Clinical trial NCT01248962
Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: BEVACIZUMAB (AVASTIN) CARBOPLATIN DEXAMETHASONE GEMCITABINE LIPODOX(LIPOSOMAL DOXORUBICIN) MONTELUKAST (SINGULAR) TAXOL (PACLITAXEL Fallopian Tubes 10-184
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2010-11-01; Completion date: 2018-08-01
Enrollment: 146 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients who have this kind of cancer are often treated with several drugs. Carboplatin is one that seems to work for many treatment cycles. Even though it may work against the cancer, the patient can become allergic to it. If that happens, they would have to stop taking the drug. The standard way to give carboplatin is by vein over 30 minutes. Some people have been given carboplatin over 3 hours rather than 30 minutes and had fewer allergies than expected.

The purpose of this study is to:

Find out if giving carboplatin over three hours can prevent the allergy.

See if medicine given before the carboplatin can help reduce the risk of allergic reactions.

Detailed description:

Arms: arm 1: This is a non-blinded randomized study comparing standard 30-minute infusion carboplatin to extended 3-hour infusion carboplatin in women with recurrent, ovary, fallopian tube, and primary peritoneal cancer who will be treated with a carboplatin containing chemotherapy regimen. arm 2: This is a non-blinded randomized study comparing standard 30-minute infusion carboplatin to extended 3-hour infusion carboplatin in women with recurrent, ovary, fallopian tube, and primary peritoneal cancer who will be treated with a carboplatincontaining chemotherapy regimen.
Interventions: intervention 1: carboplatin intervention 2: carboplatin
Intervention descriptions: intervention 1: Carboplatin Standard 30-minute infusion. All patients will receive identical chemotherapy premedications including dexamethasone 20mg the night before and morning of infusion, montelukast 10mg once daily for three days prior to carboplatin infusion, and ranitidine 50mg (or famotidine 20mg IV)IV and diphenhydramine 50mg IV before carboplatin infusion. intervention 2: Extended 3-hour infusion carboplatin. All patients will receive identical chemotherapy premedications including dexamethasone 20mg the night before and morning of infusion, montelukast 10mg once daily for three days prior to carboplatin infusion, and ranitidine 50mg IV (or famotidine 20mg IV) and diphenhydramine 50mg IV before carboplatin infusion.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
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IRB#: 10-184 A(8) 
Standard Infusion Carboplatin versus Prophylactic Extended Infusion Carboplatin in the 
Treatment of Patients with Recurrent Ovary, Fallopian Tube, and Primary Peritoneal Cancer 
 
MSKCC THERAPEUTIC/DIAGNO STIC PROTOCO L 
 
Principal Investigator/Department: Roisin E. O’Cearbhaill, MB BCh 
Medicine/Gynecologic 
Medical Oncology 
Co-Principal 
Investigator(s)/Department: 
David Hyman, MD 
David R. Spriggs, MD 
Medicine/Gynecologic 
Medical Oncology 
Investigator(s)/Department: 
Carol Aghajanian, MD 
Katherine M. Bell-McGuinn, MD, PhD 
Rachel Grisham, MD 
Martee L. Hensley, MD, MSc 
Jason A. Konner, MD 
Vicky Makker, MD 
Paul Sabbatini, MD 
William P. Tew, MD 
Jessica Gahres, PA-C 
Karen Cadoo, MB BCh 
Dmitriy Zamarin, MD, PhD 
Alexia Iasonos, PhD 
Elena Elkin, PhD 
Medicine/Gynecologic 
Medical Oncology 
Epidemiology and 
Biostatistics 
Epidemiology and 
Biostatistics: Health 
Outcomes 
Consenting 
Professional(s)/Department: 
Carol Aghajanian, MD 
Katherine M. Bell-McGuinn, MD, PhD 
Rachel Grisham, MD 
Martee L. Hensley, MD, MSc 
David Hyman, MD 
Jason A. Konner, MD 
Vicky Makker, MD 
Roisin E. O’Cearbhaill, MB BCh 
Paul Sabbatini, MD 
David R. Spriggs, MD 
William P. Tew, MD 
Karen Cadoo, MB BCh 
Dmitriy Zamarin, MD, PhD 
Medicine/Gynecologic 
Medical Oncology 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
 
 
Amended: 8/15/14 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
 
 
 
 
 
 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...........................................................................4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ....................................................................................5 
 
3.0 
BACKGROUND AND RATIONALE .........................................................................................5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................................8 
 
4.1 
Design ....................................................................................................................................8 
 
4.2 
Intervention ............................................................................................................................8 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .................................................................................8 
 
5.1 Carboplatin .................................................................................................................................8 
 
5.2 Paclitaxel ....................................................................................................................................9 
 
5.3 Gemcitabine................................................................................................................................9 
 
5.4 Liposomal Doxorubicin ...............................................................................................................9 
 
5.5 Docetaxel ....................................................................................................................................9 
 
5.6 Pemetrexed ................................................................................................................................9 
 
5.7 Bevacizumab ..............................................................................................................................9 
 
5.8 Concomitant Medications ...........................................................................................................9 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ...............................................................................11 
 
6.1 
Subject Inclusion Criteria .....................................................................................................11 
 
6.2 
Subject Exclusion Criteria ....................................................................................................11 
 
7.0 
RECRUITMENT PLAN............................................................................................................11 
 
8.0 
PRETREATMENT EVALUATION .......................................................................................... .12 
 
9.0 
TREATMENT/INTERVENTION PLAN ....................................................................................13 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .......................................................15 
 
11.0 TOXICITIES/SIDE EFFECTS ................................................................................................. .16 
 
11.1 Carboplatin Toxicities .............................................................................................................16 
 
11.2 Paclitaxel Toxicities ................................................................................................................17 
 
11.3 Gemcitabine Toxicities............................................................................................................17 
 
11.4 Liposomal Doxorubicin Toxicities ...........................................................................................18 
 
11.5 Docetaxel Toxicities ................................................................................................................18 
 
11.6 Pemetrexed Toxicities ............................................................................................................19 
 
11.7 Bevacizumab ..........................................................................................................................19 
 
11.8 Management of Adverse Events.............................................................................................19 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..........................21 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...........................................................................21 


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14.0 BIOSTATISTICS .....................................................................................................................22 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ...24 
 
15.1   Research Participant Registration .......................................................................................24 
 
15.2   Randomization .....................................................................................................................24 
 
16.0 DATA MANAGEMENT ISSUES .............................................................................................24 
 
16.1   Quality Assurance ................................................................................................................25 
 
16.2   Data and Safety Monitoring .................................................................................................25 
 
17.0 PROTECTION OF HUMAN SUBJECTS ................................................................................25 
 
17.1   Privacy .................................................................................................................................26 
 
17.2   Serious Adverse Event (SAE) Reporting .............................................................................26 
 
18.0 INFORMED CONSENT PROCEDURES ................................................................................27 
 
19.0 REFERENCES ........................................................................................................................28 
 
20.0 APPENDICE S .........................................................................................................................29 
 
Appendix A: NCI CTCAE Version 4.0, Allergic Reaction and Anaphylaxis Grading 
 
Appendix B.1: Premedication Pill Diary (Dexamethasone 20mg) 
Appendix B.2: Premedication Pill Diary (Dexamethasone 12mg) 
Appendix C.1: Dose Confirmation Form 
Appendix C.2: Dose Modification Form 
 
Appendix D: Directed Medical History Form 
 
Appendix E.1: Carboplatin Hypersensitivity Reaction Form 
 
Appendix E.2: Interval Carboplatin/Prem edication Toxicity Assessment Form 
 
Appendix F: Sample Patient Calendar for Premedication 


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MEMORIAL SLOAN-KETTERING CANCER CENTER 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Objective 
 
• 
The primary objective of this study is to perform a randomized study to determine 
whether patients treated for relapsed ovary, fallopian and primary peritoneal with 
extended infusion carboplatin have lower rates of hypersensitivity reactions compared 
to those treated with standard infusion carboplatin. 
 
Study Population 
 
• 
Eligible patients (relapsed fallopian, ovary and primary peritoneal cancer), who will be 
re-treated with a carboplatin-containing regimen. 
 
Number of Patients: 
 
• 
 Approximately 150 patients will be enrolled in order to obtain the 114 evaluable 
patients that are required to determine the primary endpoint of the study. 
 
Study Design: 
 
• 
This is a randomized, non-blinded trial, with a 1:1 randomized to the standard and 
experimental treatment arms. 
 
Therapeutic Intervention: 
 
• 
All patients receive standardized premedication with dexamethasone 20mg PO the 
night before and morning of treatment, montelukast 10mg PO once daily for the three 
days prior to carboplatin treatment, and ranitidine 50mg IV (or famotidine 20mg IV) 
and diphenhydramine 50mg IV prior to treatment to control for the contribution of 
premedication in preventing hypersensitivity reactions (see Section 5.6.3 for further 
details). 
• 
Randomize between standard (30-minute) carboplatin infusion or an extended (3- 
hour carboplatin) infusion. Extended infusion carboplatin is given in three steps, 1% 
of total dose administered over the 1st hour, 9% of total dose administered over the 
2nd hour, and the remaining 90% administered over the 3rd hour. Randomization is 
stratified by prior carboplatin (yes/no) and concurrent paclitaxel/docetaxel (yes/no). 
• 
Dose of carboplatin (AUC) for each patient in each arm is determined by treating 
physician. 
• 
Concomitant treatment with paclitaxel, docetaxel, pemetrexed, gemcitabine, 
liposomal doxorubicin and bevacizumab in both arms is determined by the treating 
physician. 
• 
Cycles are repeated every 28 days if carboplatin is given in combination with liposomal 
doxorubicin. Carboplatin given alone or with gemcitabine, paclitaxel, docetaxel or 
pemetrexed may be administered on a 21 or 28 day cycle, at the discretion of the 
Investigator. Patients are treated for 5 to 8 cycles, at the discretion of their treating 
physician. 


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Schema: 
 
 
Randomization (1:1) Stratification: 
a) Prior carboplatin (yes/no) 
b) Concurrent paclitaxel or 
docetaxel (yes/no) 
 
 
 
 
 
Arm A 
(Standard 30-minute infusion) 
Grade 1-2 HSR 
 
Arm B 
(Extended 3-hour Infusion) 
 
x 5-8 
cycles 
 
 
Grade 4 
HSR 
Grade 3 
HSR 
Crossover 
Any Grade 
HSR 
 
 
 
 
 
 
Discontinue 
Treatment 
Crossover 
(at the discretion 
of investigator) 
 
 
Discontinue 
Treatment 
 
 
HSR = Hypersensitivity Reaction, see Appendix A for CTCAE Version 4.0 Grading 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Endpoint: 
1.  Determine the rate of hypersensitivity reaction in each group 
 
Secondary Endpoints: 
1.  Determine the rate of successful planned treatment completion of carboplatin in each 
group 
2.  Perform a cost-identification analysis of extended infusion carboplatin to estimate the 
cost per hypersensitivity reaction prevented. 
3.  Perform exploratory analyses to correlate hypersensitivity rate to history of atopy, 
prior drug allergies, number of lifetime platinum cycles, duration since last platinum, 
and concomitant chemotherapy agent 
 
3.0 
BACKGROUND AND RATIONALE 
 
Epithelial ovarian cancer is the second most common gynecologic malignancy and accounts 
for almost 22,000 incident cases and 16,000 deaths per year.1  Early symptoms of ovarian 
cancer are often absent or non-specific and 75% of patients present with advanced (Stage III 
or IV) disease. These patients are offered maximal tumor debulking followed by intravenous 
or  intraperitoneal  platinum  and  taxane  chemotherapy.  Following  this  combination  of 


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therapies, 50% of patients achieve a complete remission and an additional 30% a partial 
remission.2 Of the patients in CR, 15% remain disease free for 5 years and are considered 
cured. The remaining patients will relapse and require further palliative chemotherapy. 
  
Relapsed ovarian cancer is distinct from most solid tumors in that it often retains sensitivity to 
chemotherapy, specifically platinums, over multiple relapses. The most important prognostic 
factor in relapsed ovarian cancer is platinum sensitivity (defined as relapse ≥ 6 months since 
last platinum). Patients with recurrent platinum-sensitive ovarian cancer are usually retreated 
with carboplatin either alone or in combination with paclitaxel, docetaxel, pemetrexed, 
gemcitabine or liposomal doxorubicin. These patients can maintain platinum sensitivity over 
multiple recurrences spanning many years and be successfully retreated repeatedly with 
carboplatin-based chemotherapy. Unfortunately, patients can develop hypersensitivity 
reactions (HSRs) when they are retreated with carboplatin. These reactions present with 
significant heterogeneity. In some patients HSRs occur immediately upon initiation of the 
infusion while in others the reactions occur after at least half the treatment volume has been 
given. Delayed reactions (reactions that occur after carboplatin has been completed infused) 
are very rare. This diversity suggests multiple immunological and non-immunological 
mechanisms may be involved. The symptomatology of carboplatin HSRs is similarly 
heterogeneous. Some patients will develop mild manifestations including flushing, rash, 
diaphoresis, urticaria or hypertension. Other patients will present with severe symptoms 
including potentially life-threatening bronchospasm, chest pain, shortness of breath, 
hypotension or cardiac arrest. 
 
Carboplatin HSRs rarely occur during the first course of therapy. Patients typically react early 
in their second course of therapy, most commonly during their 7th to 9th lifetime cycle of 
carboplatin.3 Reactions, however, can occur at anytime. Estimates of the frequency of 
carboplatin HSRs are fairly consistent across multiple publications. Markman et al have 
report an incidence of 27%.4 Polyzos et al report an incidence of 16%.5 Morgan et al report 
an incidence of 44%.6 The variation in these rates likely reflects the different treatment 
experience of each patient population as well as differences in the use of pre-medications. 
Carboplatin infusion rates may also play a role. Retrospective studies have suggested a 
number of risk factors for carboplatin HSR including a history of prior drug allergies, a lifetime 
platinum exposure of ≥8 prior cycles, and a treatment interval ≥12 months since last 
platinum.7-8 None of these risk factors has been validated prospectively. The choice of 
chemotherapy agent administered in combination with carboplatin may also impact the 
likelihood of a HSR. For example, a recent randomized phase III trial demonstrated a HSR 
rate in patients retreated with concurrently paclitaxel or liposomal doxorubicin of 18% versus 
5%, respectively.9 
  
Several Investigators have developed desensitization regimens in order to re-challenge 
patients who have previously reacted to platinums. Like many antibiotic desensitization 
regimens, these strategies typically involve administering escalating aliquots of carboplatin 
slowly with premedication.10-11 These procedures are labor-intensive and are typically 
performed over six or more hours under close observation in a monitored setting such as an 
intensive care unit. Many desensitization regimens utilize skin testing to risk stratify patients 
prior to re-challenge.12  All these techniques require the expertise of allergists familiar with 


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managing chemotherapy HSRs and the chance of a second reaction is high. Castels et al 
have reported on their experience at a specialized chemotherapy desensitization unit at the 
Dana Farber Cancer Center. In their series 30-40% of patients will experience a second HSR 
upon re-challenge. Although these second reactions are generally mild, a small percentage 
will be severe and life threatening. Centers specialized in managing chemotherapy HSRs 
typically treat through repeated reactions.  However, many women do not have access to 
these services. As a result, many patients will not successfully complete a planned course of 
carboplatin after developing an initial HSR and may have inferior clinical outcomes.13 What is 
therefore most needed is an effective strategy to prevent patients who are continuing to 
benefit from platinum chemotherapy from developing HSRs in the first place. 
 
The Gynecologic Medical Oncology (GMO) service at Memorial Sloan-Kettering Cancer 
Center (MSKCC) has developed 3-hour extended infusion carboplatin regimen that is a 
modification of the standard 12-step desensitization protocols used at several centers. 
Carboplatin is administered either a single agent or a carboplatin-containing combination 
treatment. Patients are premedicated with dexamethasone 20mg the night before and 
morning of chemotherapy, montelukast 10mg once daily for the three days preceding 
treatment, and ranitidine 50mg IV (or famotidine 20mg IV) and diphenhydramine 50mg IV 
prior to carboplatin. Carboplatin is given in the following manner: 1% of the total dose over 
the 1st hour, 9% of the total dose over the 2nd hour, and the remaining 90% over the 3rd hour. 
In contrast to the complex and lengthy desensitization protocols often used in post-HSR 
platinum re-challenge, this 3-hour extended infusion can be easily administered in the 
outpatient clinic setting. This extended infusion regimen is now the accepted standard of care 
at MSKCC to re-challenge patients who have developed a prior HSR to carboplatin. 
 
Several physicians in the GMO have piloted using this regimen before women develop 
HSRs. A retrospective review of this experience has been published.14 This review identified 
707 patients who had received retreatment with second-line or greater carboplatin between 
January 1998 and December 2008. Of these a total of 174 patients (25%) received 
prophylactic extended infusion schedule. A total of 117 carboplatin HSRs were identified 
among the entire cohort of 707 patients. Only 6 patients (3.4%) who received the extended 
schedule versus 111 patients (21%) who received the standard schedule developed an HSR. 
Using the Fisher exact test, there was a significant relationship between the use of the 
extended regimen and a reduced incidence of HSRs (P< 0.001). Moreover, only 20% of 
patients who developed a HSR on standard infusion were re-challenged with extended 
infusion carboplatin and of these only 57% were able to complete treatment. The end result 
is that only 11.4% of patients who experienced a carboplatin HSR were able to successfully 
complete  a  planned  course  of  therapy.  This  reinforces  the  importance  of  developing 
strategies to prevent platinum HSRs. 
 
To date, no center has reported prospectively on the prophylactic use of extended infusion 
carboplatin regimen to reduce in incidence of HSRs. This will be the first prospective 
randomized clinical trial to compare standard to prophylactic extended infusion carboplatin in 
women  with  recurrent  ovarian  cancer.  The  results  of  this  prospective  trial,  positive  or 
negative, will define the best practice for retreating women with ovarian with platinum agents. 
The implications of this strategy are not limited to patients with ovarian cancer. Several other 


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cancer types can respond repeatedly to platinum-based chemotherapy including BRCA+ 
breast cancer and endometrial cancer. In addition, colon cancer patients are routinely given 
platinum-based chemotherapy in the adjuvant setting and are then retreated with platinum on 
recurrence and can develop HSRs. The results of this study may therefore inform the design 
of future clinical trials for these diseases. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1     Design 
 
This is a non-blinded randomized study comparing standard 30-minute infusion carboplatin 
to extended 3-hour infusion carboplatin in women with recurrent, ovary, fallopian tube, and 
primary peritoneal cancer who will be treated with a carboplatin-containing chemotherapy 
regimen. 
 
4.2     Intervention 
 
All patients will receive identical chemotherapy premedications including dexamethasone 
20mg the night before and morning of infusion, montelukast 10mg once daily for three days 
prior to carboplatin infusion, and ranitidine 50mg IV (or famotidine 20mg IV) and 
diphenhydramine 50mg IV before carboplatin infusion. Patients who are intolerant to 
diphenhydramine 50mg IV can be dose reduced to 25mg IV or changed to hydroxyzine 25mg 
PO at the discretion of the Investigator. Patients will be randomized to receive standard 
infusion carboplatin or  extended infusion carboplatin in  a  1:1  manner. Patients will  be 
stratified based on history of prior carboplatin exposure (yes/no) and concurrent paclitaxel or 
docetaxel treatment (yes/no). Patients may receive carboplatin alone or in combination with 
paclitaxel, docetaxel, pemetrexed, gemcitabine or liposomal doxorubicin at the discretion of 
the Investigator. Patients may also receive concurrent bevacizumab in addition to single- 
agent carboplatin or a carboplatin doublet, at the discretion of the Investigator. Carboplatin 
dose will be decided by the Investigator. Carboplatin will be administered on day 1 of each 
cycle. If carboplatin is administered alone or in combination with paclitaxel, docetaxel, 
pemetrexed or gemcitabine, each cycle will last 21 days. If carboplatin is given alone, with 
gemcitabine or with paclitaxel or docetaxel or pemetrexed, each cycle will last either 21 or 28 
days, at the discretion of the Investigator. Patients will receive between 5 and 8 cycles, as is 
the standard of care, the exact number to be determined by their treating doctors. 
 
The goal of this study is to accrue 57 patients to each arm for a total of 114 evaluable 
patients. With an anticipated accrual rate of 5-6 patients per month, this study should take 
18-24 months to complete enrollment. Patients will be followed until they receive their last 
dose of carboplatin. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Carboplatin 
Will be prepared as per MSKCC Guidelines. For complete details, see the package insert for 
further information. 


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Mechanism of action: Carboplatin binds to DNA and causes cross-linking with a non-cell 
cycle dependent tumor cell lysis. It inhibits DNA synthesis by altering the template via the 
formation of intra-strand cross-links. 
 
 
Formulation: Carboplatin is available as a 10mg/ml solution. 
 
 
Storage: Unopened vials are stable for the life indicated on the insert if protected from light. 
 
 
Drug Administration: The total dose will be diluted in 250mls of D5W and infused over 30 
minutes (standard MSKCC protocol) or by a 3-hour infusion (standard MSKCC 
desensitization protocol) in the following manner: 1% total dose 1st hour, 9% total dose 2nd 
hour, 90% of total dose 3rd hour (desensitization MSKCC protocol). Patients must have an 
absolute neutrophil count of ≥ 1000 cells/µL, platelet count ≥ 100,000 and creatinine < 1.5 
mg/dl. See section 9.1 for MSKCC/GMO guidelines for carboplatin dosing. 
 
 
Toxicity: Myelosuppression, nausea, vomiting, alopecia, hyponatremia, hypomagnesemia, 
hypocalcemia, allergic reactions, fatigue, rare toxicities including ototoxicity (high doses), 
nephrotoxicity, edema, nervous system disorders (dizziness, blurred vision), hepatic 
dysfunction, fever, weight loss, interstitial pneumonitis, hemolytic uremic syndrome and 
uremia. 
 
5.2 Paclitaxel 
Will be prepared and administered as per MSKCC Guidelines. For complete details, see the 
package insert for further information 
 
 
5.3 Gemcitabine 
Will be prepared and administered as per MSKCC Guidelines. For complete details, see the 
package insert for further information 
 
5.4 Liposomal Doxorubicin 
Will be prepared and administered as per MSKCC Guidelines. For complete details, see the 
package insert for further information 
 
5.5 Docetaxel 
Will be prepared and administered as per MSKCC Guidelines. For complete details, see the 
package insert for further information 
 
5.6 Pemetrexed 
Will be prepared and administered as per MSKCC Guidelines. For complete details, see the 
package insert for further information 
 
5.7 Bevacizumab 
Will be prepared and administered as per MSKCC Guidelines. For complete details, see the 
package insert for further information 
 
5.8 Concomitant Medications 


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5.6.1 Anticancer or experimental therapy 
No other concurrent chemotherapy or anti-cancer therapy (other than those listed in Section 
5.1-5.5) is permitted while the patient is enrolled and receiving treatment on study. 
 
 
 
5.6.2 Hematopoietic Growth Factors 
Colony-Stimulating Factor (G-CSF, pegylated G-CSF): Colony-stimulating factors may be 
used at the discretion of the treating physician but will not be used routinely. 
 
Epoetin alfa (Procrit® or Aranesp®): Use of epoetin alfa is permitted at the discretion of the 
treating physician. 
 
5.6.3 Antiemetics and Premedications 
The premedications are required for all patients are as follows: 
 
Premedications 
Day 
Drug 
Three days prior to carboplatin 
Montelukast 10mg orally 
Night before & morning of carboplatin 
Dexamethasone 20mg orally 
Prior to carboplatin 
Diphenhydramine 50mg IV 
Ranitidine 50mg IV or Famotidine 20mg IV 
 
Premedication Adjustments: If a patient is intolerant of 20mg of dexamethasone, the dose 
may be reduced to 12mg the night before and morning of carboplatin. If the patient is 
intolerant of 12mg of dexamethasone, they will be removed from study. If a patient is 
intolerant of 50mg of diphenhydramine the dose can be reduced to 25mg IV or changed to 
hydroxizine 25mg PO once. 
 
Patients will be given a pill diary to document compliance with premedications (see Appendix 
B.1 & B.2). Patients who miss doses of premedications may begin their next cycle of 
chemotherapy at the discretion of the Investigator. 
 
Suggested Antiemetics: 
Per institutional guidelines for Carboplatin AUC ≥ 3 
  
Day 1: Palonosetron 250mcg IVPB once, Aprepitant 125mg PO once 
 
 
Day 2 to 3 after Carboplatin Infusion: Dexamethasone 12mg PO morning, Aprepitant 80mg 
PO morning, Ondansetron 8mg PO q8hr PRN and/or Metoclopramide 10 mg PO every 4 hr 
PRN and/or prochlorperazine 10mg q6hr PRN 
 
This is only a suggested antiemetic regimen, modifications are permitted. If nausea and 
vomiting are not well controlled on this regimen or a patient has intolerance to once of these 
agents, substitutions and additions of alternate antiemetics such as lorazepam may be used 
at the discretion of the treating oncologist. 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Subjects must meet the following criteria to be eligible for this protocol. 
 
6.1     Subject Inclusion Criteria 
 
1.  MSKCC histologically confirmed ovarian, fallopian tube or primary peritoneal 
carcinoma. 
2.  Patient has received at least one prior platinum-containing (cisplatin or 
carboplatin) regimen 
3.  Age ≥ 21 years old 
4.  Karnofsky Performance Status (KPS) > 70% 
5.  Adequate hematologic, hepatic and renal function as defined below: 
a.  Hemoglobin > 7.0 g/dl 
b.  Absolute neutrophil count > 1,000/mm3 
c.   Platelet count > 100,000/mm3 
d.  Serum creatinine ≤ 1.5 x the upper limit of normal or calculated creatinine 
clearance ≥ 60 mL/min 
 
6.2     Subject Exclusion Criteria 
 
1.  Prior carboplatin or cisplatin hypersensitivity reaction 
2.  Uncontrolled intercurrent illness including infection, congestive heart failure, 
myocardial infarction, transient ischemic attack or stroke within 6 months. Any such 
conditions that have occurred in the last 6 months but are no longer active at the 
time of registration are not considered exclusionary. 
3.  Patients receiving other investigational agents 
4.  Patients with HIV disease will be permitted, only if they are on effective anti- 
retroviral therapy, have a CD4 count greater than 400, and have had no 
opportunistic infections within the past 6 months 
5.  Pregnant or lactating women 
6.  Life expectancy of less than 12 weeks 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited through the outpatient gynecologic medical oncology clinics of the 
Memorial Sloan-Kettering Cancer Center. The gynecologic medical oncology service holds 
weekly meetings to review open clinical trials and identify appropriate patients. All patients 
will be under the care of attending medical oncologists of MSKCC. Members of all ethnic 
groups are eligible for this trial. All eligible patients (Section 6) will be offered enrollment on 
this study. The trial will be registered with the National Cancer Institute clinicaltrials.gov 
website. 
 
The protocol will be included on the MSKCC website describing therapeutic protocols open 
at the institution. 


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8.0 
PRETREATMENT EVALUATION 
 
Part I: Initiation of Treatment 
Screening Procedures within 28 Days Prior to Starting Treatment 
 
 
The following screening procedures must be performed within 28 days of initiating study 
treatment: 
• 
Medical history (including demographics, oncologic history, history of other active or 
resolved disease processes) 
o Directed medical history to obtain the following information: 
▪ 
History of drug allergies (the number of drug allergies will be recorded, 
counting multiple allergies within a specific drug class only once) 
▪ 
History of food allergies 
▪ 
History of environmental allergies, including seasonal 
▪ 
History of asthma 
▪ 
History of atopic dermatitis (eczema) 
▪ 
Number of documented allergies (including contrast dye and contact 
skin allergies, but not including food allergies) 
• 
Assessment of baseline symptoms and complaints 
• 
Karnofsky Performance Status (KPS) 
• 
Height and weight 
• 
Vital signs (temperature, blood pressure, heart rate, respiratory rate) 
• 
Physical examination including examination of major body systems 
• 
Review of concomitant medications/other treatments 
• 
Complete Blood Count (CBC) with differentials and platelets 
• 
Comprehensive Metabolic Panel (includes sodium, potassium, glucose, BUN, 
creatinine, calcium, ALT, AST, alkaline phosphatase, total bilirubin, total protein, 
albumin) 
  
 
Screening Procedures within 14 days Prior to Starting Treatment 
 
o Serum pregnancy test (for women of childbearing potential only) 
 
Part II: Crossover Eligibility 
o Patients randomized and treated on Arm A (standard 30 minute carboplatin infusion) 
who experience a CTCAE (version 4.0) grade 1 or 2 hypersensitivity reaction may 
crossover and receive treatment on Arm B (extended 3 hour Carboplatin infusion). 
Before patients can crossover to Arm B, the following criteria must be met: 
o Currently enrolled on Protocol IRB# 10-184 
o Randomized and treated on Arm A (standard 30 minute carboplatin infusion) 
o Patient experienced a CTCAE (version 4.0) grade 1-2 carboplatin 
hypersensitivity reaction 
OR 
Patient experienced a CTCAE (version 4.0) grade 3 carboplatin 
hypersensitivity reaction, and at the discretion of the investigator is 
appropriate for crossover to Arm B (extended 3 hour carboplatin infusion) 


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9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 Chemotherapy Administration 
 
Carboplatin Dosing: 
 
Eligible patients will be randomized in a 1:1 manner to receive carboplatin by either standard 
infusion (Arm A) or extended infusion (Arm B). Carboplatin dosing will follow the 
Gynecological Medical Oncology and MSKCC institutional guidelines. Dose reductions, 
modifications, and treatment interruptions will be decided by the Investigator. Carboplatin will 
be administered as follows: 
 
 
 
 
 
 
Arm A: 
Per standard MSKCC carboplatin protocol: 100% of carboplatin dose is administered in 
250mL of D5W over 30 minutes. Spike infusion bag with secondary set (Braun #V1921), do 
not prime. 
 
Arm B: 
Per desensitization MSKCC carboplatin protocol: Bags 1 and 2 are prepared by the 
chemopharmacy. Bag 1 contains 10% of the total dose in 100 mL of D5W and Bag 2 
contains with 90% of the total dose in 250mL of D5W. 10 mL (1% of total dose) of Bag 1 is 
infused over the first hour. If there is no evidence of hypersensitivity reaction, the remaining 
90 mL (9% of total dose) of Bag 1 is infused over the second hour. If there is still no evidence 
of hypersensitivity reaction, Bag 2 containing 90% of total dose in 250 mL is infused over the 
third hour. Spike infusion bag with IMED Alaris 2420 tubing. 
 
 
Protocol for Extended Infusion Carboplatin (Carbo) 
Infusion time 
Percentage carboplatin infused 
1st hour 
1% 
2nd hour 
9% 
3rd hour 
90% 
Total: 3-hour infusion 
100% 
 
Crossover: 
Patients treated on Arm A who experience a hypersensitivity reaction will be managed as 
follows: 
 
Arm A 
CTCAE v4 Grade 
Management 
1 or 2 
Crossover to Arm B 
3 
Crossover to Arm B at the discretion of the treating physician 
4 
Discontinuation from study 


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Patients treated on Arm B or who are crossed over to Arm B who experience a 
hypersensitivity reaction of any grade will be discontinued from study. 
Please see Section 5.6.3 for details on the required premedications. 
Concurrent Chemotherapy and Bevacizumab: 
Patients  treated  on  either  Arm  may  receive  concurrent  chemotherapy  with  paclitaxel, 
docetaxel, pemetrexed, gemcitabine, liposomal doxorubicin or bevacizumab in addition to 
carboplatin. The decision to use these medications will be left to the discretion of the treating 
physician. Bevacizumab may be administered with either single agent carboplatin or any 
carboplatin doublet. The following table describes the recommended dosing, infusion time 
and schedule for each agent. Modification of all parameters are permitted at the discretion of 
the Investigator. The cycle length of any liposomal doxorubicin-containing regimen will be 28 
days. The cycle length for all other treatment combinations will be either 21 or 28 days, at the 
discretion of the Investigator. 
 
 
Suggested Concurrent Chemotherapy Dosing, Infusion Time and Schedule 
Drug 
Dose 
Infusion Time 
Cycle Length 
(Days) 
Administration 
Dayb 
Paclitaxel 
(“standard” schedule) 
135- 
175mg/m2 
3 hours 
a 
21  or 28 
1b 
Paclitaxel 
(“weekly” schedule) 
60-80mg/m2 
1 hour 
a 
21  or 28 
1b, 8,15c 
Gemcitabine 
800mg/m2 
30 minutes 
21a or 28 
1b, 8 
Liposomal Doxorubicin 30mg/m2 
Per MSKCC 
guidelines 
28 
1b 
Docetaxel 
60-75 mg/m2 1 hour 
21 or 28 
1b 
Pemetrexed 
375-500 
mg/m2 
10 minutes 
21 or 28 
1b 
Bevacizumab 
5-15mg/kg 
Per MSKCC 
guidelines 
21 or 28 
1b, 15d 
a-  May be extended to 28 days at discretion of the Investigator 
b-  For Day 1 of each cycle after Cycle 1, -3/+7 day window is permitted, at the discretion of 
the Investigator (note: the Investigator may delay Day 1 treatment up to 2 weeks) 
c-  May be omitted at discretion of the Investigator 
d-  May be omitted at discretion of the Investigator 
 
Location: 
All therapy will be administered in an outpatient setting, under the supervision of a physician 
and/or chemotherapy nurse, as is standard for chemotherapy administration. 
 
Treatment Course: 
Patients will remain on study for up to 8 cycles. Carboplatin will be administered on day 1 of 
each cycle. Cycles will last 28 days if given in combination with liposomal doxorubicin. The 
cycle length for all other treatment combinations will be either 21 or 28 days, at the discretion 
of the Investigator. Dose delays or interruptions (for any reason) of -3 days/+7 days is 
permitted, at the discretion of the Investigator. The Investigator may delay Day 1 treatment a 


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maximum of 2 weeks. Any delay/interruption longer than 2 weeks may be considered but the 
Principal or Co-Principal Investigator must be consulted. If a patient’s Day 1 is 
delayed/interrupted, Day 8 and Day 15 treatments (if applicable) should be scheduled 
accordingly. 
 
For the secondary endpoint of determining the rate of successful treatment completion in 
each arm, we will define successful treatment completion if a patient completes at least 5 
cycles of carboplatin treatment. If the patient comes off for progressive disease before cycle 
5 then the patient would be considered inevaluable for this endpoint. If a patient comes off for 
any other reason before cycle 5 then the patient would count as a "failure" when calculating 
treatment completion rates. Discontinuation of non-carboplatin chemotherapy will not be 
considered “failure.” Treatment completion rates will be calculated on evaluable patients. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Cycle 1+ 
Pretreatment 
Evaluation 
Within 28 Days 
i 
Day 1 
+7 Days/- 3 Days 
b 
Day 8 
+/- 3 Days 
b 
Day 15 
+/- 3 Days Post-Study
Carboplatin 
X 
Concurrent 
Chemotherapy and/or 
Bevacizumab 
X
a 
X
a 
X
a 
Medical Historyc 
X 
X 
Directed Medical 
History
d 
X 
Assessment of Baseline 
Signs/Symptoms 
X 
KPS 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
Vital Signse 
X 
X 
X 
X 
X 
Physical Examf 
X 
X 
X 
Review of 
Concomitant 
Medications/  Other 
Treatments 
X 
X 
X 
CBC with differentials 
and platelets 
X 
X 
X 
X 
Comprehensive 
Metabolic Panel
g 
X 
X 
Pregnancy Testh 
X 
Toxicity Assessment 
X 
X 
X 
a-Exact schedule depends on concurrent chemotherapy / bevacizumab defined in Section 9.0 
See table “Concurrent Chemotherapy Dosing, Infusion Time and Schedule” in Section 9.1 for details. 
b-Only required if patient receiving chemotherapy/bevacizumab on this day 
c-Medical history (including demographics, oncologic history, history of other active or resolved disease 
processes) 
d-Directed medical history includes history of drug, food and environmental allergies, history of asthma and 
history or atopic dermatitis (eczema) 
e-Vital signs (temperature, blood pressure, heart rate, respiratory rate) 
f- Physical examination including examination of major body systems 


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g-Comprehensive metabolic panel includes sodium, potassium, glucose, BUN, creatinine, calcium, ALT, 
AST, alkaline phosphatase, total bilirubin, total protein, albumin. 
h-If the patient is of childbearing potential: A serum pregnancy test must be done within 14 days of first 
treatment per MSKCC guidelines. 
i- If screening is completed within 8 days of start, Cycle 1 Day 1 assessments/tests do not need to be 
repeated. 
 
Clinical Evaluation: 
All assessments on day 1 may be performed up to 3 days before the planned start of each 
cycle (on cycle 1 this may be extended to 8 days before cycle 1, day 1). Patients will have 
vitals, height (baseline only), weight, KPS, review of concomitant medications, history, 
physical examination and toxicity assessment recording at this time. Physical evaluation and 
history will include evaluation for a rash potentially related to carboplatin. Additional nurse or 
physician visits will be at the discretion of the treating physician. 
 
 
 
Laboratory Evaluation: 
All laboratory tests on day 1 may be performed up to 3 days before the planned start of each 
cycle, a CBC with differentials and platelets and comprehensive metabolic panel (including 
sodium, potassium, glucose, BUN, creatinine, calcium, ALT, AST, alkaline phosphatase, total 
bilirubin, total protein, albumin). On cycle 1 this may be extended to 8 days before cycle 1, 
day 1. For regimens including chemotherapy on day 8 and 15, a CBC with differentials and 
platelets is required prior to each treatment. 
 
For women of childbearing potential: A serum pregnancy test will be performed within 14 
days prior to the start of the first cycle in patients of childbearing potential. 
 
Radiologic Evaluation: 
As treatment response is not an endpoint for this study, radiologic evaluation will be left to 
the discretion of the treating physician. 
 
Post-Study Visit: 
Following completion of protocol directed treatment, patients will have one post-study visit to 
assess for any ongoing treatment related toxicity. This evaluation should take place within 3 
months of last treatment on study. At this time patients will be assessed with vital signs, KPS, 
weight, current medications, history, physical exam and toxicity assessment. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1 Carboplatin Toxicities 
 
 
Likely 
 
 
• 
Fatigue 
• 
Mild nausea or vomiting 
• 
Diarrhea 


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 Less Likely 
• 
Rash 
• 
Numbness, tingling and burning of hands or feet 
• 
Decrease in blood cell counts (white blood cells, red blood cells and platelets) 
• 
Hearing loss or ringing in ears 
• 
Thinning of hair 
 
 
Rare but Serious 
• 
Allergic reaction, possibly life threatening 
• 
Serious infection 
 
 
 
11.2 Paclitaxel Toxicities 
 
 
Likely 
 
 
• 
Fatigue 
• 
Mild nausea or vomiting 
• 
Joint pain and body aches 
• 
Diarrhea 
• 
Temporary loss of hair 
• 
Decrease in blood cell counts (white blood cells, red blood cells and platelets) 
 
 
 Less Likely 
• 
Rash 
• 
Mouth sores 
• 
Numbness, tingling and burning of hands or feet 
• 
Hearing loss or ringing in ears 
Rare but Serious 
• 
Allergic reaction, possibly life threatening 
• 
Serious infection 
 
11.3 Gemcitabine Toxicities 
 
 
Likely 
 
 
• 
Fatigue 
• 
Leukopenia 
• 
Thrombocytopenia 
• 
Thinning of hair 
Less Likely 
• 
Mild nausea and vomiting 
• 
Pain and irritation along vein during infusion 
• 
Swelling of legs 
• 
Diarrhea 
• 
Constipation 
• 
Mouth Sores 


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• 
Rash 
Rare but Serious: 
• 
Inflammation of the lungs 
 
11.4 Liposomal Doxorubicin Toxicities 
  
Likely 
 
 
• 
Fatigue 
• 
Mild nausea or vomiting 
• 
Pain and irritation along the vein where the drug is given 
• 
Itching, hives, or a red rash at the injection side 
• 
Pink or red urine for the first 48 hours after treatment 
 
 
Less Likely 
• 
Sensitivity, redness or peeling of the skin on your hands and feet 
• 
Thinning of hair 
• 
Diarrhea 
• 
Mouth sores 
• 
Decrease in blood cell counts (white blood cells, red blood cells and platelets) 
  
Rare but Serious 
• 
Damage to the heart muscle 
• 
Allergic reaction, possibly life threatening 
• 
Serious infection 
 
11.5 Docetaxel Toxicities 
 
 
Likely 
 
 
• 
Fatigue 
• 
Diarrhea 
• 
Hair loss 
 
 
Less Likely 
• 
Nausea and vomiting 
• 
Mouth sores 
• 
Headache 
• 
Muscle and joint aches 
• 
Ankle swelling 
• 
Rash 
• 
Nail discoloration 
• 
Decrease in blood cell counts (white blood cells, red blood cells and platelets) 
 
 
Rare but Serious 
• 
Neuropathy 
• 
Allergic reaction 


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11.6 Pemetrexed Toxicities 
 
 
Likely 
 
 
• 
Low red or white blood cell counts 
• 
Nausea or vomiting 
• 
Constipation 
• 
Loss of appetite 
Less Likely 
• 
Low platelet count 
• 
Hair loss 
• 
Diarrhea 
• 
Neuropathy 
Rare but Serious 
• 
Severe damage to liver or kidney 
• 
Fever/Infection 
 
11.7 Bevacizumab 
  
Likely 
 
 
• 
Hypertension 
Less Likely 
• 
Change in voice (hoarseness) 
• 
Proteinuria 
• 
Arthralgia 
• 
Epistaxis 
  
Rare but Serious 
• 
Bowel perforation 
• 
Blood clots 
• 
Transient ischemic attack 
• 
Chest pain 
• 
Allergic reaction causing facial flushing, trouble breathing, low blood pressure 
 
11.8 Management of Adverse Events 
 
 
All of the therapeutic agents in this trial are commercially available and have FDA approved 
or NCCN Compendia listed for the treatment of recurrent epithelial ovarian cancer. All 
treatment combinations are used in routine clinical practice. As a result, the adverse events 
associated with these treatments will not be collected as part of this protocol. The 
management of all non-hypersensitivity adverse advents including dose reductions or 
treatment delays of all agents described in Section 5 are allowed at the discretion of the 
treating Investigator. 


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Adverse events collected as part of this protocol include toxicities related to the routine use 
of premedications and allergic/anaphylaxis hypersensitivity reactions related to carboplatin 
infusion (the primary endpoint for this study). These adverse events will be graded using the 
CTCAE Version 4.0 (see Appendix A). These adverse events will be attributed to 
premedications  and  carboplatin  in  the  following  manner:  Definite,  Probable,  Possible, 
Unlikely,  and  Unrelated.  Please  note  that  hypersensitivity  reactions  to  carboplatin  are 
typically easy to recognize clinically and occur during the time of carboplatin infusion. Per 
institutional protocol, carboplatin will not be infused concurrently with other chemotherapy or 
biologic agents (bevacizumab). It is therefore unlikely there will be difficulty distinguishing 
carboplatin reactions from paclitaxel, docetaxel, pemetrexed, gemcitabine, liposomal 
doxorubicin or bevacizumab reactions as these will be temporally separated. Only reactions 
attributed as definite, probably, possible or unlikely related to carboplatin will count towards 
the primary endpoint, hypersensitivity rate. 
 
Serious adverse events (SAE) will be reported as described in Section 17.2. A SAE is 
defined as: 
• 
Is fatal or life-threatening 
• 
Is disabling 
• 
Results in hospitalization or prolongation of hospitalization 
• 
Results in a congenital anomaly or occurrence of malignancy 
• 
Jeopardizes the participant and may require medical intervention to prevent one of 
the outcomes above 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether reporting is 
appropriate  in  other  situations,  such  as  important  medical  events  that  may  not  be 
immediately life-threatening or result in  death or hospitalization but may jeopardize the 
patient or  may require intervention to  prevent one  of  the  other outcomes listed in  the 
definition above. These should also usually be considered serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. The definition of “related” is an adverse event that is attributed 
as definitely, probably or possibly related to the premedication and/or carboplatin given as 
part of this protocol. A life-threatening adverse event implies an immediate risk of death from 
the reaction as it occurred. Life-threatening does not include a reaction that, had it occurred 
in a more serious form, might have caused death. For example, drug-induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening even 
though drug induced hepatitis can be fatal. 
 
Hypersensitivity Precautions and Management: 
MSKCC guidelines for monitoring and management of hypersensitivity reactions will be 
observed for all patients treated on study as described in the link below. 
 
http://mskweb5.mskcc.org/intranet/shared/pharmacy/guidelines/Nursing%20Forms/hypersen 
sitivity%20order%20set.htm 


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12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Two  outcomes  will  be  assessed:  the  rate  and  grade  of  hypersensitivity  reactions  to 
carboplatin and successful completion of planned treatment. These outcomes are defined as 
follows: 
 
Rate of Hypersensitivity Reactions to Carboplatin: All allergic or anaphylactic reactions to 
carboplatin of any grade will be counted as an event with exception of reactions attributed as 
definitely not related to carboplatin. 
 
Successful Completion of Planned Therapy: For the secondary endpoint of determining the 
rate of successful treatment completion in each arm, we will define successful treatment 
completion if a patient completes at least 5 cycles of carboplatin treatment. If the patient 
comes off for progressive disease before cycle 5 then the patient would be considered 
inevaluable for this endpoint. If a patient comes off for any other reason before cycle 5 then 
the patient would count as a "failure" when calculating treatment completion rates. 
Discontinuation of non-carboplatin chemotherapy will not be considered “failure.” Treatment 
completion rates will be calculated on evaluable patients. 
 
13.0    CRITERIA FOR REMOVAL FROM STUDY 
 
Premature Withdrawals: 
 
Patients who discontinue participation in the clinical study on their own or patients who are 
withdrawn by the Investigator, for reasons other than those listed below will be defined as 
premature withdrawals. For the purpose of this study, they will not be considered to have 
experienced a hypersensitivity reaction but will be considered a “failure” when calculating 
planned treatment completion (defined as discontinuation of carboplatin treatment prior to 5 
cycles for reasons other than disease progression, see Section 12.0 for further details). 
 
Criteria for Stopping Therapy: 
 
• 
Hypersensitivity Reaction: According to Schema in Section 1.0 and Crossover in 
Section 9.1 
• 
Substantial non-compliance with the requirements of the study 
• 
Any adverse event which, in the Investigator or treating physician’s opinion, requires 
termination from the study 
• 
Progression of the underlying cancer unless, at the discretion of the Investigator, 
continued treatment on the study is deemed appropriate 
• 
Request by the patient or a legal representative/relative to stop the treatment 
• 
The patient uses illicit drugs or other substances that may, in the opinion of the 
Investigator, have a reasonable chance of contributing to toxicity or otherwise 
interfering with results 
• 
The development of a second malignancy that requires treatment, which would 
interfere with this study 
• 
The patient is lost to follow-up 
• 
Treatment delay of greater than 30 days 
• 
Development of an intercurrent illness or situation which would, in the judgment of the 


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Investigator, affect assessments of clinical status and study endpoints to a significant 
degree 
 
Criteria for Study Withdrawal: 
• 
Patient decides to discontinue participation in the study. Data generated during their 
participation in the protocol will be analyzed unless the patient specifically opts to 
withdraw research authorization. 
 
 
14.0 
BIOSTATISTICS 
 
This is a randomized non-blinded study with the primary objective to determine whether 
patients treated with extended infusion carboplatin have lower rates of hypersensitivity 
reaction (HSR) compared to those treated with standard infusion carboplatin. Please refer to 
Section 15.2 for details regarding randomization. Patients in second or third line treatment 
setting are eligible. We expect approximately 80% and 20% of patients to be in these two 
groups respectively. A HSR is defined as any allergic or anaphylactic reaction, regardless of 
grade, judged unlikely, possibly, potentially or definitely attributed to carboplatin while on 
study. 
Assuming type I error =10%, power 80%, one-sided test aiming to show a decrease from 
20% to 5% in HSR rates, the study would require 57 pts in each arm using a test for 
binomial proportions. Study accrual will be completed in approximately two years assuming 
50 pts are accrued per year. Discontinuation from treatment prior to 5 cycles is anticipated to 
occur very infrequently and therefore patients with early discontinuations will be included in 
the analysis of the primary endpoint. 
 
Since previous use of carboplatin might affect the HSR rates, randomization will be stratified 
by previous use of carboplatin (yes/no). The percentage of patients who get at least 1 cycle 
of carboplatin upfront is 65%, thus we expect each arm to have 37:20 pts in previous 
carboplatin (yes/no) groups. In addition patients will be stratified based on concurrent 
paclitaxel  or  docetaxel  use  (yes/no).  Patients  may  receive  carboplatin  alone  or  in 
combination with paclitaxel, docetaxel, pemetrexed, gemcitabine, liposomal doxorubicin and 
bevacizumab at the discretion of the Investigator. No analysis is planned within the taxol 
stratification factor since we expect this percentage of patients to be small (5-10%). 
 
We will employ continuous significant testing with a significance level=12% to monitor acute 
reactions (defined as a allergic or anaphylactic reaction of any grade excluding those 
attributed as definitely not related to carboplatin) within each arm separately and the 
corresponding stopping boundaries are provided in the table below: 


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Acceptable Rate of 
Acute Reactions 
(Unacceptable rate) 
Stopping boundaries 
Stop if # reactions 
exceeds (>) the 
numbers below 
Probability of 
declaring the 
treatment unsafe 
due to high number 
of reactions 
Probability of stopping the 
trial under the 
unacceptable rate of high 
number of reactions 
15% (≥25%) 
5/20 
8/30 
9/40 
13/57 
0.69 
0.61 
 
For the secondary endpoint of determining the rate of successful treatment completion in 
each arm, we will define successful treatment completion if a patient completes at least 5 
cycles of carboplatin treatment. If the patient comes off for progressive disease before cycle 
5 then the patient would be considered inevaluable for this endpoint and will not be included 
when calculating the  secondary endpoint, rate  of  successful treatment completion. If  a 
patient comes off for any other reason before cycle 5 then the patient would count as a 
"failure" when calculating treatment completion rates. Discontinuation of non-carboplatin 
chemotherapy will not be considered “failure.” Treatment completion rates will be calculated 
on evaluable patients. The rates in the two arms will be compared using two-sample test for 
binomial proportions. 
 
The analysis of the primary and secondary endpoints will include the 114 evaluable patients 
that were randomized to each arm prior to crossover. Patients who cross over from Arm A to 
B will be reported separately both in terms of HSR experience and whether they were able to 
complete 5 cycles in each arm. 
 
We will perform exploratory analyses to correlate HSR rate within each arm separately to the 
following: history of drug, food and environmental allergies, history of asthma and history or atopic 
dermatitis (eczema), number of lifetime platinum cycles, duration since last platinum, and 
concomitant chemotherapy agent. 
 
Finally, we will also perform a cost-identification analysis to assess the direct medical costs 
associated with each treatment arm. We will capture the use of all services administered at 
MSKCC from trial registration to completion of the last cycle of carboplatin. HSRs occur 
during chemotherapy infusion and are managed immediately within the medical center and 
as a result, we anticipate that surveying costs outside of MSKCC will be unnecessary. 
Because the average age of the patients enrolled is anticipated to be 60, health service 
utilization will be multiplied by unit cost values obtained from Medicare reimbursement 
schedules for outpatient and inpatient services. Costs will be summed and average direct 
medical costs estimated for each group. Because cost data are often skewed, we will first 
examine the distribution of each cost endpoint and apply a non-parametric statistical analysis 
or other method of handling skewed data as appropriate. The assessment of direct med 
costs will allow us to perform a limited cost-effectiveness analysis, estimating the incremental 
cost per HSR. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1    Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735-0008 and (646) 
735-0003. Registrations can be phoned in or faxed. The completed signature page of the 
written consent/verbal script and a completed Eligibility Checklist must be faxed to PPR. 
 
15.2    Randomization 
 
Patients will be randomized (1:1) to either Arm A: standard 30-minute infusion carboplatin or 
Arm B: extended 3-hour infusion carboplatin. After all eligibility criteria is established and 
after consent is obtained, patients will be registered through the Protocol Participant 
Registration (PPR) system and randomized using the Clinical Research Database (CRDB). 
Randomization will be accomplished by the method of random permuted block, and patients 
will be stratified by prior history of carboplatin exposure (yes/no) and concurrent paclitaxel or 
docetaxel use (yes/no). 
 
Pharmacy will view the patient’s randomization assignment in CRDB. The results will not be 
blinded. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. The data collected for this study will be entered into a secure 
database (Clinical Research Database – CRDB). Source documentation will be available to 
support the electronic patient record. The following adverse events will be recorded: allergic 
hypersensitivity reactions/anaphylaxis, mood disturbance, insomnia, and hyperglycemia. 
These will be graded using CTCAE Version 4.0 and attributed as Definitely, Probably, 
Possibly, Unlikely or Unrelated to study treatment. Laboratory data will be tabulated and 
summarized by descriptive statistics, as well as on the basis of MSKCC specified normal 
ranges. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-184 A(8) 
Amended: 8/15/14
Page 25 of 29 
Ver. Date: 06/01/09
 
 
16.1    Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
 
16.2    Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at: 
http://mskweb2.mskcc.org/irb/index.htm. 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring,  compliance  and  data  verification  audits,  therapeutic  response,  and  staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Participation in this trial is voluntary. The patients will be explained the extent of the risks, 
benefits, toxicities/side effects, alternatives/options for treatment, financial costs/burdens, 
and the voluntary nature of the study. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. 
 
Inclusion of Women and Minorities: Because this protocol requires patients to have ovarian, 
fallopian tube or primary peritoneal carcinoma it will enroll exclusively women. Patients of all 
races will be accepted into the protocol. Memorial Sloan-Kettering Cancer Center has filed 
forms HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), and 
680 (age discrimination); we also take due notice of the NIH policy concerning inclusion of 
women and minorities in clinical research populations. 


Amended: 8/15/14
Page 26 of 29 
Ver. Date: 06/01/09
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-184 A(8) 
 
 
The proposed study population is as described in section 7.0. 
 
Exclusion of Lactating or Pregnant Women: All women who are being considered for 
participation in the study and who are child bearing and not surgically sterilized or 
postmenopausal must be tested for pregnancy within 14 days of the first dose of study 
medication. 
 
Inclusion of Children in Research 
 
This protocol does not include children younger than the age of 21. Ovary, fallopian tube and 
primary peritoneal carcinoma rarely occur in this age group. 
 
Benefits: It is possible that this treatment will result in fewer hypersensitivity reactions or 
shrinkage of the tumor or in a stabilization of an otherwise progressing disease. It is not 
known, of course, whether these or any other favorable events will occur. It is not known 
whether this treatment will affect the overall survival of the patients. 
 
Costs: The patient will be responsible for the costs of standard medical care, including all 
drug administration fees and all hospitalizations, even for complications of treatment. 
Incentives: No incentives will be offered to patients/subjects for participation in the study. 
Alternatives:  For  patients  with  advanced  ovarian,  fallopian  tube  or  primary  peritoneal 
carcinoma who choose not to participate in this study a range of standard options are 
available   including   standard   infusion   carboplatin,  paclitaxel,   docetaxel,   gemcitabine, 
liposomal   doxorubicin,   pemetrexed,   topotecan,   etoposide,   vinorelbine,   bevacizumab, 
palliative surgery or best supportive care. Patients may also be eligible for other 
investigational studies. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patient’s name or any other personally identifying 
information will not be used in reports or publications resulting from this study. 
 
17.1    Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2    Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org containing the following information: 
 
Fields populated from CRDB: 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-184 A(8) 
Amended: 8/15/14
Page 27 of 29 
Ver. Date: 06/01/09
 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
17.2.1 Sponsor Adverse Events Reporting Definitions 
 
This is not an industry sponsored trial and there is no IND required. 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-184 A(8) 
Amended: 8/15/14
Page 28 of 29 
Ver. Date: 06/01/09
 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA 
Cancer J Clin 2009;59:225-49. 
2. 
Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in 
ovarian cancer. N Engl J Med 2006;354:34-43. 
3. 
Robinson JB, Singh D, Bodurka-Bevers DC, Wharton JT, Gershenson DM, Wolf JK. 
Hypersensitivity reactions and the utility of oral and intravenous desensitization in patients 
with gynecologic malignancies. Gynecol Oncol 2001;82:550-8. 
4. 
Markman M, Kennedy A, Webster K, et al. Clinical features of hypersensitivity 
reactions to carboplatin. J Clin Oncol 1999;17:1141. 
5. 
Polyzos A, Tsavaris N, Kosmas C, et al. Hypersensitivity reactions to carboplatin 
administration are common but not always severe: a 10-year experience. Oncology 
2001;61:129-33. 
6. 
Morgan JS, Adams M, Mason MD. Hypersensitivity reactions to carboplatin given to 
patients with relapsed ovarian carcinoma. Eur J Cancer 1994;30A:1205-6. 
7. 
Navo M, Kunthur A, Badell ML, et al. Evaluation of the incidence of carboplatin 
hypersensitivity reactions in cancer patients. Gynecol Oncol 2006;103:608-13. 
8. 
Schwartz JR, Bandera C, Bradley A, et al. Does the platinum-free interval predict the 
incidence or severity of hypersensitivity reactions to carboplatin? The experience from 
Women and Infants' Hospital. Gynecol Oncol 2007;105:81-3. 
9. 
Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al. Pegylated Liposomal 
Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for Patients With 
Platinum-Sensitive Ovarian Cancer in Late Relapse. J Clin Oncol 2010;28:3323-9. 
10. 
Lee CW, Matulonis UA, Castells MC. Carboplatin hypersensitivity: a 6-h 12-step 
protocol effective in 35 desensitizations in patients with gynecological malignancies and mast 
cell/IgE-mediated reactions. Gynecol Oncol 2004;95:370-6. 
11. 
Markman M, Hsieh F, Zanotti K, et al. Initial experience with a novel desensitization 
strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity 
reactions. J Cancer Res Clin Oncol 2004;130:25-8. 
12. 
Zanotti KM, Rybicki LA, Kennedy AW, et al. Carboplatin skin testing: a skin-testing 
protocol for predicting hypersensitivity to carboplatin chemotherapy. J Clin Oncol 
2001;19:3126-9. 
13. 
Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to 
chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin 
Immunol 2008;122:574-80. 
14. 
O'Cearbhaill R, Zhou Q, Iasonos A, et al. The prophylactic conversion to an extended 
infusion schedule and use of premedication to prevent hypersensitivity reactions in ovarian 
cancer patients during carboplatin retreatment. Gynecol Oncol 2010;116:326-31. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 10-184 A(8) 
Page 29 of 29 
Ver. Date: 06/01/09 
 
 
Immune system disorders 
Grade 
Adver.; e Ev ent 
1 
2 
3 
4 
5 
All ergci reacf ion 
Transienlf lushln!J or ra91, 
dfever <38 degrsC 
(<10!D _4 deg;rees F); 
nelNenti o nnoli ndi ca ted 
ln!ervemio n or inf usion 
inenupfi oo indicated; 
onds promptly to 
symplomai:c treatment (e.g., 
anbnisla rri ne s, NSAIDS. 
narco tics};p rophylacti c 
medications indcated f or 
<=2hrs 
Prolonge d(e _g,,not 
rapidly  respo osi ve Go 
sy mptomatic 
medication andlo r bf iei 
interru poi n of infusion); 
recurren ce of sy mp!oms 
following initialillljlro vem e ni ; 
hospitalizationin di cate d lor 
clinical sequelae (eg. ., 
renal impairment. 
Life-threate ning 
conse quence s;lllgent 
interventionin dci a!ed 
Death 
Definition:A dsi order characle ri zed by anadve rse l o cal or generalres p o nse from exposu re to anallergen. 
Anaphylaxis 
- 
. 
Syllljlfomatci bronch ospa sm , 
with or withouturticaria; 
parenteralinterven ti011 
indicated;a   rgy -related 
edema aioedem a; 
hy pc:ensioo 
Lif e-threatening 
consequence-s;UJQenl 
interventi o nindi ca!ed 
De.ath 
Definition:A dsi order chara cle rize d by an acute i'lfiammatory reacfonre-su-n g from the release of hsi tamine andhisl runi ne-ilke substan ce s from maslceCs,ca usni g a 
hyperse n sitivityim m un e respo nse. Oin.icall y,ilpre s.ents wi1h breathi;n ;difficuly:, dizzines.s,h ypoten si on , cyanosi:s andloss ocl onsciou s ness. andm a ylea d to cleatl1. 
fRB 
20.0  
APPENDICES 
 
Appendix A: NCI CTCAE Version 4.0, Allergic Reaction and Anaphylaxis Grading 
,- 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PB  Amended: 8/15/14