Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid - short RadioTherapy - rectum 3rd trial)

Abstract

BackgroundLocally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target.Methods/DesignTwo parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500–825 mg/m2/bid), on days 1–21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50–100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT.DiscussionThis project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28.Trial registrationClinicalTrials.gov number, NCT01898104.

Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression

“…Based on the current study and on the results that were obtained in colorectal cancer models, in which we showed a synergistic antitumor effect of the HDACi vorinostat and capecitabine, we recently launched a phase-I/II clinical study (V-ShoRT-R3 trial) to explore whether the addition of both VPA and capecitabine to short-course radiotherapy, before optimal radical surgery, might increase the pathologic complete tumor regression rate in low-moderate risk rectal cancer patients [ 53 ].…”

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

“…Currently valproate is being evaluated in combination with cisplatin in a phase 2 clinical trial in refractory and recurrent mesothelioma patients [13]. We have recently launched a Phase ½ clinical study of VPA in combination with capecitabine and short-course radiotherapy as preoperative treatment in locally advanced rectal cancer patients (EudraCT Number: 2012-002831-28) [14]. …”

Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells

“…Therefore, high concentrations of HDACi should be avoided in order to decrease side-effects in normal tissues ( 35 ). One advantage of radiotherapy is that it can directly target tumors; consequently, identification of the minimal dose of HDACi that can restore/enhance MICA/B expression following IR may facilitate clinical applications ( 36 ). Thus, we titrated vorinostat against insensitive cells to determine the lowest concentration of HDACi that can restore IR-induced MICA/B expression.…”