Recurrence with distant metastases is the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to intensify the therapeutic strategy. We have recently reported synergistic antitumor interaction between valproic acid (VPA), an histone-deacetylase inhibitor, capecitabine (CAP) and radiotherapy in colorectal cancer preclinical models.
We planned two parallel phase-1 studies in low-moderate risk LARC patients (pts) to assess the safety of preoperative short-course radiotherapy (SCRT) (5 Gy/day on days 1 to 5 days) combined with (a) CAP alone (4 increasing dose levels: 500 to 825 mg/m2/bid, on days -1 to 20), or (b) CAP as above plus VPA (orally on days -14 to 21, with an intra-patient titration for a target serum level of 50-100 μg/ml), followed by surgery 8 weeks after the end of SCRT. Within each of the two phase-1 trials, maximum tolerated dose (MTD) was defined as the dose level that produces a dose-limiting toxicity (DLT) occurring within 5 weeks from day 1 of treatment in more than one-third of pts. Correlative studies on pharmacokinetic and pharmacodynamics biomarkers on both tumor and peripheral blood samples as well as FDG-PET were also planned.
From Apr 2013 and Oct 2018, 28 pts were enrolled in the two phase-1 studies. Median age was 61 (range 46-71), 100% were PS 0. No DLT occurred with CAP alone, but a symptomatic angina occurred in a patient at the first dose level of CAP plus VPA. However, no DLT was observed within the further 3 pts enrolled at the same level, nor at the following dose levels. All but one pts underwent R0 resection. TRG1 was obtained in 6 pts, TRG2 in 11 pts, TRG3 in 8 pts and TRG4 in 3 pts.
The addition of CAP to preoperative SCRT +/- VPA is feasible and 825 mg/m2/bid is the recommended dose that will be used in an ongoing phase-2 trial, aimed to explore whether the addition of VPA and/or CAP to preoperative SCRT might increase TRG1 rate in low-moderate risk LARC pts.
Clinical trial identification
Legal entity responsible for the study
Istituto Nazionale Tumori Fondazione G. Pascale.
Italian Ministry of Health, Grant RF-2011-02346914 to AB.
All authors have declared no conflicts of interest.