Doxepin and a Topical Rinse in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Radiotherapy With or Without Chemotherapy

Patients are stratified according to sex (male vs. female), concurrent use of chemotherapy
(no vs. yes), patient age at registration (< 60 years old vs. ≥ 60 years old and RTOG acute
radiation morbidity criteria (1 vs. 2 vs 3 or more). Protocol therapy will consist of 2
cycles. Patients are randomized to one of three treatment regimens, which include doxepin,
DLA and placebo. Cycle One will consist of one day. The care provider or nurse will confirm
that the oral pain is at least 4 out of 10 severity level at the time of the rinse on the
first day of the study. Patient will be asked to complete the baseline evaluation in the
Oral Symptoms booklet. If the pain score is less than 4 then administration will be delayed
until the pain is at least 4. Cycle Two will consist of an optional continuation phase
lasting up to 7 days. Initiation of the Cycle 2/Continuation Phase may be delayed up to one
week after Cycle 1/Day 1.

Primary Objective:

1. Determine whether the doxepin rinse or DLA rinse is more effective than placebo in
reducing OM-related pain in patients undergoing RT to the oral cavity, as measured by a
patient-reported questionnaire at baseline, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2
hours, and 4 hours.

Secondary Objectives:

1. Assess the adverse event profile of the doxepin rinse, the DLA rinse agent, and the
placebo using a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1
hour, 2 hours, and 4 hours for domains of unpleasant taste, burning or stinging
discomfort, and drowsiness.

2. Compare the incidence of using additional analgesics between 1 and 4 hours after the
initial mouthwash, between the doxepin oral rinse, the DLA rinse agent, and the placebo
arms.

3. Compare the length of time that each study product is used by patients in the one-week
continuation phase.

4. Compare the daily pain scores in the one-week continuation phase for the three study
arms.

5. Compare the 24-hour morphine equivalent dose used in the continuation phase for the
three study arms.

1. Documentation of Disease: Histologic documentation of malignancy currently undergoing
a course of RT (with or without chemotherapy) including the oral cavity and/or
oropharyngeal area to a dose of at least 4500 cGy using more than 5 fractions (i.e.,
stereotactic body radiation therapy [SBRT] is not allowed).

2. Physical exam demonstrating evidence of radiotherapy-related mucositis in the visible
oral cavity and/or oropharynx consistent with mucous membrane toxicity greater than 0
using the Acute Radiation Morbidity Scoring Criteria.

3. At least 4 (out of 10) patient-reported oral pain related to oral mucositis secondary
to RT for which the patient seeks relief, as measured on the Oral Pain Assessment.

Note: The pain score must be at least 4 at the time that the patient starts the first
dose of study medication. The patient may be enrolled to the study if s/he, at times,
has a pain score of at least 4, so long as initiation of study treatment begins when
the pain score is at least 4.

4. Ability to complete questionnaire(s) by themselves or with assistance.

5. No known allergy to diphenhydramine, lidocaine, antacid (aluminum hydroxide,
magnesium hydroxide, and simethicone), doxepin, tricyclic antidepressants, or any
known component of the drug formulation in the testing arms.

6. No use of any anti-arrhythmic medication (except for beta-blockers) including
lidocaine, linezolid, ipratropium, or medications with high anti-cholinergic potency
(including neostigmine, a tricyclic antidepressant or a monoamine oxidase inhibitor)
within 2 weeks prior to registration.

7. No current diagnosed untreated or unresolved oral candidiasis or oral HSV infection.

8. No history of untreated narrow angle glaucoma within 6 weeks prior to registration.

9. No untreated urinary retention within 6 weeks prior to registration.

10. No current use of glutamine or sucralfate powders at the time of registration (no
washout required).

11. No cryotherapy for prophylactic mucosal protection within 6 weeks prior to
registration.

12. Not pregnant, because patients eligible for this study will be receiving
radiotherapy, which has known genotoxic, mutagenic and teratogenic effects.
Therefore, for women of childbearing potential only, a negative pregnancy test done ≤
28 days prior to registration is required.

13. Age ≥ 18 years

14. ECOG Performance Status 0, 1, or 2