Abstract 405P
Background
A fundamental problem in the current treatment of patients (pts) with metastatic colorectal cancer (mCRC) is a lack of new effective drugs. Bartek et al. (Nature 2017) have described the molecular mechanisms of disulfiram and copper effects on cancer cells and that disulfiram can enhance the cytotoxic anti-cancer effect of irinotecan in colorectal cancer cells. The present study is an investigator-initiated phase II study which combines irinotecan with disulfiram and cobber in patients with irinotecan-resistant mCRC (Eudract no. 2019-002748-25). The dose-finding part was presented at ESMO WCGC 2021 (Tarpgaard et al, WCGC 2021). Here, we present the first data from the completed phase II.
Methods
The primary end-point was at least 30% of pts without PD at the second scan (18 weeks after inclusion). Main inclusion criteria were irinotecan-resistant mCRC, PS 0-1, and willingness to refrain from alcohol. The dose-finding part showed that the use of continuous disulfiram 400 mg/day was too toxic. In the phase II part, we used a regimen of irinotecan 250 mg/m2 iv day 1 with disulfiram 400 mg/day, days -4 to 3 and 100-400 mg/day, days 4-10 + copper 2 mg/day, days -4 to 10. 24 pts was planned (Simon's two-stage design).
Results
Twenty-four patients were included, median age was 67 (47-78) years. Median time from metastatic disease to inclusion was 42 (11-93) months, and pts had received median 4 (2-7) prior lines of therapy. Pts received median 3 (1-9) cycles, 2 pts continue therapy, and 8 pts are still alive. Only 3 pts (13 %) had no PD after 18 weeks. Median PFS and OS were 2.6 months (95% CI 2.0-3.9) and 12.8 months (95% CI 4.9-14.9), respectively. Fatigue was the most frequent toxicity seen in 16 pts (15 grade 2, 1 grade 3). Hypertension was the only other grade 3 toxicity (n=2).
Conclusions
We have tested a repurposing strategy by combining disulfiram and copper with irinotecan. The treatment was well-tolerated, but the primary endpoint was not met. Thus, irinotecan combined with disulfiram and copper cannot be suggested as a treatment for irinotecan-resistant mCRC pts. However, pts in the study demonstrate a long OS, probably due to the selection of patients in good general condition.
Clinical trial identification
Eudract no. 2019-002748-25.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Danish Cancer Society (R236-A14830 and R231-A13971).
Disclosure
All authors have declared no conflicts of interest.