A Phase Ib Trial to Evaluate the Safety and Efficacy of Quinacrine Plus Capecitabine in Patients with Refractory Metastatic Colorectal Cancer.

e15020 Background: Acridines emerged from a cell-based screen for p53-pathway restoring compounds. Quinacrine, an acridine demonstrating p53 pathway restoration properties, displayed preclinical anti-tumor effects when used as monotherapy in colorectal cancer (CRC) cell culture and in vivo xenografts. Quinacrine suppresses survival pathways by inhibiting Mcl-1 expression, NFkB, STAT3, and angiogenesis. The combination of quinacrine plus 5-FU showed in-vivo preclinical efficacy against CRC with mutant KRAS, BRAF, or p53. Capecitabine, an oral 5-FU prodrug, is FDA-approved to treat metastatic (m)CRC. This phase I trial evaluated the safety and efficacy of quinacrine plus capecitabine in patients with refractory mCRC. Methods: Patients ≥18 years old with histologically confirmed mCRC refractory to standard therapy or with no standard therapy options available were eligible for the study. Using a modified 4B Simon’s accelerated titration design, patients were treated with a fixed dose of capecitabine 1000 mg/m2 twice daily (bid) for 14 days of a 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 to identify the maximum tolerated dose (MTD) of quinacrine in combination with capecitabine and to determine their tolerability and safety. Results: Ten patients were enrolled, median age 60-years old (range: 56-79). Quinacrine 100 mg daily and 100 mg bid were well tolerated by the first two patients. Dose Limiting Toxicities (DLTs) were seen in 3 patients treated with quinacrine 200 mg bid and included hyperbilirubinemia, transaminitis, increased alkaline phosphatase, hypokalemia, diarrhea, vomiting, and dehydration. No grade 4 or 5 toxicities were seen. 5 additional patients tolerated treatment with quinacrine 100 mg bid and capecitabine without further DLTs making this the MTD. The median time on treatment was 63 days. Three patients came off study prior to their first response evaluation. In 7 patients evaluable for response, 4 had stable disease (57%), while 3 (43%) had disease progression. Median overall survival was 196.5 days. 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 for patients with mCRC. A phase II study is ongoing. Clinical trial information: NCT01844076.