and toxicity of weight-based dose dense 
weekly paclitaxel and carboplatin in overweight patients with a 
BSA > 2.0 compared to the Japanese Gynecologic Oncology 
Group trial (JGOG 2016) during 6 – 9 cycles of chemotherapy. 
Secondary Objective(s) 
The secondary objective is to evaluate progression-free survival 
in this patient population. 
Sample Size 
28-34 females age 18 and over 
Disease sites/Conditions 
158.8 (C48.1), 180.9 (C53.9), 182.0(C54.1), 183.0 (C56.9), 
183.2 (C57.00) 
Interventions 
Paclitaxel 80mg/m2 IV days 1,8, and 15 every 21 days x 6-9 
cycles 
 
Carboplatin AUC 6 IV day 1 every 21 days x 6-9 cycles 
 
 
 


CASE 13815  
 
 
 
Page 5  
 
Version date: 08MAR2016 
 
 
ABBREVIATIONS  
 
 
 
 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CCCC 
Case Comprehensive Cancer Center 
CCF 
Cleveland Clinic Foundation 
CI 
Confidence Interval 
CRF 
Case Report Form 
c-TC 
Conventional taxol and carboplatin 
CTCAE 
Common Terminology Criteria for Adverse Events 
dd-TC 
Dose dense taxol and carboplatin 
DEHP 
Diethylhexyl phthalate 
DLT 
Dose Limiting Toxicity 
DSTC 
Data Safety and Toxicity Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
JGOG 
Japanese Gynecologic Oncology Group 
NCI  
National Cancer Institute 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PRMC 
Protocol Review and Monitoring Committee 
PVC 
Polyvinyl Chloride 
RDI 
Relative Dose Intensity 
RECIST Response Evaluation Criteria in Solid Tumors 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
Standard of Care 
WBC 
White Blood Count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background and Rationale 
 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
 
3.0 
STUDY DESIGN 
3.1 
Number of Subjects 
3.2 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2 
Premedication 
6.3      General Concomitant Medications and Supportive Care Guidelines 
6.4 
Criteria for Removal from Study 
6.5 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
7.1    Use of Hematopoietic Cytokines and Protective Agents 
7.2  
Modifications for Hematologic Toxicity 
7.3  
Guidelines for Non-hematologic Toxicity    
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Paclitaxel 
8.2 
Carboplatin 
8.3 
Definitions 
 
9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Commercial Agent(s) 
 
10.0 
STUDY PARAMETERS AND CALENDAR 
10.1 
Study Parameters 
10.2 
Calendar 
 
11.0 
MEASUREMENT OF EFFECT  
 


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12.0 
Data Reporting/Regulatory 
12.1 
Data Reporting 
12.2 
Regulatory Considerations  
12.3     Written Informed Consent 
12.4 
Subject Data Protection 
12.5  Retention of Records 
12.6  Audits and Inspections 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
REFERENCES 
 
APPENDICES 
 


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1.0 
Introduction  
 
1.1 
Background and Rationale of Study Disease  
The percentage of patients who are overweight or obese (BMI > 30) in the United States 
is increasing yearly.[1] Overweight and obese patients are at increased risk of certain 
cancers.[2]  Gynecologic cancers that are increased in obese patients include endometrial, 
cervical and ovarian cancer.  Cancer patients who are overweight or obese have poorer 
survival across many tumor types.  Suboptimal chemotherapy dose delivery is a potential 
contributing factor in this poorer survival outcome.  Retrospective studies in breast 
cancer demonstrate the relative dose intensity (RDI) of chemotherapy decreases with 
increasing body mass index.[3]  In breast cancer, survival is decreased as the RDI falls 
below 85% of prescribed dose.[4]  In 2012 the American Society of Clinical Oncology 
(ASCO) issued practice guidelines for chemotherapy dosing in the obese.[5]  These 
guidelines recommended weight-based dosing for all but a few agents (i.e. carboplatin 
and bleomycin).  Unfortunately there is a dearth of prospective studies supporting this 
approach.  This is in part due to the fact that the Gynecologic Oncology Group has 
always capped the maximum body surface area (BSA) at 2.0.  Despite the ASCO 
guidelines weight-based dosing remains controversial.[6]  Clinicians often avoid weight-
based chemotherapy dosing because of concerns of increased toxicity with these very 
large doses.   
 
In gynecologic oncology only one prospective trial evaluated the impact of BMI on 
progression-free survival (PFS) and overall survival (OS).[7]    This trial used weight-
based chemotherapy, and no difference in carboplatin or paclitaxel doses were noted 
based on BMI.   No difference on PFS or OS based on BMI was observed.  This trial was 
conducted in Scotland and BMIs >30, >40 and >50 were infrequent.  Retrospective 
studies in gynecologic oncology patients receiving weight-based chemotherapy have not 
demonstrated increased toxicity.[8,9]  Counter-intuitively, in one study patients with a 
BSA >2.0 receiving weight-based chemotherapy dosing had less toxicity than patients 
with a BSA >2.0 receiving capped BSA chemotherapy dosing.[9]    
 
Based on the practice of dose capping in the Gynecologic Oncology Group there is 
limited prospective data regarding the use of weight-based dosing in gynecologic cancers.        
 
Dose dense weekly paclitaxel has improved progression-free and survival compared to 
every three week paclitaxel in breast and ovarian cancer. The dose dense administration 
schedule of chemotherapy administers smaller more frequent doses of chemotherapy. The 
Japanese Gynecologic Oncology Group performed a randomized phase III trial of 
conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and 
carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or 
primary peritoneal cancer.[10] The patients were randomly assigned to receive 
carboplatin (AUC=6) with either paclitaxel at 180 mg/m2 on day 1 (c-TC) or paclitaxel at 
80 mg/m2 on days 1, 8, and 15 (dd-TC). The treatments were repeated every 3 weeks for 
six cycles. Of 637 patients, the median duration of PFS in the c-TC group and dd-TC 
group was 17.1 and 27.9 months, respectively (p=0.0014), and overall survival at 2 years 
was 77.7% and 83.6%, respectively (p=0.05). Grade 3 and 4 anemia was reported more 


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frequently in the dd-TC group, and other toxicities were similar in both groups. These 
authors concluded that dose dense weekly TC improves PFS as compared with c-TC in 
patients with advanced epithelial ovarian cancer. A potential advantage of weekly versus  
every 3 week chemotherapy in weight based dosing is the ability to hold or reduce 
weekly chemotherapy doses in patients who demonstrate hematologic and non-
hematologic toxicities.    
 
The European Organization for Research and Treatment of Cancer randomized patients 
to primary debulking surgery followed by platinum-based chemotherapy versus 
neoadjuvant platinum-based chemotherapy followed by debulking surgery.[11] Of 670 
patients, the hazard ratio for death in the group assigned to neoadjuvant chemotherapy 
followed by interval debulking, as compared with the group assigned to primary 
debulking surgery followed by chemotherapy, was 0.98 (90% confidence interval [CI], 
0.84 to 1.13; P = 0.01 for noninferiority), and the hazard ratio for progressive disease was 
1.01 (90% CI, 0.89 to 1.15). These investigators concluded that neoadjuvant 
chemotherapy followed by interval debulking surgery was not inferior to primary 
debulking surgery followed by chemotherapy as a treatment option for patients with 
bulky stage IIIC or IV ovarian carcinoma. Although it is not the intent of this current 
study to compare neoadjuvant chemotherapy followed by interval debulking vs. primary 
surgery with adjuvant chemotherapy, it is important to include this subset of patients in 
this clinical trial to afford them the greatest potential benefit of dose dense and weight 
based chemotherapy dosing.   
 
The purpose of the current study is to prospectively evaluate the toxicity and efficacy of 
weight-based dose dense weekly paclitaxel and carboplatin in overweight patients with a 
BSA > 2.0.    
 
 
2.0  
Objectives 
2.1  
Primary Objective  
The primary objective is to prospectively evaluate the Relative Dose Intensity (RDI) and 
toxicity of weight-based dose dense weekly paclitaxel and carboplatin in overweight 
patients with a BSA > 2.0 compared to the Japanese Gynecologic Oncology Group trial 
(JGOG 2016) during 6 – 9 cycles of chemotherapy. 
2.2 
Secondary Objective(s) 
The secondary objective is to evaluate progression-free survival in this patient 
population.  
 
3.0 
Study Design 
This is a descriptive study to determine what the relative dose intensity of patients who 
are overweight with a BSA of greater than 2.0 can achieve.  
 
3.1 
Number of Subjects 
Approximately 28- 34 subjects will be enrolled in this trial.  


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3.2  
Expected Duration of Treatment and Subject Participation 
Patients will receive carboplatin and weekly taxane therapy every 21 days for six – nine 
cycles, unless disease progression, or adverse events require discontinuing protocol 
treatment. 
 
4.0 
Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be 
considered eligible for this study.  
 
4.1 
Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 
4.11 Patients with a histologically confirmed or presumed diagnosis of 
gynecologic malignancy for whom chemotherapy with paclitaxel and carboplatin 
is planned.   
 
4.12  Body Surface area >2.0   
 
4.13 Patients must have adequate:  
4.131Renal function: Creatinine <1.5 x Institutional upper limits of normal 
(ULN) 
 
            
 4.132 Bone marrow function:  
4.1321  Absolute neutrophil count (ANC) > 1,500/mcl. This ANC 
cannot have been induced or supported by granulocyte colony 
stimulating factors.  
4.1322 Platelets > 100,000/mcl.  
 
4.133 Hepatic function:  
4.1331 Bilirubin < 1.5 x ULN.  
4.1332 AST (SGOT) ≤ 2.5 x ULN. 
4.1333 Alkaline phosphatase < to 2.5 x ULN.  
 
4.134 Neurologic function:  
4.1341  Neuropathy (sensory and motor) <  CTCAE Grade 1.  
4.14 Patients must have a Eastern Cooperative Oncology Group (ECOG) 
Performance Status of 0, 1, or 2. (Appendix I) 
 
4.15 Patients must be entered within 12 weeks of diagnosis. 
 
4.16 Age >18 years. Patients under the age of 18 are best treated by pediatric 
oncology. 
  
 


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4.17 Subjects must have the ability to understand and the willingness to sign a 
written informed consent document. 
 
4.2 
Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment. 
 
4.21    Patients who have received prior radiotherapy to any portion of the 
abdominal cavity or pelvis. Prior radiation for localized cancer of the breast, head 
and neck, or skin is permitted, provided that it was completed more than three 
years prior to registration, and the patient remains free of recurrent or metastatic 
disease.  
 
4.22   Patients who have received prior chemotherapy. 
 
4.23 Patients with acute hepatitis or active infection that requires parenteral 
antibiotics.  
 
4.24 Patients with clinically significant cardiovascular disease. This includes:   
4.241 Myocardial infarction or unstable angina < 6 months prior to 
registration.  
4.242 New York Heart Association (NYHA) Grade II or greater 
congestive heart failure (Appendix II).  
4.243 Serious cardiac arrhythmia requiring medication. This does not 
include asymptomatic, atrial fibrillation with controlled ventricular rate.  
 
4.25 Patients who are pregnant or nursing. Pregnant or breastfeeding  
women are excluded from this study because here are no adequate 
and well controlled studies using paclitaxel or carboplatin in pregnant  
women. Animals studies  have revealed evidence of embryotoxicity  
and teratogenicity.  
        
4.26 Patients under the age of 18.  
 
4.27 Patients with medical history or conditions not otherwise previously  
specified which in the opinion of the investigator should exclude  
participation in this study.  
 
4.28 Patients with known allergy to cremophor or polysorbate 80.  
 
 
4.3 
Inclusion of Women and Minorities  
Women of all races and ethnic groups are eligible for this trial. 
 
 
 
 


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5.0 
Registration 
All subjects who have been consented will be registered in the OnCore™ Database. For 
those subjects who are consented, but not enrolled, the reason for exclusion will be 
recorded. 
 
6.0  
Treatment Plan 
Each investigator must be CITI (Collaborative Institutional Training Initiative) certified 
to participate in clinical research at the Cleveland Clinic Health System.  
 
6.1 
Treatment Regimen Overview: Chemotherapy administration 
All patients will receive Paclitaxel 80 mg/m2 IV over 1 hour on days 1, 8, and 15 plus 
Carboplatin (AUC 6) IV day 1 every 21 days x 6 – 9 cycles.  
 
One cycle = 21 days. 
 
Paclitaxel dosing only will be based on actual BSA. There will be no capping of 
doses for Paclitaxel. BSA will be recalculated for a 10% weight change.  
 
Carboplatin will be recalculated each cycle. (See Appendix III for Carboplatin  Dose 
Calculations)  
 
Intravenous paclitaxel will be infused over one hour. Due to the risk of immediate 
hypersensitivity reaction, paclitaxel should always be the first drug to be infused during 
any combination. Carboplatin will be administered as a 30 minute infusion, following 
paclitaxel administration. 
 
6.2 Premedications:  
The following premedication is suggested prior to chemotherapy infusion on all days. 
 
Ondansetron 8-16 mg IV or PO 30 minutes prior to administration of chemotherapy. (On 
Day 1 of each cycle palonosetron 0.25mg IV can be given instead of ondansetron per 
physician discretion).  
Dexamethasone 20 mg PO 12 and 6 hours prior to paclitaxel or  
10-20 mg IV just prior to IV therapy.  
Diphenhydramine 25- 50 mg IV 30 minutes prior to paclitaxel.  
Famotidine 20mg IV 30 minutes prior to chemotherapy. 
 
Because the number of dexamethasone doses for a weekly paclitaxel regimen may be 
problematic for some patients, investigators can consider tapering the dexamethasone 
dose down in subsequent weeks for those patients who have no evidence of 
hypersensitivity reactions.  
 
Appropriate dose modifications for paclitaxel and carboplatin are described in Section 
7.0.  
 
 


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6.3 
General Concomitant Medications and Supportive Care Guidelines 
Subjects should receive full supportive care, including transfusions of blood and blood 
products, cytokines, antibiotics, antiemetics, etc when appropriate. 
 
6.4 
Criteria for Removal from Study 
In the absence of treatment delays due to adverse events, treatment may continue for  
6 – 9 cycles or until one of the following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• The investigator considers it, for safety reasons, to be in the best interest of the subject.  
 
• Unacceptable adverse event(s)  
 
6.5 
Duration of Follow Up 
 
Subjects will be followed for progression free survival after discontinuation from study 
treatment as follows: every 3 months for 2 years, then every 6 months for 3 years, then 
annually until disease progression.  
 
7.0  
Dose Delays/Dose Modifications 
 
General Guidelines for Hematologic Toxicity: 
In order to maintain dose-intensity and cumulative dose-delivery on this study, 
reasonable efforts will be made to minimize dose reduction and treatment delays as 
specified. Any patient whose treatment is delayed must be evaluated on a weekly basis 
until adequate hematologic and non-hematologic parameters have been met. No dose 
escalation is planned for this study. Treatment decisions will be based on the absolute 
neutrophil count (ANC) rather than the total white cell count (WBC).  
 
Day 1 of a subsequent cycle of cytotoxic chemotherapy will not be administered until the 
ANC is ≥ 1000 cells/mcl and a platelet count of 75,000/mcl.   
 
Day 8 and 15 paclitaxel dose will not be given unless the ANC is at least  
500 cells/mcl and the platelet count is at least 50,000/mcl. If not given, these doses are 
omitted and not made up.  
 
 
All treatment will be delayed for a maximum of three weeks until these values are 
achieved. Patients who fail to recover adequate counts within a three-week delay will no 
longer receive protocol-directed cytotoxic therapy.  
 
 
 


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7.1  Use of Hematopoietic Cytokines and Protective Agents  
Hematopoietic growth factors should not be used to avoid initial chemotherapy dose 
modifications as stipulated in the protocol. However, subjects may also receive growth 
factors for the management of neutropenic complications in accordance with institutional 
treatment guidelines. 
 
 
 
7.11 Patients will NOT receive prophylactic thrombopoietic agents.  
 
7.12 Patients may NOT receive amifostine or other protective reagents.  
 
7.2 Modifications for Hematologic Toxicity  
Neutropenia and thrombocytopenia events defined below will be handled according to 
Table A. 
 
7.21 Neutropenia defined as the occurrence of febrile neutropenia, prolonged 
Grade 4 neutropenia persisting ≥ 7 days, delay of treatment for more than 7 days 
because of neutropenia, ANC<1000cells/mcl on day 1, or omission of day 8 or 
day 15 paclitaxel  because of neutropenia.  
 
7.211 Febrile neutropenia is defined within the CTCAE as a disorder 
characterized by an ANC <1000/mcl and a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than one hour.  
 
7.22 Thrombocytopenia defined as any occurrence of Grade 4 thrombocytopenia 
(<25,000/mcl) or bleeding associated with Grade 3 thrombocytopenia (25,000 to 
<50,000/mcl), delay of treatment on day 1 of a cycle by more than 7 days because 
of thrombocytopenia, platelet count of <75,000/mcl on day 1, or inability to give 
day 8 or day 15 paclitaxel due to thrombocytopenia.  
7.221There will be no modifications for uncomplicated Grade 3 
thrombocytopenia except as above.  
 
 
 
 
 
 
 


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Table A  
Neutropenia 
as described 
above 
Thrombocytopenia 
as described above 
First Occurrence 
Second Occurrence  
Third Occurrence 
YES 
NO 
Reduce paclitaxel 
to 70 mg/m²  
Reduce paclitaxel to 60 
mg/m² 
Omit day 15 
paclitaxel and 
administer G-CSF 
starting after day 8 
paclitaxel 
YES 
YES 
Reduce 
carboplatin to an 
AUC of 5 and 
paclitaxel to 70 
mg/m² 
Reduce carboplatin to 
an AUC of 4 and 
paclitaxel to 60 mg/m² 
Reduce  carboplatin 
to an AUC of 4, 
Omit day 15 
paclitaxel and 
administer G-CSF 
starting after day 8 
paclitaxel 
NO 
YES 
Reduce 
carboplatin to an 
AUC of 5 
Reduce  carboplatin to 
an AUC of 4 
Reduce  carboplatin 
to an AUC of 4, 
Omit day 15 
paclitaxel  
 
7.23 There will be no dose modifications made for anemia. Patients my receive 
red blood cell transfusions per institutional guidelines. 
 
7.3 Guidelines for Non-hematologic Toxicity 
 
7.31 Peripheral Neuropathy grade 2 or higher requires treatment delay until 
recovery to grade 1 and dose reduction according to table B.  
 
7.32 Hepatic Toxicity. For a grade 3 or higher elevation in SGOT, SGPT, 
alkaline phosphatase or bilirubin delay treatment until recovery to grade 1 and 
follow table B.  
 
  
 
7.33 Hypersensitivity Reaction 
Patients who experience hypersensitivity reactions to either drug may need to 
repeat the premedication and to be rechallenged with a dilute solution and slow 
infusion per institutional guidelines. Severe hypersensitivity reactions to 
paclitaxel do not have to proceed with a rechallenge. Removal from study should 
be considered.  
 
7.34 Other grade 3 or grade 4 treatment related toxicities (except alopecia, 
nausea/vomiting, constipation, diarrhea, hypokalemia, hypocalcemia, 
hypophosphatemia, hyponatremia, or hypomagnesemia) delay treatment until 
recovery to grade 1 and dose reduce according to table B.  
 
 
 


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Table B 
Toxicity 
First Occurrence 
Second Occurrence 
Third Occurrence 
Neuropathy grade 2 or 
higher 
Decrease paclitaxel to 
70 mg/m2.  
Decrease paclitaxel to 
60 mg/m2. 
Contact PI. Consider 
study removal. 
Hepatic grade 3 or 
higher 
Decrease paclitaxel to 
70 mg/m2.  
Decrease paclitaxel to 
60 mg/m2. 
Contact PI. Consider 
study removal. 
Other grade 3 or 4 
treatment related 
Decrease one dose 
level of drug 
presumed responsible 
(Paclitaxel 70mg/m2 
or carboplatin AUC 5) 
Decrease one dose 
level of drug 
presumed responsible 
(Paclitaxel 60mg/m2 
or carboplatin AUC 4) 
Contact PI. Consider 
study removal. 
 
For any toxicity not recovering to a grade 1 or better following a 3 week delay despite 
dose reductions discuss with study PI and consider removal from study.  
 
8.0 
Adverse Events and Potential Risks  
 
8.1 
Paclitaxel  
The most common (> 10%) adverse events associated with paclitaxel are: 
● Low white blood cell counts – this may make you more open to infection 
● Low platelet count – this may make you bruise more easily and bleed longer if 
injured  
● Low red blood cell count which may cause tiredness, shortness of breath and may 
cause the need for a blood transfusion 
● Bleeding 
● Mild to severe allergic reaction which may be life-threatening with hives, wheezing 
and a change in blood pressure (low or high) 
● Changes in the nerves that can cause numbness, tingling, or pain in the hands and 
feet.  This may lead to difficulty walking, buttoning clothes, etc. 
● Nausea and/or vomiting 
● Sores in the mouth or throat (that can lead to difficulty swallowing and dehydration)  
● Local swelling, redness, or skin tissue damage if some of the drug leaks from the vein 
while it is being given  
● Diarrhea 
● Hair loss 
● Muscle and joint aches 
● Low blood pressure that may cause lightheadedness 
Please refer to the package insert(s) for the comprehensive list of adverse events. 
 
 
 


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8.2 Carboplatin  
The most common (> 10%) adverse events associated with carboplatin are: 
 Low white blood cell counts - this may make you more open to infection  
 Low platelet count - this may make you bruise more easily and bleed longer if 
injured  
 Low red blood cell count which may cause tiredness, shortness of breath or 
fatigue and may cause the need for a blood transfusion. 
 Tiredness 
 Loss of appetite and weight loss 
 Diarrhea, constipation, nausea and vomiting, and abdominal pain 
 Complete hair loss 
 Skin rash 
 Changes in taste 
 Changes in electrolytes and minerals in the blood such as magnesium, potassium, 
sodium, and calcium 
Please refer to the package insert(s) for the comprehensive list of adverse events. 
 
8.3  Definitions  
 
8.31  Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or    
psychological, associated with a research study, which causes harm or injury to a 
research participant as a result of the participant’s involvement in a research 
study. The event can include abnormal laboratory findings, symptoms, or disease 
associated with the research study. The event does not necessarily have to have a 
causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the 
research; the collection of identifiable private information in the research; an 
underlying disease, disorder, or condition of the subject; and/or other 
circumstances unrelated to the research or any underlying disease, disorder, or 
condition of the subject.  
 
8.32   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose 
that results in any of the following outcomes:  
 Results in death.  
 Is a life-threatening adverse experience.  The term life-threatening in 
the definition of serious refers to an adverse event in which the subject 
was at risk of death at the time of the event.  It does not refer to an 
adverse event which hypothetically might have caused death if it were 
more severe.  


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 Requires inpatient hospitalization or prolongation of existing 
hospitalization.  Any adverse event leading to hospitalization or 
prolongation of hospitalization will be considered as Serious, 
UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization 
may fulfill the criteria of “medically important” and as such may be reportable as 
a serious adverse event dependant on clinical judgment.  In addition where local 
regulatory authorities specifically require a more stringent definition, the local 
regulation takes precedent.  
 Results in persistent or significant disability/incapacity.  The definition of 
disability is a substantial disruption of a person’s ability to conduct normal 
life’s functions. 
 Is a congenital anomaly/birth defect.  
 Is an important medical event.  Important medical events that may not result 
death, be life-threatening, or require hospitalization may be considered a 
serious adverse experience when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples 
of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood disease or disorders, or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
8.33 
Adverse Event Evaluation  
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) criteria version 4.0 will be used to classify toxicities observed 
during treatment. The severity of each toxicity will be assessed according to the NCI 
CTCAE 4.0 grading system. Patients will be tabulated according to their maximum 
severity for each organ system or preferred term.  
 
Safety endpoints will be summarized with descriptive statistics for the patients in the 
safety analysis dataset. The safety analysis dataset will include all patients enrolled to 
the study who receive any study treatment Patients who do not receive any study 
treatment will not be included in these analyses. 
 
In addition to toxicity an important measure of tolerance of dose dense therapy is the 
ability to receive chemotherapy at the planned dose and schedule.  Comparison of the 
study patient adherence to planned dose and schedule will be computed utilizing 
relative dose intensity (RDI).  The RDI of the study population will be compared to 


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the RDI reported by Katsumata and the RDI of a CCF (Cleveland Clinic Foundation) 
cohort of patients with a BSA <2.0.     
 
9.0  Pharmaceutical Information  
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section #8.  
 
9.1 Commercial Agents 
9.11  Name of Agent: paclitaxel (NSC #673089) 
Other Names: Taxol 
 
Product description:  
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi dose vials 
containing 30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel. In addition 
to 6mg of paclitaxel, each mL of sterile non-pyrogenic solution contains 527mg 
of purified Cremophor® EL (polyoxyethylated castor oil) and 49.7% (v/v) 
dehydrated alcohol, USP. 
 
Solution preparation:  
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% 
Sodium Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose 
and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection 
to a final concentration of 0.3 to 1.2mg/mL. The solutions are physically and 
chemically stable for up to 27 hours at ambient temperature (approximately 25°C 
/ 77°F) and room lighting conditions. 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may 
be leached from PVC infusion bags or sets, diluted paclitaxel solutions should be 
stored in bottles (glass, polypropylene) or plastic (polypropylene, polyolefin) bags 
and administered through polyethylene-lined administration sets. 
Paclitaxel should be administered through an inline filter with a microporous 
membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® 
or IVEX-HP®, which incorporate short inlet and outlet PVC-coated tubing, has 
not resulted in significant leaching of DEHP. 
 
All patients should be premedicated with corticosteroids, diphenhydramine, and 
H2 antagonists prior to paclitaxel administration in order to prevent severe 
hypersensitivity reactions. Patients who experience severe hypersensitivity 
reactions to drug may need to repeat the premedication and to be rechallenged 
with a dilute solution and slow infusion. Severe hypersensitivity reactions to 
paclitaxel do not have to proceed with a rechallenge. 
 
Storage requirements:  
Unopened vials of paclitaxel are stable to the date indicated on the package when 
stored between 20 to 25°C (68 to 77°F). Protect from light. 
 


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Supplier: Commercially available both from Bristol-Myers Squibb Oncology as 
well as generic manufacturers. Consult the American Hospital Formulary Service 
Drug Information guide, Facts and Comparisons, or the package insert for 
additional information. 
 
9.12  Name of Agent: paraplatin 
Other Names:  Carboplatin 
 
Product description: Carboplatin is supplied as a sterile, pyrogen-free, 10mg/mL 
aqueous solution in multi-dose vials containing 50mg/5mL, 150mg/15mL, 
450mg/45mL, or 600mg/60mL of carboplatin. 
 
Solution preparation: Preparation: Carboplatin aqueous solution can be further 
diluted to concentrations as low as 0.5mg/mL with 5% Dextrose in Water or 0.9% 
Sodium Chloride for Injection, USP. When prepared as directed, carboplatin 
aqueous solutions are stable for 8 hours at room temperature (25°C / 77°F). Since 
no antibacterial preservative is contained in the formulation, it is recommended 
that carboplatin solutions be discarded 8 hours after dilution. Institutional 
pharmacy policy may allow refrigeration and longer storage.  
 
NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss 
of potency; therefore, needles or intravenous sets containing aluminum parts that 
may come in contact with the drug must NOT be used for the preparation or 
administration of carboplatin. 
 
Storage requirements: Unopened vials of carboplatin are stable to the date 
indicated on the package when stored at 25°C (77°F). Excursions from 15 to 30°C 
(59 to 86°F) are permitted. Protect from light. Carboplatin multi dose vials 
maintain microbial, chemical, and physical stability for up to 14 days at 25°C 
following multiple needle entries. 
 
Supplier: Commercially available both from Bristol-Myers Squibb Oncology as 
well as generic manufacturers. Consult the American Hospital Formulary Service 
Drug Information guide, Facts and Comparisons, or the package insert for 
additional information. 
 
10.0  Study Parameters and Calendar  
10.1Study Parameters 
10.11 Screening Evaluation  
Within 28 days prior to initiating protocol therapy the following are 
required: history and physical examination and a CA-125 blood test.  
An initial CT scan or MRI of at least the abdomen/ pelvis and Chest CT or 
X-ray is required to establish post-surgical baseline for the extent of 
residual disease within 4 weeks before beginning treatment. 
 


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Within 14 days prior to initiating protocol therapy: Toxicity assessment, 
CBCD, CMP, phosphorus, Magnesium and serum pregnancy test (for 
those of childbearing potential).  
 
10.12 Treatment Period 
During chemotherapy a weekly CBCD within 2 days of retreatment is 
required.  
 
Prior to each course of therapy: History and physical, toxicity assessment 
and a CA-125 is required. In addition within 2 days of retreatment: CBCD, 
CMP, Magnesium, and phosphorus. 
 
Radiographic disease assessment (the same as baseline assessment) is 
required prior to every 3 cycles.  
 
10.13   Follow up Period 
History and physical, and CA-125 is required every 3 months for 2 years, 
every 6 months for 3 years, then annually until disease progression. 
CBCD, CMP, Magnesium, and phosphorus to be performed as clinically 
indicated. Radiographic disease assessment (same as baseline) to be 
performed as clinically indicated or at least yearly.  
 
10.2 
Study Calendar  
 
 
Pre-
Treatment 
During Cytotoxic 
Chemotherapy 
Post-Treatment 
Observations and Tests 
Prior to 
Initial Study 
Treatment 
Weekly Prior to 
Each 
Course 
Prior to 
every 
other 
course 
Every 3 months 
for 2 years, every 
6 months for 3 
years, then 
annually until 
disease 
progression 
History & Physical 
1 
 
X 
 
X 
Toxicity Assessment 
2 
 
X 
 
 
CBC/Differential/Platelets 
2 
3 
3 
 
5 
Serum Creatinine 
2 
 
3 
 
5 
Bilirubin, SGOT, Alkaline 
Phosphatase 
2 
 
3 
 
5 


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Ca/PO4/Mg 
2 
 
3 
 
5 
Serum Pregnancy test (if 
childbearing potential 
exists) 
2 
 
 
 
 
 
Radiographic disease 
assessment 
4 
 
 
 
prior to 
every 3 
cycles 
5 - at least 
yearly 
Chest X-Ray (or CT 
chest) 
4 
 
 
prior to 
every 3 
cycles 
5 - at least 
yearly 
Serum CA-125 level 
1 
 
X 
 
X 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2. Must be obtained within 14 days prior to initiating protocol therapy. 
3. Must be obtained within 2 days of re-treatment with protocol therapy. 
4.  An initial CT scan or MRI of at least the abdomen/ pelvis and Chest CT or X-ray is 
required to establish post-surgical baseline for the extent of residual disease within 4 
weeks before beginning treatment. 
5. When clinically indicated 
 
11.0  Measurement of Effect  
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.0 
Data Reporting / Regulatory   
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
8.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting  
The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer 
Center, to provide data collection for both accrual entry and trial data management. 
OnCore™ is a Clinical Trials Management System housed on secure servers maintained 
at Case Western Reserve University. OnCore™. Access to data through OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the OnCore™ system 
with a user ID and password, OnCore™ defines roles for each user which limits access to 
appropriate data. User information and password can be obtained by contacting the 
OnCore™ Administrator at OnCore-registration@case.edu. 
 
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification. This study will utilize electronic 


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Case Report Form completion in the OnCore™ database. A calendar of events and 
required forms are available in OnCore™. 
 
12.2  Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable 
federal (including 21 CFR parts 56 & 50), state or local laws. 
12.3 
Written Informed Consent 
Provision of written informed consent must be obtained prior to any study-related 
procedures. The Principal Investigator will ensure that the subject is given full and 
adequate oral and written information about the nature, purpose, possible risks and 
benefits of the study as well as the subject’s financial responsibility. Subjects must also 
be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and be allowed time to consider the 
information provided.  
The original, signed written Informed Consent Form must be kept with the Research 
Chart in conformance with the institution’s standard operating procedures. A copy of the 
signed written Informed Consent Form must be given to the subject. Additionally, 
documentation of the consenting process should be located in the research chart. 
12.4 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or 
allow the sponsor, a regulatory authority, or Institutional Review Board access to 
subject’s medical information that includes all hospital records relevant to the study, 
including subjects’ medical history.  
 
12.5  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the 
retention of all documentation of adverse events, records of study drug receipt and 
dispensation, and all IRB correspondence for as long as needed to comply with local, 
national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted.  
 
12.6  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonization (ICH), and any 
applicable regulatory requirements.   
 
 


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13.0  Statistical Considerations 
The purpose of the study is to evaluate the relative dose intensity that can be achieved in 
the obese patient population.  Previous studies have demonstrated that the relative dose 
intensity of less than 85% is suboptimal and associated with a poorer survival in breast 
cancer.  In ovarian cancer, Kutsamata et al was able to deliver a relative dose intensity of 
paclitaxel of 79% and the relative dose intensity of carboplatin of 77%.  Therefore, this is 
a descriptive study to determine what the relative dose intensity of patients who are obese 
with a BSA of greater than 2.0 can achieve.   
 
Sample size calculations were performed on the primary objective of the study, 
evaluating whether RDI can be increased from 0.77 to 0.90.  We believe that the standard 
deviation of RDI will be similar in magnitude of those in Japanese GOG article.  Thus, 
we base our sample size calculations on these estimates.  Calculations assumed the use of 
a one-sided T-test with a 0.05 significance level and a standard deviation of 0.18, as 
suggested by previous research, Japanese GOG article.  Under these assumptions, there 
will be 80% power to show an increase from 0.77 to 0.90 of RDI with a total of 50 
subjects. 
 
Table 1: Sample size  
 
Null RDI  
Proposed RDI 
Standard 
Deviation 
Power 
N 
0.77 
0.90 
0.18 
0.8 
50 
The total population accrued will be evaluated to evaluate their relative dose intensity 
relative to the previous achieved results by Kutsamata et al.  Analysis of subgroups of 
patients with BMIs between 30 and <40, 40 and <50, 50 and <60, and >60 will be 
planned.   
 
 
 
 
 
 
 
 
 


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REFERENCES 
1. Ligibel JA, Alfano CM, Courneya KS, et al.   American Society of Clinical 
Oncology Position Statement on Obesity and Cancer  J Clin Oncol 2014;32:3568-
3574. 
 
2. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and 
mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J 
Med. 2003;348:1625-38. 
3. Lyman GH, Sparreboom A.   Chemotherapy dosing in overweight and obese 
patients with cancer.  Nat Rev Clin Oncol. 2013;10:451-9. 
4. Colleoni M1, Li S, Gelber RD, et al.  Relation between chemotherapy dose, 
oestrogen receptor expression, and body-mass index. Lancet. 2005;366:1108-10. 
 
5. Griggs JJ1, Mangu PB, Anderson H, et al.  Appropriate chemotherapy dosing for 
obese adult patients with cancer: American Society of Clinical Oncology clinical 
practice guideline.  J Clin Oncol. 2012;30:1553-61.  
6. Hansen J, Stephan JM, Freesmeier M, Bender D, Button A, Goodheart MJ.  The 
effect of weight-based chemotherapy dosing in a cohort of gynecologic oncology 
patients.  Gynecol Oncol. 2015;138:154-8. 
7. Barrett SV1, Paul J, Hay A, Vasey PA, Kaye SB, Glasspool RM; Scottish 
Gynaecological Cancer Trials Group.   Does body mass index affect progression-
free or overall survival in patients with ovarian cancer? Results from SCOTROC I 
trial.  Ann Oncol. 2008;19:898-902 
 
8. Au-Yeung G1, Webb PM2, DeFazio A3, Fereday S4, Bressel M5, Mileshkin L6.  
Impact of obesity on chemotherapy dosing for women with advanced stage serous 
ovarian cancer in the Australian Ovarian Cancer Study (AOCS).  Gynecol Oncol. 
2014;133:16-22. 
 
9. Schwartz J1, Toste B, Dizon DS.  Chemotherapy toxicity in gynecologic cancer 
patients with a body surface area (BSA)>2 m2. Gynecol Oncol. 2009;114:53-6.  
 
10. Katsumata N1, Yasuda M, Takahashi F, et al.  Dose-dense paclitaxel once a week 
in combination with carboplatin every 3 weeks for advanced ovarian cancer: a 
phase 3, open-label, randomized controlled trial.  Lancet. 2009;374:1331-8. 
 
11. Vergote I, Tropé CG, Amant F et al.  Neoadjuvant chemotherapy or primary 
surgery in stage IIIC or IV ovarian cancer.  N Engl J Med. 2010;363:943-5. 


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APPENDIX I 
ECOG Performance Status 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair.* 
GRADE 
ECOG 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 waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-655. 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX II 
NEW YORK HEART ASSOCIATION (NYHA) CARDIAC CLASSIFICATION 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classeso
f- 
Heart-Failure_UCM_306328_Article.jsp 
Please refer to link for most current and up to date information on heart failure 
Classification. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX III 
Carboplatin Calculations 
Dosing of Carboplatin: 
1. The carboplatin dose will be calculated to reach a target area under the curve 
(AUC) according to the Calvert formula using an estimated glomerular filtration 
rate (GFR) from the Cockcroft-Gault formula. 
 
2. The  dose of carboplatin must be calculated using GFR and recalculated each cycle. 
 
3. Carboplatin doses are required to be recalculated if the subject has a weight change 
of greater than or equal to 10%. Subjects are permitted to have chemotherapy 
doses recalculated for < 10% weight changes. 
 
4. At the time of dose modification, if the subject's age had changed (the subject has 
had a birthday), the site can use the current age. 
 
5. In subjects with an abnormally low serum creatinine (less than 0.7 mg/dl), the 
creatinine clearance should be estimated using a minimum value of 0.7 mg/dl. For 
trials where subjects enter and are treated within less than or equal to 12 weeks of 
surgery: If a more appropriate (higher) baseline creatinine value is available from the pre-
operative period (within 4 weeks of surgery that value may also be used for the initial 
estimation of GFR.  
 
CALVERT FORMULA: 
 
Carboplatin dose (mg) = target AUC × (GFR + 25) 
NOTE: the GFR used in the Calvert formula should not exceed 125 ml/min. Maximum 
carboplatin dose (mg) = target AUC (mg/min) × 150 ml/min. The maximum allowed 
doses of carboplatin are: 
● AUC 6 = 900 mg 
● AUC 5 = 750 mg 
● AUC 4 = 600 mg 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance.  
 
The estimated creatinine clearance (ml/min) is calculated by the 
method of Cockcroft-Gault using the following formula: 
 
Creatinine Clearance (mL/min) = [140-Age (years)] × Weight (kg) × 0.85 
                       72 × serum creatinine (mg/dl) 
Notes: 
1. Weight in kilograms (kg) 
a. Body Mass Index (BMI) should be calculated for each patient. A BMI 
calculator is available at the following link: http://www.nhlbisupport.com/bmi/ 


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b. Actual weight should be used for estimation of GFR for patients with BMI of 
less than 25 
c. Adjusted weight should be used for estimation of GFR for patients with BMI 
of greater than or equal to 25 
d. Adjusted weight calculation: 
● Ideal weight (kg) = (((Height (cm)/2.54) – 60) × 2.3) + 45.5 
● Adjusted weight (kg) = (Actual weight – Ideal weight) × 0.40) + Ideal 
weight 
 
2. The Cockcroft-Gault formula above is specifically for women (it includes the 
0.85 factor). 
 
At the time of a dose modification for toxicity: 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the 
time of a dose modification is higher than the creatinine used to calculate the previous 
dose, use the current (higher) creatinine. This will ensure that the patient is actually 
receiving a dose reduction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix IV 
 
RECIST 1.1  
Response Evaluation Criteria in Solid Tumors (RECIST)  
Quick Reference: 
ctep.cancer.gov/protocolDevelopment/docs/quickrcst.doc 
Eligibility 
 Only patients with measurable disease at baseline should be included in 
protocols where objective tumor response is the primary endpoint.  
Measurable disease - the presence of at least one measurable lesion. If 
the measurable disease is restricted to a solitary lesion, its neoplastic 
nature should be confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least 
one dimension with longest diameter  20 mm using conventional 
techniques or 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), i.e., bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not 
confirmed and followed by imaging techniques; and. 
 All measurements should be taken and recorded in metric notation, using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before 
the beginning of the treatment.  
 The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up.  
 Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended.  
Methods of Measurement –  
 
 CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT 
and MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous 


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reconstruction algorithm.  This applies to tumors of the chest, abdomen and 
pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. 
 
 Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.  
 
 When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, 
a possible alternative to clinical measurements of superficial palpable lymph 
nodes, subcutaneous lesions and thyroid nodules. US might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
 
 The utilization of endoscopy and laparoscopy for objective tumor evaluation 
has not yet been fully and widely validated. Their uses in this specific context 
require sophisticated equipment and a high level of expertise that may only 
be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in 
specialized centers. However, such techniques can be useful in confirming 
complete pathological response when biopsies are obtained. 
 
 Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response when all lesions have disappeared. 
 
 Cytology and histology can be used to differentiate between PR and CR in 
rare cases (e.g., after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as germ cell 
tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, representative of all involved organs should be identified as 
target lesions and recorded and measured at baseline.  
 Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated 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 by which to characterize the objective tumor. 


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 All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
Response Criteria 
Evaluation of target lesions 
* Complete 
Response (CR): 
Disappearance of all target lesions 
* Partial Response 
(PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
* Progressive 
Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions 
* Stable Disease 
(SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
Evaluation of non-target lesions 
* Complete 
Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
* Incomplete 
Response/          
Stable Disease 
(SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
* Progressive 
Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is 
exceptional, in such circumstances, the opinion of the treating 
physician should prevail.  
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment started). In general, the 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria  
 


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Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
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 
 
 Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be classified as having “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after 
discontinuation of treatment.  
 In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) to confirm the complete response status. 
 
Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating 
the response rate observed.  In cases where confirmation of response is not 
feasible, it should be made clear when reporting the outcome of such studies 
that the responses are not confirmed. 
 To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed no less than 4 
weeks after the criteria for response are first met.  
 In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval (in general, not less than 6-
8 weeks) that is defined in the study protocol.  
Duration of overall response 
 The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever status is recorded first) until the first 


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date that recurrence or PD is objectively documented, taking as reference for 
PD the smallest measurements recorded since the treatment started. 
Duration of stable disease 
 SD is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
 The clinical relevance of the duration of SD varies for different tumor types 
and grades. Therefore, it is highly recommended that the protocol specify the 
minimal time interval required between two measurements for determination 
of SD. This time interval should take into account the expected clinical benefit 
that such a status may bring to the population under study.  
Reporting of results 
 All patients included in the study must be assessed for response to treatment, 
even if there are major protocol treatment deviations or if they are ineligible.  
Each patient will be assigned one of the following categories: 1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data). 
 All of the patients who met the eligibility criteria should be included in the 
main analysis of the response rate.  Patients in response categories 4-9 
should be considered as failing to respond to treatment (disease progression).  
Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
 All conclusions should be based on all eligible patients. 
 Subanalyses may then be performed on the basis of a subset of patients, 
excluding those for whom major protocol deviations have been identified (e.g., 
early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.).  However, these subanalyses may not serve as the 
basis for drawing conclusions concerning treatment efficacy, and the reasons 
for excluding patients from the analysis should be clearly reported.   
 The 95% confidence intervals should be provided. 
 
 
 
 
 


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Appendix V 
 
General Chemotherapy Guidelines 
 
 
● A subject will be permitted to have a new cycle of chemotherapy delayed up to 
7 days  for major life events (e.g., serious illness in a family member, major holiday, 
vacation which is unable to be re-scheduled). Documentation to justify this decision 
should be provided. 
 
● It will be acceptable for individual chemotherapy doses to be delivered within 
a 24-hour window before and after the protocol-defined date for "Day 1" 
treatment. If the treatment due date is a Friday, and the subject cannot be 
treated on that Friday, then the window for treatment would include the 
Thursday (1 day earlier than due) through the Monday (Day 3 past due). 
 
● For weekly regimens, it will be acceptable for individual chemotherapy doses 
to be delivered within a "24-hour window," for example; "Day 8 
chemotherapy" can be delivered on Day 7, Day 8, or Day 9 and "Day 15 
chemotherapy" can be given on Day 14, Day 15, or Day 16. 
 
● Chemotherapy doses can be "rounded" according to institutional standards 
without being considered a protocol violation (most institutions use a rule of 
approximately ± 5% of the calculated dose). 
 
● Chemotherapy doses are required to be recalculated if the subject has a weight 
change of greater than or equal to 10%. Subjects are permitted to have 
chemotherapy doses recalculated for < 10% weight changes.