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

Primary Purpose

Colorectal Cancer

Status
Recruiting
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
preoperative radiation therapy
Valproic Acid
Capecitabine
Sponsored by
National Cancer Institute, Naples
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring rectal, low risk, moderate risk

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Istituto Nazionale Tumori Fondazione G. PascaleRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

SCRT

V-SCRT

C-SCRT

VC-SCRT

Arm Description

short course radiotherapy (SCRT) alone 25 Gy in 5 fractions over one week.

Valproic acid (V) + short course radiotherapy

capecitabine (C) + short course radiotherapy

valproic acid + capecitabine + short course radiotherapy

Outcomes

Primary Outcome Measures

maximum tolerated dose of capecitabine, given alone or in combination with valproic acid
Phase 1 primary objective
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

Secondary Outcome Measures

overall survival
number of patients alive with disease progression
number of patients with pathologic complete response
changes in quality of life from baseline

Full Information

First Posted
July 2, 2013
Last Updated
March 23, 2023
Sponsor
National Cancer Institute, Naples
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1. Study Identification

Unique Protocol Identification Number
NCT01898104
Brief Title
Preoperative Valproic Acid and Radiation Therapy for Rectal Cancer
Acronym
V-shoRT-R3
Official Title
Phase 1/2 Study of Valproic Acid and Short-course Radiotherapy Plus Capecitabine as preoperatIve Treatment in Low-moderate Risk Rectal Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 2012 (undefined)
Primary Completion Date
November 2023 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute, Naples

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer
Keywords
rectal, low risk, moderate risk

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
152 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
SCRT
Arm Type
Active Comparator
Arm Description
short course radiotherapy (SCRT) alone 25 Gy in 5 fractions over one week.
Arm Title
V-SCRT
Arm Type
Active Comparator
Arm Description
Valproic acid (V) + short course radiotherapy
Arm Title
C-SCRT
Arm Type
Active Comparator
Arm Description
capecitabine (C) + short course radiotherapy
Arm Title
VC-SCRT
Arm Type
Active Comparator
Arm Description
valproic acid + capecitabine + short course radiotherapy
Intervention Type
Radiation
Intervention Name(s)
preoperative radiation therapy
Intervention Description
25 Gy in 5 fractions over 1 week
Intervention Type
Drug
Intervention Name(s)
Valproic Acid
Intervention Type
Drug
Intervention Name(s)
Capecitabine
Primary Outcome Measure Information:
Title
maximum tolerated dose of capecitabine, given alone or in combination with valproic acid
Description
Phase 1 primary objective
Time Frame
up to 3 weeks
Title
number of patients with complete pathological tumor regression
Description
evaluated at definitive surgery, planned 8 weeks after the end of radiotherapy, in all the study arms of Phase 2
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
overall survival
Time Frame
1 year
Title
number of patients alive with disease progression
Time Frame
one year
Title
number of patients with pathologic complete response
Time Frame
2 months
Title
changes in quality of life from baseline
Time Frame
up to 3 months
Other Pre-specified Outcome Measures:
Title
evaluation of predictive factors
Description
description of predictive role of early tumor metabolic changes measured by PET scan
Time Frame
2 months
Title
predictive and prognostic factors of tumor and circulating cells
Description
descriptive exploratory analyses
Time Frame
2 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Antonio Avallone, M.D.
Phone
+39 081 5903629
Email
avalloneantonio@libero.it
First Name & Middle Initial & Last Name or Official Title & Degree
Maria Carmela Piccirillo, M.D.
Phone
+39 081 5903571
Email
marilina.piccirllo@usc-intnapoli.net
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Avallone, M.D.
Organizational Affiliation
National Cancer Institute, Naples
Official's Role
Principal Investigator
Facility Information:
Facility Name
Istituto Nazionale Tumori Fondazione G. Pascale
City
Napoli
Country
Italy
Individual Site Status
Recruiting

12. IPD Sharing Statement

Citations:
PubMed Identifier
25421252
Citation
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.
Results Reference
derived

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Preoperative Valproic Acid and Radiation Therapy for Rectal Cancer

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