Dexamethasone in Reducing Everolimus-Induced Oral Stomatitis in Patients With Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase III Placebo-Controlled Trial to Evaluate Dexamethasone Use for Everolimus-Induced Oral Stomatitis: Prevention Versus Early Treatment Approaches: MIST (My Individualized Stomatitis Treatment)

Conditions
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Malignant Neoplasm

Intervention / Treatment
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* Drug: Dexamethasone
* Other: Placebo
* Other: Questionnaire
* Other: Quality-of-Life Assessment
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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. Patients should not receive any other agent which would be considered treatment for stomatitis or impact the primary endpoint. No history of candida infection (thrush) within the last 3 months. Not currently being treated with corticosteroids. No uncontrolled diabetes mellitus, defined by hemoglobin A1C greater than 8%, although A1C is not needed for all patients, hemoglobin (Hgb)A1C < 8 is required for everyone with diabetes or suspected diabetes. Patients must be able to read and comprehend English. Local translation, including verbal translation of professionals (PROs) is not permitted. 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. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (dexamethasone)<br>Patients receive 10mg oral everolimus daily as standard of care and 10ml dexamethasone oral mouthwash, swished for 2-minutes daily, for 8 weeks. | Drug: Dexamethasone<br>* Given as mouthwash<br>Other: Questionnaire<br>* Ancillary studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Drug: Everolimus<br>* Standard of care<br>|
| Placebo Comparator: Group II (placebo)<br>Patients receive 10mg oral everolimus daily as standard of care and 10ml placebo oral mouthwash, swished for 2-minutes daily, for 8 weeks. | Other: Placebo<br>* Given as mouthwash<br>Other: Questionnaire<br>* Ancillary studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>Drug: Everolimus<br>* Standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of the mTOR Inhibitor-associated Stomatitis (mIAS)-Related Pain Based on Daily Self-reports Via the Numerical Analogue Scale | The numerical analogue mouth pain score (NAMPS) is a single item measured on a 0 to 10 scale, with 0 corresponding to No pain and 10 corresponding to Pain as bad as it can be. Will compare the incidence rate of any mouth pain (i.e., any score greater than 0) as assessed by the NAMPS between the prevention versus early treatment approaches using a Chi-square test. | Up to 8 weeks | 
| Severity of Mouth Pain Scores | Average Area Under the Curve per assessment (aAUCpa) of mouth pain scores as measured by NAMPS will be computed for each patient to summarize the sequence of numerical analogue mouth pain scores over the eight week study period. Scores are reported on a 0-100 scale, where 100 = better outcome QOL (i.e. less pain). The aAUCpa is the average of each AUC between each sequential assessment from treatment-initiation to the end of the treatment at 8 weeks post-treatment-initiation and will be compared between the two treatment arms. | Up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Grade > 2 mIAS as Measured by the SWISH Trial | Original plan for collecting and analyzing this data did not occur due to study termination. Grade 2 mIAS is defined as having at least one of the following criteria:> Oral intake assessed at 50 on the Normalcy of Diet Scale 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. The incidence of grade 2 mIAS for each treatment arm will be compared by a Chi-square test. | Up to 8 weeks | 
| Incidence of Mouth Pain | Original plan for collecting and analyzing this data did not occur due to study termination. Will determine if the initiation of dexamethasone at the start of everolimus is associated with the incidence and of mild (score of 1-3), moderate (score of 4-6) and severe (score of 7-10) mouth pain as measured by the NAMPS. Will be assessed by Chi-square tests. | Up to 8 weeks | 
| Time to Development of Mouth Pain | Original plan for collecting and analyzing this data did not occur due to study termination. Will determine if the initiation of dexamethasone at the start of everolimus is associated with the time to development of mild (score of 1-3), moderate (score of 4-6) and severe (score of 7-10) mouth pain as measured by the NAMPS. Will be assessed by Kaplan-Meier and cumulative incidence curves. | Up to 8 weeks | 
| Quality of Life Assessed by Linear Analogue Self-Assessment | Original plan for collecting and analyzing this data did not occur due to study termination. Will determine if the initiation of dexamethasone at the start of everolimus is associated with quality of life is by comparing numerical analogue scale scores as measured by the Linear Analogue Self-Assessment. The Linear Analogue Self Assessment for quality of life is measured on a 0 to 10 scale, with 0 corresponding to Quality of life as bad as it can be and 10 corresponding to Quality of life as good as it can be. Will be assessed by independent samples t-tests. | Up to 8 weeks | 
| Mouth/Throat Sore Level of Activity Interference With Daily Activities | Original plan for collecting and analyzing this data did not occur due to study termination. Will determine if the initiation of dexamethasone at the start of everolimus is associated with the level of interference with daily activities as measured by the Patient Reported Outcome (PRO) Common Terminology criteria for Adverse Events (CTCAE) mouth/throat item regarding level of interference with daily activities. The PRO-CTCAE mouth/throat item regarding level of interference with daily activities is measured on a Likert 1-5 scale, with 1 corresponding to Not at all and 5 corresponding to Very much. Will be assessed by independent samples t-tests. | Up to 8 weeks | 
| Sleep Level of Activity Interference With Daily Activities | Original plan for collecting and analyzing this data did not occur due to study termination. Will determine if the initiation of dexamethasone at the start of everolimus is associated with the level of interference with daily activities as measured by the PRO-CTCAE sleep item regarding level of interference with daily activities. The PRO-CTCAE sleep item regarding level of interference with daily activities is measured on a Likert 1-5 scale, with 1 corresponding to Not at all and 5 corresponding to Very much. Will be assessed by independent samples t-tests. | Up to 8 weeks | 
| Adherence to Everolimus Therapy Dose | Original plan for collecting and analyzing this data did not occur due to study termination. Will compare mean daily dose of everolimus between the arms. The mean daily dose of everolimus over 8 weeks will be compared between study arms using independent samples t-tests. | Up to 8 weeks | 
| Incidence of Patients Stopping Everolimus Early | Original plan for collecting and analyzing this data did not occur due to study termination. Will compare the number of patients who stopped everolimus early between the treatment arms. Will be compared using Chi-squared tests. | Up to 8 weeks | 
| Incidence of Patients Reducing Everolimus Dose | Original plan for collecting and analyzing this data did not occur due to study termination. Will compare the number of patients who reduced their everolimus dose between the treatment arms. Will be compared using Chi-squared tests. | Up to 8 weeks | 
| Dexamethasone Prescription Fill Rates | Original plan for collecting and analyzing this data did not occur due to study termination. Will compare dexamethasone prescription fill rates between the treatment groups. This will be compared using Chi-squared tests. | Up to 8 weeks | 
| Time to Dexamethasone Prescription Fill | Original plan for collecting and analyzing this data did not occur due to study termination. Will compare the time to dexamethasone prescription fill between the treatment groups. This will be compared using Kaplan-Meier and cumulative incidence curves. | Up to 8 weeks | 
| Time to Develop Mouth Sores Per Study Arm Assessed by PRO-CTCAE Mouth/Throat Sore Item Regarding Severity | Original plan for collecting and analyzing this data did not occur due to study termination. The time to develop at least mild, moderate, or severe (including Very severe) mouth sores per study arm as measured by the PRO-CTCAE mouth-throat sore item regarding severity. The PRO-CTCAE mouth-throat sore item regarding severity is measured on a Likert 1-5 scale, with 1 corresponding to None and 5 corresponding to Very severe. Will be assessed by Kaplan-Meier and cumulative incidence curves. | Up to 8 weeks | 
| Mean Degrees of Patient-reported Mouth Sores Per Study Arm Assessed by NAMPS | Original plan for collecting and analyzing this data did not occur due to study termination. The mean degrees of patient-reported mouth sores per study arm as measured by the NAMPS will be assessed by independent samples t-tests. | Up to 8 weeks | 
| Median Degree of Patient-reported Mouth Sores Per Study Arm Assessed by NAMPS | Original plan for collecting and analyzing this data did not occur due to study termination. The median degrees of patient-reported mouth sores per study arm as measured by the NAMPS will be assessed by independent samples t-tests. | Up to 8 weeks | 
| Proportion of Patients Who Experience Grade 2 Stomatitis | Original plan for collecting and analyzing this data did not occur due to study termination. The proportion of patients who experience clinician-reported grade 2 stomatitis (as measured by the CTCAE and performed at 1 and 2 months post-baseline) per study arm will be assessed by Chi-squared tests. | Up to 2 months |