Double-Blinded, Placebo-Controlled Pilot Trial to Explore Whether Lipids Prevent Carboplatin and Oxaliplatin Hypersensitivity Reactions
Phase: NA
Conditions: Advanced Malignant Neoplasm
Sponsor: Mayo Clinic



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Table of Contents 
MC16C1: Double-Blinded, Placebo-Controlled Pilot Trial to Explore Whether Lipids Prevent Carboplatin 
and Oxaliplatin Hypersensitivity Reactions .................................................................................................. 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 10 
3.0 
Patient Eligibility ........................................................................................................................ 10 
4.0 
Test Schedule .............................................................................................................................. 11 
5.0 
Stratification Factors ................................................................................................................... 11 
6.0  
Registration/Randomization Procedures ..................................................................................... 12 
7.0 
Protocol Treatment ...................................................................................................................... 14 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 15 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 15 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................................... 15 
11.0 
Measurement of Effect ................................................................................................................ 22 
12.0 
Descriptive Factors ..................................................................................................................... 23 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 23 
14.0 
Body Fluid Biospecimens ........................................................................................................... 24 
15.0 
Drug Information ........................................................................................................................ 25 
16.0 
Statistical Considerations and Methodology ............................................................................... 27 
17.0 
Pathology Considerations/Tissue Biospecimens - Not applicable .............................................. 30 
18.0 
Records and Data Collection Procedures .................................................................................... 31 
19.0 
Budget ......................................................................................................................................... 31 
20.0 
References ................................................................................................................................... 32 
 

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1.0 
Background 
1.1 
The Important Role of Carboplatin and Oxaliplatin in Cancer Treatment 
Carboplatin is a key antineoplastic agent for the treatment of ovarian cancer. Over the 
past decade, it has served as the backbone chemotherapy agent for the majority of 
postoperative ovarian cancer trials. Indeed, the well-established term “platinum sensitive 
disease” refers to the 6-month cancer-free interval after which it becomes acceptable to 
re-expose patients to this drug upon cancer recurrence, thus further underscoring the 
pivotal role of carboplatin for the treatment of this malignancy [1-5]. Carboplatin has also 
become a key drug in the treatment of other gynecological malignancies, such as 
endometrial cancer. 
The same can be said for oxaliplatin, which is used extensively in the treatment of 
patients with gastrointestinal cancers. One might argue there are few/no gastrointestinal 
cancers that cannot be treated with an oxaliplatin-based regimen. Oxaliplatin is a key 
drug as adjuvant chemotherapy in colorectal cancer patients [see extra references]. 
1.2 
Carboplatin and Oxaliplatin Hypersensitivity Reactions:  Incidence, Risk Factors, 
and Management 
Carboplatin and oxaliplatin hypersensitivity reactions can interfere with cancer treatment 
and compromise such ongoing cancer therapy. These reactions are life-threatening and 
obvious when they occur. They are characterized by itching, coryzal symptoms, nausea 
and vomiting, dyspnea, wheezing, hypotension, confusion, and, at times, even death. For 
carboplatin, reactions occur in only 10% of patients during the first 6 cycles of chemo-
therapy, but their incidence jumps to approximately 30% shortly after the 7th cycle of 
carboplatin [6]. For oxaliplatin, the incidence of appears to increase with the 7th cycle of 
treatment as well to a rate of approximately 20% with a steady increase in incidence 
thereafter [see extra references]. 
Risk factors for these reactions include a predisposition to allergies, a higher cumulative 
dose of the culpable drug, and specific choice of concurrently administered chemotherapy 
agent [6-14]. One of the most powerful risk factors is time-dependent: patients with a 13 
month or longer carboplatin-free interval have a 22-fold increased risk of a reaction 
upon re-exposure [8]. Although earlier studies had invoked skin testing to identify 
patients at risk, most medical centers do not make use of this approach because of 
suboptimal predictive sensitivity and specificity, mutilating cutaneous effects, and undue 
chemotherapy exposure for healthcare workers and the environment [15]. Vigilance 
during drug infusion and either desensitization or abandonment of either carboplatin or 
oxaliplatin post-reaction comprise the current approach to platinum drug administration. 
Desensitization enables carboplatin or oxaliplatin to be dispensed once again with small, 
incremental doses administered in a monitored setting until the entire intended dose is 
infused [16-21]. Desensitization has drawbacks: 1) a several-hour commitment with 
every infusion; 2) reduced but ongoing risks of hypersensitivity signs/symptoms with 
mounting risk over time; and 3) exorbitant cost. At our institution, over one year, we 
observed cumulative, multi-cycle patient costs with desensitization to carboplatin 
specifically of $1 million – over a 10-fold increase over that incurred from routine 
outpatient carboplatin administration. An inexpensive prophylactic intervention that 
eliminates carboplatin and oxaliplatin reactions would be advantageous for many 
reasons. 
 
 

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1.3 
Addressing a Gap 
Few studies have examined a prophylactic approach to these reactions. A commonly-
used intervention to 
prevent reactions, as 
proposed here, 
provides a safe, 
potentially cost-
effective, and novel 
way of managing the 
risk for a carboplatin 
hypersensitivity 
reaction.   
 
1.4 
Hypothesis: Lipids 
Prevent Carboplatin Hypersensitivity Reactions 
This proposal focuses on a seminal, recurrent observation: relapsed cancer patients 
who receive liposomal doxorubicin (Doxil®) with carboplatin suffer fewer carboplatin 
reactions (Table 1). Of note, in Table 1, some of the reactions with Doxil® might 
perhaps have been attributable to Doxil,® which at times can also cause hypersensitivity 
reactions – and perhaps not at all to carboplatin. Nonetheless, throughout the published 
literature, the rate of carboplatin hypersensitivity reactions is consistently <30% with the 
incorporation of Doxil®, even in single-arm trials [22-30]. The seminal observation that 
Doxil®, a liposomal form of doxorubicin, is associated with lower rates of carboplatin 
hypersensitivity reactions gives rise to the following novel HYPOTHESIS: the infusion 
of a lipid emulsion (the same used for nutrition support) – in effect, liposomal 
doxorubicin but without the doxorubicin – prevents carboplatin hypersensitivity 
reactions. 
Three points underscore the plausibility of this hypothesis. First, again, Doxil® is 
associated with fewer carboplatin hypersensitivity reactions [22-30]. Lipid emulsions, as 
commonly prescribed for parenteral nutrition, simulate Doxil® infusions by providing a 
near identical therapeutic platform -- same volume, similar lipids – but with no Doxil®. 
Second, carboplatin hypersensitivity reactions are most commonly type I hypersensitivity 
reactions (and less commonly type IV hypersensitivity), as indicated by a series of studies 
that demonstrate IgE mediation [10,11,31,32]. Lipid emulsions, particularly those that are 
heavily soy-based and commonly prescribed today, have immunosuppressive effects [33-
35]. They transiently suppress T-cell function, modulate B cell populations, and confer 
other suppressive effects on inflammation [33-35]. Of special relevance, preclinically, 
Arnaez and others, showed that, although carboplatin induces histamine release from 
mast cells, it does so by unique mechanisms – speculatively, via complement 
activation or direct mast cell degranulation -- but nonetheless unrelated to 
conventional approaches [36]. These findings are in keeping with what occurs clinically 
where carboplatin reactions remain problematic and suggest that a broad-based 
immunomodulator, such as a lipid emulsion, merits testing, as proposed here.  
Third, and very importantly, multiple reports indicate that lipid emulsions (the same 
used for nutrition support) are critically life-saving in patients with severe drug-
induced adverse events [37-47]. These reports describe the resuscitative role of lipids -- 
often as a heroic last resort -- in patients with overdoses from mepivacaine, bupivacaine, 
olanzapine, doxepin, flecainide, venlafaxine, moxidectin, atenolol, nebivolol, 
Table 1: RANDOMIZED TRIALS WITH DOXIL® + 
CARBOPLATIN VERSUS CARBOPLATIN WITH NO DOXIL® 
TRIAL 
N 
REACTION 
RATE with 
DOXIL® 
(%) 
REACTION 
RATE with 
CARBOPLATIN 
with NO Doxil® 
(%) 
Markman, 2010 [22]* 
61 
0 
30 
Bafaloukos, 2010 [23]* 
189 
8 
30 
Pujade-Lauraine, 2010 [24] 
976 
15 
33 
*Not specified whether Doxil® was infused first. 

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lamotrigine, propranolol, verapamil, diltiazem, atenolol, amitriptyline, glyphosate 
herbicide, and others [37-47]. In effect, lipids serve as a rescue for patients suffering from 
toxicity from a lipophilic drug: in some reports, patients who were suffering ventricular 
tachycardia and who were seizing recovered promptly upon receipt of a lipid infusion. It 
appears that the infused lipids bind to the lipophilic drug and displace it from the target 
organ. In the case of carboplatin and oxaliplatin – both of which are highly lipophilic 
– lipids presumably bind to it, displace it from basophils and mast cells, and thereby 
prevent the hypersensitivity reaction.  
Lipid emulsions are used as part of parenteral nutrition to increase the caloric content of 
nutrition support and to prevent essential fatty acid deficiency.  Various lipid emulsions 
are available, are commonly prescribed, and have been used for decades. Individual 
patients with bowel failure have been maintained on nutrition support for many, many 
years with weekly lipid infusions. These lipid emulsions tend to be well tolerated with 
adverse events noted in section 15.0. 
1.5 
Special Safety Considerations 
We do not know whether lipids would influence the efficacy of chemotherapy.  Two 
points suggest that lipids would not do so. First, prior studies with Doxil® and carboplatin 
show that these drugs together have favorable antineoplastic activity; analogously, a lipid 
emulsion would not appear to detract from the antineoplastic effects of either of these 
platinum-based agents [22-30].  Second, parenteral nutrition that includes concomitant 
lipid administration to increase caloric content is used often in various cancer settings, 
such as in patients undergoing bone marrow transplantation and in perioperative patients 
with severe malnutrition.   
 
However, in an effort to be extra cautious in the current study, we will monitor patients 
closely during the trial, and we will also exclude patients who are being treated with 
curative intent. 
1.6 
Pathobiology. 
Because of the life-threatening nature of carboplatin and oxaliplatin reactions, pragmatic 
considerations have resulted in sparse studies on pathobiology. These studies indicate 
these reactions are commonly type I and less commonly type IV [31,48]. First, 
emphasizing their type I nature, Iwamoto and others observed CD203c, a basophil 
surface marker of IgE-mediated type I hypersensitivity reactions, was 15% higher in 
patients who had sustained a carboplatin-induced reaction compared to those who had not 
[48]. Second, Caiado and others reported that 59% of patients who had sustained a 
carboplatin reaction had a carboplatin-specific IgE [32]. Third, Hesterberg and others 
demonstrated serum tryptase elevation in patients with a carboplatin hypersensitivity 
reaction [10]. Serum tryptase, the most abundant mediator of hypersensitivity 
reactions stored in mast cells, is one of 4 key mediators that comprise a standard panel 
of diagnostic evidence of allergic reactions: 1) serum tryptase, 2) urine 11-beta 
prostaglandin F2 alpha (PGF2a), 4) urine leukotriene 4, and 5) urine N-methylhistamine, 
the latter three of which stem from the release of prostaglandins, leukotrienes, and 
histamine, respectively. This finding of tryptase elevation with carboplatin or oxaliplatin 
reactions further emphasizes that these are type I hypersensitivity reactions and suggests 
a role for this 4-mediator panel [48-52]. Fourth, workers exposed to platinum salts show 
reactions to metals are mast cell/basophil IgE-mediated [53-55]. Finally, and of special 
relevance, preclinical work indicates that, although carboplatin induces histamine release 
from mast cells, this agent does so by unique, inexplicable mechanisms unresponsive 

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to more conventional suppressive agents; therefore, novel interventions are needed to 
prevent these reactions [48]. These findings indicate that IgE-mediation plays a complex 
but not fully elucidated role in carboplatin and oxaliplatin hypersensitivity reactions. 
Thus, it is reasonable to use a standard panel of 4 mediators -- serum tryptase; urine 11-
beta prostaglandin F2 alpha (PGF2a); urine leukotriene E4; and urine N-methylhistamine, 
the latter 3 of which have not been assessed in carboplatin or oxaliplatin reactions but 
logically stem from release of prostaglandins, leukotrienes, and histamine, respectively -- 
to understand pathobiology and its relevance [56].   
1.7 
Preliminary Data 
At the Mayo Clinic in 
Rochester, Minnesota, 
30+ unique patients 
underwent carboplatin 
desensitization over 1 
year, with cumulative, 
multi-cycle patient costs 
of $1 million – over 10-
fold greater than that 
incurred from routine 
outpatient carboplatin 
administration; these 
cost data further define 
the need for preventing 
hypersensitivity 
reactions. Although the 
number above includes 
patients other than 
those with ovarian 
cancer, maintaining a 
focus on one cancer type 
– specifically on patients with ovarian cancer – is of value, as it enables us to assess the 
clinical outcomes of a uniform patient cohort.  
Specific to ovarian cancer patients, our group reviewed recent outcome data from 18 
consecutive ovarian cancer patients who underwent a carboplatin desensitization 
procedure. This cohort yields three observations that guide our proposed study design: 
1) Patients developed a carboplatin reaction with the 8th (median) carboplatin treatment 
(range: 3, 21), thus providing justification for enrolling patients immediately before the 
7th carboplatin treatment and, thus, in conjunction with data from other investigators, 
enabling us to estimate a realistic hazard ratio for our sample size calculations. Other 
investigators have similarly found that the risk of a hypersensitivity reaction increases 
markedly after 7 chemotherapy treatments. 2) Although half this cohort is deceased, the 
median survival of patients who sustained a carboplatin reaction and then underwent 
desensitization was 1.4 years (time from having sustained a hypersensitivity reaction to 
death or last follow up) with some patients living substantially longer (Figure 1). These 
observations further underscore the fact that carboplatin is a key drug in ovarian cancer 
and provides further motivation for investigating ways to administer this drug safely. 
3) Two of these 18 patients developed repeated reactions during their desensitization. 
One required a 20-hour hospitalization for desensitization every time she received 
carboplatin; this patient continued to react to the latter and needed to have her infusion 
Figure 1:  The median survival of ovarian patients who had a carboplatin reaction 
and who underwent desensitization was 1.4 years (95% confidence intervals:  1.07, 
1.96 years).  These data show that desensitization procedures are associated with 
long survival.  These data suggest that the continued use of carboplatin and the 
investigation of approaches to reduce the risk of hypersensitivity reactions are 
justified. 

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as relevant to hypersensitivity reactions; 2) more frequent testing poses an undue patient 
burden; and 3) cost is otherwise prohibitive in this pilot trial setting.  
2.0 
Goals 
2.1 
To determine if the infusion of a lipid emulsion before each dose of chemotherapy 
appears to prevent carboplatin and oxaliplatin hypersensitivity reactions in high-risk 
patients. 
 
2.2 
To explore if lipid infusions modulate a well-established panel of mediators of 
hypersensitivity reactions and if these mediators appear to predict reactions.  
3.0 
Patient Eligibility 
3.1 
Inclusion criteria 
3.11 
Age ≥18 years 
3.12 
Advanced, incurable cancer 
3.13 
7th or later cycle of intravenous carboplatin or oxaliplatin infusion planned  or 
4 months after the first cycle of agent (whichever is of longer duration) ≤30 days 
after registration 
3.14 
Anticipated 2 or more subsequent chemotherapy infusions of either carboplatin 
or oxaliplatin at the time of study registration.  
NOTE: The dose of carboplatin or oxaliplatin, choice of other chemotherapy, and 
other ancillary treatment, such as antiemetics, will be left to the discretion of the 
treating healthcare provider. 
3.15  
Willing to provide mandatory blood and urine specimens for correlative research. 
Note: Can be waived with permission of Study Chair (documentation such as an 
email must be provided). 
3.16 
The following laboratory values obtained ≤30 days prior to registration: 
• 
Serum creatinine ≤1.5 times the institutional upper limit of normal 
(ULN)  
Note: Can be waived with permission of Study Chair (documentation 
such as an email must be provided). 
• 
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) 
<3x the upper limit of normal. 
• 
Triglycerides  <500 mg/dL 
• 
Alkaline phosphatase ≤3x the institutional upper limit of normal. 
3.2 
Exclusion Criteria 
3.21 
Concurrent liposomal doxorubicin or any other liposomal agent. 
3.22  
Prior carboplatin or oxaliplatin hypersensitivity reaction.  
3.23 
Taking aspirin, nonsteroidal anti-inflammatory agents, or zileuton ≤7 days prior 
to registration.  
Note: Can be waived with permission of Study Chair (documentation such as an 
email must be provided).  
3.24   Allergy to egg or egg byproducts. 

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4.0 
Test Schedule  
4.1 
Study Calendar 
Tests and procedures 
≤30 days  
prior to 
registration 
With the first on-study 
infusion of carboplatin 
or oxaliplatin  
Immediately before 
each infusion of 
carboplatin or 
oxaliplatin 
End of 
each cycle 
of 
carboplatin 
or 
oxaliplatin 
History and exam including 
weight 
X 
 
 
X1 
Serum creatinine 
X 
 
 
 
AST or ALT 
X* 
 
 
 
Triglycerides 
X 
 
 
 
Alkaline phosphatase 
X* 
 
 
 
Lipid/placebo infusion 
 
 
X 
 
AE Assessment 
X 
 
 
X 
Blood and urine collection for 
research purposesR 
 
X 
 
 
*Should be retested every 3 months or per the discretion of the treating oncologist. 
 
Maximum Cycle Length = 28 days (will vary by regimen) 
 
Footnotes: 
1. Weight only 
R  Research funded 
 
 
4.2 
Event Monitoring/Survival Follow-up 
Once patient is no longer on treatment for this study, no further follow-up is required. 
 
5.0 
Stratification Factors  
5.1 
Chemotherapy agent: carboplatin versus oxaliplatin  
 
 

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6.0  
Registration/Randomization Procedures  
6.1 
Registration Procedures 
6.11 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a week. 
Back up and/or system support contact information is available on the Web site. 
If unable to access the Web site, call the MCCC Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
The instructions for the registration/randomization application are available on 
the MCCC web page 
and detail the 
process for completing and confirming patient registration. Prior to initiation of 
protocol treatment, this process must be completed in its entirety and a MCCC 
subject ID number must be available as noted in the instructions. It is the 
responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact the MCCC Registration Office
. If the patient was 
fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Correlative Research 
6.121 
A mandatory correlative research component is part of this study, but it 
can be waived with prior permission from the study principal 
investigator. 
6.122 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research on cancer at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research to learn, prevent, or treat other health 
problems. 
• 
Patient has/has not given permission for MCCC to give his/her 
sample(s) to researchers at other institutions. 
 
6.2 
IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office (fax: 
). If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 

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6.3 
Verification 
Prior to accepting the registration, registration application will verify the following: 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
6.4 
Treatment location requirements 
Treatment on this protocol must commence at Mayo Clinic Rochester under the 
supervision of a medical oncologist, pain specialist, or associated allied health personnel. 
6.5 
Start of treatment 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
6.6 
Randomization and Blinding Procedures 
6.61 
The factors defined in Section 5.0 will be used as stratification factors. 
6.62  
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups. 
• 
Chemotherapy agent:  carboplatin versus oxaliplatin  
 
6.63  
The Registration Office will notify the Pharmacy of the assigned arm. 
6.64 
Blinding will be ensured by means of masking the infusion bag and the 
associated tubing.  Only the pharmacy staff will know if a specific patient is 
receiving lipids versus saline. 
 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule  
Agent/Placebo 
Dose 
Route 
Days123 
Retreatment 
Intralipid® 
100 mL 
IV 
immediately prior to each dose 
of either carboplatin or 
oxaliplatin until the patient 
demonstrates a healthcare 
provider-witnessed 
hypersensitivity reaction 
continue with 
each dose of 
chemotherapy 
Placebo 
100 mL 
IV 
immediately prior to each dose 
of either carboplatin or 
oxaliplatin until the patient 
demonstrates a healthcare 
provider-witnessed 
hypersensitivity reaction 
continue with 
each dose of 
chemotherapy 
1 
Maximum Cycle Length will be 28 days. Cycle length will vary depending on the 
cycle of the chemotherapy regimen. 
2. For all other chemotherapy agents, administer premeds, chemotherapy, lipid infusion, 
and then Carboplatin or Oxaliplatin. 
3. Initiate infusions at 30 mL/hour (0.5 mL/minute) for 15 minutes; if no untoward 
effects occur, the infusion rate may be increased to 60 mL/hour (1 mL/minute) for 
92.5 minutes. Subsequent infusions may be administered over 1 hour. 
7.2 
Blood and Urine Markers 
See Section 14.0 
7.3 
Breaking Codes in Double–Blinded Studies 
Situations requiring codes to be broken: There are three distinct situations in 
which it is appropriate to break the codes for individual patients enrolled in 
double-blind trials: 
(1) 
In the event of an emergency for an individual patient. 
(2) 
In the event that it would be helpful for the future clinical care of an 
individual patient after she/he has completed participation in the trial. 
In the event of an emergency, call the MCCC Registration Office at 
 to break the code on Monday through Friday, 8:00 a.m. to 4:30 p.m. Central 
Time. If the code must be broken after hours, assume the patient was assigned to 
active treatment and treat accordingly. Place a call to the MCCC Registration 
Office and leave a message informing them of the need to un-blind a patient. 
Provide your contact information so that MCCC Registration Office personnel 
can return the call the next business day. 
If, in the judgment of the attending physician, it would be helpful for the future 
clinical care of the individual patient, the code may be broken after the patient 
has completed the study. That is, after the patient has been fully evaluated and all 
evaluation information has been recorded by the attending physician and the 
patient (if appropriate), the MCCC Registration Office may be called 
 to find out which study therapy the patient was receiving. 
 
 

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Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 

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conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the table 
below: 
CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Immune system disorders 
Allergic reaction 
X 
X 
Investigations 
Alanine aminotransferase 
increased 
X 
X 
 
Aspartate aminotransferase 
increased 
X 
X 
 
Alkaline phosphatase 
X 
X 
 
Weight gain 
 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 1 and 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 

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10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
11.0 
Measurement of Effect 
Measurement of effect will be determined based on whether a patient developed a healthcare 
provider-witnessed hypersensitivity reaction or not per CTCAE v 4.03 
Patients who stop carboplatin or oxaliplatin for any reason other than a hypersensitivity reaction 
will be censored on the date of their last study infusion. 
 
 
 

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12.0 
Descriptive Factors  
12.1 
Cancer type: ovarian cancer vs endometrial cancer vs colon cancer vs other cancer 
 
12.2      Has the patient had an interval of 12 months or longer at any time between 
carboplatin/oxaliplatin treatments?  yes versus no 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  
• 
If the patient never received treatment, on-study material must be submitted.  
13.2 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in the 
initial therapy are severely violated that evaluability for primary end point is 
questionable. All data up until the point of confirmation of a major violation must be 
submitted.  
13.3 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. If the patient never received treatment, on-study material 
must be submitted.  
 
13.4 
Off study 
Patients will go off study for the following reasons: 
• 
Investigator discretion 
• 
Treatment related adverse event (immune reaction or unexpected CTCAE 
≥Grade 3 event) 
• 
Switching to different chemotherapy 
• 
Refusal of further treatment on this study 
• 
Death 
 
Patients will go off study and no further follow-up is required.  
 
 

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14.0 
Body Fluid Biospecimens 
14.1 
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol* 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to collect 
per tube  
(# of tubes to be 
collected) 
24 hours 
prior to 
lipid/placebo 
infusion 
Within 2 
hours 
following 
lipid 
infusion 
24 hours 
after 
chemo 
infusion 
Process 
at site?  
(Yes or 
No) 
Temperature 
Conditions for 
Storage /Shipping 
Blood 1 
(Section 14.4) 
Mandatory 
Whole 
Blood 
Red top 
10 mL 
X 
X 
X 
Yes 
-80 degrees 
Centigrade 
Urine2 
(Section 14.4) 
Mandatory 
24 hour 
urine 
 
10 mL 
X 
 
X 
Yes 
-80 degrees 
Centigrade 
1. Blood draw timed with dropping off of the 24 hour urine collection. 
2. The patient may pick up kit prior to starting the infusion but must wait to start collection until infusion has been completed. 
14.2 
Collection and Processing  
14.21 Blood samples will be centrifuged. Serum will be removed and stored at -80 degrees Centigrade for assay completion at a 
later date. 
14.22 24 hour urine samples will be have a small aliquot of 10 cc removed, frozen at  -80 degrees Centigrade and stored for 
assay completion at a later date. 
14.3 
Shipping and Handling 
14.31 Kits will not be used.  
14.32 After collection, blood and urine will be stored for future assays as noted below. 
14.4 
Background and Methodology 
14.41  Serum tryptase will be measured with a quantitative enzyme-linked immunosorbent assay [59-61]. Based on previous data 
from our group, we anticipate a level of 11 ng/mL or greater at time point #1 in patients at risk for a hypersensitivity 
reaction (we hypothesize we will subsequently observe this reaction in the placebo group, although we will be agnostic to 
biomarker results at the time of carboplatin infusion) with a drop to below this level with lipids and no change with 
placebo at time point #2, and with a sustained drop with lipids and no change with placebo at time point #3 [59-61].  
14.42 11-beta PGF2a, the most abundant prostaglandin D2 metabolite, will be assessed with a 24 hour urine collection with an 
immunoassay kit at time points #1 and #3.  We anticipate a level of >1000 ng/24 hours or greater in patients about to 
sustain a carboplatin reaction at time point #1 (we hypothesize we will subsequently observe this reaction in the placebo 
group, although we will be agnostic to real time biomarker results during the carboplatin infusion) with a drop to below 
this level with lipids and no change with placebo at time point #3 [59-61].

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14.43 Leukotriene E4 will be measured in urine with liquid chromatography-tandem 
mass spectrometry.  We anticipate a concentration of >104 pg/mg or greater at 
time at time point #1 in patients about to sustain a carboplatin reaction (we 
hypothesize we will subsequently observe this reaction in the placebo group, 
although we will again be agnostic to real time biomarker results) with a drop 
with lipids and no change with placebo at time point #3 [59-61].  
14.44 N-methylhistamine will be also assessed in urine. We anticipate a level of >200 
mcg/g or greater at time point #1 in patients about to sustain a carboplatin 
reaction (we hypothesize we will subsequently observe this reaction in the 
placebo group, although we will again be agnostic to biomarker results) with a 
drop with lipids and no change with placebo at time point #3 [59-61].  
15.0 
Drug Information  
15.1 
Intravenous Fat Emulsion 20% (Intralipid® 20%) 
15.11 Background: 
Intravenous Fat Emulsion 20% is a sterile, non‑pyrogenic fat emulsion prepared 
for intravenous administration as a source of calories and essential fatty acids. 
We will purchase this product and will test it because 1) most published reports 
on the resuscitative role of lipids for drug overdoses used the same or similar 
formulations and 2) a safety record is well-established. 
 
15.12 Formulation: 
The lipid emulsion used in this study will consist of 100 mL of Intralipid® 20%, 
which contains 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, 
and water for injection. The major fatty acid components include linoleic acid 
(44-62%), oleic (19-30%), palmitic (7-14%), linolenic (4-11%), and stearic 
(1.405.5%). Intralipid 20% is available in 100 mL, 250 mL, and 500 mL fill 
sizes. The Intralipid 20% utilized in this study will be supplied in a 100 mL bags. 
 
15.13 Preparation and storage: 
Administer by IV infusion only via a separate peripheral line. Use a Baxter 1.2 
micron in-line filter set (set #2H8486) which is a non-DEHP administration set. 
Note: Filters of less than 1.2 micron pore size must not be used. Also, 
conventional administration sets contain polyvinyl chloride (PVC) 
components that have DEHP (di(2- ethylhexyl) phthalate) as a plasticizer. 
Fat‑containing fluids such as Intralipid® 20% extract DEHP from these 
PVC components. 
Pharmacy will mask the infusion by placing an amber bag over the IV bag and 
set.  
Intralipid® 20% should not be stored above 25°C (77°F). Do not freeze 
Intralipid® 20%. If accidentally frozen, discard the bag. admixture instructions, 
light sensitivity, temperature for storage, product specific information. 
 
15.14 Administration: 
Initiate infusions of 20% emulsions at 0.5 mL/minute for 15 to 30 minutes; if no 
untoward effects occur, the infusion rate may be increased to 1 mL/minute. 
 
 

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16.0 
Statistical Considerations and Methodology  
16.1 
Endpoints 
16.11 Primary Endpoint: 
The primary endpoint of this pilot study is time-to-carboplatin or oxaliplatin 
acute hypersensitivity reaction of any grade. 
 
16.12 Translational Endpoint: 
We will measure whether lipid infusions modulate a well-established panel of 
mediators of hypersensitivity reactions that appear to predict reactions.   
16.2 
Study Design 
This is a prospective randomized study to explore whether the infusion of a lipid 
emulsion (versus placebo) prior to carboplatin or oxaliplatin in high risk patients leads to 
a decrease in incidence of hypersensitivity reactions . Patients will be randomized in a 1:1 
ratio to receive a lipid emulsion versus placebo.   
16.3 
Analysis Plan 
16.31 Primary endpoint:  The primary endpoint is the time to  healthcare provider 
reported hypersensitivity reactions from either carboplatin or oxaliplatin. Kaplan 
Meier curves will be constructed and a log-rank test will be  used to compare 
time-to-hypersensitivity reaction between treatment arms. Data will be censored 
based on last infusion with no hypersensitivity reaction with a maximum study 
treatment duration of 2 years per patient.   
 
16.32 Translational Endpoint: Mediators of hypersensitivity reactions will be assessed 
in an exploratory fashion to see if they appear to predict hypersensitivity 
reactions. Due to the nature of this pilot study, results will be summarized and 
tabulated. Graphics will be used as appropriate, and any testing will be 
hypothesis generating. 
 
16.4 
Sample size 
Our target sample size is 40 patients (20/arm).  If the true hazard ratio is 3.8 (with a 
median time to a reaction of approximately 2 months, based on our preliminary data and 
Table 1 data and based on our inclusion criterion that a patient must be starting the 7th 
cycle of chemotherapy), 20 patients total (10/arm) provides 80% power to detect a 
prolongation of time-to-hypersensitivity reaction with lipids versus placebo with a 1-
sided 5% significance level.   Because patients will be censored upon stopping 
carboplatin or oxaliplatin for a reason other than a hypersensitivity reaction (per section 
11.0), we conservatively anticipate high rates of censoring and therefore plan to accrue an 
extra 20 patients to reach our target sample size of 40 (20 per arm).  A log-rank test will 
be used to compare time-to-carboplatin reactions between arms; a p-value of < 0.05 will 
be considered statistically significant.  
 
16.5 
Accrual and Duration of Study 
We plan to accrue 40 patients (20 per arm) to this trial to ensure we have 20 (10/arm) 
evaluable patients. We estimate an accrual rate of 2 patients per month so that we expect 

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to complete accrual within 2 years.  With an expected total time of treatment of 4 months, 
the expected total duration of the study is slightly over 2 years.  
 
16.6 
Missing Data 
Missing data are expected to be low in this prospective study primarily because the 
occurrence of a hypersensivity reaction will be well-documented in a real-time manner 
based on the medical necessity. Patients will not be replaced.  Nonetheless, we will 
record and summarize the missing data and look for patterns. In the event, we were to 
identify patterns, we will decide on the appropriate strategies to account for missing data 
in our analyses plans. For now, we anticipate that we will rely heavily on censoring;  we 
have inflated our sample size based on anticipated high rates of censoring. 
16.7 
Data and Safety Monitoring 
The study chair(s) and the study statistician will review the study at least twice a year to 
identify accrual, adverse event, and any endpoint problems that might be developing. The 
Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board (DSMB) is 
responsible for reviewing accrual and safety data for this trial at least twice a year, based 
on reports provided by the MCCC Statistical Office. 
16.8 
Adverse Event Stopping Rules 
Note: Carboplatin and oxaliplatin are not the study drugs of interest. All adverse event 
attributions should be made to the lipid/placebo infusion, not to carboplatin/oxaliplatin. 
 
16.81 The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
16.82 Adverse events will be monitored separately by arm; the principal investigator 
will remain blinded. Accrual will be temporarily suspended to this study if at any 
time we observe events considered at least possibly related to study treatment 
(i.e. an adverse event with attribute specified as “possible”, “probable”, or 
“definite”) that satisfy either of the following: 
• if there are 2 or more Grade 3 or higher adverse events at least possibly 
attributable to lipids in the first 5 patients on the lipid arm. 
• if after the first 5 patients on the lipid arm have been treated, there are 40% or 
more patients with Grade 3 or higher adverse events at least possibly 
attributable to lipids.  
• if any Grade 5 adverse events are observed that are related to study treatment 
(lipids/placebo). 
 
Note: Historically, lipids have been administered frequently in cancer settings 
with minimal toxicity. We do not expect any further complications due to the 
lipids. With that in mind, we maintain a cautious mindset when monitoring 
these toxicities. 
16.83 If accrual is temporarily suspended, the study will be reviewed to determine 
whether accrual should continue or be permanently closed.  

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16.84 We note that we will review Grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
 

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16.9 
Gender and minority accrual considerations 
This study is open to patients from all races. Historical data indicate that no more than 
10% of patients will be ethnic minorities. Subset analysis along ethnic subpopulations 
will hence have a lack of power to draw substantive conclusions but will provide some 
data for future meta-analytic procedures and hypotheses generation. 
 
Ethnic Category 
Sex/Gender (%) 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
25 
14 
0 
39 
Ethnic Category: Total of all subjects 
25 
15 
0 
40 
Racial Category 
 
American Indian or Alaskan Native 
1 
0 
0 
1 
Asian 
2 
1 
0 
3 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
1 
0 
1 
White 
21 
12 
0 
33 
Racial Category: Total of all subjects* 
25 
15 
0 
40 
 
 
Ethnic Categories: Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or  
Central American, or other Spanish culture or origin, regardless of race. The  
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial Categories: American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains 
tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, 
China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have 
been recorded as Pacific Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any 
of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the  
Middle East, or North Africa. 
 
17.0 
Pathology Considerations/Tissue Biospecimens - Not applicable  
 
 
 

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Protocol version: 07Mar2018 
18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.0 and Data Submission Schedule for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
As required by the protocol – documentation from a healthcare provider proving 
hypersensitivity reaction per Section 7.0 
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 
information is received. A list of the missing documents will be made available to the 
appropriate co-sponsor/participant. 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to obtain the overdue material. 
18.9 
Corrections forms 
If a correction is necessary the Data Manager will query the site. The query will be sent 
to the appropriate site to make the correction and return the query and documentation of 
correction back to the Data Manager.  
19.0 
Budget 
19.1 
Costs charged to patient 
Routine clinical care 
19.2 
Tests that will be research funded 
Research testing on blood and urine 
19.3 
Other considerations 
Lipid emulsion and placebo will be provided by the study. 

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20.0 
References 
 
Additional  references: 
 
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treatment of colon cancer.  N Engl J Med 2004;  350:2343-51. 
 
Conroy T, Desseigne F, Ychou M, et al.  FOLFIRINOX versus gemcitabine for metastatic pancreatic 
cancer.  N Engl J Med 2011;  364:1817-25. 
 
Enzinger PC, Burtness CA, Niedzwiecki D, et al.  CALGB 80403 (Alliance)/E1206:  a randomized phase 
II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal 
junction cancers.  J Clin Oncol 2016;  34:2736-42. 
 
Oettle H, Riess H, Stieler JM, et al.  Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic 
acid and fluorouracil alone in gemcitabine-refractory pancreatic cancer:  outcomes from the CONKI-003 
trial.  J Clin Oncol 2014;  32:2423-9. 
 
Maindrault-Goebel F, Andre T, Tournigand C, et al.  Allergic-type reactions to oxaliplatin:  retrospective 
analysis of 42 patients.  Eur J Cancer 2005;  41:2262-7. 
 
Parel M, Ranchon F, Nosbaum A, et al.  Hypersensitivity to oxaliplatin:  clinical features and risk factors.  
BMC Pharmacol Toxicol 2014;  15:1. 
 
Kim BH, Bradley T, Tai J, et al.  Hypersensitivity to oxaliplatin:  an investigation of incidence and risk 
factors , and literature review.  Oncology 2009;  76:231-8. 
 
Polyzos A, Tsavaris N, Gogas H, et al.  Clinical features of  hypersensitivity reactions to oxaliplatin:  a 
10-year experience.  Oncology 2009;  76: 36-41. 
 
Mori Y, Nishimura T, Kitano T, et al. Oxaliplatin-free interval as a risk factor for hypersensitivity 
reaction among colorectal cancer patients treated with FOLFOX.  Oncology 2010;  79:136-43. 
 
Siu SW, Chan RT, Au GK, et al.  Hypersensitivity reactions to oxaliplatin:  experience in a single 
institution.  Ann Oncol 2006;  17:259-61. 
 
Levi F, Metzger G, Massari C, Milano G.  Oxaliplatin:  pharmacokinetics and chronopharmacological 
aspects.  Clin Pharmacokinet 2000;  38:1-21. 
 
 
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3. Markman M, Rothman R. Hakes T, et al.  Second-line platinum therapy in patients with ovarian 
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“platinum-refractory” ovarian cancer?  Gynecologic Oncology 1998;  69:91-92. 

MC16C1 
 
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5. Dizon DS, Dupont J, Anderson S, et al.  Treatment of recurrent ovarian cancer:  a retrospective 
analysis of women treated with single agent carboplatin originally treated with carboplatin and 
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20. Banerji A, Lax T, Guyer A, et al.  Management of hypersensitivity reactions to carboplatin and 
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MC16C1 
 
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Protocol version: 07Mar2018 
22. Markman M, Moon J, Wilzynski S, et al.  Single agent carboplatin versus carboplatin plus 
pegylated liposomal doxorubin in recurrent ovarian cancer: final results of a SWOG (S0200) 
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29. Power P, Stuart G, Oza A, et al.  Efficacy of pegylated liposomal doxorubicin plus carboplatin in 
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30. Hsiao SM, Chen CA, Ho-Hsiung L, et al.  Phase II trial of carboplatin and Lipo-Dox in recurrent 
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Gynecol Oncol 112:35-39, 2009. 
31. Iwamoto T, Hirai H, Yamaguchi N, et al.  Carboplatin-induced severe hypersensitivity reaction:  
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32. Caiado J, Venemalm L, Pereira-Santos MC, et al.  Carboplatin-, oxaliplatin-, and cisplatin-
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33. Guillou PJ.  The effects of lipids on some aspects of the cellular immune response.  Proc of the 
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34. Waitzberg DL, Lotirerzo PH, Logullo AF, et al.  Parenteral lipid emulsions and phagocytic 
systems.  Br J Nutr 87:S49-S57, 2002. 
35. Ott J, Hiesgen C, Mayer K.  Lipids in critical care medicine.  Prostaglandins, Leukotrienes, and 
Essential Fatty Acids 85:267-273, 2011. 
36. Arnaez E. Alfonso A, Estevez M, et al.  Effect of purification, theophylline and sodium fluoride 
on histamine release produced by antineoplastic drugs on rat mast cells.  A distinctive mechanism 
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