Ricerc@Sapienza

Abstract: Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose
tomodulate tumormicroenvironment 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 (50-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 dierence 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 dierence 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 aect 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.