Abstract
Simple SummaryThis is the first phase II study of high dose rabeprazole repurposing (1.5 mg/kg bid, three days a week) combined with metronomic capecitabine (mCAP), 1500 mg/daily, in gastrointestinal cancer, aimed at evaluating the activity and safety of high-dose proton pump inhibitor in combination with mCAP as salvage treatment in pretreated patients. A 3-months PFS rate of 66% and 57% was reported in the mCAP-rabeprazole and mCAP group, respectively. Although, the adjunct of high dose rabeprazole to mCAP did not improve mCAP activity, the combination of proton pump inhibitor with chemotherapy would deserve to be further investigated. Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumor microenvironment acidification thus restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). Methods: A phase II study in which patients with gastrointestinal cancer, refractory to standard treatments, who had a life expectancy >3 months, were blind randomized 1:1 to mCAP, 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg bid, three days a week. The primary endpoint was 3-months progression-free survival (PFS). The secondary endpoints were clinical benefit (CB) and overall survival (OS). Safety and plasma concentrations of capecitabine and its metabolites (5′-DFUR and 5-FU) were also evaluated. Results: Sixty-seven (median age 69 years; 63% male; 84% colorectal cancer, 76% ECOG-PS ≤ 1; 84% pretreated with two or more lines of chemotherapy) out of 90 patients screened for eligibility, were randomized to receive mCAP+rabeprazole (n = 32) vs. mCAP (n = 35). All patients were evaluable for response. No significant difference between mCAP+rabeprazole vs. mCAP, in terms of 3-months PFS rate (HR = 1.43, 95%CI 0.53–3.85; p = 0.477), median PFS (HR = 1.22, 95%CI 0.75–2.00, p = 0.420), CB (RR = 0.85, 95%CI 0.29–2.44; p = 0.786) and median OS (HR = 0.89, 95%CI 0.54–1.48; p = 0.664) was observed. However, a 3-year OS rate of 10% and 12% was reported in the mCAP-rabeprazole and mCAP groups, respectively. Overall, no grade 3 or 4 toxicity occurred but grade 1 or 2 adverse event of any type were more frequently in the mCAP+rabeprazole group than in the mCAP (OR 2.83, 95%CI 1.03–7.79; p = 0.043). Finally, there was not statistically significant difference in the plasma concentration of capecitabine and its metabolites between the two groups. Conclusions: Although the adjunct of high dose rabeprazole to mCAP was not shown to affect mCAP activity, as PPI are being investigated worldwide as drugs to be repositioned in cancer treatment and also considering the limited sample size as well as the favorable safety profile of the combination in the present study, further clinical investigations are desirable.
Highlights
The extracellular acidification of the tumor’s microenvironment was reported to underlie proliferation and metastatization of cancer cells and anticancer drugs resistance [1].the lactate production, following the increased anaerobic glycolysis, even under normal oxygen concentrations (Warburg effect), and the consequent pH decrease in the tumor microenvironment would impair the uptake of weakly basic cytotoxic drugs reducing their therapeutic effectiveness [1].the activity of vacuolar H+-ATPases (V-ATPases), which is an ATP-dependent proton pump that generate the pH gradient across both plasma and intracellular organelles membranes, is enhanced in lysosomal type vesicles of cancer cells leading to both drugs sequestration into acidic vesicles and their extrusion [2]
Because acidic microenvironment is necessary for pump inhibitors (PPIs) transformation into active molecules, PPIs should be delivered at intermittent high dose to achieve an anti-tumor effect
Between 10 February 2014, and 8 May 2019, a total of 90 patients were screened for eligibility (Figure 1)
Summary
The extracellular acidification of the tumor’s microenvironment was reported to underlie proliferation and metastatization of cancer cells and anticancer drugs resistance [1].the lactate production, following the increased anaerobic glycolysis, even under normal oxygen concentrations (Warburg effect), and the consequent pH decrease in the tumor microenvironment would impair the uptake of weakly basic cytotoxic drugs reducing their therapeutic effectiveness [1].the activity of vacuolar H+-ATPases (V-ATPases), which is an ATP-dependent proton pump that generate the pH gradient across both plasma and intracellular organelles membranes, is enhanced in lysosomal type vesicles of cancer cells leading to both drugs sequestration into acidic vesicles and their extrusion [2]. Increasing the pH of the tumor microenvironment by targeting V-ATPases would represent an intriguing way to overcome the multi-drug resistance [3] It has been demonstrated both in vitro and in vivo experiments that higher proton pump inhibitors (PPIs) doses than those used to block H+/K+-ATPase on gastric parietal cells can inhibit V-ATPases, modulate tumor acidification and restore chemotherapeutic sensitivity in drug-resistant cancer cell [4,5,6]. Proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumor microenvironment acidification restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). No significant difference between mCAP+rabeprazole vs. mCAP, in terms of 3-months
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