Topical Phenylephrine Solution in Preventing Oral Mucosa in Bone Marrow Transplant Patients Receiving Cyclophosphamide and Total Body Radiation Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I/IIa Safety and Efficacy Study of Topical Phenylephrine Applied to Oral Mucosa in Bone Marrow Transplant Patients Receiving Cytoxan Plus Total Body Irradiation

Conditions
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Neoplasm, Oral Mucosa, Transplant-Related Disorder

Intervention / Treatment
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* Drug: Topical Phenylephrine Solution


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria for transplant include: Patients who have angina and/or congestive heart failure requiring treatment, or who have had a myocardial infarction within the past year Patients who have had any complication that makes the risk of death during transplantation from non-malignant causes greater than the risk of relapse Patients who have any active infection; if the infection is successfully treated, the patient may be reconsidered for transplantation at a later date Patients with diabetes who are not controlled by medical management will be ineligible Psychiatric illness requiring psychiatric counseling or medical intervention other than antidepressant medications may make an individual ineligible and will be considered on a case-by-case basis Psychosocial assessment by the bone marrow transplant team may identify individuals for whom this form of therapy may be contraindicated; these decisions will be based upon estimated adequacy of patient support systems and prediction of patient's compliance with medications, required diagnostic procedures, and/or follow-up care Patients who have an ECOG performance status of greater than 2 Patients who have decreased pulmonary function due to any disorder as demonstrated by a diffusion capacity of less than 50% of predicted, a FEV1 of less than 60% of predicted, or a PO2 of less than 80mmHg on pulmonary function testing Patients who have a resting ejection fraction of less than 50% Patients who have renal disease as demonstrated by a serum creatinine clearance of greater than 2.0 mg/dL and/or a creatinine clearance of less than 50 mL/min Patients who are pregnant or breast feeding at the time of admission for conditioning Any mental or physical condition, in the opinion of the principal investigator (PI) or PI designee, which could interfere with the ability of the subject to understand or adhere to the requirements of the study

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (topical phenylephrine solution)<br>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. | Drug: Topical Phenylephrine Solution<br>* Given topically via spray<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 3 months | 
| 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. | 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 | 
| 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. | Date of onset of grade 3 oral mucositis to the date of resolution to grade < 3 oral mucositis, assessed up to 3 months | 
| 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. | Up to 3 months | 
| 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. | Up to 3 months | 
| 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 | During the conditioning regimen (radiation and cyclophosphamide treatment), which is anticipated to last 1 week. | 
| 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. | During the conditioning regimen (radiation and cyclophosphamide treatment), which is anticipated to last 1 week. | 
| 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 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 | 
| 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 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 |