Two Phase III Clinical Studies of Cevimeline for Post-Radiation Xerostomia in Patients with Head and Neck Cancer

English

Reviewer: S. Jack Wei, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 15 de mayo del 2005

Presenter: M.S. Chambers
Presenter's Affiliation: MD Anderson Cancer Center
Type of Session: Scientific

Background

A majority of patients with head and neck cancers receive treatment with external beam radiotherapy (EBRT).
Reduction in salivary flow occurs when the major salivary glands are included with the irradiated volume.
Symptomatic palliation of radiation-induced xerostomia with artificial saliva and sugarless gum are rarely adequate.
This xerostomia can have a major impact on QOL.
Cevimeline hydrochloride (Evoxac) is a quinuclidine derivative of acetylcholine that is FDA-approved for symptomatic treatment of dry mouth in patients with Sjogren's syndrome.
Cevimeline is a cholinergic agonist which binds to muscarinic receptors and stimulates exocrine gland tissue including salivary glands.
Cevimeline is metabolized by the cytochrome P450 isozymes and its metabolism can be affected by other drugs that interact with the cytochrome P450 system.
Two phase III trials were initiated with 12 weeks of each other for identical patient populations examining the efficacy of cevimeline in the treatment of radiation induced xerostomia.

Materials and Methods

Two concurrent trials (2011A-PRT 003 and 2011A-PRT 004) were initated within 12 weeks of each other.
Patients were randomized to cevimeline or placebo in a 1:1 distribution.
All patients were started on cevimeline at 30 mg tid for a total of 12 weeks.
The dose of cevimeline was escalated to 45 mg tid at week 6 if there was no symptomatic improvement.
The dose of cevimeline could be deescalated from 45 mg to 30 mg if the patient experienced unacceptable toxicity from therapy.
Inclusion criteria included EBRT >= 4 months prior to trial entry, >=4000 cGy EBRT, and RTOG grade 2 or 3 xerostomia.
Patients were excluded if they had previously been treated with cevimeline, had treatment with pilocarpine within one month, and were treated with beta adrenergic antagonist or anticholinergic agents.
Concurrent treatment with medications that interfere with cytochrome P450 were prohibited.
Primary endpoint was global evaluation of dry mouth was assessed by asking the patients to rate their dry mouth on a scale of: worse - no change - better - much better.
Secondary endpoints included unstimulated whole salivary flow, stimulated salivary flow with 2% citric acid, and xerostomia questionairre measuring the patients QOL over the last 3 days prior to each visit.

Results

The study populations were well balanced in both studies for age, mean weight, and race. PRT004 was well balanced for gender, but in PRT003, there was a slightly higher rate of males in the cevimeline arm (74.5% vs. 70.1%).
There were similar rates of unstimulated salivary flow, baseline dryness scores, primary head and neck tumors, and metastatic lymph node involvement in both arms of both studies.
The size of the radiation portals was similar betweem the two arms in PRT004, but was slightly larger for involvement of the parotid glands and submandibular glands in the placebo arm of PRT003.
In PRT003, 284 patients were randomized with 281 receiving at least one dose of study drug.

73.4% in the cevimeline group received a complete course of treatment compared to 80% of the placebo group.
46.1% in the cevimeline group underwent dose escalation compared to 62.5% in the placebo group.

In PRT004, 286 patients were randomized with 282 receving at least one dose of study drug.

78.4% in the cevimeline group received a complete course of treatment compared to 85.7% of the placebo group.
45.3% in the cevimeline group underwent dose escalation compared to 49.0% in the placebo group.

In PRT003, there was significant improvement in global evaluation of dry mouth with cevimeline (p=0.02)

There was also significant improvement in unstimulated whole salivary flow (p=0.009)
There was near-significant improvement in ability to speak (p=0.0526)

In PRT004, there was improvement in unstimulated whole salivary flow with cevimeline (p=0.02); however, there was no difference in global evaluation.

Although there were similar improvements in global evaluation with cevimeline compared to other trials; however, there was an unexpected high rate of improvement in patients receiving placebo in this study.

In both studies, there was no increase in toxicity with cevimeline except for increased sweating seen in both trials (PRT003 19.0% vs. 2.8%, PRT004 18.2% vs. 1.4%).

Author's Conclusions

Cevimeline relieved symptoms of radiation-induced xerostomia by global evaluation in the PRT003 study.
Cevimeline improved salivary production in both studies.
Cevimeline was well-tolerated with excessive sweating as the major toxicity.
A phase III safety study of cevimeline at 45mg tid is currently underway for patients receiving head and neck EBRT.

Clinical/Scientific Implications
Xerostomia remains one of the most common and troublesome long-term toxicities after treatment with radiation for patients receiving head and neck cancer. Severe xerostomia can significantly affect quality of life and current treatments for xerostomia are largely ineffective. The two trials presented here show improved salivary production with the use of cevimeline. However, there are conflicting results regarding patient-assessed global evaluation between the two studies. It has been well documented that objective measurements of salivary production do not necessarily correlate with patient assessment of xerostomia, and the difference between the two studies may reflect the discordance between these two factors. Given the conflicting results of subjective xerostomia between these two trials, the confirmatory trial that is currently underway will help determine the efficacy of this drug. In any case, the results of these two trials are promising as the current treatment for radiation-induced xerostomia are limited.