Risk management and eligibility criteria for QTc assessment in patients with advanced cancer

Abstract

3047 Background: Emerging regulatory and industry practices (ICH E14, 2004) require the potential for QTc interval prolongation to be characterized in a ‘Thorough QT’ (TQT) study with eligibility restricted based on screening QTc criteria (<430 ms in men, <450 ms in women) derived from non-oncology experience. For patients with advanced cancer who volunteer for Phase 1–2 clinical studies of promising new agents, risk-benefit implications of these and other TQT components have not been well defined. Methods: We surveyed baseline QTc interval in 160 adult patients with advanced malignancy enrolled into two Phase 2 trials with an experimental anticancer agent [97 GIST, 63 renal cell carcinoma; mean age 55.7 years (range 24, 87)]. QTc was measured by the ECG recorder’s automated algorithm on single 12-lead ECG obtained prior to treatment. Results: No significant differences in mean or median QTc were observed for patients aged <65 versus >=65 years. Distribution by gender-specific QTc risk categories showed that 94 men (87.9%) and 49 women (92.5%) had normal QTc (<430 and <450 ms, respectively). Eleven men (10.3%) and 4 women (7.6%) had borderline QTc (430–450 and 450–470 ms, respectively), while 2 men (1.9%) and no women had prolonged QTc (>450 and >470 ms, respectively). No QTc was >500 ms (CTCAE Grade 3). Overall, 17 of 160 patients (10.6%) had baseline QTc above the upper limits of normal. Conclusions: These data are consistent with anecdotal reports that cancer patients may have longer QTc than other segments of the population. Over 10% of our patients would have been excluded from treatment with a promising anticancer agent if eligibility criteria from TQT studies in non-oncology populations were applied. Given risk-benefit considerations and expectations for access to new agents in clinical trials, our data support alternative approaches to eligibility criteria and risk management in studies designed to evaluate QTc prolongation in patients with advanced cancer. No significant financial relationships to disclose.