Randomized phase 2 study of Valproic acid combinEd with rechallenge anti-EGFR based regimen regimens in pretreated patients with RAS/BRAF wild-type metastatic colorectal cancer - (VICTORIA -PNRR-MCNT2-2023-12377998)

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] - Digestive System Diseases [C06], Diseases [C] - Neoplasms [C04]

Trial duration

18 Dec 2024 → ongoing

Decision date (initial)

2024-09-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

Study Part 1:
to assess the antitumor activity of the experimental arm with panitumumab + irinotecan in combination with VPA (given until progression or inacceptable toxicity) as compared to standard treatment with panitumumab + irinotecan, measured as an improved rate of assessable patients alive at 16 weeks.

Study Part 2:
to assess the antitumor activity of the addition of VPA to panitumumab + irinotecan (given until progression or inacceptable toxicity), in patients progressed to standard treatment (ARM A, irinotecan + panitumumab), measured as the rate of assessable patients alive and at 8 weeks from progression to VICTORIA - Study Part 1.

Secondary objectives 2

1. Study Part 1: To assess whether an improvement in activity, safety, tolerability and quality of life can be achieved in the experimental arm as compared to the standard arm.
2. Study Part 2: To assess whether an improvement in activity, safety, tolerability and quality of life can be achieved in the experimental arm.

Conditions and MedDRA coding

RAS/BRAF wild-type metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 1. Written informed consent to study procedures and to correlative studies.
2. 2. Either sex aged ≥ 18.
3. 3. Histologically proven of colorectal adenocarcinoma
4. 4. Diagnosis of metastatic disease.
5. 5. 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.
6. 6. RAS (NRAS and KRAS exon 2,3 and 4) and BRAF wild-type in liquid biopsy at study entry (according to central testing).
7. 7. 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.
8. 8. Received a subsequent line of therapy upon progression. Note. Patients must have received at least 2 lines of treatment. Previous treatment with regorafenib, trifluridine/tipiracile, 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.
9. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 at study entry.
10. 10. Imaging-documented measurable disease, according to RECIST 1.1 criteria.
11. 11. Estimated life expectancy of more than 12 weeks.
12. 12. 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.
13. 13. 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.
14. 14. 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).
15. 15. Electrolytes (i.e. magnesium, calcium, sodium and potassium) within laboratory normal range.

Exclusion criteria 14

1. 1. 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.
2. 2. Any contraindication to panitumumab or irinotecan.
3. 3. Not received immunotherapy if dMMR or MSI-H.
4. 4. 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.
5. 5. Major surgical intervention within 4 weeks prior to enrollment.
6. 6. Pregnancy and breast-feeding.
7. 7. Any brain metastasis.
8. 8. Patients with long QT-syndrome or QTc interval duration > 480 msec or concomitant medication with drugs prolonging QTc
9. 9. 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.
10. 10. 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.
11. 11. Participation in any interventional drug or medical device study within 30 days prior to treatment start.
12. 12. 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.
13. 13. History of interstitial pneumonitis or pulmonary fibrosis.
14. 14. History of corneal perforation or ulceration keratitis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Study Part 1_Progression-free survival (PFS) rate at 16 weeks: measured as the time from the date of randomization until the date of the first observation of disease progression or death due to any cause, whichever occurs first.
2. Study Part 2_PFS rate at 8 weeks: defined as the rate of assessable patients alive and not progressed after 8 weeks from initiation of VICTORIA - Study Part 2 (i.e End of Treatment Visit with documentation of progression to VICTORIA - Study Part 1, for patients randomized to ARM A - standard treatment).

Secondary endpoints 14

1. Study Part 1: Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1.
2. Study Part 1: Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
3. Study Part 1: Progression-free survival (PFS) measured as the time from the date of randomization until the date of the first observation of disease progression or death due to any cause, whichever occurs first.
4. Study Part 1: Overall survival (OS) calculated as the time from the date of randomization until the date of death from any cause.
5. Study Part 1: Safety evaluated as adverse events graded according NCI CTCAE v. 5.0.
6. Study Part 1: Quality of life (QoL) investigated through the EORTC QLQ-C30 and CR29 questionnaires.
7. Study Part 1: Patient Report Outcome (PRO)-CTCAE with items dedicated in particular to diarrhea and skin toxicity to evaluate the effect of the treatment on the health-related QoL.
8. Study Part 2: Progression-free survival (PFS) measured as the time from the date from initiation of VICTORIA - Study Part 2 (i.e. at End of Treatment Visit with documentation of progression to VICTORIA - Study Part 1) until the date of the first observation of disease progression or death due to any cause, whichever occurs first.
9. Study Part 2: Overall survival (OS) calculated as the time from the date from initiation of VICTORIA - Study Part 2 (i.e. at End of Treatment Visit with documentation of progression to VICTORIA - Study Part 1) until the date of death from any cause.
10. Study Part 2: Objective Tumor Response Rate (ORR) assessed according to RECIST criteria 1.1.
11. Study Part 2: Disease Control Rate (DCR) defined as the proportion of patients with complete/partial response and stable disease as their best response.
12. Study Part 2: Safety evaluated as adverse events graded according NCI CTCAE v 5.0.
13. Study Part 2: Quality of life (QoL) investigated through the EORTC QLQ-C30 and CR29 questionnaires.
14. Study Part 2: Patient Report Outcome (PRO)-CTCAE with items dedicated in particular to diarrhea and skin toxicity to evaluate the effect of the treatment on the health-related QoL.

Investigational products

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

Test 4

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

Antonio Avallone

Public contact point

Organisation

IRCCS Istituto Nazionale Tumori Fondazione Pascale

Contact name

Antonio Avallone

Locations

1 EU/EEA country · 10 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 61 files

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

Application history

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