Neoplasm, Oral Mucosa, Transplant-Related Disorder
Conditions
Brief summary
This phase I/II trial studies the safety of topical phenylephrine solution and to see how well it works in preventing oral mucosa (mouth sores) in bone marrow transplant patients receiving cyclophosphamide and total body radiation therapy. Topical phenylephrine solution may prevent or lessen the severity of oral mucosa in patients receiving cyclophosphamide and total body radiation prior to undergoing a bone marrow transplant.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of phenylephrine (topical phenylephrine solution) applied topically to the oral mucosa of bone marrow transplant patients treated with cyclophosphamide plus total body irradiation. II. To determine the maximum tolerated dose (MTD) and recommended phase II dose of phenylephrine applied topically to the oral mucosa of bone marrow transplant patients treated with cyclophosphamide plus total body irradiation. III. To evaluate the efficacy of phenylephrine applied topically to the oral mucosa in preventing and/or decreasing severity of oral mucositis in bone marrow transplant patients treated with cyclophosphamide plus total body irradiation. OUTLINE: This is a phase I, dose-escalation study of topical phenylephrine solution followed by a phase II study. Patients undergoing a cyclophosphamide and total body irradiation regimen receive topical phenylephrine solution via spray to the oral mucosa 15-20 minutes prior to each cyclophosphamide infusion, 25-30 minutes after the beginning of each cyclophosphamide infusion, and 15-20 minutes prior to each radiation treatment. After completion of study treatment, patients are followed up weekly for 2 weeks and then at 3 months.
Interventions
Given topically via spray
Sponsors
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be planning to receive a conditioning regimen for stem cell transplant (SCT) consisting of cyclophosphamide and total body irradiation and must meet inclusion criteria for SCT which include: * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less * Patients must have no evidence of active infections at the time of transplantation * Patients must be human immunodeficiency virus (HIV) non-reactive * Females of childbearing potential must not be pregnant or breastfeeding on admission for conditioning for SCT and a pregnancy test will be required for all females of child-bearing potential * Patients must have a pre-transplant multi-organ assessment with the following outcome: * A resting ejection fraction of 50% or greater which increases with exercise as demonstrated by resting/exercise multigated acquisition (MUGA) * A forced expiratory volume in one second (FEV1) of 60% or greater, a diffusion capacity of 50% or greater, and a oxygen partial pressure (PO2) of 80 mm mercury (Hg) or greater on pulmonary function testing * A serum creatinine of equal or less than 2.0mg/Dl and a creatinine clearance of 50 mL/min or greater on 24 hour urine collection * A total bilirubin of less than 2.5 mg/dL, unless these values are due to underlying hematologic malignancy * An aspartate aminotransferase (AST) less than 2 times the upper limit of normal, unless these values are due to underlying hematologic malignancy * Be able to tolerate topical application of phenylephrine to the oral mucosa * All patients must sign a written informed consent
Exclusion criteria
* Open or unhealed wounds or ulcers in the oral cavity * Current use or use within past two weeks of an monoamine oxidase inhibitor (MAOI) * Primary or secondary tumor in the oral cavity * Known allergy to phenylephrine * Uncontrolled hypertension (defined as blood pressure in adults \> 150/95) * Patients on anti-hypertensive medications are eligible if blood pressure is controlled * Enrollment in any other mucositis prevention study from screening up to day 45 post-stem cell transplant * Patients who are not eligible to receive SCT with cyclophosphamide and total body irradiation (TBI) conditioning because they do not meet transplant criteria are also not eligible for this phenylephrine study * General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) for the Oral Mucositis Severity | Up to 3 months | The mucositis AUC will be estimated using the trapezoid method and summarized in terms of means, standard deviation, median and range. This analysis will be performed in both the extended cohort as well as in the historical controls. |
| Duration of Grade 2 Oral Mucositis | Date of onset of grade 2 oral mucositis to the date of the resolution of the grade 2 oral mucositis, assessed up to 3 months | If the grade 2 oral mucositis has not been resolved (to a grade \< 2) by the last day of toxicity assessment, then the duration will be censored at the last date of toxicity assessment. Will be analyzed using the Kaplan-Meier method. The median duration of grade 2/grade 3 oral mucositis will be calculated and reported along with the corresponding 95% confidence interval. This analysis will be performed in both the extended cohort as well as in the historical controls. |
| Duration of Grade 3 Oral Mucositis | Date of onset of grade 3 oral mucositis to the date of resolution to grade < 3 oral mucositis, assessed up to 3 months | If the grade 3 oral mucositis has not been resolved (to a grade \< 3) by the last day of toxicity assessment, then the duration will be censored at the last date of toxicity assessment. Will be analyzed using the Kaplan-Meier method. The median duration of grade 2/grade 3 oral mucositis will be calculated and reported along with the corresponding 95% confidence interval. This analysis will be performed in both the extended cohort as well as in the historical controls. |
| Efficacy Response Rate for Preventing Oral Mucositis With Sufficient Accuracy | Up to 3 months | If a patient experiences no higher than grade 2 oral mucositis, then s/he will be defined as a responder. If a patient experiences grade \>= 3 oral mucositis, s/he will be defined as a non-responder. Specifically, the efficacy response rate will be estimated with a standard error of less than 15% and the length of the 95% confidence interval will be less than 50%. The efficacy response rate will be summarized in tabular format. The Wilson score method will be used to calculate the 95% confidence interval for the efficacy response rate for the extended cohort. |
| Incidence of Adverse Events, Graded According to the Common Terminology Criteria for Adverse Events Version 4.0 | Up to 3 months | Adverse events (AEs) will be presented in the summary tables by preferred term nested within the System Organ Class. Verbatim description, preferred term, and system organ class for all AEs will be contained in the patient data listings. All AEs occurring after enrollment and throughout the study period will be recorded. Each toxicity event will be assigned an attribution: unrelated, unlikely, possibly, probably, or definitely phenylephrine treatment related. |
| Maximum Tolerated Dose (MTD), Defined as the Highest Dose Level of Phenylephrine Applied to the Oral Mucosa Where 0/3, 0/6, or 1/6 Patients Experience a Dose-limiting Toxicity | During the conditioning regimen (radiation and cyclophosphamide treatment), which is anticipated to last 1 week. | Determine Maximum Tolerated Dose (MTD), the highest dose level of phenylephrine applied to the oral mucosa |
| Recommended Phase IIa Dose | During the conditioning regimen (radiation and cyclophosphamide treatment), which is anticipated to last 1 week. | The dose of topical phenylephrine solution which will be recommended for a larger follow-up phase II efficacy study will be established after the dose cohort at the MTD has been expanded to a total of 12 patients. |
| Time to Onset of Grade 2 Oral Mucositis | Time between the first date of radiation or cyclophosphamide treatment to the date of the onset of grade 2 oral mucositis, assessed up to 3 months | Will be analyzed using a parametric (one-parameter exponential) cure rate model. Will be performed in both the extended cohort as well as in the historical controls. |
| Time to Onset of Grade 3 Oral Mucositis | Time between the first date of radiation or cyclophosphamide treatment to the date of the onset of grade 3 oral mucositis, assessed up to 3 months | Will be analyzed using a parametric (one-parameter exponential) cure rate model. Will be performed in both the extended cohort as well as in the historical controls. |
Countries
United States
Participant flow
Recruitment details
This study enrolled adult participants undergoing hematopoietic stem cell transplantation (SCT) who were to receive cyclophosphamide and TBI as the conditioning regimen. Participants were recruited from the University of Wisconsin Hospitals and Clinics between May 2015 and December 2015.
Participants by arm
| Arm | Count |
|---|---|
| Supportive Care (Topical Phenylephrine Solution) Patients undergoing a cyclophosphamide and total body irradiation regimen receive topical phenylephrine solution via spray to the oral mucosa 15-20 minutes prior to each cyclophosphamide infusion, 25-30 minutes after the beginning of each cyclophosphamide infusion, and 15-20 minutes prior to each radiation treatment.
Topical Phenylephrine Solution: Given topically via spray | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Supportive Care (Topical Phenylephrine Solution) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
Area Under the Curve (AUC) for the Oral Mucositis Severity
The mucositis AUC will be estimated using the trapezoid method and summarized in terms of means, standard deviation, median and range. This analysis will be performed in both the extended cohort as well as in the historical controls.
Time frame: Up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and AUC could not be estimated or analyzed.
Primary
Duration of Grade 2 Oral Mucositis
If the grade 2 oral mucositis has not been resolved (to a grade \< 2) by the last day of toxicity assessment, then the duration will be censored at the last date of toxicity assessment. Will be analyzed using the Kaplan-Meier method. The median duration of grade 2/grade 3 oral mucositis will be calculated and reported along with the corresponding 95% confidence interval. This analysis will be performed in both the extended cohort as well as in the historical controls.
Time frame: Date of onset of grade 2 oral mucositis to the date of the resolution of the grade 2 oral mucositis, assessed up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and the median duration of oral mucositis could not be analyzed.
Primary
Duration of Grade 3 Oral Mucositis
If the grade 3 oral mucositis has not been resolved (to a grade \< 3) by the last day of toxicity assessment, then the duration will be censored at the last date of toxicity assessment. Will be analyzed using the Kaplan-Meier method. The median duration of grade 2/grade 3 oral mucositis will be calculated and reported along with the corresponding 95% confidence interval. This analysis will be performed in both the extended cohort as well as in the historical controls.
Time frame: Date of onset of grade 3 oral mucositis to the date of resolution to grade < 3 oral mucositis, assessed up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and the median duration of oral mucositis could not be analyzed.
Primary
Efficacy Response Rate for Preventing Oral Mucositis With Sufficient Accuracy
If a patient experiences no higher than grade 2 oral mucositis, then s/he will be defined as a responder. If a patient experiences grade \>= 3 oral mucositis, s/he will be defined as a non-responder. Specifically, the efficacy response rate will be estimated with a standard error of less than 15% and the length of the 95% confidence interval will be less than 50%. The efficacy response rate will be summarized in tabular format. The Wilson score method will be used to calculate the 95% confidence interval for the efficacy response rate for the extended cohort.
Time frame: Up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and the efficacy response rate could not be estimated.
Primary
Incidence of Adverse Events, Graded According to the Common Terminology Criteria for Adverse Events Version 4.0
Adverse events (AEs) will be presented in the summary tables by preferred term nested within the System Organ Class. Verbatim description, preferred term, and system organ class for all AEs will be contained in the patient data listings. All AEs occurring after enrollment and throughout the study period will be recorded. Each toxicity event will be assigned an attribution: unrelated, unlikely, possibly, probably, or definitely phenylephrine treatment related.
Time frame: Up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and no study conclusions could be made.
Primary
Maximum Tolerated Dose (MTD), Defined as the Highest Dose Level of Phenylephrine Applied to the Oral Mucosa Where 0/3, 0/6, or 1/6 Patients Experience a Dose-limiting Toxicity
Determine Maximum Tolerated Dose (MTD), the highest dose level of phenylephrine applied to the oral mucosa
Time frame: During the conditioning regimen (radiation and cyclophosphamide treatment), which is anticipated to last 1 week.
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and MTD could not be determined.
Primary
Recommended Phase IIa Dose
The dose of topical phenylephrine solution which will be recommended for a larger follow-up phase II efficacy study will be established after the dose cohort at the MTD has been expanded to a total of 12 patients.
Time frame: During the conditioning regimen (radiation and cyclophosphamide treatment), which is anticipated to last 1 week.
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and the dose of topical phenylephrine solution for a larger follow-up phase II efficacy study could not be recommended.
Primary
Time to Onset of Grade 2 Oral Mucositis
Will be analyzed using a parametric (one-parameter exponential) cure rate model. Will be performed in both the extended cohort as well as in the historical controls.
Time frame: Time between the first date of radiation or cyclophosphamide treatment to the date of the onset of grade 2 oral mucositis, assessed up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and time to onset of grade 2 oral mucositis could not be analyzed.
Primary
Time to Onset of Grade 3 Oral Mucositis
Will be analyzed using a parametric (one-parameter exponential) cure rate model. Will be performed in both the extended cohort as well as in the historical controls.
Time frame: Time between the first date of radiation or cyclophosphamide treatment to the date of the onset of grade 3 oral mucositis, assessed up to 3 months
Population: This study was closed prematurely due to decreased numbers of eligible subjects. The full target accrual number was not achieved, and time to onset of grade 3 oral mucositis could not be analyzed.