VshoRT-R3: Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperatIve treatment in low-moderate risk rectal cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Jan 2013 → ongoing

Decision date (initial)

2024-06-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-513920-40-00

EudraCT number

2012-002831-28

ClinicalTrials.gov

NCT01898104

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Pharmacokinetic, Therapy

Phase 1: to determine the MTD of Capecitabine given alone or in combination with valproic acid during preoperative short-course radiotherapy (SCRT).
Phase 2 (comparative):
• To explore whether the addition of valproic acid to short-course radiotherapy before optimal radical surgery might increase the pathologic complete tumor regression (TRG1) rate in patient with low-moderate risk rectal cancer.
• To explore whether the addition of capecitabine to short-course radiotherapy before optimal radical surgery might increase the pathologic complete tumor regression (TRG1) rate in patient with low-moderate risk rectal cancer.

Secondary objectives 1

1. To compare within each planned phase 2 comparison: • Local control, disease free survival and overall survival. • Pathological CRM negative (margin >1 mm) and lymph node negative rate • Short and long-term toxicity • Surgical Complications • Quality of Life • To validate the predictive role of early tumor metabolic changes measured by PET scan (both phase 1 and 2) • To explore diagnostic accuracy of pre-surgical rectal biopsy (both phase 1 and 2) • Biomarker studies on tumor and blood samples.

Conditions and MedDRA coding

low- risk rectal cancel

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. • 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 minimum distance of1 mm from mesorectal fascia (MRF) evaluated by MRI. • Age ≥18 and ≤ 75 • ECOG Performance Status ≤1 • Effective contraception for both male and female patients if the risk of conception exist • Signed written informed consent

Exclusion criteria 1

1. • 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Fase 1 : MTD capecitabina MTD capecitabina + acido valproico Fase 2: tasso di TRG1

Secondary endpoints 1

1. Local control, disease free survival and overall survival. • Pathological CRM negative (margin >1 mm) and lymph node negative rate • Short and long-term toxicity • Surgical Complications • Quality of Life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Sponsor organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Address

Via Mariano Semmola 52

City

Naples

Postcode

80131

Country

Italy

Scientific contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Maria Carmela Piccirillo

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Maria Carmela Piccirillo

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications