Hydroxychloroquine Plus Itraconazole Shows No Antitumor Activity in Advanced EOC

Although the combination of hydroxychloroquine and itraconazole was shown to be feasible in heavily pre-treated patients with platinum-resistant epithelial ovarian cancer (EOC), the regimen did not show any antitumor activity, according to study findings presented at the virtual 2020 ASCO Annual Meeting.

“In preclinical studies the itraconazole effect can be enhanced by combining it with the autophagy inhibitor hydroxychloroquine. Drug repurposing studies with itraconazole have shown a signal of activity in prostate, lung and basal cell carcinoma,” wrote Ainhoa Madariaga, MD, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada, and colleagues.

Using a rolling-6 phase I design, Dr Madariaga enrolled 11 patients with platinum-resistant/refractory EOC who were given itraconazole 300 mg twice daily plus hydroxychloroquine (range 200-600 mg twicedaily)continuously in a 28-day cycle.

The main end point was a maximum-tolerated dose, and secondary end points were response rate and progression free survival (PFS). Biopsies were mandatory before and during therapy to evaluate exploratory objectives.

Patients in the study had a histology that was high 91% and low-grade serous 9%, and had previously received 7 median lines of therapy. Overall, 9 patients were evaluable for efficacy.

The investigators observed 1 DLT in dose-level 2 (grade 3 hypertension); grade 3 hypokalemia and grade 4 QTc prolongation were also observed in 1 patient given dose level 3.

According to the findings, no patients had objective responses and 1 had stable disease; the median PFS was 1.6 months.

Ten patients had biopsies from before and during treatment available, and IHC revealed increases in autophagy related protein, LC3, P62 and lysosomal marker, LAMP1, expression in 3 patients.

There were no differences between samples taken before and during therapy with regard to cholesterol homeostasis, angiogenesis, lysosomal-autophagy, and PI3K-mTOR pathways, according to RNAseq.

“The combination of itraconazole and hydroxychloroquine was feasible but did not show anti-tumour activity in this heavily pre-treated platinum resistant EOC population. Increase of IHC expression in autophagy related proteins was detected in 30% of patients but did not correlate with patient benefit,” Dr Madariaga and co-investigators concluded. —Hina Porcelli