Acute radiation enteritis is caused by radiation-induced death of the normal cells in the lining of the bowel. As bowel cells die and are not replaced, gastrointestinal toxicity develops over the next few days and weeks with chronic diarrhea, vomiting and pain being the major symptoms. The addition of chemotherapy often exacerbates the onset, severity, and debilitation related to intestinal symptoms. Radiation enteritis often results in delay or interruption of the cancer treatment. There are over 100,000 patients who receive abdominal or pelvic external beam radiation treatment for cancer in the US. These patients are at risk of developing acute and chronic radiation enteritis. The proposed study is a multicenter, open-label, sequential, dose-escalation, Phase 1/2 clinical trial. Up to 48 subjects will be enrolled in four groups. Each dose level will be completed and the first cycle of treatment determined to be safe prior to administration at the next dose level. Emergent signs and symptoms referable to the GI tract, AEs, and concomitant medications will be recorded in all patients enrolled throughout RT and up to the study visit at 4-weeks post-RT, or until the patient is withdrawn earlier from the study, and will be reviewed for assessment of DLT. The safety results will be reviewed by the Principal Investigator(s) (PIs) and the DOR Medical Monitor. Any clinically significant anomaly or change from baseline will be noted. If dose escalation is not permitted, the preceding dose level will be considered the MTD. There will be no expansion of the patient cohort at the DLT. Key endpoints being evaluated include, but are not limited to: 1. dose-limiting toxicity;2. maximum tolerated dose;3. incidence and severity of AEs probably related (i.e., probably and highly probably related) to study treatment;4. grade of gastrointestinal toxicity;and 5. duration of RT emergent diarrhea as assessed by subject diary. At the completion of the trial DOR intends to evaluate the data generated with the intent of designing additional clinical studies to demonstrate the safety and efficacy of DOR201 for the prevention of acute radiation enteritis.
This grant application requests funding to initiate (via a Phase 1/2 clinical study) the clinical evaluation of DOR201, enteric-coated oral beclomethasone dipropionate (BDP) for use in preventing acute radiation enteritis in patients undergoing radiation and chemotherapy for rectal cancer. The development of acute radiation enteritis significantly impacts the patient's quality of life and may result in modification of the cancer treatment. Based on the pharmacology of BDP, DOR201 has the potential to prevent the onset of acute radiation enteritis thereby addressing an important unmet medical need. Upon completion of the proposed clinical study, DOR intends to evaluate the data generated with the intent on designing additional clinical studies to demonstrate both the safety and efficacy of DOR201 for the prevention of acute radiation enteritis.
