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

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.

2012-05-01

2023-11-01

2024-04-01

Recruiting

Early phase I

152

Inclusion Criteria: • Patients with histologically confirmed diagnosis of adenocarcinoma of rectum falling into one of the following categories: T2N0 located at \<2 cm from anal verge T2N1 or T3N0-N1, 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.

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE1', 'PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 152, 'type': 'ESTIMATED'}}

2023-03-24