SAN FRANCISCO—Phase III data show that iseganan, a selectively decontaminating rinse for the oral mucosa, increases by at least 30% the proportion of patients who get through stomatotoxic chemotherapy without developing ulcerative oral mucositis. An error in the randomization system, however, resulted in about one third of the 323 patients being given at least one drug bottle opposite to their randomization assignment and greatly reduced the power of the study, noted Williamson Z. Bradford, MD, PhD. Dr. Bradford is director of clinical science at IntraBiotics Pharmaceuticals Inc., Mountainview, California. IntraBiotics manufactures iseganan and sponsored the trial.
Dr. Bradford told Oncology News International in an interview that the randomization error is expected to delay approval of iseganan but that the study investigators are still quite encouraged by the results. "A rigorous, intention-to-treat efficacy analysis that included the improperly treated patients still showed that iseganan significantly decreased mouth pain and stomatitis compared to placebo, and that the increase in the proportion of patients without ulcerative mucositis approached statistical significance (P = 0.067). We saw consistent responses across multiple endpoints despite the drug dispensing error, and we will probably be moving quickly to repeat the study," he said.
Lessens Mucositis Severity
Ulcerative oral mucositis is a frequent, debilitating, and sometimes dose-limiting complication of chemotherapy and radiotherapy. It is associated with systemic infections, pain, and difficulty swallowing. According to Dr. Bradford, endogenous oral flora are believed to play a pivotal role in the pathogenesis of oral mucositis. Previous studies suggested that selective oral decontamination can reduce mucositis severity after radiotherapy.
Iseganan (IB-367) is a synthetic 17-amino acid peptide that has rapid microbicidal activity against oral microflora including gram-positive and gram-negative bacteria and yeast.
Dr. Bradford said that in a phase II trial of patients receiving myeloablative chemotherapy and bone marrow transplantation, iseganan reduced the average oral mucositis severity as defined by mean Oral Mucositis Assessment Scale (OMAS) score by 22% (P = 0.049) in the 134 evaluable patients and by 40% (P = 0.047) in the 76 patients who started IB-367 more than 3 days prior to transplantation.
The phase III trial reported at ASCO was designed to further evaluate the safety and efficacy of an iseganan mouthwash in reducing the incidence of ulcerative oral mucositis and its clinical sequelae, including pain, difficulty swallowing, fevers, and systemic infections.
The study included researchers from 24 centers in the United States and Europe, with a total of 323 patients randomized to placebo (n = 160) or 9 mg iseganan administered as an oral rinse (n = 163). Treatment was administered six times daily for at least 21 and up to 28 days and was begun on the first day of chemotherapy or total body irradiation.
At entry, patients were over age 7 years, free of mucositis, and scheduled to receive a chemotherapy regimen associated with a greater than 50% incidence of grade 2 or worse oral mucositis. About 95% of patients were to receive ablative chemotherapy as preparation for either bone marrow or peripheral blood stem cell transplant, primarily for hematologic or lymphoid tumors.
Dispensing Error
Patients were issued drug bottles containing a 5-day supply of either placebo or iseganan. Dr. Bradford said that due to a dispensing error, 49 patients randomized to iseganan (30.1%) and 53 randomized to placebo (33.1%) received at least one drug bottle opposite their randomization assignment. Fifty-five of these 102 patients received only one wrong bottle over the 3-week treatment period.
The primary efficacy endpoint was a Kaplan-Meier estimate of the proportion of patients not developing ulcerative oral mucositis through study day 21. The study was powered to detect an increase in patients free of mucositis from 36% expected with placebo to 55% with iseganan. Dr. Bradford reported that the proportion of patients free of mucositis on day 21 was 33% with placebo vs 43% with iseganan. He added that statistically significant reductions in mouth pain, throat pain with swallowing, and the National Cancer Institute Common Toxicity Criteria stomatitis scale were observed in the iseganan group:
Generally Well Tolerated
"In this trial, iseganan increased the proportion of patients who did not develop ulcerative oral mucositis following stomatotoxic chemotherapy by 30% despite a drug dispensing error. Iseganan reduced the severity of mouth pain and throat pain, often cited as the most debilitating symptoms associated with oral mucositis," Dr. Bradford said.
"Iseganan was generally well tolerated, although its use may be associated with a modest increase in frequency of esophagitis," he continued. The proportion of patients experiencing adverse events was similar in both treatment groups.
"These data suggest that iseganan is effective and safe for preventing ulcerative oral mucositis and reducing its clinical sequelae," Dr. Bradford said.
"Selective oral decontamination is an exciting new concept in the management of these treatment-related problems," noted discussant Edward Brenner, MD, of the University of Texas M. D. Anderson Cancer Center in Houston. "Subjective outcomes such as pain and dysphagia need to be measured more routinely in patients, and we should also consider whether there is a role for earlier intervention, before the beginning of chemotherapy or radiotherapy, in patients who are likely to develop these problems."
