preoperative valproic acid and radiation therapy for rectal cancer

Conditions: Colorectal Cancer

Summary: the purpose of this study is to first determine the maximum tolerated dose of capecitabine given alone or in combination with valproic acid during preoperative short-course radiotherapy (phase 1). the next part of the study (phase 2)will explore whether the addition of valproic acid or the addition of capecitabine to short-course radiotherapy, before optimal radical surgery might increase the pathologic complete tumor regression rate in patients with low-moderate risk rectal cancer.


Eligibility criteria:
inclusion criteria: • patients with histologically confirmed diagnosis of adenocarcinoma of rectum falling into one of the following categories: t2n0 located at \ 5 cm and \<12 cm from anal verge and infiltration of perirectal fat up to a distance of 1 mm from mesorectal fascia (mrf) evaluated by mri. * age ≥18 and ≤ 70 * ecog performance status ≤1 * effective contraception for both male and female patients if the risk of conception exist * signed written informed consent exclusion criteria: * any previous treatment for rectal cancer * previous pelvic radiotherapy * presence of metastatic disease * recurrent rectal tumor * patient with familial adenomatosis polyposis (fap) or hereditary non-polyposis colorectal cancer (hnpcc) * history of inflammatory bowel disease or active disease * any concurrent malignancy except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of cervix uteri. patients with a previous malignancy but without evidence of disease for 5 years will be allowed to enter the trial. * neutrophils \< 2000/mm3 or platelets \< 100.000/ mm3 or haemoglobin \<9 gr/dl. * creatinine levels indicating renal clearance of \<50 ml/min * got and/or gpt \> 2.5 time the unl and/or bilirubin \>1.5 time the upper-normal limits (unl) * significant cardiovascular comorbidity (e.g. myocardial infarction, superior vena cava \[svc\] syndrome, patients with an ejection fraction of \<50%) or presence of cardiac disease that in the opinion of the investigator increases the risk of ventricular arrhythmia. * history of arrhythmia (multifocal premature ventricular contractions \[pvcs\], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (ctcae grade 3) or asymptomatic sustained ventricular tachycardia. * patients with long qt-syndrome or qtc interval duration \> 480 msec or concomitant medication with drugs prolonging qtc (see list in the appendix) * known dihydropyrimidine dehydrogenase (dpd) deficiency * hiv positive patients * patients who cannot take oral medication, who require intravenous alimentation, have had prior surgical procedures affecting absorption, or have active peptic ulcer disease. * known or suspected hypersensitivity to any of the study drugs. * patient who have had prior treatment with an hdac inhibitor and patients who have received compounds with hdac inhibitor-like activity, such as valproic acid. * concurrent uncontrolled medical conditions that might contraindicate study drugs. * major surgical procedure, within 28 days prior to study treatment start. * pregnant or lactating women. * women of childbearing potential with either a positive or no pregnancy test at baseline (nb. postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. * sexually active males and females (of childbearing potential) unwilling to practice contraception during the study.

Keywords: rectal low risk moderate risk