Preoperative Valproic Acid and Radiation Therapy for Rectal Cancer

Study Overview
=================
Brief 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.

Official Title
-----------------
Phase 1/2 Study of Valproic Acid and Short-course Radiotherapy Plus Capecitabine as preoperatIve Treatment in Low-moderate Risk Rectal Cancer

Conditions
-----------------
Colorectal Cancer

Intervention / Treatment
-----------------
* Radiation: preoperative radiation therapy
* Drug: Valproic Acid
* Drug: Capecitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SCRT<br>short course radiotherapy (SCRT) alone 25 Gy in 5 fractions over one week. | Radiation: preoperative radiation therapy<br>* 25 Gy in 5 fractions over 1 week<br>|
| Active Comparator: V-SCRT<br>Valproic acid (V) + short course radiotherapy | Radiation: preoperative radiation therapy<br>* 25 Gy in 5 fractions over 1 week<br>Drug: Valproic Acid<br> <br> |
| Active Comparator: C-SCRT<br>capecitabine (C) + short course radiotherapy | Radiation: preoperative radiation therapy<br>* 25 Gy in 5 fractions over 1 week<br>Drug: Capecitabine<br> <br> |
| Active Comparator: VC-SCRT<br>valproic acid + capecitabine + short course radiotherapy | Radiation: preoperative radiation therapy<br>* 25 Gy in 5 fractions over 1 week<br>Drug: Valproic Acid<br> <br> Drug: Capecitabine<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose of capecitabine, given alone or in combination with valproic acid | Phase 1 primary objective | up to 3 weeks | 
| number of patients with complete pathological tumor regression | evaluated at definitive surgery, planned 8 weeks after the end of radiotherapy, in all the study arms of Phase 2 | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | 1 year | 
| number of patients alive with disease progression |  | one year | 
| number of patients with pathologic complete response |  | 2 months | 
| changes in quality of life from baseline |  | up to 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
rectal, low risk, moderate risk