A Phase 2 interventional study of irinotecan and panitumumab in Colorectal Cancer Metastatic, sponsored by National Cancer Institute, Naples. Recruiting at 8 sites in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-12-17.
Sponsored by National Cancer Institute, Naples · Phase 2, Interventional, and Treatment
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.
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.
5,599 studies on the registry are indexed under Colorectal Neoplasms; 1,459 are open to participants now.
This study's planned enrollment of 130 is above the median of 77 across 4,123 interventional studies indexed under Colorectal Neoplasms.
Browse Colorectal Neoplasms studies →National Cancer Institute, Naples is the lead sponsor of 112 studies on the registry; 39 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria (Study Part 1):
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.
Exclusion Criteria (Study Part 1):
Known urea cycle disorders.
1. Have provided written informed consent to study procedures and to correlative studies.
2. Enrolled in VICTORIA - Study Part 1 and randomized to ARM A (control arm) 3. Progressed to treatment within ARM A (control arm). 4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
5. Imaging-documented measurable disease, according to RECIST 1.1 criteria. 6. Estimated life expectancy of more than 12 weeks. 7. 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. 8. 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. 9. 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). 10. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.
-Exclusion Criteria (Study Part 2):
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
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)
Administered at the dosage of 180 mg/m2 over 60 minutes
Administered as 60 minutes, or 90 minutes for doses over 1000 mg, intravenous infusion at the dosage of 6 mg/kg
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 - 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.
Time frame: up to 16 weeks from randomization
Study Part 1: Progression free survival (PFS)
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.
Time frame: up to 1 year last patients randomized
Study Part 1 - Overall survival (OS)
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.
Time frame: up to 1 year last patients randomized
Study Part 1: Objective Tumor Response Rate (ORR)
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.
Time frame: up to 1 year last patients randomized
Study Part 1: Disease Control Rate (DCR)
Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
Time frame: up to 1 year last patients randomized
Study Part 1: Overall Toxicity rate
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.
Time frame: up to 1 year last patients randomized
Study Part 1 - Quality of life (QoL)
Quality of life (QoL) investigated through the EORTC QOL-C30 questionnaires at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death.
Time frame: up the date of first documented progression (assessed up to 1 year)
Study Part 1 - Quality of life (QoL)
Quality of life (QoL) investigated through the CR29 questionnaires at baseline (prior to treatment start, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death.
Time frame: up the date of first documented progression (assessed up to 1 year)
Study Part 1 - Quality of life (QoL)
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.
Time frame: up the date of first documented progression (assessed up to 1 year)
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
National Cancer Institute, Naples