Clinical trial NCT03839940
Conditions: Malignant Neoplasm
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2019-06-03; Completion date: 2022-08-03
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase III trial studies how well dexamethasone works in reducing everolimus-induced oral stomatitis in patients with cancer. Dexamethasone may help to reduce the everolimus-induced oral stomatitis so as to improve quality of life in cancer patients.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if the initiation of dexamethasone at the start of everolimus treatment prevents mTOR inhibitor-associated stomatitis (mIAS)-associated pain, compared to the initiation of placebo.

II. To determine if the initiation of dexamethasone at the start of everolimus treatment will be superior compared to the initiation of placebo in terms of the overall severity of mIAS-associated pain.

SECONDARY OBJECTIVES:

I. To utilize the same measurement method that was reported in the SWISH trial: A combination of a patient reported pain scale, data from a normalcy of diet questionnaire, and clinician grading of stomatitis to determine the incidence of \> grade 2 mIAS.

II. To determine if the initiation of dexamethasone at the start of everolimus increases time to development of mouth pain using daily numerical analog scale patient-reported data collection.

III. To assess if quality of life is better when dexamethasone mouth rinse use starts at the same time as everolimus use versus at the time when mouth pain begins.

IV. To investigate if starting dexamethasone mouth rinse concurrent with starting everolimus improves patients' ability to adhere to everolimus therapy.

V. To compare dexamethasone prescription fill rates and timing between patients who received placebo versus study drug at the initiation of everolimus.

Trial Design:

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive everolimus orally (PO) once daily (QD) as standard of care and dexamethasone as mouthwash over 2 minutes 4 times per day (QID) for 8 weeks.

GROUP II: Patients receive everolimus PO QD as standard of care and placebo as mouthwash over 2 minutes QID for 8 weeks.

Arms: arm 1: Patients receive 10mg oral everolimus daily as standard of care and 10ml dexamethasone oral mouthwash, swished for 2-minutes daily, for 8 weeks. arm 2: Patients receive 10mg oral everolimus daily as standard of care and 10ml placebo oral mouthwash, swished for 2-minutes daily, for 8 weeks.
Interventions: intervention 1: Dexamethasone intervention 2: Placebo intervention 3: Questionnaire intervention 4: Quality-of-Life Assessment intervention 5: Everolimus
Intervention descriptions: intervention 1: Given as mouthwash intervention 2: Given as mouthwash intervention 3: Ancillary studies intervention 4: Ancillary studies intervention 5: Standard of care

Protocol documents:
Prot_SAP_000.pdf: 
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Update #03  
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A221701 
PHASE III PLACEBO-CONTROLLED TRIAL TO EVALUATE DEXAMETHASONE USE FOR EVEROLIMUS-
INDUCED ORAL STOMATITIS: PREVENTION VERSUS EARLY TREATMENT APPROACHES: MIST  
(MY INDIVIDUALIZED STOMATITIS TREATMENT) 
A limited access study 
Supplied agent: Dexamethasone; (IND: exempt) 
ClinicalTrials.gov Identifier: NCT03839940 
 
Study Chair 
Kathryn J. Ruddy MD 
Mayo Clinic  
 
 
 
 
Study Co-Chair 
Community Oncology Co-chair 
Correlative Study Co-chair 
  
 
 
 
 
  
  
 
 
 
 
 
 
Pharmacogenomics and Population 
Pharmacology Co-Chair 
Symptom Intervention 
Committee Chair 
  
 
  
   
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
 
 
  
  
 
 
 
Data Manager 
Protocol Coordinator 
   
 
 
 
 
 
 
Limited Access Institutions, See Page 2 
Participating Organizations:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-ACRIN Cancer Research Group, 
NRG / NRG Oncology, SWOG / SWOG 


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Limited access institutions  
Altru Cancer Center (ND028)(Alliance) 
Illinois CancerCare-Princeton (IL358)(Alliance, 
SWOG, ECOG,NRG) 
Cancer Care Center of O'Fallon (IL413) (Alliance, 
SWOG, ECOG,NRG) 
Decatur Memorial Hospital (IL094) (Alliance, 
SWOG, ECOG,NRG) 
Centralia Oncology Clinic (IL385) (Alliance, SWOG, 
ECOG,NRG) 
Springfield Clinic (IL194) (Alliance, SWOG, 
ECOG,NRG) 
Crossroads Cancer Center  (IL208) (Alliance, 
SWOG, ECOG,NRG) 
South Illinois University School of Medicine 
(IL096) (Alliance, SWOG, ECOG,NRG) 
Great Lakes Cancer Management Specialists-Van 
Elslander Cancer Center (MI202) (Alliance, SWOG, 
ECOG,NRG) 
IHA Hematology Oncology Consultants-Ann 
Arbor (MI349) (Alliance, SWOG, ECOG,NRG) 
Illinois CancerCare-Bloomington (IL352)(Alliance, 
SWOG,ECOG, NRG) 
Sanford Thief River Falls Medical Center (MN137) 
(Alliance, ECOG, NRG) 
Illinois CancerCare-Canton (IL361)(Alliance, 
SWOG,ECOG,NRG) 
Sanford Bismarck Medical Center (ND007) 
(Alliance, ECOG, NRG) 
Illinois CancerCare-Carthage (IL362) (Alliance, 
SWOG, ECOG, NRG) 
Sanford Roger Maris Cancer Center (ND005) 
(Alliance, ECOG, NRG) 
Illinois CancerCare-Eureka (IL366) (Alliance, 
SWOG, ECOG, NRG) 
Sanford Broadway Medical Center (ND003) 
(Alliance, ECOG, NRG) 
Illinois CancerCare-Galesburg (IL188) (Alliance, 
SWOG, ECOG, NRG) 
Sanford USD Medical Center - Sioux Falls 
(SD003) (Alliance, ECOG, NRG) 
Illinois CancerCare-Kewanee Clinic (IL344) 
(Alliance, SWOG, ECOG, NRG) 
Sanford Cancer Center Oncology Clinic (SD004) 
(Alliance, ECOG, NRG) 
LSU Health Sciences Center at Shreveport (LA017) 
(Alliance, SWOG, ECOG, NRG) 
Legacy Salmon Creek Hospital (WA179) (Alliance, 
SWOG, NRG) 
Mayo Clinic (MN026) (Alliance, SWOG, ECOG, 
NRG) 
Mayo Clinic Health System –Franciscan Healthcare 
(WI077) (Alliance, ECOG, NRG) 
Mayo Clinic Health System- Eau Claire Clinic 
(WI045) (Alliance, ECOG, NRG) 
Sainte Genevieve County Memorial Hospital 
(MO188) (Alliance, SWOG, ECOG,NRG) 
Mayo Clinic Health System Eau Claire Hospital-
Luther Campus (WI036) (Alliance, ECOG, NRG) 
Missouri Baptist Medical Center (MO046) 
(Alliance, SWOG, ECOG,NRG) 
Memorial Medical Center (IL097) (Alliance, SWOG, 
ECOG,NRG) 
Cancer Care Center of O'Fallon (IL413) (Alliance, 
SWOG, ECOG,NRG) 
Missouri Baptist Outpatient Center-Sunset Hills 
(MO191) (Alliance, SWOG, ECOG,NRG) 
SIH Cancer Institute (IL414) (Alliance, SWOG, 
ECOG,NRG) 
Missouri Baptist Sullivan Hospital (MO190) 
(Alliance, SWOG, ECOG,NRG) 
Saint Francis Medical Center in Cape Girardeau 
(MO009) (Alliance, SWOG, ECOG,NRG) 
Parkland Health Center – Farmington (MO199) 
(Alliance, SWOG, ECOG,NRG) 
Cancer Care Specialists of Illinois – Decatur 
(IL185) (Alliance, SWOG, ECOG,NRG) 
Self Regional Healthcare (SC015) (Alliance, SWOG, 
NRG) 
Eastern Maine Medical Center Cancer Care 
(ME040)(Alliance) 
Siteman Cancer Center at Christian Hospital 
(MO020)(Alliance, ECOG, NRG) 
Illinois CancerCare-Peoria (IL101)(Alliance, 
SWOG, ECOG, NRG) 
Siteman Cancer Center at Saint Peters Hospital 
(MO152)(Alliance, ECOG, NRG) 
Illinois CancerCare-Peru (IL353)(Alliance, 
SWOG,ECOG, NRG) 
Siteman Cancer Center at West County Hospital 
(MO053) (Alliance, ECOG,NRG) 
Illinois CancerCare-Ottawa Clinic (IL277) 
(Alliance, SWOG, ECOG,NRG) 
Siteman Cancer Center-South County 
(MO187)(Alliance, ECOG,NRG) 
Illinois CancerCare-Pekin (IL354) (Alliance, 
SWOG, ECOG,NRG) 
Washington University School of Medicine 
(MO011)(Alliance, ECOG,NRG) 
Illinois CancerCare-Macomb (IL355) (Alliance, 
SWOG, ECOG,NRG) 


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Study Resources: 
Expedited Adverse Event Reporting 
 
 Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
 Biospecimen Management System 
 
 
Protocol Contacts: 
A221701 Nursing Contact 
 
 
 
 
A221701 Pharmacy Contact 
 
 
 
Alliance Biorepository at Mayo Clinic 
  
 
 
 
Drug Distribution Contact 
  
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
appropriate Alliance Biorepository  
Questions regarding drug supply and 
administration 
Pharmacy Contact 
 
 
 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For data submission:  
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
(Sign in at 
 and 
select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 
 
to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email : 
 
 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the protocol 
for further instructions.  
 
Do not submit study data or forms 
to the CTSU. Do not copy the 
CTSU on data submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website 
. Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
Institutions will order the following supplies from the CTSU Operations Office: Questionnaire booklets.  
Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on 
the protocol-specific page on the CTSU website) and submitting it as instructed on the form. 
For clinical questions (i.e., patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 
 All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 


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PHASE III PLACEBO-CONTROLLED TRIAL TO EVALUATE DEXAMETHASONE USE FOR 
EVEROLIMUS-INDUCED ORAL STOMATITIS: PREVENTION VERSUS EARLY 
TREATMENT APPROACHES 
Eligibility Criteria (see Section 3.0) 
Required Initial Laboratory Values 
• Current cancer diagnosis, about to receive everolimus See 3.2.1 
• Not currently receiving chemotherapy See 3.2.2 
None   
• 
Not currently suffering from stomatitis/mucositis or mouth ulcers See 3.2.3 
• 
Patients should not receive any other agent considered treatment for stomatitis. See 3.2.4 
• 
No history of candida infection (thrush) within the last 3 months See 3.2.5 
• 
Not currently being treated with corticosteroids See 3.2.6 
• 
No uncontrolled diabetes mellitus defined by hemoglobin A1C greater than 8% See 3.2.7  
• 
Patients must be able to read and comprehend English See 3.2 8 
• 
Not pregnant and not nursing See 3.2.9 
• 
ECOG Performance Status ≤ 2 
• 
Age ≥18 years. 
Schema 
 
 
R  
Initial Dexamethasone 
A  
Alcohol-free 0.5 mg/5 mL dexamethasone 
N  
Swish 10 mL for 2 mins and spit QID 
D  
 
O  
 
M  
 
I 
 
Initial Placebo  
Z  
Swish 10 mL Placebo for 2 mins and spit QID 
E  
 
 
Duration of treatment is 8 weeks from start of protocol treatment. 
 
A dexamethasone prescription will be provided to all participants when they enroll to the trial.  If mouth 
pain related to stomatitis develops at any time during the 8 week study period, patients may fill the 
prescription for dexamethasone oral solution from their local pharmacy. Patients will not be unblinded at 
this time and will continue with all study procedures (such as questionnaires, phone calls and physical 
exams). They will be instructed to stop taking the initially provided study medication if they start taking 
the prescription dexamethasone. 
 
 
Please refer to the full protocol text for a complete description of the eligibility criteria and 
treatment plan. 
 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the credited 
Group may apply. 
 
 


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Table of Contents 
 
1.0 
Background .................................................................................................................... 9 
1.1 
Introduction ................................................................................................................ 9 
1.2 
Larger phase II trials of corticosteroids for prevention of everolimus-associated stomatitis ...... 9 
1.3 
Rationale for a randomized phase III trial .......................................................................10 
1.4 
Study design...............................................................................................................10 
1.5 
Potential study populations ...........................................................................................11 
1.6 
Methods and Assessment Procedures .............................................................................11 
2.0 
Objectives .....................................................................................................................13 
2.1 
Co-Primary objectives .................................................................................................13 
2.2 
Secondary objectives ...................................................................................................13 
2.3 
Pharmacogenetics objectives (also see Section 14.1.2) ......................................................13 
2.4 
Pharmacokinetics objectives (also see Section 14.2.2).......................................................13 
3.0 
Patient Selection.............................................................................................................14 
3.1 
On-Study Guidelines ...................................................................................................14 
3.2 
Eligibility Criteria .......................................................................................................14 
4.0 
Patient Registration.........................................................................................................16 
4.1 
Investigator and Research Associate Registration with CTEP.............................................16 
4.2 
CTSU Site Registration Procedures................................................................................17 
4.3 
Patient Registration Requirements .................................................................................19 
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) ...................................19 
4.5 
Registration to Correlative and Companion Studies ..........................................................20 
4.6 
Stratification Factors and Treatment Assignments ............................................................20 
4.7 
Procedures for Double-Blinding the Treatment Assignment ...............................................21 
5.0 
Study Calendar...............................................................................................................22 
6.0 
Data and Specimen Submission ........................................................................................23 
6.1 
Data Collection and Submission ....................................................................................23 
6.2 
Specimen collection and submission ..............................................................................25 
7.0 
Treatment Plan/Intervention .............................................................................................28 
7.1 
Everolimus.................................................................................................................28 
7.2 
Initial Dexamethasone/Placebo......................................................................................28 
7.3 
Open label dexamethasone ...........................................................................................28 
8.0 
Dose and Treatment Modifications, Unblinding ..................................................................29 


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8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ....................................29 
8.2 
Dose Modifications .....................................................................................................29 
8.3 
Unblinding Procedures.................................................................................................29 
9.0 
Adverse Events ..............................................................................................................31 
9.1 
Routine Adverse Event Reporting..................................................................................31 
9.2 
CTCAE Routine Reporting Requirements .......................................................................32 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .........................................................32 
10.0 
Drug Information............................................................................................................36 
10.1 
Dexamethasone Oral Solution .......................................................................................36 
10.2 
Placebo Oral Solution ..................................................................................................38 
11.0 
Measures.......................................................................................................................39 
11.1 
Numerical Analogue Mouth Pain Scale (Appendix II) ......................................................39 
11.2 
Numerical Analogue Self-Assessment (Appendix III) .......................................................39 
11.3 
PRO-CTCAE items (Mouth/throat sores, Sleep and Fatigue items) (Appendix IV) ................39 
11.4 
Patient reported Mouthwash Use frequency (Appendix V).................................................39 
11.5 
Nurse\Research coordinator weekly phone call assessments (Appendix VI) .........................39 
11.6 
Normalcy of Diet Scale (Appendix VII) .........................................................................40 
12.0 
End of Treatment/Intervention ..........................................................................................40 
12.1 
Duration of Protocol Treatment .....................................................................................40 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention .........................................40 
12.3 
Follow-up ..................................................................................................................41 
12.4 
Extraordinary Medical Circumstances ............................................................................41 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention .41 
13.0 
Statistical Considerations .................................................................................................42 
13.1 
Study Design ..............................................................................................................42 
13.2 
Sample Size, Accrual time and Study Duration ................................................................42 
13.3 
Primary objectives and endpoints ..................................................................................42 
13.4 
Secondary objectives and endpoints ...............................................................................42 
13.5 
Analysis Plan and Sample Size Justification ....................................................................43 
13.6 
Interim data analysis and stopping rule ...........................................................................45 
13.7 
Primary Endpoint Justification: CTCAE items .................................................................45 
13.8 
Sample Size and Power Considerations ..........................................................................46 
13.9 
Study Monitoring ........................................................................................................48 
13.10 
Missing Data and sensitivity analysis..........................................................................48 
13.11 
Inclusion of Women and Minorities............................................................................50 
14.0 
Correlative And Companion Studies ..................................................................................51 


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14.1 
Pharmacogenomics and Everolimus induced stomatitis A221701-ST1 ................................51 
14.2 
Population Pharmacokinetics (PK) of Everolimus A221701-PP1 ........................................55 
15.0 
References.....................................................................................................................57 
16.0 
Model Consent Form ......................................................................................................62 
Appendix I 
Patient Questionnaire............................................................................................76 
Appendix II 
Numerical Analogue Mouth pain Scale....................................................................78 
Appendix III 
Numerical Analogue Self-Assessment..................................................................79 
Appendix IV 
PRO-CTCAE ...................................................................................................80 
Appendix V 
Patient Reported Mouthwash Use frequency ............................................................81 
Appendix VI 
Nurse Weekly Phone Call Assessment Script ........................................................82 
Appendix VII 
 Normalcy of Diet Scale.....................................................................................83 
Appendix VIII  Pharmacokinetics Patient Questionnaire ..............................................................84 
Appendix IX 
Patient instruction sheet .....................................................................................85 
 
 
 
 


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1.0 
BACKGROUND 
1.1 
Introduction 
Tyrosine kinase inhibitors (TKIs) result in stomatitis, which can significantly impair quality of 
life in cancer patients. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that 
is used (sometimes in combination with other drugs) to treat a variety of cancers including 
metastatic breast cancer. In the BOLERO-2 study, there was a 59% rate of stomatitis and a 30% 
rate of grade 2 or 3 stomatitis with everolimus and exemestane therapy in breast cancer patients.1 
In a meta-analysis of BOLERO-2, RECORD-2 (for renal cell carcinoma), RADIANT-2 (for 
carcinoid), RADIANT-3 (for pancreatic neuroendocrine tumors), and EXIST-1 and 2 (for 
tuberous sclerosis complex), the rate of everolimus-induced stomatitis was also 67%, and the 
rate of grade 3 or 4 stomatitis was 9%2.  It was noted that 89% of these events occurred within 
8 weeks of starting everolimus.  
1.1.1 
Topical corticosteroids appear to treat benign aphthous ulcers 
For patients with recurrent aphthous ulcers, topical steroids appear to reduce pain and 
promote healing.3,4  Oral steroid paste, ointment, or solution has been found to be effective 
against the symptoms of this condition, which mimics drug-induced stomatitis. In patients 
with Behcet’s syndrome, who are prone to oral ulcers, a randomized trial of triamcinolone 
vs. phenytoin syrup revealed substantially more improvement in ulcer symptoms in those 
who received triamcinolone.5  In some severe cases of aphthous ulcers that are refractory 
to topical treatments, systemic steroids have been beneficial.6,7 The proposed mechanism 
by which corticosteroids are thought to decrease mucosal ulcer pain is via decreased 
production of lymphocytes and other cytokines involved in the inflammatory response.8  
1.1.2 
Topical corticosteroids appear to treat and/or prevent everolimus-induced 
stomatitis-early reports 
The underlying pathogenesis of stomatitis due to TKIs appears to be inflammatory, like 
aphthous ulcers. In 2011, a report was published regarding 17 patients with mTOR 
inhibitor-associated stomatitis (mIAS) who were treated with a topical corticosteroid, 
including topical oral dexamethasone solution; this was put in the oral cavity and then 
expectorated. Over 85% of these patients appeared to improve with this therapy.9 In another 
trial involving 15 women, 7 of whom (47%) had developed greater than or equal to grade 
2 stomatitis, their ulcers, treated with topical dexamethasone, all appeared to resolve over 
a median of 2 weeks.10 In addition, an early report suggested that patients treated with a 
prophylactic hydrocortisone, tetracycline, nystatin, and diphenhydramine mouthwash 
prevented mIAS in patients who were receiving everolimus.11  
1.2 
Larger phase II trials of corticosteroids for prevention of everolimus-associated 
stomatitis 
In the SWISH study, an alcohol-free, dexamethasone-based mouthwash was investigated as a 
means to prevent stomatitis in patients with advanced breast cancer receiving everolimus and 
exemestane.12 Patients receiving 10 mg of everolimus in combination with exemestane started 
an alcohol-free dexamethasone solution simultaneously. Patients were asked to swish, hold for 
2 minutes, then spit out 10 ml of a 0.5 mg/5 ml dexamethasone solution. In this study, the 8 
weeks incidence of CTCAE grade 1 stomatitis was 19% and grade 2 stomatitis was only 2%, 
resulting in an overall stomatitis incidence rate at 8 weeks of only 21% (n=18, 95% CI 13.06-
31.39), significantly lower than that seen in BOLERO-2 historical controls (p<0.001). In 
SWISH, 95% of patients used dexamethasone mouthwash 3-4 times/day (median 3.95 [range 
1.9-4]), and more than 70% remained on all 3 drugs for at least 8 weeks. The median dose 
intensities of everolimus and exemestane were 10 mg and 25 mg, respectively. SWISH did not 


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evaluate the frequency of mouthwash use, or if delayed start of dexamethasone at the time of 
development of stomatitis would be as effective as use in the preventive setting.  
At the San Antonio Breast Cancer Symposium in 2016, a separate prospective phase 2 
randomized trial of 2 steroid-based mouth rinses as oral prophylaxis for patients receiving 10 
mg of everolimus combined with exemestane was presented.13 These two rinses included the 
following: 1) 320 ml diphenhydramine, 2g tetracycline, 80mg hydrocortisone, 40mg Nystatin, 
and water; or 2) prednisolone 15mg/ml and 1.8% alcohol. Four times a day, participants were 
instructed to swish and spit one of these two solutions, and the incidence of stomatitis and all 
grade related adverse events appeared to be relatively low in both arms of the study (29% and 
27.5% in arms 1 and 2, respectively over twelve weeks). The incidence of grade 2 adverse events 
was 12% and 8% in arms 1 and 2, respectively.  
While a variety of topical steroids have shown promise in treatment of recurrent aphthous ulcers, 
we have selected dexamethasone solution as the intervention to be tested in this trial (as opposed 
to another corticosteroid medication) because of the strong data from the previous SWISH 
single-arm study showing excellent tolerability and encouragingly low rates of stomatitis 
incidence (only 2% ≥grade 2) in patients receiving exemestane, everolimus, and dexamethasone 
swish and spit. 
1.3 
Rationale for a randomized phase III trial  
The results of these two phase II trials assessing prevention of mIAS with oral corticosteroid 
medications are quite impressive. They strongly suggest that this therapy is helpful for 
preventing mIAS. It has been recommended that this approach be utilized in clinical practice, 
and many physicians have been using this approach.  This sets the stage for a definitive 
randomized phase 3, placebo controlled clinical trial to address whether a steroid mouthwash 
will prevent mIAS.  
An early change from placebo to a corticosteroid medication is incorporated in this protocol so 
that patients that develop mIAS are treated early with dexamethasone, expecting that this will 
provide benefit and prevent patients from developing the severe mIAS that was seen in the 
BOLERO-2 trial. 
1.4 
Study design  
We have proposed, as is illustrated in the study schema, to conduct a placebo-controlled trial 
investigating a dexamethasone preparation for prevention of stomatitis. To address the potential 
concern that we are holding back medication that looks quite effective for prevention of 
everolimus-induced stomatitis, we will allow a patient to start getting a corticosteroid 
preparation at the initiation of any pain associated with mouth sores. Thus, this protocol is 
designed to test 1) a prevention approach versus 2) an early treatment intervention approach.  
Instead of having the patient have to come back into the clinic and get such a preparation, we 
have opted to provide a prescription for all patients who can then quickly get this filled and start 
on dexamethasone treatment should mouth sores develop.  If and when the patient decides to 
switch to prescription dexamethasone, he/she will be asked to notify a protocol nurse and/or 
clinician. Weekly phone calls from a study nurse will also collect information about whether the 
prescription was filled.  If the corticosteroid preparation is helpful for preventing the stomatitis, 
then we would expect the placebo arm patients to be more likely to fill the corticosteroid 
prescription and to do that earlier in the course, compared with patients who were actually 
receiving the corticosteroid preparation initially.  Whether a patient chooses to go to prescription 
dexamethasone, and when that happens, will be prominent study endpoints. 
The primary reason that a phase III trial is needed is that there really is equipoise as to which of 
our 2 proposed study arms is best. While some might say that the phase II study data 


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convincingly show that the use of a corticosteroid QID is beneficial in patients starting 
everolimus (which is hard to argue, compared to not ever using a corticosteroid), there may be 
an advantage for the initial placebo arm (understanding that a patient would be instructed to start 
prescription dexamethasone if they developed any painful mouth sores), in that about a third of 
patients will likely be spared the hassle and expense and potential toxicities (e.g. thrush) of using 
a corticosteroid mouthwash, because about a third of patients did not experience any mIAS in 
the BOLERO trial. It might well be that starting use of dexamethasone at the beginning of any 
mouth pain will effectively prevent the development of moderate to severe pain. The need to 
compare a prevention versus treatment strategy is highlighted in the excellent editorial by Spring 
and Bardia.14 These authors state, “Because the development of everolimus-induced oral 
mucositis is usually preceded by a prodrome, treatment with steroid rinses at the earliest 
indication of stomatitis, rather than attempts at prevention, could be an alternative approach for 
some patients”.  
1.5 
Potential study populations  
We initially considered only studying patients receiving everolimus in combination with 
endocrine therapy, to mimic the two large phase II trials described above. However, hearing 
from practicing clinicians that they frequently use everolimus in clinical practice for a more 
diverse group of patients with a variety of conditions (such as renal cell and islet cell cancer), 
and that these patients have similar mIAS problems, we opted to be more inclusive in this 
clinical trial and include any cancer patient being treated with everolimus (10 mg/day). This 
makes sense as it is the everolimus that causes mIAS, not the antiestrogen therapies.  
1.6 
Methods and Assessment Procedures  
We plan to collect all of the data elements from the SWISH trial (CTCAE delineation of 
mucositis, pain, normalcy of diet scale), obtained in the same manner, in addition to other data 
elements. 
The endpoint that was developed and used de novo in the SWISH trial used composite criteria, 
with a clarification that a grade 2 or higher designation needed to be confirmed by 1) an oral 
pain score of greater than 8/10 on 1 occasion or 7/10 for 2 days, or 2) that patients could only 
eat soft chewable foods (or less, like liquids alone) as determined by a Normalcy of Diet Scale 
score less than or equal to 50/100.  With this rule, a patient with classic CTCAE determination 
of grade 2 stomatitis could have been downgraded to grade 1 stomatitis if they did not meet the 
pain or diet criteria to keep them at grade 2 stomatitis (noting that this only happened for 2 
patients in the SWISH trial—unpublished data provided to us).  This composite clinician-
determined measurement is not well validated psychometrically by itself, or by adding the 2 
criteria noted above, so this will be a secondary endpoint for our trial.  
For our primary endpoint, we will use a numerical analog scale of patient-reported mouth pain. 
We have validated these numerical analog scales for symptom collection in numerous trials.15  
PRO measures are believed to be more accurate than clinicians’ CTCAE reporting for many 
toxicities.16,17  For example, in a prospective study including lung cancer patients, PRO 
measurements of toxicities better reflected patients’ underlying state and functional status than 
clinicians’ evaluations.18  As in multiple previous Alliance trials,19,20,21 patient questionnaires 
will be utilized to obtain outcome data. Daily data collection by patient questionnaires will allow 
us to more accurately see daily changes on the days before and after patient actually took 
prescription dexamethasone (which they would have started because they developed mouth 
pain); we might not be able to collect data at that exact time, if we used the SWISH measurement 
method. 


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Further supporting the use of a PRO measure of mouth sore related pain is that the SWISH 
definition of grade 2 or 3 mucositis is primarily based on pain, as is illustrated in the table below 
(thus the mouth pain that patients developed would have been the predominant factor to 
determine their score). 
Grade: 
1 
2 
3 
4 
5 
Mucositis 
oral 
Asymptomatic or 
mild symptoms; 
intervention not 
indicated 
Moderate pain 
or ulcer that 
does not 
interfere with 
oral intake; 
modified diet 
indicated 
Severe pain; 
interfering 
with oral 
intake 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Thus, we propose to use the PRO pain score as our primary measurement tool, while using the 
SWISH trial method as a secondary endpoint for both concurrent validation of the SWISH 
approach and comparison of the two results. 
These patient-reported study data will be collected by daily patient logs and a more extensive 
survey weekly.  There will also be weekly nurse phone calls (Appendix VI). The daily logs will 
collect a numerical analog mouth pain score, as shown in the Appendix II. Once a week, patients 
will also be asked to respond to a single-item overall quality of life (QOL) linear analogue self-
assessment (Appendix III), as well as two NCI-developed PRO-CTCAE items regarding mouth 
sores, two regarding insomnia, and two regarding fatigue (as shown in Appendix IV).21,22,23,24  A 
mouthwash use questionnaire (Appendix V) will also be included in the weekly survey.  
Patients will be strongly encouraged during each weekly nurse phone call (Appendix VI) to 
immediately report back by phone if they fill the prescription for dexamethasone mouthwash in 
between the routine weekly calls. Weekly nurse phone calls will also be used to remind the 
patients to: 
• 
Fill out the daily mouth pain form (Appendix II) 
• 
Fill out the weekly PRO-CTCAE items 21,22,23,24(Appendix IV),  
• 
and mouthwash use questionnaire (as shown in Appendix V). 
The nurses will also collect information on (Appendix VI):  
• 
Everolimus dose (and reasons for any dose reductions) 
• 
Study mouthwash use frequency 
• 
Whether and when the patient obtained the prescription mouthwash 
• 
CTCAEs; and 
• 
Normalcy of Diet Scale data 
There are data to support the utility and validity of the above measures. The numerical analog 
mouth pain scale (Appendix II) was used effectively to assess patient-reported mouth pain in 
the SWISH study.2  The single-item overall QOL assessment (Appendix III) is a simple linear 
analogue scale that has been successfully used in multiple trials including patients with 
advanced cancer,25,26,27,28and is routinely included in most Alliance trials. The three 2-item PRO-
CTCAE assessments (Appendix IV) were recently developed and validated for use in 
cooperative group clinical trials.21,22,23 PRO-CTCAE is a library of questions asking patients 
about specific symptomatic adverse events associated with cancer therapy. They are meant to 
be used in combination with clinician-determined CTCAE, so both PRO-CTCAE and CTCAE 


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collection will be performed weekly, and all three symptoms that will be collected by PRO-
CTCAE (mouth sores, insomnia, and fatigue) will be collected by CTCAE as well. CTCAE 
assessments will also be performed to assess for other toxicities of dexamethasone for which 
PRO-CTCAE items are not available (i.e., thrush, hyperglycemia, irritability) weekly during the 
study period (during the nurse phone calls if a patient is not scheduled to be seen in the clinic 
that week). 
Survey items about frequency of use of study and prescription mouthwashes (Appendix V) were 
adapted from multiple previous Alliance symptom intervention trials, as was the nurse telephone 
assessment form (Appendix VI). 
2.0 
OBJECTIVES 
2.1 
Co-Primary objectives  
2.1.1 
To determine if the initiation of dexamethasone at the start of everolimus treatment 
prevents mIAS-associated pain, compared to the initiation of placebo. 
2.1.2 
To determine if the initiation of dexamethasone at the start of everolimus treatment will be 
superior compared to the initiation of placebo in terms of the overall severity of mIAS-
associated pain. 
2.2 
Secondary objectives 
2.2.1 
To utilize the same measurement method that was reported in the SWISH trial: A 
combination of a patient reported pain scale, data from a normalcy of diet questionnaire, 
and clinician grading of stomatitis to determine the incidence of ≥ grade 2 mIAS.  
2.2.2 
To determine if the initiation of dexamethasone at the start of everolimus increases time 
to development of mouth pain using daily numerical analog scale patient-reported data 
collection. 
2.2.3 
To assess if quality of life is better when dexamethasone mouth rinse use starts at the 
same time as everolimus use versus at the time when mouth pain begins. 
2.2.4 
To investigate if starting dexamethasone mouth rinse concurrent with starting everolimus 
improves patients’ ability to adhere to everolimus therapy. 
2.2.5 
To compare dexamethasone prescription fill rates and timing between patients who 
received placebo versus study drug at the initiation of everolimus. 
2.3 
Pharmacogenetics objectives (also see Section 14.1.2) 
2.3.1 
To derive tagSNPs for FBXW7 and together with SNPs reported (Table 1), genotype all 
patient samples for those SNPs. 
2.3.2 
To explore the association of the genotypes with severity of everolimus-related stomatitis 
(mIAS-associated pain) within the patients who initially received placebo at the start of 
everolimus treatment. 
2.3.3 
To explore the association of the genotypes with severity of everolimus-related stomatitis 
(mIAS-associated pain) within the patients who initially received dexamethasone at the 
start of everolimus treatment. 
2.4 
Pharmacokinetics objectives (also see Section 14.2.2) 
2.4.1 
To determine the intrapatient and interpatient variability of everolimus exposure (C0) in 
cancer patients being treated with everolimus. 


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2.4.2. To correlate everolimus exposure (C0) with toxicity. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make 
this protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin 
cancers or cervical carcinoma in situ. Patients are not considered to have a “currently 
active” malignancy if they have completed therapy and are free of disease for ≥ 3 years. 
3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
___ 
3.2.1 
Documentation of Disease: 
Current cancer diagnosis, about to receive oral everolimus 10 mg/day with or without 
an endocrine agent. Patients about to receive everolimus for off label use for any cancer 
are also eligible.  
___ 
3.2.2 
Prior Treatment  
• 
Not currently receiving chemotherapy or any other agent known to cause mucositis 
or stomatitis. Trastuzumab and ovarian function suppression are allowed. 
• 
Any prior chemotherapy or other stomatitis/mucositis-causing therapy must be 
completed at least 2 weeks prior to registration. 
___ 
3.2.3 
Not currently suffering from stomatitis/mucositis or mouth ulcers. Patients 
should not have had any stomatitis or mouth pain for at least 7 days prior to registration.  
___ 
3.2.4 
Patients should not receive any other agent which would be considered 
treatment for stomatitis or impact the primary endpoint. 
___ 
3.2.5 
No history of candida infection (thrush) within the last 3 months 
___ 
3.2.6 
Not currently being treated with corticosteroids  


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Update #03 
___ 
3.2.7 
Comorbid conditions 
No uncontrolled diabetes mellitus, defined by hemoglobin A1C greater than 8%, 
although A1C is not needed for all patients, HgbA1C <8 is required for everyone 
with diabetes or suspected diabetes. 
___ 
3.2.8 
Patients must be able to read and comprehend English. Local translation, 
including verbal translation of PROs is not permitted. 
___ 
3.2.9 
Not pregnant and not nursing, because this study involves an investigational 
agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown.  
Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 
days prior to registration is required. 
___ 
3.2.10 ECOG Performance Status 0, 1 or 2.  
___ 
3.2.11 Age ≥ 18 years  
___ 
3.2.12 Required Initial Laboratory Values: None  
 
 




Alliance A221701 
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• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log 
(DTL).  
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
RCR Help Desk by email at 
 
4.2 
CTSU Site Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but 
sites 
are 
required to 
contact 
the 
CTSU 
Regulatory Office 
at 
 to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 


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• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 
in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
4.2.1 
Additional site registration requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Protocol Specific Requirements for Site Registration  
Limited access information 
With Update 2 to the protocol, this is a limited access study. Institutions that have 
previously enrolled participants and have expressed continued interest in participating in 
this study have been identified and listed on Page 2 of the protocol. 
4.2.3 
Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol. One way to search for a protocol is listed 
below.  
• 
Log in to the CTSU members’ website 
 using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select [Alliance], 
and protocol number [A221701]. 
• 
Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB, IRB data will load automatically to the 
CTSU.)  
4.2.4 
Submitting regulatory documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 
 in order to 
receive further instruction and support. 


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Update #03 
4.2.5 
Checking your site’s registration status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.3 
Patient Registration Requirements 
Informed consent: the patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
Patient completed booklets: Patient questionnaire booklets are to be ordered prior to the 
registration of any patients. Patient completed booklets can be ordered by downloading and 
completing the CTSU supply request form (located under the site registration documents section 
of the A221701 CTSU site) and submitting it through the CTSU regulatory portal. Samples of 
the questionnaires included in the booklets are found in Appendices II-V, which are to be used 
for reference and IRB submission only. They are not to be used for patient completion. 
Protected Health Information: Whole blood samples collected for the pharmacokinetics sub-
study A221701-PP1 will be sent directly to the University of Pittsburgh Cancer Center. These 
samples will be labeled with patient initials, study ID and collection date/time.  
4.4 
Patient Enrollment (registration/randomization procedures (Step 1)) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 


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Update #03 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
 or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
. For any additional questions, contact the CTSU 
Help Desk at 
. 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
4.5 
Registration to Correlative and Companion Studies 
4.5.1 
Registration to Substudies described in Section 14.0  
There are two substudies within Alliance A221701. These correlative science studies must 
be offered to all patients enrolled on Alliance A221701 (although patients may opt to not 
participate). These substudies do not require separate IRB approval. The substudies) 
included within Alliance A221701 are: 
• 
Pharmacogenomics and Everolimus induced stomatitis, Alliance A221701-ST1 
(Section 14.1) 
• 
Population Pharmacokinetics of Everolimus, Alliance A221701- PP1 (Section 14.2) 
If a patient answers “yes” to “My samples and related information may be used for the 
additional studies described above,” Question #2 in the model consent “I agree that my 
samples and related health information may be used for the laboratory study described 
above”, they have consented to participate in the substudies described in Section 14.0. The 
patient should be registered to Alliance A221701-ST1 and A221701- PP1 at the same time 
they are registered to the treatment trial (A221701). Samples should be submitted per 
Section 6.2.   
4.6 
Stratification Factors and Treatment Assignments 
4.6.1 
Stratification factors  
a) 
Age (<50 versus 50-65 versus >65) 
b) 
Cancer type (breast versus other) 
4.6.2 
Treatment Assignments and Blinding 
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 2 treatment groups using the 
Pocock-Simon dynamic allocation procedure which balances the marginal distributions of 
the stratification factors between the treatment groups70.  


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Patients will be randomized in a 1:1 fashion to receive one of two treatments:  
• 
Intervention Group: Participants will receive Dexamethasone mouthwash for 8 weeks. 
• 
Control Group: Participants will receive placebo for 8 weeks. 
After the treatment assignment has been ascertained in the OPEN application, the patient’s 
study medication code number will be displayed on the confirmation of registration screen. 
The pharmacist or designated contact person at the treating site will maintain records that 
indicate the identity of the patient and their corresponding study medication code number. 
4.7 
Procedures for Double-Blinding the Treatment Assignment 
After the treatment assignment has been ascertained by randomization, the Registration 
Specialist will notify the designated data manager/nurse/pharmacist at the patient’s institution. 
The name of this contact person is to be indicated in the OPEN registration system at the time 
of registration. This contact person may not be involved in assessing adverse events or any other 
outcome measure and should not be the same person listed on page one of the OPEN registration 
Form as the person completing the form. The OPEN registration form should provide the source 
of communication, either fax or e-mail, and the appropriate contact information. The 
Registration Specialist will then communicate the treatment assignment “active or placebo” to 
designated contact at the patient’s institution. 
Once the treatment assignment has been communicated, the designated contact should prepare 
dexamethasone mouthwash or placebo mouthwash for delivery to the patient.  
The dose will be prepared and labeled as “dexamethasone/placebo” so that the contents are not 
discernible to the person administering the treatment. 
The pharmacist or designated contact person will maintain records that indicate the identity of 
the patient and their corresponding treatment assignment. The pharmacist or designated contact 
person at the treating site will maintain records that indicate the identity of the patient and their 
corresponding study medication code number. 
 
 


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5.0 
STUDY CALENDAR 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
Pre-Study Testing Intervals:  
To be completed ≤ 28 DAYS before registration: All laboratory studies, history and physical. 
 
Prior to 
Registration 
Baseline* 
Weekly, for 8 
weeks from start 
of treatment  
4 and 8 weeks 
after start of 
treatment 
Tests & Observations: 
 
 
 
 
History and physical, weight, PS 
X 
 
 
 
Adverse Event Assessment 
 
X 
X (1) 
 
Serum or Urine HCG  
X(2) 
 
 
 
PRO/QOL assessments: 
 
 
 
 
Numerical Analogue Mouth Pain 
Scale (Appendix II) 
 
X 
A 
 
Numerical Analogue Self-
Assessment (Appendix III) 
 
 
X 
 
PRO-CTCAE assessments 
(Appendix IV) 
 
X 
X 
 
Patient reported Mouthwash use 
frequency (Appendix V) 
 
 
X 
 
Other assessments: 
 
 
 
 
Nurse Weekly Phone call 
(Appendix VI) 
 
 
X (1) 
 
Normalcy of Diet scale 
(Appendix VII) 
 
 
X (1) 
 
Correlative Studies 
Whole Blood 
 
X 
 
X (3) 
* 
To be completed within 7 days prior to the start of treatment. 
A To be completed daily  
1 
Nurse/Research Coordinator will contact the patient every week to remind patients to complete 
questionnaires, answer questions, to assess adverse events and ask normalcy of diet scale 
questions (see Appendices VI and VII).  
2 
For women of childbearing potential (see Section 3.2). Must be done ≤ 7 days prior to registration 
3 
For patients who consent to the correlative studies described in Section 14.0.  Week 4 sample and 
questionnaire is not required for patients who are not scheduled to come back to the clinic for a 
week 4 visit.  See Section 6.2. 
 


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6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 Data submission schedule: 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The Data Submission Schedule is also available on the CTSU 
site within the study-specific Case Report Forms folder.  
6.1.2 Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to
 for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
e-mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
 using their CTEP-IAM username and password 
and click on the accept link in the upper right-corner of the iMedidata page. Site staff will 
not be able to access the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) 
and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the eLearning will appear 
under the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be granted, 
and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the 
CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at 
 or by contacting the CTSU Help Desk at 
 or by e-mail at 
. 


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Patient-completed questionnaire booklets for this study are to be ordered prior to the 
registration of any patients (see Section 4.3). Samples of questionnaire booklets are 
available in Appendices II- VII for reference and IRB submission only. They are not to be 
used for patient completion.  
Weekly Booklets: Eight booklets to be completed weekly must be given to patients to 
complete at home and patients should be instructed to return the booklets by mail weekly 
or to return the booklets at their regularly scheduled clinic visit.  Institutions must provide 
patients with sufficient self-addressed stamped envelopes for this purpose.  Site staff will 
enter patient responses into Rave upon receipt of the completed booklets. 
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available 
to access details and reports of unanswered queries, delinquent forms, and timeliness 
reports. Review the DQP modules on a regular basis to manage specified queries and 
delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization for delinquent form details and reports to be available on the 
DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
 
 


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6.2 
Specimen collection and submission  
For patients registered to substudies A221701-ST1 and A221701-PP1, all participating 
institutions must ask patients for their consent to participate in these correlative substudies, 
although 
patient participation is 
optional. Pharmacogenetic (A221701-ST1) and 
pharmacokinetic (A221701- PP1) studies will be performed. Rationale and methods for the 
scientific components of these studies are described in Section 14.0. For patients who consent 
to participate, blood will be collected at the following time points for these studies: 
 
 
Prior to 
Treatment 
4 weeks   
(+/-7 days)  
after start of 
study 
medication 
8 weeks 
(+/- 7 days) 
after start of 
study 
medication 
Storage/ 
Shipping 
conditions  
Submit to: 
For patients registered to A221701-ST1 and A221701-PP1, submit the following: (optional) 
Number and volume of tubes to draw 
Whole blood (1)  
(EDTA/lavender top) 
(See Section 6.2.2) 
1 x 10 mL*  
 
 
Cool 
pack/ship 
overnight 
Mayo BAP  
Freezer 
Whole blood (2) 
(EDTA/lavender top) 
(see Section 6.2.3) 
1 x 5 mL 
1 x 5 mL** 
1 x 5 mL 
Cool 
pack/ship 
overnight 
University 
of 
Pittsburgh  
* 
Can be collected at a subsequent visit if the sample cannot be obtained prior to treatment  
** Not required for patients who are not scheduled to come back to the clinic for a week 4 visit  
1 
Pharmacogenomic analyses described in Section 14.1  
2 
Pharmacokinetic analyses described in Section 14.2. Patients will be asked to complete a 
pharmacokinetics questionnaire (Appendix VIII) at the 4 week and 8-week visits (not 
required at the Baseline visit). The questionnaire can be completed before or after the blood 
draw. A copy of the questionnaire will be sent by site staff along with the samples to the 
University of Pittsburgh.  Questionnaire responses are to be entered into Rave by site staff.  
6.2.1 
Specimen Submission Using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL:  
 using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, 
and training videos.  To report technical problems, such as login issues or application 
errors, please contact: 
. For assistance in 
using the application or questions or problems related to specific specimen logging, please 
contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 


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All submitted specimens must be labeled with the appropriate protocol number (either 
A221701-ST1 or A221701- PP1), Alliance patient number, patient’s initials, date and type 
of specimen collected (i.e., whole blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in 
the shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
6.2.2 
Blood submission (for pharmacogenomic studies); A221701- ST1 
For patients who consent to participate, (model consent question, “I agree to have my 
specimen collected and I agree that my specimen sample and related information may be 
used for the laboratory study described above”), whole blood samples will be used for the 
pharmacogenomic studies described in Section 14.1. This sample should be collected prior 
to the initiation of protocol treatment. 
Collect 10 mL of peripheral venous blood in an EDTA (lavender) tube. The tubes should 
be inverted several times to mix the EDTA and refrigerated until shipped on cool pack by 
overnight mail to the Alliance Biorepository. The samples should be shipped the same day 
that the blood is drawn per Section 6.2.1.  
Label samples with the following identification: 
1) Procurement date/time of collection 
2) Alliance patient number 
3)  Patient initials 
4) Alliance study number (i.e., A221701- ST1) 
5) Specimen type (i.e., whole blood) 
The 10 mL of blood can be collected in one 10 mL EDTA tube, or two 5 mL EDTA tubes 
or three 3 mL EDTA tubes, as long as the final volume is ~10 mL. 
Ship specimens on Monday through Friday. Shipping by overnight service to assure receipt 
is encouraged. Do not ship specimens on Saturdays.  
These specimens should be sent to the following address: 
 
 
 
 
 
6.2.3 
Blood submission (for pharmacokinetic studies); A221701- PP1 
For patients who consent to participate, (model consent question, “I agree to have my 
specimen collected and I agree that my specimen sample and related information may be 
used for the laboratory study described above”), whole blood samples will be used for the 
pharmacokinetic studies described in Section 14.2. This sample should be collected prior 
to the initiation of protocol treatment, at 4 week visit (prior to everolimus dosage), (+/- 7 
days) and at 8 weeks (prior to everolimus dosage), (+/- 7 days). 
At week 4 visit and at week 8 visit, patients enrolled to the pharmacokinetics substudy will 
be asked to complete a questionnaire (see Appendix VIII), which will provide information 


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Update #03 
about the prior 48-hour dosing of everolimus (details of dose, time and relationship to 
food). A de-identified copy of the form must be included along with the blood samples, 
and shipped to the address listed at the end of this section. Questionnaire responses are to 
be entered into Rave by site staff. 
Collect 5 mL of peripheral venous blood in an EDTA (lavender) tube. The tubes should be 
inverted several times to mix the EDTA and refrigerated until shipped on cool pack by 
overnight mail to the University of Pittsburgh. The samples should be shipped the same 
day that the blood is drawn per Section 6.2.1.  
Label samples with the following identification: 
1) Procurement date/time of collection 
2) Alliance patient number 
3)  Patient initials 
4) Alliance study number (i.e., A221701- PP1) 
5) Specimen type (i.e., whole blood) 
Samples should be shipped Monday-Thursday for next day delivery. DO NOT SHIP 
SAMPLES ON A FRIDAY OR A WEEKEND OR BEFORE A HOLIDAY.  
Send samples and copies of the completed Pharmacokinetics questionnaires to the 
following address:  
  
  
  
  
  
  
 
 
 


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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 14 days of registration. Protocol treatment must be initiated on 
the same day as the first dose of everolimus. 
For questions regarding treatment, please see the study contacts page.  
From the start of the study, all patients will be provided information to perform good oral care. This 
consists of brushing teeth twice a day with a soft brill toothbrush and continuing to floss (if the patient 
was flossing). 
A dexamethasone prescription will be provided to all participants following registration.  This will 
be intended for individual patients to obtain from their local pharmacy if mouth pain related to 
stomatitis develops at any time during the 8 week study period. Treating physicians should provide a 
prescription for dexamethasone mouthwash with the same concentration as the study drug 
mouthwash described in Section 10.1.  
Agent 
Dose 
Route 
Everolimus 
10 mg once daily for 8 weeks 
p.o. 
Dexamethasone/placebo 
10 mL four times daily for 8 weeks* 
Oral swish for 2 minutes 
then spit 
* 
Patients who develop any mouth pain related to mouth sores should fill the prescription for 
dexamethasone oral solution, and initiate open label swish-and-spit use of dexamethasone four 
times daily for 2 minutes each time until 8 weeks from the start of treatment.  
7.1 
Everolimus 
Everolimus should be taken once per day, preferably swallowed with food.  
7.2 
Initial Dexamethasone/Placebo 
Dexamethasone/placebo 10 mL will be swished in the mouth for two minutes, four times per 
day. The patient should take nothing by mouth for thirty minutes before swishing the 
mouthwash, and for at least an hour after each mouthwash. Except patients may take Nystatin® 
if the patient develops any evidence of thrush.  
7.3 
Open label dexamethasone 
Patients should be instructed that if they develop any mouth pain related to mouth sores, they 
should fill the prescription for oral dexamethasone solution, and initiate swish-and-spit use of 
this four times daily for 2 minutes each time.  If the patient determines that they should fill their 
prescription, they should contact the study nurse as soon as is feasible. 
Patients will be instructed to stop taking the initially provided study medication if they start 
taking the prescription dexamethasone. Patients will not be unblinded at this time and will 
continue with all study procedures (such as questionnaires, phone calls and physical exams) 
until eight weeks from start of protocol treatment.   
Patients should also be instructed that if they develop moderate or greater mouth pain that 
somewhat or greater interferes with their usual daily activities, they should call their treating 
physician to discuss holding and/or reducing the dose of the everolimus (per provider 
discretion). 


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8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other agent to attempt to prevent mucositis/stomatitis at 
the start of the study; if mouth pain develops, clinicians will be allowed to treat this with 
additional agents if needed per their discretion. All topical (not ingested) topical 
anesthetics are allowed. Examples of such medicines include: Lidocaine, magic 
mouthwash, and biotene.  
8.1.2 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
8.1.3 
Antiemetics may be used with the exception of oral steroids, at the discretion of the 
attending physician. 
8.1.4 
Diarrhea management is per the discretion of the treating physician. Diarrhea could be 
managed conservatively with medications such as loperamide. 
• 
Patients with severe diarrhea should be assessed for intravenous hydration and 
correction of electrolyte imbalances. 
8.2 
Dose Modifications 
There will be no dose modifications to the dexamethasone mouthwash on this study.  
Everolimus dose modifications will be left to the discretion of the treating physician. 
However, the patient will be allowed to hold the study mouthwash during everolimus dose holds 
according to the treating physician’s discretion, and allowed to resume the study mouthwash 
once the patient resumes everolimus.  
If a CTCAE grade 3-4 toxicity develops that is probably or definitely attributable to 
dexamethasone mouth rinse or everolimus, study therapy will stop but follow-up assessments 
will continue until the end of the eight week study period. 
8.3 
Unblinding Procedures  
Unblinding can be done only in cases of an emergency or at the end of protocol treatment. 
Follow the directions below to unblind patient treatment. Please note that if a treatment 
assignment is unblinded, the patient must discontinue protocol therapy. 
8.3.1 
Emergency Unblinding Procedures 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
, pressing 1 to 
speak  
• 
with an operator, and then asking for pager ID 8625 to return the call.  
• 
The institution must provide the following information to the Alliance Executive 
Officer:  


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Update #03 
• 
Alliance study ID (i.e., “A221701”)  
• 
Alliance patient ID number (e.g., “999999”)  
• 
Patient initials (e.g., “L,FM”)  
• 
Institution name  
• 
Name and telephone number of treating physician  
• 
Name and contact information of person requesting the unblinding procedure  
• 
Name and contact information of person to inform of treatment assignment  
• 
Reason for emergency unblinding  
• 
Please remember that emergency unblinding request may be authorized only by an 
Alliance Executive Officer, and emergency unblinding applies only if unblinding 
would influence management of the medical situation. After the Executive Officer 
deems unblinding is warranted, the treatment assignment will be provided to the 
contact person at the treating site. 
 
 


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9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
. Attribution to protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
NOTE: PRO-CTCAE data should not be used for determining attribution, or reporting of adverse 
events. 
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the Adverse Event Solicited 
form is used for routine AE reporting in Rave. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and weekly throughout 
the eight weeks of treatment by CTCAE, PRO-CTCAE or both.  
CTCAE v5.0 Term 
PRO-CTCAE v1.0 Term 
CTCAE v5.0 System Organ Class (SOC) 
Mucositis oral 
Mouth/throat sore 
Gastrointestinal Disorders 
Oral pain 
Mouth/throat sore 
Gastrointestinal Disorders 
Insomnia 
Sleep 
Psychiatric Disorders 
Fatigue 
Fatigue 
General Disorders and administration site 
conditions 
Mucosal infection 
N/A 
Infections and Infestations 
Hyperglycemia 
N/A 
Metabolism and Nutrition Disorders 
Irritability 
N/A 
Psychiatric Disorders 
 
 


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9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) 
Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their 
Institutional Review Board if a patient has a reportable serious adverse event. The descriptions 
and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5 will be utilized for AE reporting.  The CTCAE is identified and located on 
the CTEP website at: 
 
All appropriate treatment areas should have access to a copy of the CTCAE. All reactions 
determined to be “reportable” in an expedited manner must be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
PRO-CTCAE data should not be used for determining attribution, or reporting of serious adverse 
events. 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
 
 




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Update #03 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 
9.3.2 
Expedited AE reporting timelines defined 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 
calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse 
events that precipitate hospitalization or prolong an existing hospitalization must be 
reported via CTEP-AERS. 
Reporting of cases of secondary AML/MDS is to be done using the NCI/CTEP Secondary 
AML/MDS Report Form. New primary malignancies should be reported using study Form, 
Notice of New Primary. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 


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In CTCAE version 5.0, the new malignancies (both second and secondary) may be reported 
as one of the following: (1) Leukemia secondary to oncology chemotherapy, (2) 
Myelodysplastic syndrome, (3) Treatment-related secondary malignancy, or (4) 
Neoplasms benign, malignant and unspecified-other. Whenever possible, the CTEP-AERS 
reports for new malignancies should include tumor pathology, history or prior tumors, prior 
treatment/current treatment including duration, any associated risk factors or evidence 
regarding how long the new malignancy may have been present, when and how the new 
malignancy was detected, molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor, and new malignancy treatment and outcome, if 
available. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
• 
Grade 1-3 nausea or vomiting and hospitalization resulting from such do not 
require AERS reporting, but should be reported via routine AE reporting 
• 
Grade 3 nausea or vomiting does not require AERS reporting, but should be 
reported via routine AE reporting.  
• 
Grade 1-3 diarrhea/constipation and hospitalization resulting from such do not 
require AERS reporting, but should be reported via routine AE reporting.  
• 
Grade 1-3 hematosuppression (leukopenia, neutropenia, lymphopenia, anemia, 
and thrombocytopenia) with hospitalization resulting from such do not require 
AERS reporting, but should be reported via routine AE reporting.  
CTEP-AERS reports should be submitted electronically. 
When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, or “Neonatal 
loss”, the Pregnancy Information Form should be completed and submitted, along with any 
additional medical information (form is available on the CTEP website at 
 The potential risk of exposure of the fetus to the investigational 
agent(s) or chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
Pregnancy loss  
• Pregnancy loss is defined in CTCAE as “Death in utero.”  
• Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under 
the Pregnancy, puerperium and perinatal conditions SOC.  
• A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this 
event as a patient death.  
 
 


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10.0 DRUG INFORMATION 
10.1 Dexamethasone Oral Solution 
Dexamethasone is an adrenal corticosteroid compound. Dexamethasone decreases inflammation 
by suppression of neutrophil migration, decreased production of inflammatory mediators, and 
reversal of increased capillary permeability; suppresses normal immune response. 
IND Exempt: Dexamethasone is IND exempt as used in this trial. This exemption has been 
determined by attestation that neither the investigator nor sponsor intends to seek a new 
indication for use or to support any other significant change in the labeling or product advertising 
for dexamethasone; this investigation will use an approved route of administration and dosage 
of dexamethasone and has no factors that increase the risk of the product; this investigation will 
be in compliance with 21CFR parts 56, 50, and 312.7; and neither the investigator nor sponsor 
will promote or represent that dexamethasone is safe or effective for the context that is under 
investigation in this study. 
Procurement  
Dexamethasone 0.5mg/5 mL oral solution (240 mL) and ORA-Sweet® Solution (480 mL) stock 
bottles will be provided and shipped by Fisher Clinical Services to sites.  
After receiving IRB approval for this study, each participating institution will order a starter 
supply of twenty bottles of dexamethasone oral solution and ten bottles of ORA-Sweet® solution 
from Fisher Clinical Services, Inc. by faxing or emailing the Drug Order/Return Form to: 
 
 
 
 
 
 
 
The A221701 Dexamethasone/Placebo Order Form can be found on the A221701 study page of 
the Alliance and CTSU websites. 
Each site is responsible for monitoring their inventory and ordering additional bottles as needed.  
Each site will provide their own 16 oz. amber bottles.  
Main member institutions will be provided a per patient reimbursement by the Alliance for their 
rebottling services and supplies.   
Within ninety days after the last patient is treated at the institution, any expired or remaining 
supplies should be destroyed according to institutional procedure. 
Preparation 
The designated unblinded person at each institution will transfer either dexamethasone 0.5 mg/5 
mL oral solution or ORA-Sweet® solution into five – 16 oz amber bottles based on the patient’s 
treatment assignment. A total of 480 mL should be added to each bottle.  This should be a 
sufficient supply for the entire 8 weeks of treatment.  The five bottles (480 mL each) will be 
labeled “dexamethasone 0.5 mg/5 mL or placebo solution”.  Assign an expiration date of one 
year.  If the expiration date of the stock bottle is less than one year, use the expiration date listed 
on the stock bottle.  
Drug Accountability 


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NCI version date 8/14/2020 
 
Update #03 
Drug accountability logs must be kept for the dexamethasone 0.5 mg/5 mL oral solution and the 
ORA-Sweet® oral solution. 
Formulation 
Dexamethasone oral solution 0.5 mg/5mL is a dye-free, sugar-free solution with a cherry brandy 
flavor.  The solution contains citric acid, disodium edetate, flavoring, glycerin, methylparaben, 
propylene glycol, propylparaben, sorbitol and water.   
Administration 
Dexamethasone/placebo will be administered at a dosage of 10 mL four times daily.  Patients 
should be instructed to swish the solution in their mouth for two minutes.  They should not eat 
or drink anything for thirty minutes before each mouthwash and at least one hour after each 
mouthwash.   
Pharmacokinetics 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 4 ± 0.9 hours; Biological half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine (~10%) 
Drug Interactions 
Substrate of CYP3A4 (major), P-glycoprotein/ABCB1; Induces CYP2A6 (weak/moderate), 
2C9 (weak/moderate), 3A4 (weak), UGT1A1 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel blockers, 
cyclosporine, estrogens, and macrolides may increase the serum levels of corticosteroids. 
Corticosteroids may increase the hypokalemic effects of amphotericin B or potassium-wasting 
diuretics (loop or thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the absorption of 
corticosteroids; may reduce the absorption of corticosteroids; separate administration by 2 
hours. Aminoglutethimide, barbiturates, and CYP3A4 inducers may reduce the serum 
levels/effects of dexamethasone and dexamethasone may decrease the levels/effects of other 
CYP3A4 substrates. Serum concentrations of isoniazid may be decreased by corticosteroids. 
Corticosteroids may lead to a reduction in warfarin effect. Corticosteroids may suppress the 
response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw, Echinacea (have immunostimulant properties) 
Adverse Events 
Known potential adverse events: Consult the package insert for the most current and complete 
information.  
Common known potential toxicities, frequency not defined:   


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NCI version date 8/14/2020 
 
Update #03 
Fluid and electrolyte disturbances, congestive heart failure in susceptible persons, hypertension, 
euphoria, personality changes, insomnia, exacerbation of infection, exacerbation or symptoms 
of diabetes, psychosis, muscle weakness, osteoporosis, vertebral compression fractures, 
pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, convulsions, vertigo and 
headache, endocrine abnormalities, ophthalmic changes, and metabolic changes. Some patients 
have experienced itching and other allergic, anaphylactic or hypersensitivity reactions. 
Withdrawal from prolonged therapy may result in symptoms including fever, myalgia and 
arthralgia. 
Storage and Stability 
Store at Controlled Room Temperature, 20- 25°C (68°-77°F); excursions permitted to 15–30°C 
(59–86°F). 
10.1.1 Nursing Guidelines 
1. 
For this protocol dose to be used is 10cc which converts to two teaspoons for patients. 
2. 
Instruct patients to shake solution well before use. 
3. 
Patients should have a clean mouth before using the rinse, no eating for 30 min prior 
to use. 
4. 
Two teaspoons should be swished in the mouth for two minutes then spit out; do not 
swallow. 
5. 
Patients should refrain from eating or drinking for one hour after rinsing. 
6. 
Patients should refrain from eating foods with high acid content, and limit alcohol and 
caffeine intake, as these food items can irritate the mouth further. 
7. 
Monitor regularly for hypertension, CHF and other evidence of fluid retention. 
8. 
Advise patient of possible mood or behavioral changes, i.e., depression, euphoria, 
insomnia, even psychosis.  Instruct patient to report any suspected changes to 
healthcare team. 
9. 
Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest antacids.  
Instruct patient to report symptoms to healthcare team if unable to control. 
10. Evaluate for signs and symptoms of throat candida infection (thrush), and treat 
appropriately. 
11. Monitor blood glucose frequently especially if diabetic. 
12. Instruct patient to report frequent, unrelenting headaches or visual changes to 
healthcare team. 
13. Advise patient that easy bruising is a side effect. 
10.2 Placebo Oral Solution 
The placebo for this study will be ORA-Sweet®.  This is a berry citrus flavored (contains FD&C 
Red #40) inert syrup vehicle.  The ORA-Sweet® contains purified water, sucrose, glycerin, and 
sorbitol. It is buffered with citric acid and sodium phosphate, and preserved with methylparaben 
and potassium sorbate.    
 
 


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11.0 MEASURES 
We plan to collect all of the data elements from the SWISH trial (Clinician grading of mucositis, 
patient reported pain, normalcy of diet scale), obtained in the same manner as in the SWISH study, 
in addition to other data elements. We will use daily logs to collect a numerical analogue mouth pain 
score, as shown in Appendix II. This was used effectively to assess patient-reported mouth pain in 
the SWISH study2. Once a week, patients will also be asked to respond to a numerical analogue 
single-item overall quality of life (QOL) self-assessment (Appendix III), two NCI-developed PRO-
CTCAE items regarding mouth sores (as shown in Appendix IV)21,22,23,24, two NCI-developed PRO-
CTCAE items regarding insomnia, and two regarding fatigue (possible side effects of 
dexamethasone), as shown in Appendix III, PRO measures are believed to be more accurate than 
clinicians’ CTCAE reporting for many toxicities.17,18  For example, in a prospective study including 
lung cancer patients, PRO measurements of toxicities better reflected patients’ underlying state and 
functional status than clinicians’ evaluations.18  As in multiple previous Alliance legacy trials,19,20,21 
patient questionnaires will be utilized to obtain outcome data. 
11.1 Numerical Analogue Mouth Pain Scale (Appendix II) 
This patient-reported mouth pain tool utilizes a numerical analogue scale methodology, which 
we have validated in numerous trials.29 Completion of the Numerical Analogue Mouth Pain 
Scale will take less than one minute. 
11.2 Numerical Analogue Self-Assessment (Appendix III) 
The single-item Numerical Analogue Scale for quality of life (QOL) has been widely used in a 
variety of clinical trials for many years,15,30,31 including in patients with advanced 
cancer,25,26,27,28, and is routinely included in most Alliance trials. When administered prior to 
initiation of therapy, better scores on this measure may be prognostic for survival in cancer 
patients, independent of performance status.32 This measure will be included to assess how the 
study medication impacts overall quality of life during treatment with everolimus. Completion 
of this single-item will take less than one minute. 
11.3 PRO-CTCAE items (Mouth/throat sores, Sleep and Fatigue items) (Appendix IV)  
The three 2-item PRO-CTCAE assessments regarding mouth/throat sores, sleep, and fatigue 
(Appendix IV) were recently developed and validated for use in cooperative group clinical 
trials.21, 22, 23 PRO-CTCAE is a library of questions asking patients about specific symptomatic 
adverse events associated with cancer therapy. Completion of the six total PRO-CTCAE items 
will take less than one minute to complete. 
11.4 Patient reported Mouthwash Use frequency (Appendix V) 
This measure was created specifically for use in this study so that we could collect data regarding 
how much mouthwash was actually used by the participants (how many of the recommended 
28 doses per week were taken), as well as data regarding whether or not (and when) the optional 
prescription dexamethasone was initiated. It also includes two questions regarding everolimus 
to allow us to assess what proportion of patients are able to stay on the full 10 mg starting dose 
of that drug on each study arm. This measure will take less than one minute to complete. 
11.5 Nurse\Research coordinator weekly phone call assessments (Appendix VI) 
Although patient-reported study data will be collected by daily patient logs and weekly 
questionnaires, there will also be weekly nurse phone calls to remind patients to fill out the 
patient booklets and to collect additional information (Appendix VI).  During these 
approximately 5-minute weekly calls, nurses will remind participants to: 


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• 
Fill out the daily mouth pain form  
• 
Fill out the weekly questionnaires (including PRO-CTCAE) and a mouthwash use 
questionnaire (as shown in Appendix V). 
The nurse or research coordinator will also collect information on:  
• 
Everolimus dose (and reasons for any dose reductions) 
• 
Study mouthwash use frequency 
• 
If and when the patient obtained the prescription mouthwash 
• 
CTCAEs; and 
• 
Normalcy of Diet Scale data (See Section 11.6) 
Items about frequency of use of study and prescription mouthwashes (Appendix V) were 
adapted from multiple previous Alliance symptom control clinical trials, as was the nurse 
telephone assessment form (Appendix VI). 
CTCAE assessments will be performed during these calls to collect mouth symptoms and to 
assess for toxicities of dexamethasone (i.e., thrush, hyperglycemia, irritability, fatigue, and 
insomnia) weekly during the study period (during the nurse phone calls if a patient is not 
scheduled to be seen in the clinic that week). 
11.6 Normalcy of Diet Scale (Appendix VII) 
The Normalcy of Diet Scale is part of the Performance Status Scale for Head and Neck Cancer 
Patients33, and was chosen for use here primarily because this was used in the SWISH study12 
and will allow us to assess the same composite endpoint that was the primary endpoint in that 
study. This measure will be administered over the phone by a study nurse, who will begin by 
asking the patient what kinds of foods (s) he has been eating, and then ask what foods are 
difficult to eat. The nurse will then ask about specific examples of foods, working up from the 
bottom of the scale (or from the middle if the patient says he/she can eat everything), stopping 
at the item the patient cannot eat (and giving the patient the score below that item). This allows 
us to assess how stomatitis related to everolimus reduces a patient’s ability to eat a normal diet 
on both arms of the study. 
12.0 END OF TREATMENT/INTERVENTION 
12.1 Duration of Protocol Treatment  
Protocol treatment is to continue until 8 weeks after start of everolimus treatment. Please see 
the study calendar (Section 5) and the treatment section (Section 7) for treatment and follow up 
time periods. 
12.2 Criteria for Discontinuation of Protocol Treatment/Intervention 
Treatment will continue until one of the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Pregnancy  


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o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
• 
Termination of the study 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 Follow-up  
12.3.1 Duration of Follow-up  
There will be no follow up after the eight week treatment period. 
12.3.2 Follow-up for Patients who Stop Study Treatment Early  
When patients stop protocol treatment early, they should be encouraged to complete QOL 
submissions but can stop if they prefer.  
12.4 Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 Managing ineligible patients and registered patients who never receive protocol 
intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), baseline and off-treatment notice data submission is required. See the 
Data Submission Schedule accompanying the All Forms Packet. 


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13.0 STATISTICAL CONSIDERATIONS 
13.1 Study Design 
This trial is designed as a multi-center, randomized, double-blind, placebo-controlled phase III 
study where patients will be randomly assigned to receive either dexamethasone mouth rinse or 
placebo mouth rinse. The respective research hypotheses for the co-primary objectives 2.1.1 and 
2.1.2 are: 
 
1) 
Pain will be less common in patients who take dexamethasone preventatively 
(dexamethasone group) compared with those who initiate dexamethasone at the onset of mouth 
pain (placebo group). The research hypothesis for this first co-primary objective is: 
Dexamethasone taken preventively will substantially decrease the number of patients who 
develop mIAS. 
2) 
The research hypothesis for this second co-primary objective is: The average severity of 
mIAS-associated pain over the eight week treatment period will be greater in those who initiate 
dexamethasone at the onset of mouth pain (placebo group) compared to those who take 
dexamethasone preventatively (dexamethasone group). 
13.2 Sample Size, Accrual time and Study Duration 
To account for 10% ineligible patients and cancelations, the targeted sample size is 279 patients 
(evaluable patients for data analysis are 254). Under a constant accrual rate of 10-15 patients 
per month, the study will last 28 months from initiation until the final patient is accrued, and 
another 2 months until the final patient completes treatment.  
13.3 Primary objectives and endpoints  
There are two co-primary endpoints in this study. Patient-reported mouth pain is measured by a 
simple 11-item response scale [0, 1, 2, …, 10] with zero indicating “no pain” and ten indicating 
“pain as bad as can be” (Appendix II), and obtained at baseline (within seven days prior to the 
start of treatment) and then daily for 8-weeks.  
13.3.1 First co-primary endpoint 
The objective is to compare the incidence rate of mIAS-associated mouth pain between the 
two arms using a Chi-square test. The first co-primary endpoint is the binary outcome 
mouth pain (yes; no) defined as a patient reporting at least one serially measured mouth 
pain score greater than zero during the eight-week study period.   
13.3.2 Second co-primary endpoint 
The objective is to compare the average AUC of the serially measured mIAS-associated 
mouth pain scores between the two arms using a two-sample t-test. The second co-primary 
endpoint is the area under the curve (AUC) summary measure calculated for each patient 
based on the patient’s serially measured patient-reported mouth pain scores; the AUC 
calculated for each patient is scaled according to the number of assessable patient-reported 
mouth pain scores to obtain a transformed AUC score on a scale of 0-100.   
13.4 Secondary objectives and endpoints 
13.4.1 (Objective 2.2.1) Using the same measurement method that was reported in the SWISH 
trial, we will generate an endpoint that consists of a combination of a patient reported pain 
scale, data from a normalcy of diet questionnaire, and CTCAE grading of 
stomatitis/mucositis to determine the incidence of  ≥ grade 2 mIAS. Grade ≥ 2 mIAS is 
defined as having at least one of the following criteria: 


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1) 
Oral intake assessed at <50 on the Normalcy of Diet Scale 
2) 
Patient’s reported oral pain (using visual analogue scale 0-10) that meets one of 
the following: 
• 
rating of 7 on two consecutive days 
• 
rating of 8, 9, or 10 on any one day 
Our hypothesis is that dexamethasone will substantially decrease the number of patients 
who develop grade ≥ 2 mIAS. 
13.4.2 (Objective 2.2.2) We will determine if the initiation of dexamethasone at the start of 
everolimus increases time to development of mouth pain. Our hypothesis is that daily 
numerical analogue scale data will reveal longer time to the development of at least mild, 
at least moderate, and severe mouth pain in the upfront dexamethasone arm compared to 
the placebo arm. 
13.4.3. (Objective 2.2.3) We will assess if quality of life and adverse related domains are better, 
as we hypothesize that it will be, when dexamethasone mouth rinse use starts at the same 
time as everolimus use versus at the time when mouth pain begins by comparing numerical 
analogue scale scores (Appendix III) and PRO-CTCAE mouth/throat and sleep items 
regarding level of interference with daily activities (Appendix IV). 
13.4.4. (Objective 2.2.4) We will investigate if starting dexamethasone mouth rinse concurrent 
with starting everolimus improves patients’ ability to adhere to everolimus therapy by 
comparing mean daily dose of everolimus between the arms, as well as the number of 
patients who stopped everolimus early and the number who reduced the dose of everolimus 
per arm between the groups. 
13.4.5. (Objective 2.2.5) We will compare dexamethasone prescription fill rates and time to these 
fills between patients who received placebo versus study drug at the initiation of 
everolimus. 
13.5 Analysis Plan and Sample Size Justification 
The primary analyses will be based on the intent-to-treat (ITT) population, defined as all patients 
randomized who completed the numerical analogue mouth pain scale at least once during the 
study.  For the co-primary endpoints, a fixed-sequence statistical strategy will be used to control 
the Type I error rate at 0.05.  The first co-primary endpoint will be tested, followed by the second 
co-primary endpoint, both at the same significance level of 0.05, such that the second co-primary 
endpoint is only tested if statistical significance was achieved on the first co-primary endpoint.  
Although both co-primary endpoints are clinically relevant, the testing sequence was ordered 
largely by the likelihood of success.  
13.5.1 First co-primary endpoint 
The sample size was determined based on the between arm comparison of the incidence 
rate of mIAS-associated mouth pain using a Chi-square test. The incidence rate for each 
arm is defined as the proportion of patients reporting any pain score greater than zero 
during the eight week study period, based on the single item numerical analogue mouth 
pain scale (Appendix II). Based on prior studies (Section 13.7), we assumed that the 
incidence rate of mIAS-associated mouth pain in the placebo group is 50%, and 
hypothesized that the incidence rate of mIAS-associated mouth pain in the dexamethasone 
group will be 32%.  To detect this difference in the incidence rate of mIAS-associated 
mouth pain with 80% power, 127 patients are needed per group or 254 patients total.  The 


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sample size calculation was based on a Chi-square test with a 5% Type I error rate under 
two-sided alternative. 
13.5.2 Second co-primary endpoint:  
With 127 patients per group (254 total), the study is adequately powered to detect a 
moderate effect size for the second co-primary endpoint.  Specifically, 127 patients per 
group will provide 97% power to detect a moderate effect size of 0.5 (equivalent to 10 
points on the transformed AUC score scaled from 0-100 divided by an assumed standard 
deviation of 20 points). We assumed that the placebo group would have a higher 
transformed mean area under the curve (AUC, equivalent to increased mIAS-associated 
mouth pain) than dexamethasone group. This power calculation was based on a two-sample 
t-test with a two-sided 5% Type I error rate. 
13.5.3 Secondary endpoints: 
The SWISH trial approach incidence rate of grade 2 or higher stomatitis for each treatment 
group will also be compared by a Chi-square test. 
The planned tests for the other secondary endpoints are detailed in the table below: 
Study item 
Measurement method 
Statistical test 
Time to develop at least mild 
mouth sores per study arm. 
PRO-CTCAE 
Mouth/throat sore items 
(Appendix IV) 
Kaplan-Meier and 
cumulative incidence curves 
Time to develop at least moderate 
mouth sores per study arm.  
PRO-CTCAE 
Mouth/throat sore items 
(Appendix IV) 
Kaplan-Meier and 
cumulative incidence curves 
Time to develop at least severe 
mouth sores per study arm. 
PRO-CTCAE 
Mouth/throat sore items 
(Appendix IV) 
Kaplan-Meier and 
cumulative incidence curves 
Mean and median degrees of 
patient-reported mouth sores per 
study arm.  
Numerical analogue 
mouth pain scale 
(Appendix II) 
Independent samples T-tests  
Incidence and time to develop at 
least mild mouth pain (pain scores 
of 1-3/10) per study arm. 
Numerical analogue 
mouth pain scale 
(Appendix II) 
Chi-squared tests and 
cumulative incidence curves, 
respectively 
Incidence and time to develop at 
least moderate mouth pain (pain 
scores of 4-6/10) per study arm.  
Numerical analogue 
mouth pain scale 
(Appendix II) 
Chi-squared tests and 
cumulative incidence curves, 
respectively 
Incidence and time to develop at 
least severe mouth pain (pain 
scores of 7-10/10) per study arm. 
Numerical analogue 
mouth pain scale 
(Appendix II) 
Chi-squared tests and 
cumulative incidence curves, 
respectively 
Quality of life over time per study 
arm. 
Linear Analogue Self-
Assessment (Appendix 
III) 
Independent samples t-tests  


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Study item 
Measurement method 
Statistical test 
Level of activity interference with 
daily activities 
PRO-CTCAE 
Mouth/throat sore items 
(Appendix IV) and PRO-
CTCAE Sleep Items 
(Appendix IV) 
Independent samples t-tests 
Mean daily dose of everolimus 
over 8 weeks 
Appendix VI 
Independent samples t-tests 
Number of patients who stopped 
everolimus per arm 
Appendix VI 
Chi-square tests 
Number of patients who reduced 
the dose of everolimus per arm 
Appendix VI 
Chi-square tests 
Proportion of patients who 
experience grade 2 stomatitis  
Clinician-reported 
stomatitis performed at 1 
and 2 months 
Chi-squared tests 
Number of patients who chose to 
fill their dexamethasone 
prescription per study arm and 
mean time until this happened 
This information will be 
collected by patient 
questionnaire (Appendix 
V) and also will be nurse 
delineated (Appendix VI). 
Conflicts will be 
adjudicated by an 
investigator who is 
blinded to study arm. 
Chi-squared tests and 
cumulative incidence curves 
respectively 
13.6 Interim data analysis and stopping rule 
No interim data analysis was planned for this trial. 
Note: The statement regarding the interim analysis in previous Section 13.8 of the protocol was 
inadvertently carried over from another protocol. It was not meant to be included. 
13.7 Primary Endpoint Justification: CTCAE items 
One option for our primary analysis would be to use the identical endpoint measurement 
criterion that was developed and used de novo in the SWISH trial.  This composite endpoint 
required that grade 2 or higher stomatitis needed to be confirmed by the investigator or treating 
physician and at least one of the following: 1) an oral pain score of greater than 8/10 on 1 
occasion or 7/10 for 2 days, or 2) that patients could only eat soft chewable foods (or less, like 
liquids alone) as determined by a Normalcy of Diet Scale score less than or equal to 50/100.  
With this rule, a patient with classic CTCAE determination of grade 2 stomatitis could have 
been downgraded to grade 1 stomatitis if they did not meet the pain or diet criteria to keep them 
at grade 2 stomatitis (noting that this only happened for 2 patients in the SWISH trial—
unpublished data provided to us).  The main reason to consider choosing this measurement 
method is that it was used in the previously published SWISH trial.  However, the downsides of 
utilizing this novel measurement is that this composite CTCAE clinician-determined 
measurement is not well validated psychometrically by itself, or by adding the 2 criteria noted 
above.  


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Additionally, data that can be collected daily by patient questionnaires will allow us to more 
accurately see daily changes on the days before and after patient actually took prescription 
dexamethasone (which they would have started because they developed mouth pain); we may 
not be able to collect CTCAE data at that exact time, if we used the SWISH measurement 
method. 
Further supporting the use of a PRO measure of mouth sore related pain is that the definition of 
grade 2 or 3 CTCAE-determined mucositis is primarily based on pain, as is illustrated in the 
table below (thus the mouth pain that patients developed would have been the predominant 
factor to determine their CTCAE score). 
Grade: 
1 
2 
3 
4 
5 
Mucositis 
oral 
Asymptomatic or 
mild symptoms; 
intervention not 
indicated 
Moderate pain 
or ulcer that 
does not 
interfere with 
oral intake; 
modified diet 
indicated 
Severe pain; 
interfering 
with oral 
intake 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Thus, we propose to use the PRO pain score as our primary measurement tool, while using the 
SWISH trial method as a secondary endpoint for both concurrent validation of the SWISH 
approach and comparison of the two results. This primary measurement tool will be used both 
to determine if initial dexamethasone is superior in preventing the development of any mouth 
sores-related pain compared to initial placebo, and to determine if the average severity of mIAS-
associated pain over the eight week study period is greater in those who initiate dexamethasone 
at the onset of mouth pain compared to those who take dexamethasone preventatively, 
corresponding to the first and second co-primary objectives, respectively. 
13.8 Sample Size and Power Considerations 
13.8.1 Co-primary endpoint original consideration 
The effect size estimates from the preliminary trials are profound, exceeding one standard 
deviation for multiple primary and secondary endpoints. For example, by 8 weeks, the 
incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29–8·24), 
versus 159 (33%) of 482 patients (95% CI 28·8–37·4) for the duration of the BOLERO-2 
study. This represents an effect size in excess of 5 standard deviations and would require 
only 29 patients per group, an impractically small sample size. Hence, we will use 
established norms for reasonable clinically meaningful effect sizes established by our 
group over fifteen years ago and used in numerous clinical trials by ourselves and others 
for the purposes of power calculations35, 36. Our clinical colleagues’ expert opinions as to 
what constitutes a clinically significant effect size were used as a confirmatory check on 
our effect size estimates.  
For the first co-primary endpoint, a Chi-square test with 77 patients per group will have 
99% power to detect a difference in the rate of mIAS pain (>50% in the placebo versus 
<15% in the dexamethasone treatment group) with a two-sided alternative and a 5% Type 
I error rate. These estimates are based on the SWISH and Bolero trial data.  
For the second co-primary endpoint, the independent samples t-test using the simple 
summary AUC measure will have 87% power to detect a difference in the first co-primary 
endpoint of AUC for the 8-week period for the severity of mIAS-associated pain as 
assessed by the single item measure of 50% times the standard deviation (a moderate effect 
size equivalent to 10 points on the transformed AUC score scaled from 0-100, assuming a 


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standard deviation of 20 points in the AUC) among the two arms of 77 patients each, 154 
patients total (type I error rate set at 5% and a two-tailed alternative). This effect size is 
considered clinically non-ignorable 37 and is a conservative estimate of efficacy given the 
profound results of the pilot test results.  
13.8.2 Re-design co-primary endpoint consideration as a result of NCI CIRB review 
Questions were raised regarding the sample size by the NCI CIRB regarding: 
1) Calculation of initial effect size 
2) Potential for patients to use the treatment more because they have ready access to 
what they believe is a pain ameliorating intervention.  
Consideration of effect size: As indicated above in the introduction (section 1.2), the 
multiple phase II trials that have used this treatment have indicated effect sizes of more 
than five standard deviations in assessing reduction of the incidence of pain reported 
by patients or assessed by clinicians. The table below illustrates this point in using 
incidence rates for any stomatitis and grade 2+ stomatitis from the two pilot studies 
and historical control data from the Bolero study. More specifically, the effect sizes 
are all well above one standard deviation and require as few as 22 patients per group 
for a chi-square test for equality of proportions to achieve 80% power with a 5% Type 
I error rate. The sample size could be as large as 71 per group if we consider the San 
Antonio study and grade 2+ stomatitis. This is still less than the 77 patients per group 
required to detect a moderate effect size as described above as a non-ignorable 
clinically meaningful effect 38  
Source 
Clinician-reported 
stomatitis incidence 
Effect Size  
 
Sample size to detect 
effect 
size 
(per 
group) with 80% 
power and 5% type I 
error 
Historical Control 
(Bolero) 
67% (any), 
 
 
 
SWISH 
21% (any) 
46% 
22 
San Antonio study 
29%, 27.5% (any) 
 
38%, 39.5% 
31, 29 
Historical Control 
(Bolero) 
33% (gr 2+) 
 
 
Bolero-2 
2% (gr 2+) 
31% 
29 
San Antonio study 
12%, 8% (gr 2+) 
21%, 25% 
71, 48 
We consider the possibility that some patients fill the dexamethasone prescription when 
they really do not actually have pain, because they think it will prevent them from getting 
pain.  One could assert that the likelihood of doing this should be equivalent between the 
treatment and placebo preparations and dismiss potential effect size confounder. However, 
in case that is not the case, in the extreme case that 1 out of every 6 patients in the treatment 
arm reports pain in the absence of pain, in order to gain permission to fill the 
dexamethasone script, compared to none in the placebo group (personal communication, 
CIRB), this would reduce our initially estimated effect size by 16.7%.  


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Recall that since the preliminary effect sizes were so large, we used a conservative estimate 
of effect size of ½ standard deviation to come up with our sample size of 71 per group to 
have 80% power. Our original power calculation was based on an incidence rate of pain in 
the control and treatment groups of >50% and <15% respectively. This provided the chi-
square test a sample size of 33 patients per group to detect this difference with 80% power, 
or more than 99% power with 71 patients per group. If we modify the efficacy rate in the 
treatment group by 17% (rounding from 16.7%), then we would be comparing a stomatitis 
pain incidence of at least 50% in the control group with a rate of 32% (15+17 percent). For 
the chi-square test to have 80% power to detect this reduced efficacy rate, we would need 
127 patients per group.   
The table below provides required sample size for various assumed percentages of patients 
unnecessarily taking medication. It indicates that our conservative sample size of 71 
patients per group can accommodate just over 10% of the patients taking medication when 
unnecessary. To ensure we cover the proposed estimate of 16.7% of “contamination” rate, 
we recommend increasing the sample size to 127 patients per group. 
Estimated 
rate 
of 
medication 
taken 
when not needed 
Resultant effect size 
in treatment group 
Effect size in control 
group 
Required sample size 
per group for 80% 
power 
0% 
15% 
50% 
33 
5% 
20% 
50% 
45 
10% 
25% 
50% 
66 
16.7% 
32% 
50% 
127 
25% 
40% 
50% 
408 
In summary, then, taking these two issues under consideration, the ultimate sample size 
will be 279 patients in total (127 per group plus 10% for ineligibles and cancelations). 
The revised sample size of 127 patients per group will provide at least as much power 
specified for the AUC co-primary t-test specified for the original sample size in section 
13.7.1.  More specifically, however, 127 patients per group will provide over 95% power 
to detect a non-ignorable clinically meaningful difference in average AUC of 50% times 
the standard deviation (a moderate effect size equivalent to 10 points on the transformed 
AUC score scaled from 0-100, assuming a standard deviation of 20 points in the AUC, type 
I error rate set at 5% and a two-tailed alternative).  Further, there will be 80% power for 
the t-test to detect a difference of 35% of the standard deviation (equivalent to 7 points on 
the 0-100 point transformed AUC score between average AUC in the two groups.  In 
summary, the expanded sample size will provide sufficient power for both co-primary 
endpoints to detect small to moderate effect sizes. 
13.9 Study Monitoring  
This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an NCI-
approved functioning body. Reports containing efficacy, adverse event, and administrative 
information will be provided to the DSMB every six months as per NCI guidelines. 
13.10 Missing Data and sensitivity analysis 
As a further sensitivity analysis of our primary results, we will employ a further method due to 
Fairclough et al to producing the area under the curve (AUC) estimates based on using estimated 
parameters from a repeated-measures (means) mixed model with a random intercept34.  The 


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outcome measures used in the repeated-measures (means) mixed model are the serially 
measured patient-reported mouth pain scores obtained at baseline and daily during the eight 
week study period.  The covariates included in the model are indicator variables for all 
assessment time points, an indicator for the treatment approach (initial dexamethasone; initial 
placebo), and the corresponding two-way interaction terms.  This macro will rerun the primary 
analyses with each alternative approach to imputation to demonstrate the veracity of the results 
in the presence of missing data. This analytic approach to compare the prevention approach vs 
early treatment approach will maintain the ITT principle and allow for missing data (i.e. under 
the reasonable assumption of missing at random).  Furthermore, it has been shown that this 
analytic approach is superior to a simple AUC summary measure in terms of both bias and 
precision in the presence of missing data34.  In this supplemental analysis, we will also account 
for the two stratification factors in the model, as well as potentially other baseline covariates. 
To maintain the 5% significance level, this statistical test will only be performed if the first 
primary endpoint is met. 
 




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14.0 CORRELATIVE AND COMPANION STUDIES  
There will be 2 substudies and all patients are encouraged to participate.  
14.1 Pharmacogenomics and Everolimus induced stomatitis A221701-ST1 
14.1.1 Background 
The increased toxicity that has accompanied the everolimus plus exemestane therapy has 
been the primary reason for patients’ discontinuation of treatment. While some patients 
experience severe oral mTOR inhibitor-associated stomatitis (mIAS), others do not; this is 
possibly due in part to genetic variability in genes that biotransform everolimus. 
Everolimus is metabolized by CYP3A4, CYP3A5 and transported by p-glycoprotein.  It 
binds with high affinity to FK506 binding protein -12 to form a complex that inhibits 
mTOR activation and reduces activity of effectors downstream, blocking cell cycle 
progression from G1 to S phase and leading to cell growth arrest and apoptosis. These 
proteins are encoded by genes that are genetically polymorphic and whose activities result 
in variability in the extent of metabolism of everolimus and variability in signaling 
associated with the mTOR pathway—all of which might lead to variations in everolimus 
sensitivity. 
A recent next-generation sequencing study of tumor samples from patients identified 
somatic mutations as genetic markers in mTOR signaling pathway (TSC1, TSC2, MTOR 
alterations) to be associated with everolimus sensitivity 58 On the other hand, studies have 
reported single nucleotide polymorphisms (SNPs) in genes involved in everolimus 
pharmacokinetics and pharmacodynamics to be associated with everolimus clinical 
outcomes with varying results. For example in two studies examining FGFR4 rs351855 
SNP in neuroendocrine tumors, one reported no association with everolimus efficacy 44and 
the other reported reduced sensitivity to everolimus and increased tumor progression 45 .  
A recent review covering pharmacogenetics of mTOR inhibitors’ role in the 
pharmacodynamics of immunosuppressive drugs,46 it was highly recommended that 3 
MTOR SNPs namely rs2024627, rs2295080, rs1883965 be investigated in studies as these 
were associated with decreases in hemoglobin levels in solid organ transplantation.  
In the only study to date exploring the impact of germline variation on exemestane-
everolimus outcome in 90 women with metastatic breast cancer, Pascual et al. (2017)47 
reported that CYP3A4 rs35599367 was associated with higher concentrations of 
everolimus in blood. The global minor allele frequency of the CYP3A4 rs35599367 SNP 
is low, 0.015, however in Caucasians the frequency ranges from 0.03-0.05. In this study by 
Pascual et al (2017), they found 4 patients with rs35599367 genotype out of 37 patients 
who had PK data on day 14 of the first everolimus cycle and were able to associate the 
genotype with plasma everolimus concentration levels. We will not genotype for the 
CYP3A4 rs35599367 SNP in this study because of its low allele frequency. Polymorphisms 
in CYP3A5 and CYP2C8 (everolimus metabolism) and in ABCB1 (everolimus transport), 
and also in genes belonging to the PI3K/AKT/mTOR pathway (FGFR4, PHLPP2, AKT2, 
PIK3R1, RAPTOR, AKT) have also been evaluated for their association with everolimus 
sensitivity. While SNPs in FGFR4, RAPTOR and PIK3R1 were associated with toxicities 
such as leucopenia, hyperglycemia and lymphopenia, only ABCB1 rs1045642 SNP was 
associated with mucositis47. 
Furthermore in a GWAS study evaluating everolimus sensitivity in lymphoblastic cell 
lines,48 showed that 10 SNPs (rs218869, rs7694207, rs10987149, rs12932018, rs2702449, 
rs16887552, rs2832270, rs1460196, rs4148330, rs13272072) were highly associated with 
everolimus sensitivity (p=10-6) even though they did not reach the expected genome-wide 


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significance of p<10-8 (Table 1). Six other SNPs that showed some association with 
everolimus after functional studies were reported in the same study (Table 1). The most 
significant gene whose expression has been reported to associate with everolimus 
sensitivity is FBXW7, p=4x10-7.48 This FBXW7 gene encodes a member of the F-box 
protein family and functions by binding directly to multiple substrates including cyclin E 
and targeting cyclin E for ubiquitin-mediated degradation 49,50. Other substrates include c-
Myc, c-Jun, Notch, Mcl-1 and mammalian target of rapamycin (mTOR)51, all of which are 
involved in cell division, growth, survival and differentiation 50,52,53  FBXW7 also functions 
as a tumor suppressor and inactivation of the protein is associated with deregulation of well
‑known oncoproteins some of which are indicated above 51,52 and is also one of the most 
frequently  mutated genes in human cancers.49,51  FBXW7 is genetically polymorphic 
although no SNP was observed in the GWAS study48 . However, polymorphisms in this 
gene have been reported in relation to blood pressure 55and epilepsy56. As such, we will 
derive tagSNPs for FBXW7 and explore correlations of the polymorphisms with stomatitis. 
Given that the SNPs mentioned here (see also Table 1 : SNPs1-16, 22- 26) have previously 
been associated with everolimus and everolimus sensitivity (indicated above) and that oral 
mIAS  results from sensitivity to everolimus intake, we will investigate these SNPs in this 
study to determine if they appear to predispose patients to different levels of stomatitis 
severity. In addition, we will explore any correlations that the FBXW7 tagSNPs we derive 
will have on stomatitis severity. Moreover since the study proposes the use of 
dexamethasone to substantially decrease severity in mIAS-associated pain in the patients 
on treatment, we will evaluate if the use of dexamethasone changes any observed mIAS-
SNP associations in the study. 
Therefore, we will validate SNPs that have been associated with everolimus sensitivity by 
associating them with severity of stomatitis.  TagSNPs for FBXW7 will be explore for their 
associations with stomatitis severity. We propose to do this by following the objectives 
below: 
14.1.2 Objectives 
1) 
To derive tagSNPs for FBXW7 and together with SNPs reported (Table 1), genotype 
all patient samples for those SNPs 
2) 
To explore the association of the genotypes with severity of everolimus-related 
stomatitis (mIAS- 
associated pain) within the patients who initially received placebo 
at the start of everolimus treatment. 
3) 
To explore the association of the genotypes with severity of everolimus-related 
stomatitis (mIAS- 
associated pain) within the patients who initially received 
dexamethasone at the start of everolimus treatment. 
14.1.3 Methods 
DNA Isolation, SNP selection and Genotyping: 
Whole blood sample will be collected in 1 x10 mL EDTA vacutainer tube (purple top) 
from patients at start of study for germline DNA isolation. Blood samples will be sent to 
the Alliance Biorepository at Mayo Clinic and DNA will be isolated in the Biospecimen 
Accessioning and Processing (BAP) laboratory. 
SNP selection for FBXW7: Genotype data from the National Center for Biotechnology 
Information (NCBI) dbSNP database will be used with programs in National Institute of 
environmental Health Sciences 
 and Genome variation 




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study will mirror that of the main study. For the purpose of the correlative, we will compare 
the difference in average PRO pain score within each arm separately and use each candidate 
SNP that meets the threshold of the cutoff (as defined in section 14.1.3) as the primary 
covariate of interest.   The Bonferroni method will be applied to control the Type I error 
rate at 5% for each of the different models. Markers that do not meet the threshold of the 
cutoff will be summarized descriptively.  
 


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14.2 Population Pharmacokinetics (PK) of Everolimus A221701-PP1 
14.2.1 Background 
In transplantation settings, where therapeutic drug monitoring (TDM) aided dose-
adjustment is common, everolimus should be generally targeted to a trough concentration 
(C0) of 3–8 ng/mL when used in combination with other immunosuppressive drugs 
(calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the 
everolimus target C0 range should be 6–10 ng/mL. Further studies are required to determine 
the clinical utility of TDM in nontransplantation settings59. In oncology settings, 10 mg/day 
seems to be the maximum tolerated dose. At this dose, everolimus C0 of up to 17.0 ng/mL 
have been observed, with large interindividual differences. In patients with metastatic renal 
cell carcinoma (n = 42), the median everolimus C0 was 14.1 ng/mL (range, 2.6–91.5 
ng/mL). Fourteen (67%) versus 8 (38%) patients with median everolimus C0 above or 
below 14.1 ng/ mL, respectively, were progression-free at 6 months (P =0.06); median 
progression-free survival was 13.3 versus 3.9 months, respectively [hazard ratio (HR), 
0.66; 95% CI, 0.33–1.31; P = 0.23], and median overall survival was 26.2 versus 9.9 
months, respectively (HR, 0.62; 95% CI, 0.28–1.37; P =0.24).59 
Everolimus is orally active, with linear (dose-proportional) PK. Absorption is rapid, with 
peak concentration reached within 1.5–2 hours. The free fraction of everolimus (EVR) in 
plasma is approximately 0.26. There is a good correlation between predose or C0 and area 
under the concentration–time curve (AUC) at steady state. In blood, everolimus is highly 
incorporated into erythrocytes, and there is evidence that this binding is concentration 
dependent, justifying the use of whole blood rather than plasma for EVR quantification. 
Everolimus has a long half-life of approximately 30 hours. Steady-state concentrations are, 
therefore, generally achieved within 4–7 days. 
Everolimus is a substrate of both the efflux pump known as the ATP-binding cassette 
subfamily B member 1 (ABCB1; P-glycoprotein) and the CYP metabolic enzyme 
(particularly CYP3A4, with CYP3A5 and CYP2C8 playing minor roles). Everolimus is 
prone to substantial PK variability and numerous drug-drug interactions because of the 
involvement of ABCB1 and CYP3A4 in its PKs. Data regarding the effect of CYP3A4 
genetic variations on EVR PK (or pharmacodynamics) are still scarce. The CYP3A4*1B 
allele (rs2740574; c.-392G.A) showed no association with EVR dose-normalized 
concentrations in lung transplant recipients. No significant influence on everolimus PK 
was observed in relation to the CYP3A4*22 (rs35599367; c.522191C.T) variant, which was 
found in 9 of 97 patients; 8 were heterozygous carriers and 1 was a homozygous carrier of 
the CYP3A4*22 allele. Six studies have been reported to date, showing no association 
between the common CYP3A5*3 allele (rs776746; c.219-237G.A) and everolimus blood 
concentrations, dose requirement, or PK parameters estimated using population PK 
approaches. No studies found a significant relationship between everolimus dosing or 
blood concentrations and CYP2C8 genotype, which denotes 2 highly linked variants, 
rs11572080 (c.416G.A; p.R139K) and rs10509681 (c.1196A.G; p.K399R), occurring at 
relatively high frequency in whites (11%–14%), but rarely in Asians and Africans. This is 
consistent with its minor role in everolimus metabolism. A study in lung transplant 
recipients failed to demonstrate any association with CYP2C8*2 (rs11572103: c.805A.T; 
p.Ile199Phe) and CYP2C8*4 alleles (rs1058930: c.792C.G; p.Ile264Met), and a study in 
heart transplant recipients found no association between CYP2C8*3 and everolimus 
adverse effects. Three pharmacogenetic studies also investigated the effects of ABCB1 
genetic polymorphisms on everolimus PK in solid organ transplantation and none reported 
significant associations. 


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Population PK models of everolimus have been developed. A model in heart transplant 
recipients reported an apparent clearance and distribution volume of 3.33 ± 0.20 L/h and 
146 ± 33 L, respectively, and a significant influence of bilirubin concentration on 
clearance. In kidney transplant recipients, using a 2-compartment structural model with 
first-order absorption with lag time, ideal body weight was found to be significantly related 
to the volume of distribution. 
The intrapatient PK variability of everolimus is reported to be high (45% for C0, 27% for 
the AUC in de novo kidney transplant recipients administered CsA), as is interindividual 
variability (55% for C0, 31% for the AUC). 
In a multiple-dose study in kidney transplant recipients, a high-fat meal delayed tmax by a 
median of 1.75 hours and reduced Cmax by 53% and AUC by 21%. Everolimus C0 showed 
no food effect, suggesting that although overall exposure is prone to a food effect, this does 
not translate into C0 variations. 
We believe we will find in this study that the interpatient variability in everolimus exposure 
(C0) exceeds 50% and that there is a correlation between everolimus exposure (C0) and its 
toxicity and the use of dexamethasone. 
14.2.2 Objectives 
1. To determine the intrapatient and interpatient variability of everolimus exposure 
(C0) in cancer patients being treated with everolimus. 
2. To explore the association of everolimus exposure (C0) with toxicity 
14.2.3 Methods 
Venous blood samples for everolimus trough concentrations (C0) will be obtained at 
baseline, and at the 8 weeks scheduled follow-up clinic visit (and optional at 4 weeks) 
while still receiving study drug therapy. These samples will have the time of day they were 
obtained documented. At these follow up visits a patient questionnaire will be filled in 
which will request information about the timing of prior dosing of everolimus (See 
Appendix VIII). This will detail the time of day the last dose of study drug was taken. 
Drug concentrations will be measured in whole blood using an Liquid Chromatography 
Tandem-Mass Spectrometry (LC-MS-MS) assay to be implemented in the Alliance 
Pharmacology/Pharmacokinetic core lab at the University of Pittsburgh using a 
modification of e.g. the assay published by Tszyrsznic, W et al.60 
Frequentist approaches will be used for correlation, and if data permits, population 
modeling approaches may also be employed. 
14.2.4 Analyses 
Objective 1: We will calculate C0 variability at 8 weeks as a metric of interpatient 
variability; while the inclusion of data from 4 week samples will allow calculation of 
intrapatient variability. We will approach this using a frequentist approach. 
Objective 2:  We will explore relationships between C0 and mucosal toxicity, and 
dexamethasone use. 
 
 
 


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Opazo N. DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated 
with increased BP in Sardinian males. Physiol Genomics. 2011 Nov 7;43(21):1219-25. doi: 
10.1152/physiolgenomics.00012.2011. Epub 2011 Aug 23. PubMed PMID: 21862670; PubMed Central 
PMCID: PMC3217322 
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Wight JE, Nguyen VH, Medina MT, Patterson C, DurÃ³n RM, Molina Y, Lin YC,MartÃ-
nez-JuÃ¡rez IE, Ochoa A, Jara-Prado A, Tanaka M, Bai D, Aftab S, Bailey JN, Delgado-Escueta AV. 
Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis 
applied to epilepsy and EEG 3.5-6.0Â Hz polyspike waves. Mol Genet Genomic Med. 2016 Jan 
23;4(2):197-210.  doi:10.1002/mgg3.195. eCollection 2016 Mar. PubMed PMID: 27066514; PubMed 
Central PMCID: PMC4799870. 
 
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J.A. Sloan, D. Vargas-Chanes, C.C. Kamath, D.J. Sargent, P.J. Novotny, P. Atherton, C. 
Allmer, B.L.Fridley, M.H. Frost, C.L. LoprinziDetecting worms, ducks and elephants: a simple approach 
for defining clinically relevant effects in quality-of-life measures J Cancer Integr Med, 1 (2003), pp. 41-
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Lim SM, Park HS, Kim S, Kim S, Ali SM, Greenbowe JR, Yang IS, Kwon NJ, Lee JL, 
Ryu MH, Ahn JH, Lee J, Lee MG, Kim HS, Kim H, Kim HR, Moon YW, Chung HC, Kim JH, Kang YK, 
Cho BC. Next-generation sequencing reveals somatic mutations that confer exceptional response to 
everolimus. Oncotarget. 2016 Mar 1;7(9):10547-56. doi: 10.18632/oncotarget.7234.PMID:26859683  
59. 
Shipkova M, Hesselink DA, Holt DW, Billaud EM, van Gelder T, Kunicki PK, et al. 
Therapeutic Drug Monitoring of Everolimus: A Consensus Report. Therapeutic drug monitoring. 
2016;38(2):143–69. Epub 2016/03/18. pmid:26982492 
60. 
Tszyrsznic, W., Borowiec, A., Pawlowska, E., Jazwiec, R., Zochowska, D., 
Bartlomiejczyk, I., Dadlez, M. (2013). Two rapid ultra-performance liquid chromatography/tandem mass 
spectrometry (UPLC/MS/MS) methods with common sample pretreatment for therapeutic drug 
monitoring of immunosuppressants compared to immunoassay. Journal of Chromatography B, 928, 9-15. 
doi:https://doi.org/10.1016/j.jchromb.2013.03.014 
 
61. 
Foote RL, Loprinzi CL, Frank AR, et al: Randomized trial of a chlorhexidine mouthwash 
for alleviation of radiation-induced mucositis. J Clin Oncol 12:2630-3, 1994 
 
62. 
Leenstra JL, Miller RC, Qin R, et al: Doxepin rinse versus placebo in the treatment of 
acute oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy: 
a phase III, randomized, double-blind trial (NCCTG-N09C6 [Alliance]). J Clin Oncol 32:1571-7, 2014 
 
63. 
Loprinzi CL, Cianflone SG, Dose AM, et al: A controlled evaluation of an allopurinol 
mouthwash as prophylaxis against 5-fluorouracil-induced stomatitis. Cancer 65:1879-82, 1990 
 
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Loprinzi CL, Ghosh C, Camoriano J, et al: Phase III controlled evaluation of sucralfate to 
alleviate stomatitis in patients receiving fluorouracil-based chemotherapy. J Clin Oncol 15:1235-8, 1997 
 
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Mahood DJ, Dose AM, Loprinzi CL, et al: Inhibition of fluorouracil-induced stomatitis 
by oral cryotherapy. J Clin Oncol 9:449-52, 1991 


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66. 
Okuno SH, Foote RL, Loprinzi CL, et al: A randomized trial of a nonabsorbable 
antibiotic lozenge given to alleviate radiation-induced mucositis. Cancer 79:2193-9, 1997 
 
67. 
Okuno SH, Foote RL, Olmscheid MA, et al: Evaluation of an oral capsaicin lozenge for 
preventing radiation-induced mucositis. J Cancer Integrative Med 2:179-83, 2004 
 
68. 
Okuno SH, Woodhouse CO, Loprinzi CL, et al: Phase III controlled evaluation of 
glutamine for decreasing stomatitis in patients receiving fluorouracil (5-FU)-based chemotherapy. Am J 
Clin Oncol 22:258-61, 1999 
 
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Rocke LK, Loprinzi CL, Lee JK, et al: A randomized clinical trial of two different 
durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72:2234-8, 1993 
 
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Factors in the Controlled Clinical Trial. Biometrics 31(1):103-115, 1975 Mar 
 
 


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16.0 MODEL CONSENT FORM 
Study Title for Participants: Testing the use of dexamethasone mouthwash to prevent or 
treat painful mouth sores in patients being treated with everolimus 
 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: Protocol 
Alliance A221701, “Phase III placebo-controlled trial to evaluate dexamethasone use for 
everolimus-induced oral stomatitis: prevention versus early treatment approaches: MIST 
(My Individualized Stomatitis Treatment)”,  
(NCT03839940) 
 
Overview and Key Information  
 
 
What am I being asked to do? 
 
We are asking you to take part in a research study.  We do research studies to try to answer 
questions about how to prevent, diagnose, and treat diseases like cancer; to reduce side effects 
from cancer and cancer treatment and to improve the quality of life of cancer patients. 
 
We are asking you to take part in this study because you have been diagnosed with cancer and 
you will be receiving a drug called everolimus as part of your usual care. It is known that this 
drug can cause painful mouth sores, which can interfere with activities of daily living, including 
eating and drinking. Patients who are not in this study are usually treated for these sores with 
rinses (or mouthwashes) containing different drugs such as lidocaine to numb the pain. Previous 
small studies have shown that dexamethasone can help with treating mouth sores.  This study is 
being done to see if dexamethasone can help prevent getting the mouth sores.  
 
 
Taking part in this study is your choice.  
 
You can choose to take part or you can choose not to take part in this study.  You also can 
change your mind at any time.  Whatever choice you make, you will not lose access to your 
medical care or give up any legal rights or benefits. 
 
This document has important information to help you make your choice. Take time to read it.  
Talk to your doctor, family, or friends about the risks and benefits of taking part in the study.  
It’s important that you have as much information as you need and that all your questions are 
answered.  See the “Where can I get more information?” section for resources for more clinical 
trials and general cancer information. 
 
This study is conducted by the Alliance for Clinical Trials in Oncology, a national clinical 
research group supported by the National Cancer Institute (NCI). The Alliance is made up of 
cancer doctors, health professionals, patient advocates and laboratory researchers, whose goal is 


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to develop better treatments for cancer, to prevent cancer, to reduce side effects from cancer, and 
to improve the quality of life of cancer patients. 
 
 
Why is this study being done? 
 
This study is being done to answer the following question: 
Can we lower the chance of getting painful mouth sores by treating you with a dexamethasone 
mouthwash at the start of your cancer treatment?  
 
We are doing this study to find out if this approach is better or worse than the usual approach for 
preventing painful mouth sores.  The usual approach is defined as care most people get for 
painful mouth sores.  
 
 
What is the usual approach to preventing painful mouth sores?  
The usual approach is to wait until mouth sores develop before they are treated with medications 
that have been approved by the Food and Drug Administration (FDA).   
 
 
What are my choices if I decide not to take part in this study? 
 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different research study, if one is available. 
• You may choose to not get treated.  
 
 
What will happen if I decide to take part in this study? 
 
If you decide to take part in this study, you will either get dexamethasone mouthwash for up to 
eight weeks, or you will get placebo for up to eight weeks, or until you develop mouth pain at 
which time you will be asked to fill a prescription to start a dexamethasone mouthwash.  
During the eight week study period, your doctor will watch you for side effects. 
 
 
 


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What are the risks and benefits of taking part in this study? 
 
There are both risks and benefits to taking part in this study.  It is important for you to think 
carefully about these as you make your decision. 
 
Risks 
 
We want to make sure you know about a few key risks right now.  We give you more 
information in the “What risks can I expect from taking part in this study?” section. 
If you choose to take part in this study, there is a risk that the mouth pain will be worse than it 
would have been otherwise.  
 
There is also a risk that you could have side effects from the dexamethasone mouthwash.  These 
side effects may be worse and may be different than you would get with the usual approach for 
treating mouth sores.   
 
Some of the most common side effects that the study doctors know about are: 
• Increased blood sugars 
• Insomnia 
• Change in energy level 
• Stomach Upset  
 
There may be some risks that the study doctors do not yet know about. 
Benefits 
 
There is evidence that dexamethasone mouthwash is effective in treating mouth sores, so taking 
it before mouth sores start may help prevent you from developing mouth pain. It is not possible 
to know if the mouthwash will prevent your mouth sores as compared to the usual approach.  
This study will help the study doctors learn things that will help other people in the future. 
 
 
If I decide to take part in this study, can I stop later? 
 
Yes, you can decide to stop taking part in the study at any time.  
 
If you decide to stop, let your study doctor know as soon as possible.  If you stop, you can decide 
if you want to keep letting the study doctor know how you are doing. 
 
Your study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
 
 


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Are there other reasons why I might stop being in the study? 
 
Yes.  The study doctor may take you off the study if: 
 
• Your health changes and the study is no longer in your best interest. 
• New information becomes available and the study is no longer in your best interest. 
• You do not follow the study rules. 
• For women: You become pregnant while on the study. 
• The study is stopped by the Institutional Review Board (IRB), Food and Drug 
Administration (FDA), or study sponsor (NCI). The study sponsor is the organization 
who oversees the study.   
 
 
It is important that you understand the information in the informed consent before making 
your decision. Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask your study doctor or nurse. 
 
 
What is the purpose of this study? 
You have cancer and will be receiving everolimus, which may cause painful mouth sores. The 
purpose of this study is to test whether a mouthwash made with a drug called dexamethasone can 
prevent or reduce the pain caused by mouth sores resulting from everolimus treatment. The 
effects of a dexamethasone mouthwash will be compared to a placebo. A placebo is a liquid that 
looks like the study drug but contains no medication.  
 
Dexamethasone has already been approved by the Food and Drug Administration (FDA) to treat 
other disorders. The dexamethasone used in this study is considered investigational, which 
means it has not been approved by the FDA for the use described in this study. There will be 
about 279 people taking part in this study. 
 
 
What are the study groups? 
This study has 2 study groups.  You will not be told which group you are in.  
 
• Group 1  
If you are in this group, you will get dexamethasone mouthwash, which you will swish 
about 2 teaspoons for two minutes in your mouth and spit, four times per day, for eight 
weeks. You should take nothing by mouth for thirty minutes before each mouthwash and 
at least an hour after each mouthwash. However, you may take nystatin for treatment of 
thrush (a fungal infection of the mouth). You will also be asked to complete a daily pain 
log and weekly questionnaires.  It should take about one minute to complete the daily log 
and about five minutes to complete the weekly questionnaire.  
 
There will be about 140 people in this group.  




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What exams, tests, and procedures are involved in this study? 
 
Before you begin the study, your doctor will review the results of your exams, tests, and 
procedures.  This helps your doctor decide if it is safe for you to take part in the study.  If you 
join the study, you will have more exams, tests, and procedures to closely monitor your safety 
and health.  Most of these are included in the usual care you would get even if you were not in a 
study. 
As part of this study, a nurse will call you every week to remind you to complete your forms, 
check on your condition, to follow the effects of study treatment, including managing side 
effects.  
 
Some exams, tests, and procedures are a necessary part of the research study, but would not be 
included in usual care.  Listed below are procedures that will be done for research purposes only. 
 
If you speak English, and choose to take part in this study, you will be asked to fill forms with 
questions about mouth pain and sores, sleep, fatigue and your general quality of life.  Researchers 
will use this information to learn more about how cancer treatment affects people.  
Since these forms are being used for research, the responses you provide will not be shared with 
your study doctor.  If you have any serious health issues or other concerns, please talk with your 
doctor or nurse right away. 
 
You will be asked to fill out forms,  
• before you start treatment 
• every day while you are using the mouthwash you will be asked about your mouth pain 
• every week while you are using the mouthwash and after 8 weeks of using the 
mouthwash you will be asked questions about mouth sores, sleep, fatigue, and your 
general quality of life. 
• You will also receive weekly phone call reminders from your nurse to use your 
mouthwash and complete the forms. The nurse will ask you some additional questions 
about your mouthwash use, your everolimus use, and about the types of food you are 
eating, as well.  
 
The daily pain log will take less than a minute to complete and the weekly forms will take about 
five minutes to complete.  Each phone call will take about five minutes.  You don’t have to 
answer any question that makes you feel uncomfortable. 
 
What risks can I expect from taking part in this study? 
General Risks 
If you choose to take part in this study, there is a risk that the study approach may not be as good 
as the usual approach at preventing or treating your painful mouth sores.  
You also may have the following discomforts: 
 
• Spend more time in the hospital or doctor’s office. 


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• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
 
The medications used in this study could be very harmful to an unborn or newborn baby.  There 
may be some risks that doctors do not yet know about.  It is very important that you check with 
your study doctor about what types of birth control or pregnancy prevention to use during the 
study. 
 
Side Effect Risks 
 
The drug used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood.  The study doctor will test your blood and let you know if changes 
occur that may affect your health. 
 
There is also a risk that you could have other side effects from the study drug.  
 
Here are important things to know about side effects: 
 
1. The study doctors do not know who will or will not have side effects. 
2. Some side effects may go away soon, some may last a long time, and some may never go 
away. 
 
You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
Drug Risks 
 
The table below shows the most common and most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of DEXAMETHASONE Mouthwash  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving DEXAMETHASONE, from 4 to 20 may have: 
• Fungal infection (termed thrush when it is in the mouth or throat) 
• Irritability 
• Insomnia 
• Changes in energy 
• High blood sugars 
• Stomach Upset  


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Additional Drug Risks 
 
Rarely, there are problems getting enough supplies of the study drug.  If that happens, your 
doctor will talk with you about your options. 
 
What are my responsibilities in this study? 
 
If you choose to take part in this study you will need to: 
 
• Keep your study appointments. 
• Tell your doctor about: 
o all medications and supplements you are taking 
o any side effects  
o any doctors’ visits or hospital stays outside of this study  
o if you have been or are currently in another research study. 
• Fill out forms  
 
For women: Do not get pregnant or breastfeed while taking part in this study. Tell your study 
doctor right away if you think that you have become pregnant during the study.  
 
What are the costs of taking part in this study? 
You and/or your insurance plan will need to pay for the costs of medical care you get as part of 
the study, just as you would if you were getting the usual care for taking everolimus.  This 
includes: 
 
• the costs of tests, exams, procedures, and drugs that you get during the study to monitor 
your safety, and prevent and treat side effects.   
• your insurance co-pays and deductibles. 
 
Talk to your insurance provider and make sure that you understand what your insurance pays for 
and what it doesn’t pay for if you take part in this clinical trial.  Also, find out if you need 
approval from your plan before you can take part in the study.  
 
Ask your doctor or nurse for help finding the right person to talk to if you are unsure which costs 
will be billed to you or your insurance provider.  
 
You or your insurance provider will not have to pay for the study medication that is provided as 
part of the study. However, if you develop painful mouth sores and fill the prescription for 
dexamethasone mouthwash, this will be billed to you and your insurance company.  
You will not be paid for taking part in this study.  The research may lead to new tests, drugs, or 
other products for sale.  If it does, you will not get any payment. 
 


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What happens if I am injured because I took part in this study? 
If you are injured as a result of taking part in this study and need medical treatment, please talk 
with your study doctor right away about your treatment options.  The study sponsors will not pay 
for medical treatment for injury.  Your insurance company may not be willing to pay for a study-
related injury.  Ask them if they will pay.  If you do not have insurance, then you would need to 
pay for these medical costs. 
 
If you feel this injury was caused by medical error on the part of the study doctors or others 
involved in the study, you have the legal right to seek payment, even though you are in a study.  
Agreeing to take part in this study does not mean you give up these rights. 
 
Who will see my medical information? 
 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The 
study doctors have a privacy permit to help protect your records if there is a court case.  
However, some of your medical information may be given out if required by law.  If this should 
happen, the study doctors will do their best to make sure that any information that goes out to 
others will not identify who you are.  
 
Some of your health information, such as your response to cancer treatment, results of study 
tests, and medicines you took, will be kept by the study sponsor in a central research database. 
However, your name and contact information will not be put in the database.  If information 
from this study is published or presented at scientific meetings, your name and other personal 
information will not be used.  
 
There are organizations that may look at your study records.  Your health information in the 
research database also may be shared with these organizations.  They must keep your 
information private, unless required by law to give it to another group.  
 
Some of these organizations are: 
 
• The Alliance for Clinical Trials in Oncology 
• The IRB, which is a group of people who review the research with the goal of protecting 
the people who take part in the study. 
• The FDA and the groups it works with to review research. 
• The NCI and the groups it works with to review research. 
 
 
Where can I get more information? 
You may visit the NCI web site at http://cancer.gov/ for more information about studies or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  Contact the study doctor (*insert name of study doctor[s]*) at 
(*insert telephone number, and email address if appropriate*). 
 
For questions about your rights while in this study, call the (*insert name of organization or 
center*) Institutional Review Board at (*insert telephone number*).  
 
 
Optional studies that you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in.  They 
are separate from the main study described above.  These optional studies will not benefit your 
health.  The researchers leading this optional study hope the results will help other people with 
cancer in the future. The results will not be added to your medical records and you or your study 
doctor will not know the results. 
 
Taking part in this optional study is your choice.  You can still take part in the main study even if 
you say “no” to this study.  There is no penalty for saying “no.” You and your insurance 
company will not be billed for this optional study.  If you sign up for, but cannot complete this 
study for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for the following study. 
 
Optional sample collections for known laboratory studies and/or storage for 
possible future studies 
Researchers are trying to learn more about cancer and other health problems using blood and 
tissue samples from people who take part in clinical trials.  By studying these samples, 
researchers hope to find new ways to prevent, detect, treat, or cure diseases. 
 
Some of these studies may be about how genes affect health and disease.  Other studies may look 
at how genes affect a person’s response to treatment.  Genes carry information about traits that 
are found in you and your family.  Examples of traits are the color of your eyes, having curly or 
straight hair, and certain health conditions that are passed down in families.  Some of the studies 
may lead to new products, such as drugs or tests for diseases. 
 
 


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Known future studies 
 
If you choose to take part in the optional studies, researchers will collect two teaspoons of blood 
before you start study treatment, for research on why people have different side effects from the 
treatment. For this study, your blood will be sent to the Alliance biorepository at Mayo Clinic 
with your initials and collection date on it. These initials will be removed along with other 
identifiers before the researchers analyze the samples. Please see the “How will information 
about me be kept private” section below.  
 
In addition, one teaspoon of blood will also be collected before you start study treatment, at your 
4 week clinic visit and at your 8 week clinic visit for research on how the study drug changes in 
your body over time and if  that can change your side effects. If you are not scheduled to come 
back for a 4 week visit, you don’t need to provide this sample. You will also complete a form 
every time blood is collected for this research. It will take less than five minutes to complete this 
form. For this study, your blood will be sent to researchers at the University of Pittsburgh Cancer 
Center with your initials and collection date on it.  
 
 
What is involved in this optional sample collection? 
 
If you agree to take part, here is what will happen next: 
 
1. About a total of five teaspoons of blood will be collected from a vein in your arm.   
2. Your sample will be stored in the biobank.  There is no limit on the length of time we will 
keep your samples and research information.  The samples will be kept until they are 
used for research or destroyed. 
3. Researchers can only get samples from the biobank after their research has been 
approved by experts. Researchers will not be given your name or contact information. 
4. Some of your genetic and health information may be placed in central databases for 
researchers to use.  The databases will not include your name or contact information. 
 
 
What are the risks in this optional sample collection? 
• The most common risks related to drawing blood from your arm are brief pain and maybe 
a bruise.   
• Your medical and genetic information is unique to you.  There is a risk that someone 
outside of the research study could get access to your study records or trace information 
in a database back to you.  They could use that information in a way that could harm you.  
Researchers believe the chance that someone could access and misuse your information is 
very small.  However, the risk may increase in the future as people find new ways of 
tracing information.  
• In some cases, this information could be used to make it harder for you to get or keep a 
job and get or keep health insurance. 
 


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How will information about me be kept private? 
 
Your privacy is very important to the study researchers and biobank.  They will make every 
effort to protect it.  Here are just a few of the steps they will take: 
 
 
1. They will remove identifiers, such as your initials, from your sample and information.   
They will replace them with a code number.  There will be a master list linking the code 
numbers to names, but they will keep it separate from the samples and information. 
2. Researchers who study your sample and information will not know who you are.   They 
also must agree that they will not try to find out who you are. 
3. Your personal information will not be given to anyone unless it is required by law.  
4. If research results are published, your name and other personal information will not be 
used. 
 
 
What are the benefits to taking part in this optional sample collection? 
 
You will not benefit from taking part. 
 
The researchers, using the samples from you and others, might make discoveries that could help 
people in the future. 
 
 
Are there any costs or payments to this optional sample collection? 
 
There are no costs to you or your insurance.  You will not be paid for taking part in this study.  
The research may lead to new tests, drugs, or other products for sale.  If it does, you will not get 
any payment. 
 
 
 


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What if I change my mind about this optional sample collection? 
If you decide you no longer want your samples to be used, you can call the study doctor, (*insert 
name of study doctor for main trial*), at (*insert telephone number of study doctor for main 
trial*), who will let the biobank know.  Then, any sample that remains in the biobank will be 
destroyed or returned to your study doctor.  This will not apply to any samples or related health 
information that have already been given to or used by researchers. 
 
 
What if I have questions about this optional sample collection? 
If you have questions about the use of your samples for research, contact the study doctor, 
(*insert name of study doctor for main trial*), at (*insert telephone number of study doctor for 
main trial*). 
 
 
Please circle your answer below to show if you would or would not like to take part in each 
optional study: 
 
Samples for known future studies: 
 
I agree that my samples and related health information may be used for the laboratory study 
described above. 
 
 
YES 
 
NO 
 
Contact for Future Research 
 
I agree that my study doctor, or someone on the study team, may contact me or my doctor to see 
if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 
My signature agreeing to take part in the study 
 
 
I have read this consent form or had it read to me.  I have discussed it with the study doctor and 
my questions have been answered.  I will be given a signed and dated copy of this form.  I agree 
to take part in the main study.  I also agree to take part in any additional studies where I circled 
“yes”. 
 
 


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Participant’s signature 
 
 
 
 
Date of signature 
 
 
 
 
Signature of person(s) conducting the informed consent discussion 
 
 
 
 
Date of signature 
  
 
 
 


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APPENDIX I 
PATIENT QUESTIONNAIRE 
 
PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet (Baseline) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
1. This booklet is to be completed day 1 during your clinic visit prior to treatment. 
 
2. The booklet contains 2 set of questions: 
a. PRO-CTCAE  
b. Numerical Analogue Mouth Pain Scale  
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. Please return your booklet when you are finished. 
 
 
Thank you for taking the time to help 
 
 


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PATIENT INFORMATION SHEET 
TREATMENT 
Patient Completed Quality of Life Booklet (Weekly) 
________________________________________________________________________ 
 
You have been given a booklet to complete for this study.  The booklet contains some questions 
about your ‘quality of life’ as a patient receiving treatment for cancer.  Your answers will help us to 
better understand how the treatment you are receiving is affecting the way you feel. 
 
1. This booklet is to be completed every day for one week, starting on the first day of study 
treatment. You will be asked to record your mouth pain every day and to complete a 
questionnaire at the end of the week.  Please answer the mouth pain question at the same time 
each day, preferably in the evening.  
 
2. The booklet contains 2 groups of questions: 
TO BE COMPLETED DAILY: 
a. Numerical Analogue Mouth Pain Scale  
 
TO BE COMPLETED AT THE END OF THE WEEK: 
b. Numerical Analogue Self-Assessment 
c. PRO-CTCAE 
d. Patient Reported Mouthwash Use Frequency 
 
3. Directions on how to complete this set of questions are written on the top of the page. 
 
4. You may call a member of the study team to answer any questions you might have.  You will be 
given a name and telephone number.  You can call anytime with any concerns or questions. A 
nurse/research coordinator will also call you once a week and they can answer questions you 
might have.  
 
5. It is very important that you return the booklet to us, whether you finish the study or not. 
 
6. Please mail your completed booklet at the end of the week in the stamped pre-addressed 
envelope.  
 
 
Thank you for taking the time to help 
 
 


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APPENDIX II 
NUMERICAL ANALOGUE MOUTH PAIN SCALE  
Please circle the number that best reflects your response to the following question during the past 24 
hours. 
Which number represents the worst severity of your mouth pain over the past 24 hours that 
you think was caused by your cancer medication? 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
Day ______ 
0           1            2             3             4             5             6            7             8             9             10 
(No pain)                                                                                                          (pain as bad as it can be) 
 
 


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APPENDIX III NUMERICAL ANALOGUE SELF-ASSESSMENT 
Directions: Please circle the number (0-10) best reflecting your response to the following 
question that describes your feelings during the past week, including today. 
1. During the past week, including today, how would you describe your overall Quality of 
Life? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
 
 
 
 
 
 
 
 
it can be 
 
 


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APPENDIX IV PRO-CTCAE 
PRO-CTCAE Mouth/throat sore items: 
1. 
In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at 
their WORST: 
 
None / Mild / Moderate / Severe / Very severe 
 
2. 
In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your 
usual or daily activities: 
 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
PRO-CTCAE- Sleep Items  
1.  
In the last 7 days, what was the SEVERITY of your INSOMNIA (INCLUDING 
DIFFICULTY FALLING ASLEEP, STAYING ASLEEP, OR WAKING UP EARLY) at 
its WORST: 
None / Mild / Moderate / Severe / Very severe 
2.  
In the last 7 days, how much did INSOMNIA (INCLUDING DIFFICULTY FALLING 
ASLEEP, STAYING ASLEEP, OR WAKING UP EARLY)  INTERFERE with your 
usual or daily activities: 
Not at all / A little bit / Somewhat / Quite a bit / Very much 
PRO-CTCAE Fatigue items: 
1. 
In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR 
LACK OF ENERGY at its WORST: 
 
None / Mild / Moderate / Severe / Very severe 
 
2. 
In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY 
INTERFERE with your usual or daily activities: 
 
  
Not at all / A little bit / Somewhat/ Quite a bit / Very much 
 
 


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APPENDIX V 
PATIENT REPORTED MOUTHWASH USE FREQUENCY 
The first question below relates to how often you took the original study mouthwash that you 
were assigned when you started this study.  Please skip this question if you are no longer taking 
the original study mouthwash that you were assigned when you started this study. 
 
1. 
If you are still taking the study mouthwash, how many doses did you take over the last 
week, understanding that you would have taken 28 doses if you did not miss any doses: 
A.__28 
B.__21-27 
C.__14-20 
D.__<14 
 
2. 
Did you fill the optional dexamethasone prescription at a pharmacy and start using it? 
 
No 
 
Yes—if yes, what date did you first use this:  __/___/______ 
 
3. 
If you are using the optional dexamethasone, are you using it every day or as needed?  
________ 
 
4. 
If you are using the optional dexamethasone, how many times a day are you using it? 
__________  
 
5. 
Are you still taking the everolimus? Y/N   
 
6. 
If yes, how many milligrams per day (understanding that all patients started at 10 
mg/day)?   __ mg 
 
If less than 10mg/day, why was the dose decreased? 
______________________________________________________________________________
______ 
 
 


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APPENDIX VI NURSE WEEKLY PHONE CALL ASSESSMENT SCRIPT  
Hello, this is _________ , a nurse from the _________study.  
How are you? 
Do you have any questions about this study? 
Are you still filling out your forms every day?  Did you mail last week’s booklet to your clinic?  
Are you still taking the everolimus? Y/N  ; If yes, how many milligrams per day? ___MG;__If 
less than 10mg, why did you decrease the dose? _________________ 
Are you still taking the study mouthwash?  Y/N  ;If yes, approximately how many times per day?  
___ ; Approximately how many doses did you take in the last week? (prompting with the total 
number of expected doses being 28) ___  
Did you fill the optional additional dexamethasone prescription at the pharmacy? Y/N  ;If so, 
have you started to take it? Y/N  ;What date did you take your first dose? DATE  ;If you are 
using the optional dexamethasone, are you using it every day or as needed. How many times a 
day?  ___ ; Remind the patient that, if she/he is now taking the prescription dexamethasone, 
she/he should not be taking the study mouthwash any more.  
Information to inform clinician-grading: Are you having any trouble with any of the following 
(asking follow-up questions to grade): 
A white coating on your tongue or throat; 2) high blood sugars; 3) irritability; 4) fatigue; 5) 
difficulty sleeping; 6) mouth or throat sores or pain  
If the nurse has suspicion for thrush, have patient evaluated and/or start an antifungal medication. 
 
 


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APPENDIX VII  
NORMALCY OF DIET SCALE  
What kind of foods have you been eating?  What foods are difficult to eat?  (Nurse will ask about 
the specific options below.  If the patient initially reports that s/he is eating everything, nurse will 
start with those scored 50 and move up until the patient cannot eat a category of food, and then 
will select the highest score of the category of food the patient can eat from the below options): 
 
100:Full diet (no restrictions) 
90: Full diet (liquid assist) 
80: All meat 
70: Raw carrots, celery 
60: Dry bread and crackers 
50: Soft chewable foods (e.g., macaroni, canned/soft fruits, cooked vegetables, fish, hamburger, 
small pieces of meat) 
40: Soft foods requiring no chewing (e.g., mashed potatoes, apple sauce, pudding) 
30: Pureed foods (in blended) 
20: Warm liquids 
10: Cold liquids 
0 
Non-oral feeding (tube fed) 
 
 


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APPENDIX VIII  PHARMACOKINETICS PATIENT QUESTIONNAIRE 
Please advise patient not take their Everolimus dose prior to the clinic visit at Week 4 and Week 8. 
Note:  This form is to be completed for the following blood draw time points associated with the 
pharmacokinetic sub study A221701-PP1: Week 4 and Week 8.   
 
Date:  
 
The following questions refer to the day before yesterday (2 days ago):  
What time did you take your study medication (everolimus)? _ _ : _ _ AM / PM  
What time did you last eat before taking your study medication (everolimus)? _ _ : _ _ AM / PM  
What time did you first eat after taking your study medication (everolimus)? _ _ : _ _ AM / PM  
 
The following questions refer to yesterday (1 day ago):  
What time did you take your study medication (everolimus)? _ _ : _ _ AM / PM  
What time did you last eat before taking your study medication (everolimus)? _ _ : _ _ AM / PM  
What time did you first eat after taking your study medication (everolimus)? _ _ : _ _ AM / PM  
 
The following questions refer to today (ONLY APPLIES IF YOU HAVE TAKEN YOUR STUDY 
MEDICATION BEFORE BEING SEEN IN THE CLINIC TODAY):  
What time did you take your study medication (everolimus)? _ _ : _ _ AM / PM  
What time did you last eat before taking your study medication (everolimus)? _ _ : _ _ AM / PM  
What time did you first eat after taking your study medication (everolimus)? _ _ : _ _ AM / PM  
 
 
 


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APPENDIX IX PATIENT INSTRUCTION SHEET  
Dexamethasone  
(dex-a-METH-a-sone) 
 
How to take the mouthwash:  
• Shake solution well before use.  
• Swish about 2 teaspoons (10 cc) in your mouth and spit, four times a day, for eight 
weeks. Do not swallow.   
• You should take nothing by mouth for thirty minutes before each mouthwash and at 
least an hour after each mouthwash. However, you may take nystatin for treatment of 
thrush (a fungal infection of the mouth).  
 
Where to store your medication:  
• Store the medication in a closed container at room temperature, away from heat, 
moisture, and direct light.  The expiration date will be printed on the bottle. Please 
do not use the medication after this date.  
• Keep medication out of the reach of children. 
 
Foods to avoid:  
• Please avoid eating foods with high acid content, limit alcohol and caffeine intake as 
these food items can irritate the mouth further.  
 
Possible side effects: 
• Increased blood sugars 
• Insomnia 
• Change in energy level 
• Stomach Upset  
 
 
When to call your doctor:  
• If you experience mood or behavioral changes (i.e. depression, euphoria, insomnia, 
psychosis) 
• If you experience frequent, unrelenting headaches or visual changes  
• If you experience symptoms of a gastric ulcer 
o You may use antacids for symptoms of symptoms of gastric ulcer, heartburn 
or gastritis. If the antacids don’t control these symptoms, call your doctor.  
• If you experience easy bruising   
If you notice other side effects that you think are caused by this medication, tell your doctor.