Preoperative Valproic Acid and Radiation Therapy for Rectal Cancer (V-shoRT-R3)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: Capecitabine; Radiation: preoperative radiation therapy; Drug: Valproic Acid

• Study Type: Interventional
• Enrollment (Anticipated): 152
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Antonio Avallone, M.D.; Phone Number: +39 081 5903629; Email: avalloneantonio@libero.it
• Study Contact Backup: Name: Maria Carmela Piccirillo, M.D.; Phone Number: +39 081 5903571; Email: marilina.piccirllo@usc-intnapoli.net

Study Locations

• Italy
  • Napoli, Italy
    • Recruiting
    • Istituto Nazionale Tumori Fondazione G. Pascale

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

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	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
evaluation of predictive factors	description of predictive role of early tumor metabolic changes measured by PET scan	2 months
predictive and prognostic factors of tumor and circulating cells	descriptive exploratory analyses	2 months

Collaborators and Investigators

• Sponsor: National Cancer Institute, Naples

Publications and helpful links

General Publications

• Avallone A, Piccirillo MC, Delrio P, Pecori B, Di Gennaro E, Aloj L, Tatangelo F, D'Angelo V, Granata C, Cavalcanti E, Maurea N, Maiolino P, Bianco F, Montano M, Silvestro L, Terranova Barberio M, Roca MS, Di Maio M, Marone P, Botti G, Petrillo A, Daniele G, Lastoria S, Iaffaioli VR, Romano G, Caraco C, Muto P, Gallo C, Perrone F, Budillon A. 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). BMC Cancer. 2014 Nov 24;14:875. doi: 10.1186/1471-2407-14-875.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Anticipated): November 1, 2023
• Study Completion (Anticipated): April 1, 2024

Study Registration Dates

• First Submitted: July 2, 2013
• First Submitted That Met QC Criteria: July 9, 2013
• First Posted (Estimate): July 12, 2013

Study Record Updates

• Last Update Posted (Actual): March 24, 2023
• Last Update Submitted That Met QC Criteria: March 23, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: rectal; low risk; moderate risk
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Capecitabine; Valproic Acid
• Other Study ID Numbers: V-shoRT-R3; 2012-002831-28 (EudraCT Number)