Evaluation of Efficacy of Trifluridine/Tipiracil Plus an Anti-IL-1α True Human Antibody Versus Trifluridine/Tipiracil Plus Placebo in Metastatic Colorectal Cancer Patients After Failure of Oxaliplatin, Irinotecan, Fluoropyrimidine

Metastatic Colorectal Cancer Clinical Trial

— TASKIN  

Official title:

Multicentric Randomized Phase I/II Study to Evaluate Efficacy of Trifluridine/Tipiracil Plus XB2001 (Anti-IL-1α True Human Antibody) Versus Trifluridine/Tipiracil Plus Placebo in Metastatic Colorectal Cancer Patients After Failure of Oxaliplatin, Irinotecan, Fluoropyrimidine

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05201352
• Other study ID #: 2020-004601-31
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: October 13, 2022
• Est. completion date: October 13, 2026

Study information

• Verified date: February 2024
• Source: Centre Georges Francois Leclerc
• Contact: François GHIRINGHELLI, PU-PH
• Phone: 03.80.73.77.14
• Email: fghiringhelli[@]cgfl.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Unresectable metastatic colorectal cancer (mCRC) remains an incurable disease. After failure of conventional treatments involving fluoropyrimidines, oxaliplatin and irinotecan in combination or not with biotherapies targeting EGFR and VEGF; regorafenib shows a modest improvement in overall survival. Recently, trifluridine/tipiracil has also shown efficacy in phase 3 with an overall survival of around 7 months. Trifluridine/tipiracil has become the standard of care for advanced mCRC in most western countries. However, the objective response rate remains very low and the survival gain remains moderate (+2 months). Therefore, new strategies are needed to ensure that mCRC patients who have received multiple lines of therapy can receive more effective treatments. Based on previous clinical trials on IL-1 inhibition and our preclinical data, IL-1 inhibition may increase the efficacy of trifluridine/tipiracil. The goal is to test whether the addition of XB2001 to trifluridine/tipiracil could be synergistic.

Description:

This project proposes to evaluate trifluridine/tipiracil plus XB2001 in patients with metastatic colorectal cancer previously treated with oxaliplatin, fluoropyrimidine and irinotecan in combination or not with an anti-angiogenic and an anti-EGFR for RAS Wild type tumor. The project will consist of a randomized (1:1 ratio), double-blind, non-comparative, multi-center Phase II study with two treatment arms: - Experimental arm: trifluridine/tipiracil + XB2001 - Control arm: trifluridine/tipiracil + placebo

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: October 13, 2026
• Est. primary completion date: October 13, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female that must have signed a written informed consent prior to any study specific procedures
• Aged = 18 years at randomization
• Patient with histologically proven metastatic colorectal cancer previously treated for metastatic disease by chemotherapy treatment including oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenic (anti-VEGF: bevacizumab or aflibercept) and anti-EGFR (cetuximab or panitumumab) if indicated (MSI tumor could be included if previously pretreated with anti PD1/PDL1 therapy)
• Have a performance status of 0 or 1 according to the WHO Easter Cooperative Oncology Group (ECOG)
• Knowledge of RAS, BRAF, Microsatellite status
• Baseline tumoral evaluation (thoraco-abdomino-pelvic computed tomography) perfromed within 21 days before randomization with at least one measurable lesion according to RECIST 1.1 criteria.
• Patient willing and able to comply with protocol for the duration of the study including: scheduled visits and exams, visits during the follow-up and treatment compliance.
• Adequat hepatic, renal and bone marrow function within the following limits:
• Total bilirubin = 1,5 times the upper limit of normal (ULN) (unless documented Gilbert's syndrome);
• ASAT et ALAT = 5 times ULN;
• Measured Creatinine clearance (Cockcroft and Gault) > 30 ml / min
• Absolute Neutrophil Count (ANC) > 1,5. 109 / L;
• Platelet count = 150. 109 / L;
• Haemoglobin = 9 g / dL (patients can be included even if they have been transfused)
• Albuminemia = 30 g / L;
• Negative Hepatitis B, C and HIV serologies, or absence of active B or C hepatitis
• Urea protein, urine dipstick should be less than 2 crossese or <1g/kg
• Availability of tumor material dated less than 2 years with sufficient quantity (15 to 20 whithe slides)
• Patient must be affiliated to a social health insurance
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients (urine within 72h or serum pregnancy within 14 days prior to inclusion).
• Women of childbearing potential willing to use adequate contraception method (including the use of a mechanical method of contraception in the event of hormonal contraceptive treatment) during the treatment period and 6 months following the end of treatment.
• Male patients with a partner of childbearing potential should use effective contraception during treatment and for up to 6 months after stopping treatment.
• Normal ECG or ECG without clinically significant findings with QTc < 470 ms.

Exclusion Criteria:

• Other concurrent malignancies the last 3 years, except adequately treated cone-biopsied in situ carcinoma of the cervix, basal cell, squamous cell carcinoma of the skin or low risk prostate cancer. Patient who have had potentially curative therapy for a prior malignancy are eligible provided there has been no evidence of disease for = 5 years and the risk of recurrence is considered low.
• Symptomatic brain metastases
• Estimated prognosis <3 months.
• Mutational status BRAF mutant
• Participation in progress, or in the 30 days preceding the first scheduled day of dosing in this study, in another therapeutic trial with an experimental molecule or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer.
• Severe unbalanced illness, underlying infection that may prevent the patient from receiving treatment. Patients with a clinically important and unresolved Grade 3 or 4 non-haematologic adverse reaction related to previous therapies. Also participant with any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
• Bowel obstruction or sub-obstruction or a history of inflammatory bowel disease or significant gasto intestinal disorder
• History of autoimmune or inflammatory disease or interstitial lung disease.
• Patient with congenital galactosemia, total lactase deficiency (lactose intolerance) or glucose-galactose malabsorption syndrome
• Severe arterial thromboembolic events less than 6 months before randomization
• New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure (defined as = 160/100 mm Hg)
• Clinically significant decrease in performance status (medical records) within 2 weeks of intended first dose administration.
• -Contraindication to receive a treatment with trifluridine/tipiracil or an anti-IL-1a (XB2001 True Human antibody)
• Concomitant systemic treatment with immunotherapy, immunosuppressants, corticosteroid therapy = 10 mg equivalent prednisone/prednisolone or hormone therapy: corticosteroid therapy administered chronically, immunosuppressive treatment, biotherapy administered as part of the management of an inflammatory disease (anti-TNF, anti-IL6, anti-IL1, anti PD-1, anti EGFR etc.) and live virus vaccines administered up to 14 days prior the first scheduled dose of treatement administration.
• Current pregnancy (mandatory pregnancy test at baseline for female of childbearing potential) or breastfeeding.
• Patient with any psychiatric, psychological, sociological, geographical problem or other severe concomitant disease, disorder or condition that potentially compromising the understanding of the information, the safety of the patient, the interpretation of study results or the conduct of the study compliance with the study protocol and follow-up schedule.
• Patient deprived of their liberty or under guardianship, curatorship or safeguard of justice.
• Known or suspected history of immunosuppression, including history of invasive opportunistic infections (e.g tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution. Presence or suspicion of active bacterial, fungal or viral infections, or uncontrolled fever.
• Major surgery within 2 weeks prior to randomization or have an unhealed operation wounds.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• trifluridine/tipiracil + XB2001
trifluridine/tipiracil every 28 days + XB2001 1000mg intravenous infusion every 2 weeks
• trifluridine/tipiracil + placebo
trifluridine/tipiracil every 28 days + Placebo intravenous infusion every 2 weeks

Locations

Country	Name	City	State
France	ICO Angers	Angers
France	Institut Sainte Catherine	Avignon
France	CHU Jean Minjoz	Besançon
France	Institut Bergonié	Bordeaux
France	Centre Hospitalier Carcassonne	Carcassonne
France	CHU Estaing	Clermont-Ferrand
France	Centre Georges-François Leclerc	Dijon	Bourgogne
France	CHU Dijon	Dijon	Bourgogne
France	Hopital Franco-Britannique	Levallois-Perret
France	CHU Dupuytren	Limoges
France	CHU Nantes	Nantes
France	Cario-Hpca	Plérin
France	Institut Jean Godinot	Reims
France	Institut de Cancérologie de l'Ouest	Saint Herblain

Sponsors (1)

Lead Sponsor	Collaborator
Centre Georges Francois Leclerc

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose (MTD) of XB2001		At the end of Cycle 1 (each cycle is 28 days)
Primary	Overall survival		6-month