Pilot Clinical Trial Evaluating the Utility of Topical Cryotherapy to Decrease Chemotherapy-Induced Peripheral Neuropathy (CIPN) and Paclitaxel-Induced Acute Pain Syndrome (P-APS): A Randomized Controlled Trial
Phase: NA
Conditions: Breast Carcinoma
Sponsor: Academic and Community Cancer Research United



 
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Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           
 
 
 
 
 
 
 
 
Treatment cycle length: 7 days during paclitaxel. Propose using this therapy for the 12 weeks of adjuvant 
paclitaxel.  
Observation cycle length: 30 days for 6 months after completion of paclitaxel. 
 
  
Randomization   
Cryotherapy 
Control  
 
Observation   
  
Off Study  

 
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1.0 
Background   
 
1.1 
Paclitaxel causes peripheral numbness, tingling, and pain 
 
It is well appreciated that paclitaxel, one of the more widely used chemotherapeutic agents 
in oncologic practice, can cause peripheral numbness, tingling and pain, usually starting in 
the hands and feet. These symptoms often begin in the first several weeks of therapy, 
become more prominent over time with continued drug use, and tend to improve over time, 
after paclitaxel is discontinued.  It is well accepted that these symptoms are related to nerve 
pathology and this has been termed chemotherapy-induced peripheral neuropathy (CIPN), 
which is also caused by other neurotoxic chemotherapy agents.  
 
 
The EORTC CIPN-20 instrument was utilized in a recent NCCTG natural history trial 
(N08C1) to obtain paclitaxel-induced peripheral neuropathy data.  Two cohorts of patients 
from this study have been analyzed: a group who received weekly paclitaxel (70-90 mg/m2) 
without another neurotoxic agent and another group who received higher doses of 
paclitaxel (i.e. 175 mg/m2) every 3 weeks, concomitantly with carboplatin. The data from 
the first cohort of patients are provided below; data from the second cohort show similar 
findings.1   
 
The EORTC CIPN-20 instrument provides sensory, motor, and autonomic subscales. 
Figure 1, derived from the weekly paclitaxel cohort, illustrates changes in these scores, 
over time.  Mean decreases from baseline, until the 12th dose of paclitaxel, were 23.4 
points for the sensory score, 11.5 points for the motor score and 5.8 points for the 
autonomic score.  To test which type of neuropathy was most problematic, the changes 
from baseline were tested between each pair of variables. With this, the change in sensory 
scores was greater than the change in the autonomic scores and the change in the motor 
scores.2 
 
Figure 1:  
 
 
These sensory neuropathy changes were evaluated in more detail in this same cohort by 
examining data from the following three individual questions, which the EORTC CIPN-20 
instrument contains (which are used, with other questions, to determine the sensory 
neuropathy subscale of this tool):  
• 
Do you have tingling fingers or hands?  
• 
Do you have numbness in your fingers or hands? 
• 
Do you have shooting or burning pain in your fingers or hands? 

 
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Figure 2 illustrates that, during the time of paclitaxel therapy, numbness and tingling are 
very closely related to each other, while pain is less prominent.  Three questions, similar to 
the ones above, are also asked by the EORTC QLQ-CIPN20 instrument, relating to the toes 
and feet, as opposed to the fingers and hands. Data from the lower extremities closely 
replicate what is observed in the upper extremities. Data from the cohort of patients 
receiving higher dose paclitaxel and carboplatin every 3 weeks revealed similar data for 
both hands and feet.1 
 
Figure 2:  
 
 
Data from Hershman et al. reveal that, while neuropathy tends to improve after completion 
of chemotherapy, about 50% of patients can still have some problematic paclitaxel-induced 
neurotoxicity a year following drug discontinuation.3  
 
 
1.2 
Paclitaxel acute pain syndrome (P-APS) 
 
Paclitaxel also produces a disabling syndrome of sub-acute aches and pains that had been 
commonly referred to as arthralgias and myalgias, in a majority of patients.4  Until recently, 
the exact characterization of P-APS had not been well defined.  There had been little 
known about how patients characterize these symptoms or how these symptoms compare 
to, or contrast with, symptoms of neuropathy. Based on animal data that illustrated that rat 
dorsal root ganglions had evidence of nerve toxicity 24 hours after they received a 
clinically appropriate dose of paclitaxel (illustrated by increased expression of ATF-3, a 
marker of nerve injury), it was hypothesized that this pain syndrome may be from nerve 
pathology.5  Subsequent discussions with patients suffering from this syndrome supported 
that the pains did not appear to be of joint or muscle origin.  To obtain further information, 
18 patients at the Mayo Clinic, who noted the presence of sub-acute aches and pains 
following paclitaxel, participated in structured interviews to characterize their symptoms.6 
Eighty-three percent of the patients (15/18) specifically denied joint or muscle pain.  The 
pain commonly started 1-2 days after the paclitaxel infusion, with the median duration of 
pain being 4-5 days. Patients commonly described the discomfort as “aching” or “deep 
pain” that was “radiating,” “stabbing,” or “shooting.”  The pain was usually generalized 
and located in the back, hips, shoulders, thighs, legs and feet and, at times, radiated down 
the legs, arms, or back.  It was concluded that the sub-acute paclitaxel-induced pain 
appeared to be likely related to a pathologic process in nerve tissue (e.g. sensitization of 
nociceptors or nociceptive fibers) as opposed to being from a musculoskeletal injury.   
 
 

 
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The natural history of the P-APS was further investigated in the above noted prospective 
natural history study that was also designed to detail the natural history of paclitaxel-
induced peripheral neuropathy, including an attempt to define the relationship, if any, that 
might exist between these two entities.  It was hypothesized that a correlation between the 
degree of P-APS and subsequent neuropathy would support that the P-APS was a form of 
neurotoxicity.  It was felt that a greater understanding of the nature and etiology of the P-
APS might provide further insight into ways to potentially alleviate this bothersome 
toxicity.   
 
 
In this study, patients were asked, daily for the first six days after the first dose of 
paclitaxel, “Please rate any aches/pains that are NEW since your last dose of paclitaxel, and 
that you think might be related to your chemotherapy treatment by circling ONE number 
that best describes your aches/pains at its WORST in the last 24 hours.” Seventy-one 
percent of the patients noted pain, ranging from 1-10 on a 0-10 scale. With each subsequent 
dose of paclitaxel, affirmative answers were seen in 56-69% of respondents. The pain 
associated with paclitaxel administration peaked on day 4 status post-paclitaxel 
commencement.  Figure 3 illustrates the data from a cohort of patients receiving weekly 
paclitaxel, at a dose of 70-90mg/m2. 
 
Figure 3: 
 
 

 
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With regards to analgesic use for this problem, non-prescription medications were used, 
over the 12 weekly cycles of therapy by 30-41% of patients per week, while opioids were 
used by 12-20% of patients during their weekly cycles of therapy (Figure 4). 
 
Figure 4:  
 
 
 
Data from the second cohort of patients, receiving higher paclitaxel doses every 3 weeks, 
demonstrated similar findings except that the pain was more severe (mean scores P-APS 
scores of about 4, on a 10-point scale, versus about 1.5, on a 10 point scale, with the lower 
dose weekly treatments) and patients took more analgesics.1  At this time, these data, in 
total, strongly support that it is much more likely that this acute pain syndrome is related to 
nerve injury as opposed to being related to muscle or joint pathology.  
 
1.3 
Prevention/treatment approaches for P-APS and paclitaxel induced peripheral 
neuropathy 
 
Given that both of these paclitaxel toxicity syndromes appear to be related to nerve 
pathology, studying agents that treat neuropathic pain makes sense, as a means of trying to 
prevent and treat both of these problems. The first published randomized, placebo-
controlled, double-blinded, cross-over trial published to date, examining a treatment to 
prevent the P-APS, was done by our group, evaluating glutamine.7  More recently, we 
published the results of a placebo-controlled, pilot trial, evaluating the utility of pregabalin 
for  P-APS and paclitaxel-induced peripheral neuropathy.  Unfortunately, the results did not 
support further evaluation of this approach.   
 
1.4 
Topical Cryotherapy for preventing CIPN 
 
A relatively recent review article, titled:  Supportive Cryotherapy: A Review from Head to 
Toe, details the history of cryotherapy as a part of the management of patients with cancer 
(Kadakia et al., 2014). Cryotherapy was initially reported to be helpful for decreasing 
Adriamycin-induced alopecia, with initial studies dating back to the 1970s.  There has been 
a recent resurgence of this approach with newer methods of providing scalp cryotherapy.  
Oral cryotherapy was first reported to be helpful for preventing 5-fluorouracil induced 
mucositis in 1991, in a manuscript published by the NCCTG and now is recommended for 
clinical use, by MASCC mucositis guidelines, following multiple confirmatory trials.  
Cryotherapy has also been reported to be beneficial for decreasing 5-fluorouracil-induced 

 
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ocular toxicity.  Additionally, it has been shown to decrease chemotherapy-induced 
onycholysis (Matsumoto 2009). 
   
There are several sources of information that support that cryotherapy can decrease 
paclitaxel-induced neuropathy.  I (CLL) initially heard about cryotherapy potentially being 
helpful for preventing paclitaxel-associated neuropathy in about 2011, when 
 
 mentioned it to me.  I was aware of it being helpful for preventing docetaxel-
associated nail toxicity, but not neuropathy. 
 
In September 2012, I saw a communication from 
 who wrote the 
following: 
 
“I saw a 36 yr old female with T3N0 triple-negative left breast cancer last week. 
Her lumpectomy specimen after 6 cycles of TAC chemotherapy showed complete 
sterilization of disease. She will now be starting radiation by me. Her major 
problem is severe numbness and tingling of fingers and toes. I have searched 
Pubmed and found no reliable treatment options for CIPN. 
 
My daughter was diagnosed with triple-negative breast cancer in October 2010 at 
age 31 and also had a complete pathologic response after TAC.  During the hour 
long infusion of Taxol every 21 days, she kept her fingers and toes in ice water 
slush to ensure vascular constriction around peripheral nerve endings during first 
pass of Taxol. She never experienced any hint of neuropathy and at present has no 
numbness or tingling, patiently awaiting the birth of her first child later this month. 
Since Finger/Toe cryotherapy during taxane infusion has become standard at my 
cancer center, we have seen no more Grade 2 or 3 taxane-induced neuropathy. 
Prevention is the way to go.”  
 
Follow-up discussions in 2015 revealed that 
 continues to use topical 
cryotherapy in his practice and remains impressed with its benefit. 
 
In 2012, a protocol was underway at Northwestern University try to study this issue, using 
a frozen glove product, but there was notation that the study was a challenge.  Part of the 
challenge was related to the gloves being labor intensive and having to change gloves 
midway through the chemotherapy treatment.  Results of this trial have not become 
available. 
 
To the best of my recollection, a Canadian group was also trying to study this issue a few 
years ago.  Again, no report has become available regarding this effort. 
 
In 2013/2014, I had a patient who had previously received paclitaxel and had developed 
marked fingernail toxicity along with some peripheral neuropathy.  A few years later, when 
I saw her again, she had developed another primary breast cancer.  Her neuropathy had 
resolved along with her fingernail problems.  This time, to prevent nail toxicity, we had her 
keep her fingers and toes in an ice slush bath during her paclitaxel therapy.  With this, she 
did not develop anything nail toxicity and she also did not develop any recurrent 
neuropathy. 
 
 
 

 
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In April 2015, 
 a dermatologist now at 
 contacted me 
with the following e-mail message: 
 
“The reason that I am emailing you is because I have been having patients placing 
ice packs on hands and feet during taxane therapy...which has resulted of course in 
few if any cases of grade 2 changes BUT they are also reporting NO neuropathy, 
as you showed with ice chips for 5FU mucositis.”  
 
After I asked him to provide more detail regarding how they provided the cryotherapy, 
because I thought this was worth studying further, I received the following message:  
 
“I was at the breast center today, and what they use (we tried the gel gloves but 
logistically not feasible, too much time, space were needed) is just small biohazard 
bags and ice from the ice machines patients use. We could standardize the size of 
the bags, and patients to hold them 15 before, during, and 15 min after. 
 
Pretty much every patient here is being given the ice bags, and anecdotally, no nail 
changes (as reported by Scotte JCO 2005) and minimal to no neuropathy. Patients 
that are receiving taxanes for a second time as for recurrent disease are emphatic 
about the absence of neuropathy.” 
 
Additionally, a retrospective report, regarding docetaxel-induced peripheral neuropathy 
among 1725 Danish breast cancer patients, noted that patients who used frozen gloves and 
socks (40% of the patients) during treatment had a 44% reduction in subsequent neuropathy 
problems (P < 0.0001) (Eckhoff et al., 2013).  
 
When I presented this concept proposal at the 2015 Spring Alliance meeting, three 
physicians claimed to be using topical cryotherapy practice (out of about 20 physicians 
present).  Afterwards, I spoke with 
 who noted that they have an 
ongoing phase II clinical trial (no control arm).  There was a patient advocacy group who 
was a strong proponent of this approach, not allowing her to have a control group. As of 
May 2015, they had enrolled 33 of 39 planned patients. 16 patients had completed the trial. 
To this date, 3 patients had experienced grade 1 neuropathy and 1 patient grade 2. The 
patients with grade 1 neuropathy only reported paresthesias in their feet. The patient who 
experienced grade 2 neuropathy did have a history of pre-existing neurologic disease which 
may have contributed to her symptoms.  
 
As far as proposing a mechanism that can explain why cryotherapy might be beneficial, 
there are data to demonstrate that patients receiving paclitaxel lose epithelial nerve fibers 
(Ko et al., 2014, Boyette-Davis et al., 2013, and Bennett et al., 2011).  Potentially, this is 
from a local reaction from chemotherapy getting to the distal epithelial nerve fibers.  
Cryotherapy should cause vasoconstriction and decrease the amount of paclitaxel getting to 
the distal epithelial nerve fibers, thus resulting in decreased neuropathy. 
 
A potential concern regarding this approach is that paclitaxel has a reported half-life of 
about five hours (Gianni et al., 1995). Given this, it would seem that decreasing blood flow 
during the time of chemotherapy administration would not have much effect.  However, 
docetaxel has a terminal half- life of 13.5 hours (Extra et al., 1993), yet cryotherapy has 
repeatedly been shown to decrease nail toxicity (Kadakia et al., 2014). Additionally, 
Adriamycin has reported half-life of 30 hours (Benjamin et al., 1977), yet scalp cryotherapy 
can decrease alopecia, when only given for a couple of hours (Kadakia et al., 2014).  In all 

 
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three of these situations, it may be that the cryotherapy decreases blood flow to target 
tissues when there are peak drug concentrations in the plasma, and this decreases the 
toxicity. 
 
The above data support further evaluation of cryotherapy as a means to prevent paclitaxel-
associated neuropathy.  Pilot study data are needed prior to connecting a larger phase III, 
more definitive, trial.  The data from this trial will provide an estimate of the amount of 
potential benefit from this approach.  
 
1.5 
Proposed Clinical Trial Design 
 
This trial will be a controlled pilot study of topical cryotherapy versus a control arm. 
There will not be a double-blinded placebo arm, as it is virtually impossible to try to 
replicate cryotherapy treatment, in a double blinded manner.   
 
1.6 
Treatment duration 
 
We propose using this therapy for the 12 planned weeks of adjuvant paclitaxel.   
 
2.0 
Goals    
 
2.1 
To estimate whether topical cryotherapy can alleviate paclitaxel-induced peripheral 
neuropathy. 
  
     
2.2 
To estimate whether topical cryotherapy can alleviate P-APS.  
    
2.3     To examine the possible relative toxicities related to topical cryotherapy in this 
study situation.  
 
3.0 Patient Eligibility    
 
3.1 
Inclusion Criteria 
 
3.11 
Age ≥ 18 years 
 
 
 
3.12 
Ability to complete questionnaires by themselves or with assistance. 
  
  
3.13 
Planned paclitaxel at a dose of 80 mg/m2 I.V. given, in the adjuvant breast cancer 
(postoperative or neo-adjuvant) setting, every week for a planned course of 12 
weeks without any other concurrent cytotoxic chemotherapy (NOTE: trastuzumab 
and/or other antibody and/or small molecule treatment is allowed, except for PARP 
inhibitors), at the entering ACCRU institution. 
 
  
3.14 
Life expectancy >6 months 
 
3.15 
ECOG performance status 0 or 1. (Form is available on the ACCRU web site 
https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html)  
3.16  
Patient has score of 0 or 1 on the neurotoxicity evaluation, as determined by the 
healthcare provider (Appendix X). 
 
 
 

 
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3.2 
Exclusion Criteria 
 
3.21 
Previous diagnosis of diabetic neuropathy or peripheral neuropathy from any cause.   
3.22 
Diagnosis of fibromyalgia 
3.23 
Any prior exposure to neurotoxic chemotherapy. 
3.24 
History of Raynaud’s disease, cryoglobulinemia. 
 
4.0 
Test Schedule 
 
 
Tests and 
procedures 
 
Active Monitoring Phase 
Baseline 
≤ 28 days 
prior to 
registration 
Day 1 
Days 2-7 
of 
paclitaxel 
cycle 
Day 8 
Prior to 
each 
paclitaxel 
cycle 2 
Observation 
once 
every 30 days 
+/- 5 days 
following 
completion  of 
paclitaxel 
treatment for 6 
months 
 
History and exam, 
performance status 
X 
 
 
 
 
Baseline Pre-Paclitaxel 
Questionnaire  
        (App. III) 
X4 
 
 
 
 
Daily Post-Paclitaxel 
Questionnaire (App. IV) 
 
 
X 
 
 
Acute Pain Syndrome 
Symptom Summary 
Questionnaire (App.V)    
 
 
 
X2 
 
EORTC QLQ-CIPN20 
Questionnaire (App.VIII) 
X4 
 
 
X2 
X 
Monthly Questionnaire 
(App.VI) 
 
 
 
 
X 
Nurse Follow-up Phone 
Call (App.VII) 
 
 
X1 
 
X 
CTCAE neuropathy 
grading  (App. X) 
X 
 
 
X 
 
Cryotherapy toleration 
form (App. IX) 
 
X3 
 
 
 
 
1. Call patients on day 2 of cycle 1 (or one business day after initiation of cycle 1 paclitaxel) to 
encourage compliance with questionnaires and answer patient questions.  The only 
documentation necessary is the date of the phone call. 
2.  To be completed day 1 of each subsequent paclitaxel treatment PRIOR to receiving paclitaxel. 
For the last cycle of paclitaxel, day 8 will obviously not be the day of the next cycle of paclitaxel. 
3.   To be completed after  treatment by the nurse on day 1 of each paclitaxel cycle if patient is 
enrolled to cryotherapy arm. 
4.   This should be done after registration, but prior to chemotherapy. 
 

 
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5.0 
Stratification Factors:  
5.1 
Age (years): <50 vs. >50 
 
5.2 
History of diabetes: yes vs. no 
 
6.0  
Registration/Randomization Procedures 
 
6.1  Registration Procedures 
 
6.11 
To register a patient, access the ACCRU web page at 
 click on “Training 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 
Academic and Community Cancer Research United (ACCRU) 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 using the 
Help button.  Prior to initiation of protocol treatment, this process must be completed in 
its entirety and a ACCRU subject ID number must be available as noted in the 
instructions.  It is the responsibility of the individual and institution 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 ACCRU Registration Office 
.  If the patient was 
fully registered, the ACCRU 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 
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 
  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. 
 
6.13 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 

 
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• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
6.14 
Treatment cannot begin prior to registration and must begin ≤28 days after 
registration. 
 
6.15 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.16 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a health care professional, with plans for all the paclitaxel to be 
given at this institution 
 
6.17 
Patient questionnaire booklet is available on site; copies are not acceptable for this 
submission.  
 
6.2 
Randomization Procedures  
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.22  
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 (Pocock & Simon 1975):   
• topical cryotherapy 
• control 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule  
 
Agent 
Cycle 1 - 12 
Topical 
cryotherapy 
 Cryotherapy will be used 
for 15 minutes prior to each 
paclitaxel dose, during 
paclitaxel infusion and for 
15 minutes following 
paclitaxel completion.  
 
 
 
7.2 
Methods of delivering cryotherapy 
 
Hands 
 
• 
Fill provided quart bag (with outside pocket/sleeve) 2/3 full of crushed ice.   
• 
Fill another quart bag (no sleeve on this one) 2/3 full of crushed ice.  

 
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RU221511I 
 
• 
Put light cotton mitten on one hand and put the hand in the pocket/sleeve of the one 
ice bag (use of the mittens is recommended, but optional).  
• 
Place this bag (with the hand in the pocket/sleeve) in another one gallon bag.   
• 
Put the other bag over the hand, inside the gallon bag. 
• 
Put a towel underneath to catch any leakage and then consider putting all on a tray.   
• 
Repeat for the other hand. 
• 
Note that, if an IV is in a hand, then that site should not be covered by a glove or 
by ice (so that nurses and patients can see the site in the rare case that there is a 
drug extravasation).  The hand can still have the palmar surface on the ice. 
 
Feet 
• 
Fill provided quart bag (with outside pocket/sleeve) 2/3 full of crushed ice.   
• 
Fill a 1-gallon ice bag ½ full of crushed ice. 
• 
Put light cotton ped on one foot (use of the peds is recommended, but optional). 
• 
Put one foot into the sleeve and then on the bottom of an 11 x 13 x 6 inch plastic container. 
• 
Put the second ice bag over the foot.  
• 
Repeat for the other foot.  
• 
Can use both feet in one container or use individual containers for each foot.   
• 
An alternative is to use a 1-gallon ice bag ½ full of crushed ice (instead of the pocket bag), 
put this bag in the container, place a foot on it and put another ice bag over the top of the 
foot. 
 
General  
• 
Make sure that ice is replenished if it melts.  
• 
If the treatment gets too cold, the patient can temporarily remove extremity from part or all 
of the ice contact, understanding that the goal is to keep the extremities as cold as is 
possible to decrease blood supply when there are high concentrations of the paclitaxel in the 
blood.  
 
 
7.3 
At clinician’s discretion participants will also be recommended a usual regimen of non-
opioid analgesic (acetaminophen 500mg every 6 hours as needed) for “breakthrough” pain 
on the days following chemotherapy (i.e. the paclitaxel acute pain syndrome) with the 
option of low dose opioid pain medications agents (e.g., oxycodone 5mg every 1-2 hours as 
needed).   
 
 
8.0 
Treatment Modification Based on Adverse Events  
 
8.1    Cryotherapy   
 
 
If the patient develops any clinically significant adverse event attributed to topical 
cryotherapy it should be temporarily or permanently stopped, per nurse/physician 
discretion. Temporary cessation can consist of having a patient withdraw fingers/feet from 
the ice and put them back in the cryotherapy as tolerated.   The patient should continue to 
be followed according to protocol criteria; this includes completing questionnaires. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Other treatment as necessary for the control of chemotherapy related symptoms is allowed, 
with the exception of therapy for prevention of paclitaxel-associated acute pain syndrome 
and/or prevention of paclitaxel-induced peripheral neuropathy (noting that treatment of 
pain can be used, as outlined in section 7.2).  

 
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10.0 
Adverse Event (AE) Reporting and Monitoring 
 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure.  
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected.  
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk 
for human subjects, including reports of mutagenicity, teratogenicity, or 
carcinogenicity.  
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not 
conducted by the sponsor, that suggest a significant risk in humans exposed to the 
drug.  
• 
Any clinically important increase in the rate of a serious suspected adverse reaction 
over the rate stated in the protocol or Investigator’s Brochure (IB).  
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
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: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)     
 
a. Adverse event monitoring and reporting is a routine part of every clinical 
trial.   

 
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RU221511I 
 
 
b. Identify the grade and severity of the event using the CTCAE version 4.0.   
 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
 
d. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
 
f. Determine if other reporting is required (see Section 10.5). 
 
g. 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). 
 
10.11 Each CTCAE term in the current version is a unique representation of a 
specific event used for medical documentation and scientific analysis 
and is a single MedDRA Lowest Level Term (LLT). 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the 
same as serious AE which is defined in the table 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. 
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 

 
18 
RU221511I 
 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
 
 

 
20 
RU221511I 
 
 
Follow site-specific reporting guidelines. 
 
Commercial agent expedited reports must be submitted to the FDA via MedWatch.3500A   
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
 
or  
 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/ListFormsAlphabetically/default.htm 
 
Instructions for completing the MedWatch 3500A:  
 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/UCM387002.pdf 
 
Submit copies to the ACCRU SAE Coordinator via fax 
  The ACCRU SAE 
Coordinator will forward to (insert sponsor name). 
 
The ACCRU SAE Coordinator will forward to
 as appropriate. 
The ACCRU IND Coordinator will assist the sponsor-investigator in notifying the FDA if required.  
 
NOTE:  The Grade 4 or 5 Non-AER Reportable Events/Hospitalization Form is not being used for 
this study. 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
None 
 
 
 
 
10.52 Submit via appropriate Academic and Community Cancer Research United (ACCRU) Case 
Report Forms (i.e., paper or electronic, as applicable) the following AEs experienced by a 
patient and not specified in Section 10.5: 
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study treatment 
or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.523  Grade 5 AEs (Deaths) 
 
10.5231 Any death within 30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
 
10.5232 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. 

 
21 
RU221511I 
 
 
11.0 
Treatment Evaluation Using RECIST Guideline: None 
 
12.0 
Descriptive Factors: None 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
 
13.1 
A patient is deemed ineligible if at the time of registration, the patient did not satisfy each 
and every eligibility criteria for study entry. The patient may continue treatment off-
protocol at the discretion of the physician as long as there are no safety concerns, and the 
patient was properly registered.  The patient will go directly off of the study.  
• 
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 
A patient is deemed a major violation if protocol requirements regarding treatment in cycle 
1 of 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.  The patient may continue treatment off-protocol at the discretion of the 
physician as long as there are no safety concerns, and the patient was properly registered.   
13.3 
A patient is deemed a cancel if he/she is removed from the study for any reason before any 
study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  
 
13.4 
If the patient starts any additional neurotoxic chemotherapy, or changes to a different 
paclitaxel treatment regimen, the patient should be taken off study. All protocol procedures 
should be stopped. 
 
13.5 
If the patient stops topical cryotherapy but continues paclitaxel, the patient should continue 
to fill out weekly questionnaires on-study as long as the patient is on the paclitaxel. 
 
13.6 
At the end of paclitaxel chemotherapy treatment, the patient will continue to be followed on 
study as part of the observation phase.  Monthly questionnaires will be completed for 6 
months from the completion of paclitaxel treatment.  
 
13.7  
If the paclitaxel dose is delayed, missed, or skipped the patient should continue to fill out 
weekly questionnaires.  
 
14.0 
Body Fluid Biospecimens: None 
 
15.0 
Drug Information: N/A 
 
 
15.1 
Nursing Guidelines:  
Educate the patient regarding the cryotherapy procedure.   
If a patient’s hand(s) or foot/feet become painful while receiving cryotherapy, then examine 
them to make sure that color is good.  If there is concern about frostbite or pain, then you 
can remove part (e.g., top bag) or all of the ice, temporarily or permanently, as clinically 
indicated.   
 
 
 

 
22 
RU221511I 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Study Design 
 
This study is a prospective, randomized pilot study comparing topical cryotherapy to 
control in patients receiving paclitaxel given every week for a planned course of 12 weeks.  
The purpose of this pilot is to estimate the treatment effects of topical cryotherapy and 
control arms using patient-reported outcome assessment tools, to provide preliminary 
efficacy information to warrant a large scale randomized phase III clinical trial. The focus 
of this pilot study is more on estimation rather than hypothesis testing. 
 
16.2 
Statistical Endpoints and Analyses 
 
The primary goals of this trial are to obtain pilot data regarding the possible effect of 
topical cryotherapy on the prevention of paclitaxel-induced CIPN and the P-APS.  An 
additional goal is to look at the potential toxicities of topical cryotherapy in this study. 
 
We hypothesize that we will not see any differences in the paclitaxel acute pain syndrome 
results between the two study arms, because these problems are usually more central and 
would not be expected to be altered with peripheral extremity cryotherapy.  This will serve 
as a good control.   
 
We also hypothesize that differences will occur between the cryotherapy and control 
groups for peripheral chemotherapy-induced neuropathy symptoms.  The primary 
measurement of this will be with the use of the EORTC CIPN-20 instrument, sensory scale.  
While we will have little power to detect a small difference between the two study arms, 
given the small patient numbers in this pilot trial, if the true response is large, there is a 
high likelihood that we will observe a statistically significant difference (see Section 16.3). 
 
Due to the nature of pilot study, descriptive statistics and statistical plots will be mainly 
utilized.  Statistical hypothesis testings will be used in an exploratory manner and shall be 
interpreted accordingly.   The difference between the topical cryotherapy and control arms 
will be compared in an exploratory fashion to determine if the difference, if any, is 
clinically meaningful and important, and worthy of further studies.   
 
Statistical endpoints for goals 2.1, 2.2, and 2.3 will be analyzed in similar manners, where 
means and 95% CIs will be produced for continuous data for both the topical cryotherapy 
arm and the control arm.  For categorical/discrete data, frequency counts and percentage 
will be produced.  The mean estimates will be compared and differences in frequency 
distributions noted.   
 
 

 
23 
RU221511I 
 
The endpoints for these goals are listed in the following table.   
 
Goal 
Endpoint 
2.1: To 
estimate 
whether 
topical 
cryotherapy 
can 
alleviate 
paclitaxel-
induced 
peripheral 
neuropathy. 
1. Subscales of the EORTC CIPN-20 (sensory, motor, and 
autonomic) (Appendix VIII). 
2. Individual items of the EORTC CIPN-20 instrument (Appendix 
VIII)  
3. Maximum of each EORTC CIPN-20 variable. 
4. Area under the curve (AUC) of  each EORTC CIPN-20 variable. 
5. The worst pain scores in the first cycle of therapy (question 1 from 
Appendix IV and question 2 from Appendix V) and the subsequent 
neuropathy scores as judged from the daily questions. 
6. Individual items from the monthly follow-up questionnaire 
(Appendix VI). 
 
 
2.2 To 
estimate 
whether 
topical 
cryotherapy 
can 
alleviate P-
APS. 
Cycle 1 data: 
1. Maximum of the worst pain scores (item 1, Appendix IV) over the 
period from treatment initiation to day 7 (for cycle 1). 
2. Maximum of the average pain score (item 3, Appendix IV). 
3. Area under the curve (AUC) of worst, average and least pain 
(items 1-3, Appendix IV). 
4. The proportion of patients who use non-prescription pain 
medications (item 4, Appendix IV). 
5. The proportion of patients who use opioids (item 7, Appendix IV). 
6. The proportion of patients who report the development of new 
aches/pains that they attribute to paclitaxel (item 1, Appendix V). 
7. The worst pain reported at the end of the week for the overall week 
(item 2, Appendix V). 
8. The proportion of patients who report, at week’s end, using non-
prescription pain medications (item 3, Appendix V). 
9. The proportion of patients who report, at week’s end, using 
opioids (item 6, Appendix V). 
 
Cycles 2-12 data: 
Secondary endpoints for each subsequent cycle will be summarized 
in a similar fashion to the data from cycle 1. 
 
 
2.3: To 
examine the 
possible 
relative 
toxicities 
related to 
topical 
cryotherapy 
therapy in 
this study 
situation. 
1. The proportion of patients who report the toxicity as determined by 
nurses report (Appendix IX), by patient reports (question 11, 
Appendix V) and by CTCAE reported events. 
 
 

 
24 
RU221511I 
 
16.3 
Sample Size, Power, Accrual time, and Study Duration (primary endpoint completion time) 
 
Due to the exploratory nature of this pilot study, the sample size of 46 (23 patients per arm) 
is determined by logistical and financial considerations, rather than based on a formal 
hypothesis testing of the primary endpoint. However, in terms of the primary endpoint of 
the CIPN-20 sensory subscale, converted into a 0-100 scale, the following table provides 
some power analysis for various effect size based on a two-sided two-sample t test at the α 
= 0.05 for a fixed sample size of 46 patients.  
 
Two sample t-test of equal means (equal n's) 
 Effect size, Δ = | µ 1 -  µ 2| / σ 
0.500
    0.750
    0.850
    0.950
    1.000
 Power ( % ) 
     38
     70
     80
     88
     91
  
For example, we will have 80% power to detect an effect size of 0.85 in CIPN-20 sensory 
score with a sample size of 46 patients.  
 
Based on past experience of patient accrual in previous trials and the frequency of weekly 
paclitaxel treatment in oncology practice, we estimate an accrual rate of approximately 5 
patients per month and thus expect to complete accrual of 46 patients in approximately 10 
months. 
 
16.4 
Adverse Event stopping rule 
 
The stopping rule specified below is based on the knowledge available at study 
development. We do 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. 
 
Accrual will be temporarily suspended to this study if at any time we observe events that 
the study team considers to be at least possibly related to study treatment (i.e., an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy the 
following: 
 
If there are 10 or more patients on the topical cryotherapy arm and a 50% increase 
in grade 4 or higher non-hematologic adverse events (compared to the control arm) 
in the first 20 treated patients; or a 25% increase in grade 4 or higher 
nonhematologic adverse events on the topical cryotherapy arm compared to the 
control arm after 20 patients total are accrued. 
 
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. 
 
 

 
25 
RU221511I 
 
16.5 
Study monitoring 
 
The efficacy and toxicity data for this study will be reviewed semiannually by the Mayo 
Clinic Data Safety Monitoring Board (DSMB). Early termination of accrual will be 
considered if there is evidence of unacceptable toxicity. 
 
17.0  
Pathology Considerations/Tissue Biospecimens: None 
 
 

 
26 
RU221511I 
 
18.0 
Records and Data Collection Procedures  
 
18.1 Submission Timetables 
 
Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study  
≤2 weeks  after registration 
End of Active Treatment/Cancel Notification  
Submit ≤2 weeks  after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire Booklet(Baseline Pre-Paclitaxel 
Questionnaire, EORTC QLQ-CIPN20)1 
≤ 28 days after registration – Patient questionnaire 
booklet must be used; copies are not acceptable for this 
submission. 
Booklet Compliance  
≤ 28 days after registration – This form must be 
completed only if the booklet/s contains absolutely NO 
patient provided assessment information. 
Neurotoxicity Evaluation 
≤ 28 days prior to registration 
Deviation 
Submit only if applicable during all phases of the study  
(initial, active and observation) 
1. 
Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
 
Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Nurse/CRA Evaluation 
X 
X 
 
Nurse Evaluation of Cryotherapy Tolerance  
X 
 
 
Nurse/CRA Evaluation/Observation 
 
 
X2 
Neurotoxicity Evaluation 
X 
 
 
Other Adverse Event 
X 
 
 
Patient Questionnaire Booklets:1 
• Daily Post-Paclitaxel Questionnaire  
• Acute Pain Syndrome Symptom Summary 
Questionnaire 
• EORTC QLQ-CIPN20 Questionnaire 
• Monthly Questionnaire 
 
X 
X 
 
X 
 
 
 
 
 
 
X2 
X2 
Booklet Compliance 3 
X3 
 
X3 
End of Active Treatment/Cancel Notification  
 
X 
 
ADR/AER 
At each occurrence (see Section 10.0) 
1. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
2. Complete at each evaluation during Observation (see Section 4.0). 
3. This form must be completed only if the booklet/s contains absolutely NO patient provided assessment 
information. 
4. Submit only if applicable. 
 

 
27 
RU221511I 
 
19.0  
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site.  Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
19.2 
Tests to be research funded: N/A 
 
 
20.0 
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