Open-label, Phase II Study of Stomatitis Prevention With a Steroid-based Mouthwash in Post-menopausal Women With Estrogen-receptor-positive (ER+), Human Epidermal Growth Factor Receptor 2 (HER2)- Metastatic or Locally Advanced Breast Cancer

Study Overview
=================
Brief Summary
-----------------
Open-label, Phase II study of Stomatitis prevention with a steroid-based mouthwash in Post-menopausal women with ER+, HER2- Metastatic or Locally Advanced Breast Cancer

Official Title
-----------------
A Phase II, Single Arm Study of the Use of Steroid-based Mouthwash to Prevent Stomatitis in Postmenopausal Women With Advanced or Metastatic Hormone Receptor Positive Breast Cancer Being Treated With Everolimus Plus Exemestane

Conditions
-----------------
Advanced Breast Cancer

Intervention / Treatment
-----------------
* Drug: Dexamethasone based mouthwash
* Drug: Everolimus
* Drug: Exemestane


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult women > 18 years of age with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy Histological or cytological confirmation of hormone-receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer Postmenopausal women. Postmenopausal status is defined either by: Age ≥ 55 years and one year or more of amenorrhea Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml Surgical menopause with bilateral oophorectomy Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression Patient has been assessed by treating physician to be appropriate candidate for everolimus plus exemestane therapy as treatment of advanced or metastatic breast cancer and plans to prescribe everolimus 10mg PO QD in combination with exemestane 25mg PO QD Patient must start everolimus 10mg plus exemestane 25mg treatment on Cycle 1 Day 1 of trial ECOG Performance status ≤ 2 Adequate renal function: serum creatinine ≤ 1.5x ULN; Willingness to self-report level of oral pain using Visual Analog Scale (VAS) and the Normalcy Diet Scale (NDS) throughout each stomatitis event, as required in the patient diary. At baseline, patient's self-reported oral pain level, using VAS, must be 0 and the normalcy diet scale score should ≥ 60 Signed informed consent obtained prior to any screening procedure Exclusion criteria: Patients currently receiving anticancer therapies (except biphosphonate, denosumab); Patients who currently have stomatitis/oral mucositis/mouth ulcers; Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus); Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus; Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary; Patients who have any severe and/or uncontrolled medical conditions such as: Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease Symptomatic congestive heart failure of New York heart Association Class III or IV active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease (except for Hep B and Hep C positive patients) Known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air) active, bleeding diathesis; Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed; Known history of HIV seropositivity; Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines; Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for ≥3 years; Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study or patient diaries; Patients who are currently part of any clinical investigation or who has not had resolution of all acute toxic effects or prior anti-cancer therapy to NCI CTCAE version 4.03 Grade 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexamethasone based mouthwash<br>Participants swished and spat 10mL of 0.5mg/5mL dexamethasone steroid mouthwash (investigational treatment) 4 times daily (qid) orally for 2 minutes each for 8 weeks. Participants remained without food or drink (NPO) for one hour after administration of the mouthwash. Also, participants received everolimus 10 mg and exemstane 25 mg (study treatments) according to local regulations. | Drug: Dexamethasone based mouthwash<br>* Dexamethasone steroid-based oral solution, comprised of 0.5 milligrams per 5mL of alcohol-free dexamethasone.<br>Drug: Everolimus<br>* Commercially available everolimus 10 mg was prescribed to participants by the Investigator according to local regulations.<br>Drug: Exemestane<br>* Commercially available exemestane 25 mg was prescribed to participants by the Investigator according to local regulations.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Stomatitis Grade ≥ 2 | The incidence of grade ≥ 2 stomatitis was reported. Grade 1 = minimal symptoms, normal diet; grade 2 = symptomatic, but able to swallow a modified diet; grade 3 = symptomatic and unable to aliment or hydrate orally; and grade 4 = symptoms associated with life-threatening consequences. | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Resolution of Stomatitis From Grade 2 or Greater to Grade 1 or Less | The number of days to achieve resolution of stomatitis from grade 2 or greater to grade 1 or less was assessed. Grade 1 = minimal symptoms, normal diet; grade 2 = symptomatic, but able to swallow a modified diet; grade 3 = symptomatic and unable to aliment or hydrate orally; and grade 4 = symptoms associated with life-threatening consequences. | 56 days | 
| Median Number of Mouthwashes Per Day | The median number of mouthwashes per day was assessed. | 56 days | 
| Number of Participants With All Grades of Stomatitis | The number of participants with all grades of stomatitis was defined as the number of participants who had stomatitis grade 1 or higher. Grade 1 = minimal symptoms, normal diet; grade 2 = symptomatic, but able to swallow a modified diet; grade 3 = symptomatic and unable to aliment or hydrate orally; and grade 4 = symptoms associated with life-threatening consequences. | 56 days | 
| Dose Intensity of Everolimus and Exemestane | The dose intensity was calculated as the cumulative dose of everolimus or exemestane divided by the length of time on treatment during the first 56 days of treatment. | 56 days | 
| Blood Concentration of Everolimus and Exemestane | Blood samples were collected and analyzed. | 28 days (pre-dose) |