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

Phase 2

Not yet recruiting

• Conditions: Colorectal Cancer Metastatic
• Interventions: Drug: irinotecan; Drug: panitumumab; Drug: Valproic Acid (VPA)

• Registration Number: NCT06714357
• Lead Sponsor: National Cancer Institute, Naples

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.

Detailed Description

This study is a multicentric open label academic randomized phase-2 study. The study population will include patients with advanced or metastatic colorectal cancer, RAS/BRAF wt mCRC, eligible for a rechallenge setting (third or later line), with RAS/BRAF wt ctDNA status at study entry. A total of 130 patients (65/arm) will be required.

The VICTORIA - Study Part 1 is a phase 2, open label, randozimed study. Before starting study Part 1 treatment, at the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (standard treatment: irinotecan + panitimumab) and ARM B (VPA + irinotecan + panitumumab) Each cycle will be administered every two weeks for both arms. Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria.

All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected.

VPA will be administered per os daily with a titration strategy (table 2 of the protocol) to improve the compliance for the treatment, with a target serum level between 50 and 100 μg/mL that represents the recommended values for epilepsy and also a useful concentration to produce the desired synergistic effect with chemotherapy based on preclinical studies (0.5- 1mM).

An initial safety run-in phase involves a safety evaluation after the first 6 patients are randomly assigned to Arm B. Enrollment will be paused after the first 6 patients randomly assigned to Arm B complete 2 cycles of treatment. The enrollment will be interrupted if the treatment combination will be judged not feasible and major safety concerns will arise. A safety review will be conducted, and recommendations will be made by the Steering Committee. The study will continue if there are 2 or fewer adverse events (AEs) of grade 3 or higher deemed related to the addition of valproic acid to the panitumumab + irinotecan.

All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal.

Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0.

Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire.

Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.

To detect a difference between the two groups of 20%; considering 5% of drop out, 61 patients in each arm will be required to achieve 80% power.

A null hypothesis of 0.50 is based on the assumption that the median PFS for RAS wt patients rechallenged with anti-EGFR is approximately 16 weeks. An alternative hypothesis of 0.70 represents a potential target of interest for further studies in this setting with the experimental treatment.

The test statistic used will be the one-sided stratified (for the stratification factors) Fisher's Exact Test. The significance level of the test is targeted at 0.10. The date of end of study will be the date of the last visit of the last patient.

Randomization will be performed with a stratified procedure that will account for tumor sidedness (left vs right), number of metastatic sites (1 vs ≥ 2), previous lines of treatment (2 vs ≥ 3 lines).

The VICTORIA - Study Part 2 is a phase 2, single arm study, designed according to the Fleming single-stage design.

In patients in ARM A, at time of disease progression, a second study will explore if the addition of VPA to irinotecan and panitumumab might revert the occurrence of resistance.

According to the Fleming single-stage design, under the null hypothesis of 0.05, based on the assumption that treatment with standard rechallenge treatment beyond progression usually leads to an extremely low PFS, and under the alternative hypothesis of a PFS rate at 8 weeks of 0.20 with the experimental treatment (a potential target of interest for further studies), considering one-sided alpha and beta errors of 0.05 and 0.20 (80.32) respectively, a total of 27 patients will be required.

A null hypothesis of 0.05 is based on the assumption that treatment beyond PD usually leads to an extremely low PFS. An alternative hypothesis of 0.20 represents a potential target of interest for further studies in this setting with the experimental treatment.

Null hypothesis will be rejected if at least 4 patients will be free of progression at 8 weeks with the experimental treatment.

Study Timeline

• Status Verified: 2024-11
• Study First Submitted: 2024-11-22
• Study First Submitted QC: 2024-11-28
• Study First Posted: 2024-12-03
• Last Update Submitted: 2025-02-27
• Last Update Posted: 2025-02-28
• Study Start: 2025-03
• Primary Completion: 2026-12-20
• Study Completion: 2027-06-20

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 130

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
STUDY PART 1 - ARM A - control arm	irinotecan	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.
STUDY PART 1 - ARM A - control arm	panitumumab	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.
STUDY PART 1 - ARM B - experimental arm	irinotecan	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.
STUDY PART 1 - ARM B - experimental arm	panitumumab	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.
STUDY PART 1 - ARM B - experimental arm	Valproic Acid (VPA)	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.

Primary Outcome Measures

Name	Time	Method
Study Part 1 - Progression Free Survival rate at 16 weeks in the two arms.	up to 16 weeks from randomization	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.

Secondary Outcome Measures

Name	Time	Method
Study Part 1 - Overall survival (OS)	up to 1 year last patients randomized	Overall survival (OS) calculated as the time from randomization until the date of death from any cause. OS will be censored at the last date the patient was known to be alive for patients alive at the time of analysis.
Study Part 1: Progression free survival (PFS)	up to 1 year last patients randomized	Progression free survival (PFS) calculated as the time from randomization until the date of death from any cause until the date of the first observation of disease progression or death due to any cause, whichever occurs first. PFS will be censored at the time of the last available tumor assessment documenting absence of progressive disease for patients alive at the time of analysis.
Study Part 1: Objective Tumor Response Rate (ORR)	up to 1 year last patients randomized	Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1, as the proportion of patients achieving complete or partial response relative to total enrolled patients.
Study Part 1: Disease Control Rate (DCR)	up to 1 year last patients randomized	Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
Study Part 1: Overall Toxicity rate	up to 1 year last patients randomized	Overall Toxicity rate defined as adverse events graded according NCI CTCAE v 5.0. as the proportion of patients experiencing any grade AE accordingly to the NCI Common Terminology Criteria of Adverse Events (NCI CTC-AE) Version 5, relative to the total of patients receiving at least one cycle of treatment.AE will be listed individually by the patient and summarized overall (severity grades 1-4) and for grade ≥3 by treatment received.
Study Part 1 - Quality of life (QoL)	up the date of first documented progression (assessed up to 1 year)	Quality of life (QoL) investigated through the PRO-CTCAE questionnaire at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death.

Trial Locations

Locations (2)

AORN Sant'Anna e San Sebastiano; 🇮🇹 Caserta, CE, Italy

Istituto Nazionale Tumori IRCCS Fondazione G. Pascale; 🇮🇹 Napoli, Italy