Alliance A221805: Duloxetine to prevent oxaliplatin-induced chemotherapy-induced peripheral neuropathy (CIPN)—A randomized, double-blind, placebo-controlled phase II study.

12010 Background: Standard-of-care chemotherapy treatment regimens for colorectal cancer (CRC) include oxaliplatin, a drug known for causing CIPN. CIPN is characterized by upper and lower extremity numbness and tingling, and pain that can persist for years beyond chemotherapy completion, causing impaired function and poor quality of life. According to the American Society of Clinical Oncology’s (ASCO) 2020 Clinical Practice Guidelines, there are no known effective preventative interventions. While the ASCO guidelines recommend duloxetine to treat established painful CIPN, its efficacy to prevent CIPN has not been established. Methods: A221805 (NCT04137107) was conducted within the National Cancer Institute-supported Community Oncology Research Program; Alliance for Clinical Trials in Oncology was the coordinating group. The randomized, 3-arm, double-blind, placebo-controlled, noncomparative, multicenter phase II study screened 2 doses of daily duloxetine to prevent sensory CIPN. Enrollment occurred between May 1, 2020, and March 24, 2023. Patients (pts) were randomized 1:1:1 to 30 or 60 mg of daily duloxetine, or daily placebo. Eligible pts had stage II-III CRC and no baseline neuropathy, were ≥ 25 years of age and scheduled to receive oxaliplatin via one of the following schedules: 85 mg/m2 every 2 weeks (wks; 6 or 12 doses) or 130 mg/m2 every 3 wks (4 doses). Duloxetine/placebo was taken once daily beginning on day 1 of cycle 1 and continued for 17 wks. Blinding was achieved via drug encapsulation. The primary outcome was measured on wk 19-21 using a validated patient-reported outcome measure: 6 sensory items from the EORTC QLQ-CIPN20. Responders were pts who reported little to no CIPN; their highest score was ≤ 2 (i.e., 1 = “Not at all”; 2 = “A little”) on any of the 6 items. Results: 199 pts were accrued (n = 66, 30 mg duloxetine; n = 66, 60 mg, duloxetine; Placebo, n = 67); based on modified intent-to-treat criteria, 46, 47, and 50 pts (N = 143, 71.8%) respectively, were evaluable for the primary endpoint analysis. The pt mean age was 55.1 years (SD = 10.43). Most were White (n = 113, 80.7%) and male (n = 82, 58.6%).There was no difference in the proportion of responders when comparing those who received either duloxetine 30mg (65.2%), 60mg (66.0%), or placebo (68.0%). Fatigue (51.9%) and nausea (46.5%) were the most common solicited adverse events. Duloxetine adherence rates, measured via pill counts, in the 30mg (44.44%), 60mg (50.92%), and placebo (65.57%) groups were low ( < 75%). Conclusions: We were unable to show that any dose of duloxetine was more promising than placebo, possibly due to an unexpectedly high placebo response rate. Low duloxetine/placebo adherence may have compromised efficacy. Placebo-response mitigation methods should be considered in future CIPN clinical trials. Clinical trial information: NCT04137107 .