Advanced Breast Cancer
Conditions
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
Interventions
DRUGDexamethasone based mouthwash
Dexamethasone steroid-based oral solution, comprised of 0.5 milligrams per 5mL of alcohol-free dexamethasone.
DRUGEverolimus
Commercially available everolimus 10 mg was prescribed to participants by the Investigator according to local regulations.
DRUGExemestane
Commercially available exemestane 25 mg was prescribed to participants by the Investigator according to local regulations.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Stomatitis Grade ≥ 2 | 56 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Resolution of Stomatitis From Grade 2 or Greater to Grade 1 or Less | 56 days | 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. |
| Median Number of Mouthwashes Per Day | 56 days | The median number of mouthwashes per day was assessed. |
| Number of Participants With All Grades of Stomatitis | 56 days | 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. |
| Dose Intensity of Everolimus and Exemestane | 56 days | 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. |
| Blood Concentration of Everolimus and Exemestane | 28 days (pre-dose) | Blood samples were collected and analyzed. |
Countries
United States
Participant flow
Pre-assignment details
A total of 92 participants were enrolled into the study and received study treatments of everolimus and exemestane. Of these, 86 participants were confirmed to have also received the investigational treatment of dexamethasone steroid mouthwash and comprised the full analysis set (FAS). The patient disposition is based on the FAS.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 86 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal laboratory values | 1 |
| Overall Study | Administrative problems | 1 |
| Overall Study | Adverse Event | 10 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 14 |
| Overall Study | New cancer therapy | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Dexamethasone Based Mouthwash |
|---|---|
| Age, Continuous | 61.02 Years STANDARD_DEVIATION 10.921 |
| Sex/Gender, Customized Female | 86 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 72 / 92 |
| serious Total, serious adverse events | 20 / 92 |
Outcome results
Primary
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.
Time frame: 56 days
Population: Full analysis set (FAS): The FAS consisted of all participants who received at least one dose of study treatment (everolimus and/or exemestane) and at least one dose of investigational treatment (dexamethasone mouth wash).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dexamethasone Based Mouthwash | Number of Participants With Stomatitis Grade ≥ 2 | Stomatitis grade >=2: Yes | 2 Participants |
| Dexamethasone Based Mouthwash | Number of Participants With Stomatitis Grade ≥ 2 | Stomatitis grade >=2: No | 83 Participants |
| Dexamethasone Based Mouthwash | Number of Participants With Stomatitis Grade ≥ 2 | Stomatitis grade >=2: Not evaluable | 1 Participants |
Comparison: A test of the incidence rate R was performed with null hypothesis H0: R\>= 0.33 and alternative hypothesis Ha: R\<0.33 with a one-sided significance level of 0.05. If the test statistic was negative (actual incidence rate was \<0.33), the one-sided p-value for the null hypothesis R\>=0.33 was presented. The null hypothesis was rejected if the statistic was negative and the corresponding p-value for the one-sided test was \<0.5.p-value: <0.001Incidence rate R
Secondary
Blood Concentration of Everolimus and Exemestane
Blood samples were collected and analyzed.
Time frame: 28 days (pre-dose)
Population: The PK analysis set, which was a subset of the FAS, was considered for the analysis. However, only participants who had evaluable data were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dexamethasone Based Mouthwash | Blood Concentration of Everolimus and Exemestane | Everolimus (n=42) | 12.047 ng/mL | Geometric Coefficient of Variation 56.492 |
| Dexamethasone Based Mouthwash | Blood Concentration of Everolimus and Exemestane | Exemestane (n=48) | 0.657 ng/mL | Geometric Coefficient of Variation 234.578 |
Secondary
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.
Time frame: 56 days
Population: FAS: The FAS consisted of all participants who received at least one dose of study treatment (everolimus and/or exemestane) and at least one dose of investigational treatment (dexamethasone mouth wash).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dexamethasone Based Mouthwash | Dose Intensity of Everolimus and Exemestane | Exemestane | 25.0 mg/day |
| Dexamethasone Based Mouthwash | Dose Intensity of Everolimus and Exemestane | Everolimus | 10.0 mg/day |
Secondary
Median Number of Mouthwashes Per Day
The median number of mouthwashes per day was assessed.
Time frame: 56 days
Population: FAS: The FAS set consisted of all participants who received at least one dose of study treatment (everolimus and/or exemestane) and at least one dose of investigational treatment (dexamethasone mouth wash).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexamethasone Based Mouthwash | Median Number of Mouthwashes Per Day | 3.95 Number of mouthwashes |
Secondary
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.
Time frame: 56 days
Population: The FAS, consisting of all participants who received at least one dose of study treatment (everolimus and/or exemestane) and at least one dose of investigational treatment (dexamethasone mouth wash), was considered for the analysis. However, only those participants, who were evaluable for stomatitis grade, were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dexamethasone Based Mouthwash | Number of Participants With All Grades of Stomatitis | Stomatitis all grade | 18 Participants |
| Dexamethasone Based Mouthwash | Number of Participants With All Grades of Stomatitis | Not evaluable | 1 Participants |
Secondary
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.
Time frame: 56 days
Population: FAS: The FAS consisted of all participants who received at least one dose of study treatment (everolimus and/or exemestane) and at least one dose of investigational treatment (dexamethasone mouth wash).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexamethasone Based Mouthwash | Time to Resolution of Stomatitis From Grade 2 or Greater to Grade 1 or Less | NA Days |