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

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

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

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Dexamethasone based mouthwash; Drug: Everolimus; Drug: Exemestane

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group Highlands Oncology Group (22)
  • California
    • Anaheim, California, United States, 92807
      • Kaiser Permanente Medical Group Kaiser Permanente-Moanalua M.C
    • Los Angeles, California, United States, 90017
      • Los Angeles Hematology/Oncology Medical Group
    • Los Angeles, California, United States, 90095-6956
      • University of California at Los Angeles UCLA and TRIO Network
    • Orange, California, United States, 92868
      • University of California Irvine UC Irvine Medical Center
    • San Francisco, California, United States, 94101
      • University of California San Francisco UCSF Medical Center
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center SC
  • Connecticut
    • Farmington, Connecticut, United States, 06030-3940
      • University of Connecticut Health Center
  • Georgia
    • Newnan, Georgia, United States, 30265
      • Southeastern Regional Medical Center
  • Hawaii
    • Aiea, Hawaii, United States, 96701
      • OnCare Hawaii
  • Illinois
    • Evanston, Illinois, United States, 60201
      • North Shore University Health System NorthShore University
    • Park Ridge, Illinois, United States, 60068-0736
      • Oncology Specialists, SC Onc Specialists
  • Maryland
    • Baltimore, Maryland, United States, 21201-1559
      • University of Maryland School of Medicine University of Maryland
    • Rockville, Maryland, United States, 20850
      • Kaiser Permanente - Mid Atlantic Permanete Research Institut Kaiser Permanente Mid-Atlantic
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Karmanos Cancer Institute (2)
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital/Marion Bloch Neuroscience Institute Cancer Institute
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08003
      • Regional Cancer Care Associates Cancer and Hematologic Disease
    • Morristown, New Jersey, United States, 07962
      • Hematology Oncology Associates of Northern New Jersey PA DeptofHem-OncofNorthern NJ (2)
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • M. Francisco Gonzalez, MD.PA Hematology Oncology Center
  • Texas
    • Houston, Texas, United States, 77024
      • Oncology Consultants Oncology Consultants, P.A.
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(2)
  • Virginia
    • Portsmouth, Virginia, United States, 23704
      • Delta Oncology Associates Delta Hematology/Oncology
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties Northwest Medical - Puyallup

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Adult women > 18 years of age with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy
2. Histological or cytological confirmation of hormone-receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer

3. 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
4. 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
5. Patient must start everolimus 10mg plus exemestane 25mg treatment on Cycle 1 Day 1 of trial
6. ECOG Performance status ≤ 2
7. Adequate renal function: serum creatinine ≤ 1.5x ULN;
8. 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
9. Signed informed consent obtained prior to any screening procedure

Exclusion criteria:

1. Patients currently receiving anticancer therapies (except biphosphonate, denosumab);
2. Patients who currently have stomatitis/oral mucositis/mouth ulcers;
3. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus);
4. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus;
5. 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;

6. 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;
7. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed;
8. Known history of HIV seropositivity;
9. 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;
10. 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;
11. 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;
12. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dexamethasone based mouthwash; 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; Dexamethasone steroid-based oral solution, comprised of 0.5 milligrams per 5mL of alcohol-free dexamethasone.; Drug: Everolimus; Commercially available everolimus 10 mg was prescribed to participants by the Investigator according to local regulations.; Drug: Exemestane; Commercially available exemestane 25 mg was prescribed to participants by the Investigator according to local regulations.

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)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Niikura N, Nakatukasa K, Amemiya T, Watanabe KI, Hata H, Kikawa Y, Taniike N, Yamanaka T, Mitsunaga S, Nakagami K, Adachi M, Kondo N, Shibuya Y, Hayashi N, Naito M, Kashiwabara K, Yamashita T, Umeda M, Mukai H, Ota Y. Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial. Oncologist. 2020 Feb;25(2):e223-e230. doi: 10.1634/theoncologist.2019-0382. Epub 2019 Oct 8.
• Niikura N, Nakatukasa K, Amemiya T, Watanabe KI, Hata H, Kikawa Y, Taniike N, Yamanaka T, Mitsunaga S, Nakagami K, Adachi M, Kondo N, Shibuya Y, Hayashi N, Naito M, Kashiwabara K, Yamashita T, Umeda M, Mukai H, Ota Y. Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial. Oncologist. 2019 Oct 8:theoncologist.2019-0382. doi: 10.1634/theoncologist.2019-0382. Online ahead of print.
• Rugo HS, Seneviratne L, Beck JT, Glaspy JA, Peguero JA, Pluard TJ, Dhillon N, Hwang LC, Nangia C, Mayer IA, Meiller TF, Chambers MS, Sweetman RW, Sabo JR, Litton JK. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 2017 May;18(5):654-662. doi: 10.1016/S1470-2045(17)30109-2. Epub 2017 Mar 15.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: February 20, 2014
• First Submitted That Met QC Criteria: February 20, 2014
• First Posted (Estimate): February 21, 2014

Study Record Updates

• Last Update Posted (Actual): February 13, 2017
• Last Update Submitted That Met QC Criteria: December 20, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Stomatognathic Diseases; Mouth Diseases; Breast Neoplasms; Stomatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Dexamethasone; Everolimus; Exemestane
• Other Study ID Numbers: CRAD001JUS226