title: 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: 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
  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-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov number, NCT01898104.
authors.forename: Antonio
authors.initials: A
authors.lastname: Avallone
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Piccirillo
authors.forename: Paolo
authors.initials: P
authors.lastname: Delrio
authors.forename: Biagio
authors.initials: B
authors.lastname: Pecori
authors.forename: Elena
authors.initials: E
authors.lastname: Di Gennaro
authors.forename: Luigi
authors.initials: L
authors.lastname: Aloj
authors.forename: Fabiana
authors.initials: F
authors.lastname: Tatangelo
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Angelo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Granata
authors.forename: Ernesta
authors.initials: E
authors.lastname: Cavalcanti
authors.forename: Nicola
authors.initials: N
authors.lastname: Maurea
authors.forename: Piera
authors.initials: P
authors.lastname: Maiolino
authors.forename: Franco
authors.initials: F
authors.lastname: Bianco
authors.forename: Massimo
authors.initials: M
authors.lastname: Montano
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Silvestro
authors.forename: Manuela
authors.initials: M
authors.lastname: Terranova Barberio
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Roca
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Maio
authors.forename: Pietro
authors.initials: P
authors.lastname: Marone
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.forename: Antonella
authors.initials: A
authors.lastname: Petrillo
authors.forename: Gennaro
authors.initials: G
authors.lastname: Daniele
authors.forename: Secondo
authors.initials: S
authors.lastname: Lastoria
authors.forename: Vincenzo R
authors.initials: VR
authors.lastname: Iaffaioli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romano
authors.forename: Corradina
authors.initials: C
authors.lastname: Caracò
authors.forename: Paolo
authors.initials: P
authors.lastname: Muto
authors.forename: Ciro
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Clinical Trials Unit, Istituto Nazionale Tumori "Fondazione G, Pascale" - IRCCS, Via M, Semmola 80131, Napoli, Italy. f.perrone@istitutotumori.na.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perrone
authors.forename: Alfredo
authors.initials: A
authors.lastname: Budillon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D011878:Radiotherapy / Q000379:methods; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy*; D012107:Research Design; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D003841:Deoxycytidine; D014635:Valproic Acid; D000069287:Capecitabine; D005472:Fluorouracil