Treatment of Radiation and Cisplatin Induced Toxicities With Tempol

Study Overview
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Brief Summary
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A 10 week trial to assess the ability of Tempol to prevent and/or reduce toxicities associated with cisplatin and radiation treatment in head and neck cancer patients. Over the course of the 10 week trial, mucositis, nephrotoxicity, and ototoxicity will be monitored and assessed.

Detailed Description
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One hundred and twenty (120) participants with head and neck cancer are scheduled to undergo combined radio- and chemotherapy (n = 120). Nearly all (90% to 97%) participants receiving radiotherapy in the head and neck will develop some degree of mucositis. Of these participants treated with radiotherapy with or without chemotherapy, 34% to 43% will present severe mucositis. As a result, the participant's quality of life is affected, hospital admittance rates are higher, the use of total parenteral nutrition is increased and interruption of treatment is more frequent, all of which compromise tumor control. Mucositis causes 9% to 19% of chemotherapy and radiotherapy interruption. A common chemotherapeutic agent used in head and neck cancer is Cisplatin. Cisplatin (cis- diamminedichloroplatinum(II), CDDP) is an antineoplastic drug used in the treatment of many cancers including testicular cancer, ovarian cancer, bladder cancer, head and neck cancer, esophageal cancer, small and non-small cell lung cancer, breast cancer, cervical cancer, stomach cancer, prostate cancer, brain tumors, neuroblastoma, sarcomas, multiple myeloma, melanoma, mesothelioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, and thyroid cancer. While toxicities include ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions, the main dose-limiting side effect of cisplatin is nephrotoxicity followed by ototoxicity. Tempol is a piperidine nitroxide. Nitroxides are a class of stable free radical compounds that protects mammalian cells against numerous toxic agents. Tempol protects normal cells from radiation and cisplatin-induced damage; however, in cancerous or tumor cells, Tempol is reduced to its hydroxylamine form that does not and cannot protect the cells from radiation and cisplatin induced damage. This distinction is of particular importance in the setting of cancer treatment, in which both normal and tumor tissue is exposed to radiation and chemotherapy. Without using Tempol, both normal cells and cancer cells suffer from toxicity. Tempol is the only known compound to possess this functional duality. This compound has the potential to prevent many of the toxicities associated with cisplatin and radiation treatment including the prevention of mucositis, nephrotoxicity, and ototoxicity.

Official Title
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A Double Blind, Placebo Controlled Dose Range Finding Study to Assess the Safety, Pharmacokinetics, and Efficacy of Tempol for the Reduction of Severe Mucositis in Head and Neck Cancer Patients Undergoing Combined Radio- and Chemotherapy

Conditions
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Mucositis, Nephrotoxicity, Ototoxicity

Intervention / Treatment
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* Drug: Tempol
* Drug: Placebo Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be ≥18 years of age with medically diagnosed squamous cell cancer of the head and neck (SCCHN); Be scheduled to receive radiotherapy or proton therapy administered with a curative intent; If female and of child bearing potential, be using an effective birth-control method with a history of reliability for the individual participant; If male and of child bearing potential, adequate methods of contraception must be employed including use of condoms with spermicide. No sperm donation for 90 days until after the conclusion of the study; Must be receiving cisplatin for chemotherapy; Be properly informed of the nature and risks of the clinical investigation, comply with all clinical investigation-related procedures, and sign an Informed Consent Form prior to entering the clinical investigation; Must have a score 2 or less on the ECOG performance status; Participant life expectancy ≥ 6 months; and Adequate baseline organ function (hematologic, liver, renal, nutritional and metabolic): Haematology: Absolute neutrophil count (ANC) ≥1.5 Hemoglobin ≥ 10 g/dL Platelets ≥ 100,000 per microliter of blood Hepatic: Total bilirubin ≤ 2 X (Upper limit normal) ULN Alanine amino transferase (ALT) and Aspartate aminotransferase (AST) ≤5 x ULN Renal: Serum creatinine ≤ ULN or, if > ULN calculated creatinine clearance (CrCl) ≥ 60 mL/min. Nutritional and metabolic: Urine Albumin < 3.0 mg/dl Exclusion Criteria: Prior radiotherapy of the head and neck; Have a clinically significant infection defined as any acute viral, bacterial or fungal infection, which requires specific therapy. Anti-infectious therapy must have been completed within 14 days of starting study treatment; Be taking any non-approved therapy for oral mucositis, including β-carotene, tocopherol, laser irradiation, brushing the oral mucosa with silver-nitrate prophylactically, systemic TGF-β (transforming growth factor beta), or systemic KGF (keratinocyte growth factor) during or within 14 days of starting treatment; Be taking mugard; Be taking prostaglandins, pentoxifylline or leucovorin during or within 14 days of starting treatment; Be rinsing with allopurinol, hydrogen peroxide, sucralfate, or chlorhexidine mouthwashes during or within 14 days of starting treatment; Have had a recent, serious, non-malignant medical complication that, in the opinion of the investigator, makes the individual unsuitable for study participation; Have used an investigational drug within 28 days of the initiation of study treatment; Have a history of a positive blood test for HIV; At the time of screening, having a significant active medical illness which, in the opinion of the investigator, would preclude completion of the study; Participants with a treatment plan consisting of chemoradiation followed by further chemotherapy; Participants with body weight less than 35 kg, 77 lbs; Women who are pregnant or who are breastfeeding; Participants with known intolerance to platin drugs; History of insulin-dependent Diabetes Mellitus; and Participants with Hepatitis B/C.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active 1000 mg Tempol Solution<br>Patients will take 1000 mg of Tempol a day for the duration of radiation treatment (6-8 weeks) | Drug: Tempol<br>* Investigational product is Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) oral solution. Tempol solution is an orange-colored, aqueous solution containing 7% Tempol along with xanthan gum, xylitol, aspartame, acesulfame potassium, sodium saccharin, alcohol, peppermint and wintergreen oils.<br>* Other names: 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl;|
| Placebo Comparator: Placebo Solution<br>Patients will take placebo solution everyday for the duration of radiation treatment (6-8 weeks) | Drug: Placebo Solution<br>* The placebo contains the same excipients as the active product plus FD&C Yellow #6 for color matching.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mucositis | To determine the efficacy of Tempol in reducing the incidence severe mucositis defined as grade 3 or 4 on the World Health Organization (WHO) scale. The incidence will measure the number of patients who experience grade 3 or 4 mucositis according to the World Health Organization (WHO) scale. A reduction in the number of patients who receive grade 3 or 4 mucositis over the course of the treatment is considered a positive change in incidence. | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mucositis | To determine the efficacy of Tempol in reducing the duration severe mucositis defined as grade 3 or 4 on the World Health Organization (WHO) scale. This duration will be measured by total number of days number a patient experiences grade 3 or 4 mucositis according to the World Health Organization (WHO) scale. A reduction in the total number of days a patient receives grade 3 or 4 mucositis over the course of the treatment is considered a positive change in duration. | 10 weeks | 
| Nephrotoxicity | Reduction in Serum Creatinine levels in active arm versus placebo arm. | 10 weeks | 
| Nephrotoxicity | Reduction in Blood Urea Nitrogen levels in active arm versus placebo arm. | 10 weeks | 
| Mucositis | To determine the efficacy of Tempol in reducing the time to onset of grades 1-4 mucositis on the World Health Organization (WHO) scale. This time to onset will measure the number of days after exposure to cisplatin before a patient experiences grade 1 through 4 mucositis according to the World Health Organization (WHO) scale. An increase in the total number of days before a patient receives grade 1 through 4 mucositis after cisplatin exposure is considered a positive change in time to onset. | 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cisplatin toxicity