First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer

Abstract

Quinacrine and 5-fluorouracil (5-FU) have preclinical activity against colorectal cancer. This phase 1b clinical trial evaluated the safety and efficacy of quinacrine and the 5-FU analog capecitabine in patients with treatment-refractory metastatic CRC (mCRC). The maximally tolerated dose was determined; we observed 1 partial response and 5 stable disease. This regimen may be an option for patients with treatment-refractory mCRC. Background: Quinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC. Patients and Methods: Using a modified Simon accelerated titration design, adults with treatmentrefractory mCRC were treated with capecitabine 1000 mg/m 2 twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP). Results: Ten patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients. Conclusion: Capecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m 2 by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.

Repurposing of Anti-Malarial Drug Quinacrine for Cancer Treatment: A Review

“…However, all of the patients selected for this study either had EGFR-negative adenocarcinoma or squamous cell carcinoma, which technically could limit the effects of erlotinib, as shown in various earlier phase II/III studies of erlotinib in EGFR negative and SCC patients. Another phase Ib clinical study completed this year assessed the combination of quinacrine and capecitabine in metastatic colon cancer patients (clinical trial identifier NCT01844076) [106]. Three patients showed SD and one showed PR in the dose-finding cohort of the study, while two out of the seven patients in the expansion cohort showed SD on 100 mg/kg QC.…”

Quinacrine binds to the kinase domain of FGFR1 and inhibits its activity

“…Quinacrine, a synthetic acridine-based anti-malarial drug, has been well studied and documented for its antineoplastic activity in numerous preclinical and clinical studies [12][13][14]. The molecular mechanisms of its anti-cancer effects have been reported to be mediated through the activation of p53 signaling, induction of autophagy, DNA and mitochondrial damage, and facilitation of interaction between TRAIL and death receptor DR5 [15][16][17][18].…”

Quinacrine, an Old Drug with Potentially usefull in the Treatment for COVID-19

“…Recently, Qx has been tested in several cancer trials (NCT01839955, NCT00417274, NCT01844076) and prion disease (NCT00183092, NCT00104663). Moreover, it was found that the maximum tolerated dose of Qx was 100 mg twice daily per 21 d in a colorectal cancer study ( 12 ).…”