First-in-Human Phase Ib Trial of Quinacrine plus Capecitabine in Patients with Refractory Metastatic Colorectal Cancer

Abstract Background Quinacrine plus a fluoropyrimidine has in-vivo efficacy against metastatic colorectal cancer (mCRC). This phase Ib trial evaluated the combination of quinacrine plus capecitabine in patients with refractory mCRC. Methods Using a modified Simon’s accelerated titration design, adults with refractory mCRC were treated with capecitabine 1000 mg/m2 twice daily (bid) for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg bid, and 200 mg bid for 21 days. The primary endpoint was identifying the maximum tolerated dose (MTD), determining tolerability and safety. In an expansion cohort, it was overall response rate (ORR) and time to tumor progression (TTP). Results Ten patients were enrolled, median age 60-years old. The first two quinacrine dosing levels were well-tolerated. Dose Limiting Toxicities (DLTs) were seen in 3 patients treated with quinacrine 200 mg bid. 5 additional patients tolerated quinacrine 100 mg bid without further DLTs thus establishing the MTD. 7 additional patients enrolled in the expansion before quinacrine manufacturing ceased within the USA. 5 patients had stable disease, one achieved a partial response and 10 had disease progression. Median TTP overall was 2.12 months and median overall survival was 5.22 months for the 17 patients. Conclusions Capecitabine and quinacrine can be safely administered at the MTD of capecitabine 1000 mg/m2 PO bid D1-14 and quinacrine 100 mg PO bid D1-21 of a 21-day cycle in mCRC patients. While the expansion was halted early, TTP was in line with other refractory mCRC studies suggesting activity of this regimen in heavily pretreated patients.