6 research outputs found
A multidisciplinary approach is required to increase the quality of phase II/III clinical studies on biotherapies in oncology
Cycloossigenase 2 expression is associated with increased size in human sporadic colorectal adenomas
Primary gastrointestinal stromal tumor of the liver with lung metastases successfully treated with STI-571 (imatinib mesylate)
EARLY IDENTIFICATION OF LEFT VENTRICULAR DYSFUNCTION WITH SPECKLE TRACKING ECHOCARDIOGRAPHY IN ANTINEOPLASTIC THERAPY-INDUCED CARDIOTOXICITY.
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).
Background: Locally 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/Design: Two 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-istones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT.
Discussion: This 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 registration: ClinicalTrials.gov number, NCT0189810