ValproIc Acid to Potentiate Anti-EGFR Treatment Efficacy and Prevent/Revert Resistance in Colorectal Cancer

NCT06714357 | Recruiting Phase 2

• 2 other identifiers: VICTORIA2024-514420-16-00
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 8

Brief Summary

The investigators hypothesize that the epigenetic agent valproic acid improve the activity of anti-EGFR agents, prevent and revert the emergence of EGFR resistance, in a rechallenge setting. Correlative mechanistic studies on tissue and blood samples, liquid biopsies, could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti- EGFR treatment strategy.

Conditions

Colorectal Cancer Metastatic

Keywords

Metastatic colorectal cancer; RAS/BRAF wt; Liquid biopsy; Valproic Acid; anti-EGFR treatment; epigenetic reprogramming

Outcome Measures

Primary Outcomes (1)

• Study Part 1 - Progression Free Survival rate at 16 weeks in the two arms.

  Progression Free Survival rate at 16 weeks (PFS rate at 16-weeks) is defined as the rate of assessable patients alive and not progressed after 16 weeks from initiation of VICTORIA - Study Part 1 (i.e randomization) to the first documentation of objective disease progression by RECIST 1.1 criteria, or death due to any cause, whichever occurs first.

  up to 16 weeks from randomization

Secondary Outcomes (8)

• Study Part 1: Progression free survival (PFS)

  up to 1 year last patients randomized

• Study Part 1 - Overall survival (OS)

  up to 1 year last patients randomized

• Study Part 1: Objective Tumor Response Rate (ORR)

  up to 1 year last patients randomized

• Study Part 1: Disease Control Rate (DCR)

  up to 1 year last patients randomized

• Study Part 1: Overall Toxicity rate

  up to 1 year last patients randomized

Study Arms (2)

STUDY PART 1 - ARM A - control arm

ACTIVE COMPARATOR

Patients will continue to receive standard rechallenge with irinotecan and panitumumab until treatment failure, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria.

Drug: irinotecan; Drug: panitumumab

STUDY PART 1 - ARM B - experimental arm

EXPERIMENTAL

Patients will continue to receive standard rechallenge with irinotecan and panitumumab in combination with VPA until treatment failure, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria.

Drug: irinotecan; Drug: panitumumab; Drug: Valproic Acid (VPA)

Interventions

irinotecan DRUG

Administered at the dosage of 180 mg/m2 over 60 minutes

STUDY PART 1 - ARM A - control arm; STUDY PART 1 - ARM B - experimental arm

panitumumab DRUG

Administered as 60 minutes, or 90 minutes for doses over 1000 mg, intravenous infusion at the dosage of 6 mg/kg

STUDY PART 1 - ARM A - control arm; STUDY PART 1 - ARM B - experimental arm

Valproic Acid (VPA) DRUG

VPA will be administered in each patient with a titration strategy to improve the compliance for the treatment, looking for a target serum level between 50 and 100 μg/mL that represents the recommended values for the treatment of epilepsy and also a useful concentration to produce the desired synergistic effect with chemotherapy based on preclinical studies. Administrated at the dosage of 500 mg/three times a day (after 7 days of gradual dose escalation).

STUDY PART 1 - ARM B - experimental arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent to study procedures and to correlative studies.
• Either sex aged ≥ 18.
• Histologically proven of colorectal adenocarcinoma.
• Diagnosis of metastatic disease.
• RAS/BRAF wild-type status at initial diagnosis assessed at local centers according with a validated method defined by EMA and known MMR/MSI status
• RAS (NRAS and KRAS exon 2,3 and 4) and BRAF wild-type in liquid biopsy at study entry (according to central testing).
• Patient candidate to anti-EGFR rechallenge therapy with panitumumab and irinotecan as clinical practice; Efficacy of anti-EGFR drug in any line of treatment with a major response achieved (i.e. complete or partial response according to RECIST criteria v1.1) or stable disease ≥ 6 months and received a subsequent line of therapy upon progression.
• a. Note. Patients must have received at least 2 lines of treatment. Previous treatment with regorafenib, trifluridine/tipiracile, trifluridine/tipiracile + bevacizumab or fruquintinib is allowed. Previous rechallenge with anti-EGFR MoAb is NOT allowed. Adjuvant treatment will be considered as one line of therapy in case of progression within 6 months from the last dose of treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
• Imaging-documented measurable disease, according to RECIST 1.1 criteria.
• Estimated life expectancy of more than 12 weeks
• Adequate bone marrow hematological function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L and platelet count ≥ 100 x 109/L and hemoglobin ≥ 9 g/dL.
• Adequate liver function: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 2 (in case of biliary stent) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5 X ULN.
• Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥50 mL/min in females (calculated according to Cockroft-Gault formula).
• Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.

You may not qualify if:

• Prior malignancy within five years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Any contraindication to panitumumab or irinotecan.
• Not received immunotherapy if dMMR or MSI-H.
• Patients who have had prior treatment with an HDAC inhibitor and patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid.
• Major surgical intervention within 4 weeks prior to enrollment.
• Pregnancy and breast-feeding.
• Any brain metastasis.
• Patients with long QT-syndrome or QTc interval duration \> 480 msec or concomitant medication with drugs prolonging QTc .
• Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol, or would interfere with the results of the study.
• History of poor co-operation, non-compliance with medical treatment, unreliability or any condition that may impair the patient's understanding of the Informed consent form.
• Participation in any interventional drug or medical device study within 30 days prior to treatment start.
• Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.
• History of interstitial pneumonitis or pulmonary fibrosis.
• History of corneal perforation or ulceration keratitis.
• Hypersensitivity to valproic acid or any of listed excipients.

Sponsors & Collaborators

• National Cancer Institute, Naples: lead

Study Sites (8)

AORN Sant'Anna e San Sebastiano

Caserta, CE, Italy

RECRUITING

Università degli studi della Campania Luigi Vanvitelli

Naples, Italia, Italy

RECRUITING

AORN San Giuseppe Moscati Avellino

Avellino, Italy, Italy

ACTIVE NOT RECRUITING

Azienda Sanitaria Universitaria Friuli Centrale

Udine, Italy, Italy

NOT YET RECRUITING

Pia Fondazione Di Culto E Religione Card G Panico

Tricase, Lecce, Italy

NOT YET RECRUITING

Ospedale Civile San Giovanni di Dio

Frattamaggiore, Napoli, Italy

NOT YET RECRUITING

Istituto Nazionale Tumori IRCCS Fondazione G. Pascale

Naples, Napoli, 80131, Italy

RECRUITING

Presidio Ospedaliero "Santa Maria delle Grazie"

Pozzuoli, PZ, Italy

NOT YET RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Irinotecan; Panitumumab; Valproic Acid

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Central Study Contacts

Antonio Avallone, MD

CONTACT

08117770357; a.avallone@istitutotumori.na.it

Alfredo Budillon, MD

CONTACT

08117770583; a.budillon@istitutotumori.na.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2024
• First Posted: December 3, 2024
• Study Start: March 12, 2025
• Primary Completion (Estimated): December 20, 2026
• Study Completion (Estimated): June 20, 2027
• Last Updated: December 17, 2025

Record last verified: 2025-12

Locations

IT (8)