Cevimeline in Treating Patients With Dry Mouth Caused by Radiation Therapy for Head and Neck Cancer

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Cevimeline in the Treatment of Xerostomia Secondary to Radiation Therapy for Cancer in the Head and Neck Region

RATIONALE: Cevimeline may be effective in treating dry mouth that is caused by radiation therapy for head and neck cancer. It is not yet known if cevimeline is more effective than no therapy in treating dry mouth caused by radiation therapy.

PURPOSE: Randomized phase III trial to determine the effectiveness of cevimeline in treating patients who have dryness of the mouth caused by radiation therapy for head and neck cancer.

OBJECTIVES:

• Compare the efficacy of cevimeline vs placebo, in terms of dryness of the oral cavity and salivary flow, in patients with xerostomia secondary to radiotherapy for cancers in the head and neck region.
• Assess the safety of this drug in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral cevimeline 3 times daily for 12 weeks in the absence of unacceptable toxicity.
• Arm II: Patients receive oral placebo as in arm I.

PROJECTED ACCRUAL: A total of 280 patients (140 per arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Received more than 4,000 cGy of prior external beam radiotherapy for cancer in the head and neck region

  • Radiotherapy completed more than 4 months prior to study

• Clinically significant salivary gland dysfunction with grade 2 or 3 xerostomia

• At least 1 anatomically intact parotid gland

• No suspected or confirmed bilateral physical closure of salivary gland ducts

• No history of primary or secondary Sjogren's syndrome or other underlying systemic illness known to cause xerostomia independent of prior radiotherapy exposure

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 70-100%
• ECOG 0-2

Life expectancy:

• At least 6 months

Hematopoietic:

• Hemoglobin at least 9.0 g/dL
• No anemia

Hepatic:

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• SGOT/SGPT no greater than 2 times ULN
• Lactate dehydrogenase no greater than 2 times ULN
• No evidence of active liver disease

Renal:

• Creatinine no greater than 2.5 mg/dL
• BUN no greater than 50 mg/dL
• No history of nephrolithiasis within the past 6 months

Cardiovascular:

• No history of significant cardiovascular disease
• No active congestive heart failure
• No uncontrolled angina
• No significant arrhythmia
• No myocardial infarction within the past 6 months

Pulmonary:

• No history of significant pulmonary disease
• No controlled or uncontrolled asthma
• No chronic bronchitis or chronic obstructive pulmonary disease that would limit avocational activities

Gastrointestinal:

• No history of significant gastrointestinal disorder
• No active pancreatic disease
• No gastroduodenal ulcers within the past 6 months
• No hypersensitive bowel conditions requiring pharmacologic therapy
• No inflammatory bowel disease
• No history of cholelithiasis within the past 6 months (unless cholecystectomy performed)

Other:

• No clinically significant laboratory abnormality
• No history of alcohol or drug abuse within the past 6 months that would preclude study
• No prior or concurrent acute iritis or narrow-angle (angle closure) glaucoma
• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No concurrent chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• See Disease Characteristics
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• At least 30 days since other investigational new drug
• At least 4 weeks since prior systemic or ophthalmic pilocarpine
• No prior cevimeline
• No concurrent hyperbaric oxygen therapy
• No concurrent beta adrenergic antagonists, anticholinergic agents, cevimeline metabolism inhibitors, or other medications known to effect salivary function
• No other concurrent investigational drugs