Doxepin Hydrochloride in Treating Esophageal Pain in Patients With Thoracic Cancer Receiving Radiation Therapy to the Thorax With or Without Chemotherapy

Study Overview
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Brief Summary
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This randomized pilot clinical trial studies the effects of taking doxepin hydrochloride as compared to placebo (inactive drug) in treating esophageal pain in patients with cancer located in the chest area receiving radiation therapy to the thorax with or without chemotherapy. Doxepin hydrochloride is a tricyclic antidepressant drug which was recently shown to be helpful for mouth pain in patients receiving radiation therapy. Doxepin hydrochloride affects the surface of the esophagus, which may be helpful in reducing the pain caused by radiation therapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To provide baseline data regarding the effectiveness of doxepin (doxepin hydrochloride) in reducing esophagitis-related pain in patients undergoing radiation therapy (RT) to the thorax, as measured by a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hour and then at 2 and 4 hours on day 1. SECONDARY OBJECTIVES: I. To assess the adverse event profile of doxepin swish and swallow using a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hour and then at 2 and 4 hours using Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG) acute toxicity criteria, and also for domains of unpleasant taste, burning/stinging discomfort, and drowsiness. II. To evaluate the effectiveness of doxepin in reducing esophagitis-related pain in patients undergoing RT to the thorax, as measured by a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hours and then at 2 and 4 hours on days 1 and 3 (including the cross-over phase). III. To compare and provide baseline data regarding alternative analgesic use between the doxepin and placebo arms. IV. To provide baseline data regarding the patients? preference for continued therapy with doxepin or placebo after initial test dose or after the cross-over phase, as measured by items 9 and 10 in the patient-reported questionnaire at 4 hours after administration of the study medication and the actual participation rate. TERTIARY OBJECTIVES: I. To assess pain reduction and other adverse event profile in the optional continuation phase of doxepin oral rinse therapy. (Only applies to patients who have the optional continuation of doxepin oral rinse after the first two phases) OUTLINE: Patients are randomized to 1 of 2 treatment groups. GROUP I: Patients receive doxepin hydrochloride oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm II on day 3. GROUP II: Patients receive placebo oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm I on day 3. In both arms, patients may continue to receive doxepin hydrochloride oral solution every 4 hours as needed during radiation therapy.

Official Title
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A Pilot, Double-Blind, Randomized, Two-Arm Crossover Study of Doxepin Versus Placebo for Esophagitis-Induced Pain in Patients Receiving Radiotherapy to the Thorax With or Without Chemotherapy

Conditions
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Esophageal Carcinoma, Hypopharyngeal Carcinoma, Laryngeal Carcinoma, Lymphoma, Mesothelioma, Metastatic Malignant Neoplasm in the Lung, Metastatic Malignant Neoplasm in the Pleura, Metastatic Malignant Neoplasm in the Spinal Cord, Non-Small Cell Lung Carcinoma, Sarcoma, Small Cell Lung Carcinoma, Thymic Carcinoma, Thymoma, Thyroid Gland Carcinoma

Intervention / Treatment
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* Drug: Doxepin Hydrochloride
* Other: Placebo
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmation of thoracic malignancies including non-small cell lung cancer (NSCLC), small lung cancer (SCLC), esophageal cancer, hypopharyngeal and laryngeal cancers (for which esophagitis symptoms can be relieved by doxepin swallow), lymphoma, thyroid, thymoma, thymic carcinoma, mesothelioma, sarcoma, and spinal, pulmonary or pleural-based metastases Planned RT (with or without chemotherapy) to a dose of >= 20 Gray (Gy) using 1.60 Gy per daily fraction; if radiation is given twice daily, a cumulative planned dose of >= 15 Gy using at least 1.25 Gy per fraction is required; hypofractionated and stereotactic body radiation therapy regimen are allowed At least 5 cm of the esophagus must be planned to receive radiotherapy, with a minimum dose of at least 10 Gy >= 3 esophageal pain, either at rest or during swallowing, felt to be related to esophagitis for which the patient wants relief, as measured by asking the following question ?On a scale of 0 to 10 (0 = no pain; 10 = worst pain), what number best describes your chest pain* (right now) due to your radiation treatment?? Radiation can cause inflammation in your esophagus which can feel like a chest pain, either at rest or during swallowing Able to swallow the study medication Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Negative pregnancy test done =< 28 days prior to registration, for women of childbearing potential only Ability to complete questionnaire(s) by themselves or with assistance Provide informed written consent Willingness to complete evaluation and questionnaires per protocol at the participating institution for follow-up (during the active monitoring phase of the study) Exclusion Criteria: Known allergy to doxepin, tricyclic antidepressants, or any known component of the drug formulation Histologic proof of and getting treatment for esophageal, stomach, spinal cord, thyroid, breast, and head and neck cancers and vertebral metastases Use of a tricyclic antidepressant or monoamine oxidase inhibitor within the 2 weeks prior to registration The presence or strong clinical suspicion of a tracheoesophageal fistula, or known esophageal invasion by cancer Current untreated or unresolved esophageal candidiasis or herpes simplex virus (HSV) infection Current untreated narrow angle glaucoma Current untreated urinary retention =< 6 weeks prior to registration Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Any of the following Pregnant women Nursing women Current use of doxepin or doxepin rinse as a swallow preparation

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (doxepin hydrochloride)<br>Patients receive doxepin hydrochloride oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm II on day 3. | Drug: Doxepin Hydrochloride<br>* Given orally<br>* Other names: Sinequan;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Group II (placebo)<br>Patients receive placebo oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm I on day 3. | Other: Placebo<br>* Given orally<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mouth Pain as Measured by Average Area Under the Curve Per Assessment | Average Area Under the Curve per assessment (aAUCpa) of pain for the first cycle of treatment. Scores are reported on a 0-100 scale, where 100=better outcome QOL. The aAUCpa is the average of each AUC between each sequential assessment. Patients will assess their pain at baseline and at 5, 15, 30, 60, 120, and 240 minutes after treatment. The AUC calculation is based on the assessment number (1,2,3,4,5,6) instead of the actual number of minutes (5,15,30,60,120,240). This results in an AUC measure that is the average pain score across all of the measurements and is not a function of the number of minutes from treatment. The area under the curve of these 6 time points will be adjusted by their baseline pain score. The pain scores at each time point are given equal weights in the AUC calculation and the AUC calculation does not use the number of minutes after treatment. Therefore, the AUC measurement scale is the same as the original pain score scale. | Baseline and 5, 15, 30, 60, 120, and 240 minutes after treatment on day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Any Grade 3 or Higher Adverse Events Using Common Terminology Criteria for Adverse Events (CTCAE) | Incidence of any grade 3 or higher adverse events using Common Terminology Criteria for Adverse Events (CTCAE). Number or patients reporting a grade 3 or higher adverse event according to CTCAE | Up to 4 hours after treatment | 
| Use of Alternative Analgesics | Subgroup analyses will be performed to determine differential effects within the two stratification factors. | Up to 4 hours after treatment | 
| Patient Preference for Continued Therapy at Initial Dose and Crossover |  | At initial Day 1 dose and Day 3 crossover dose. |