High‑dose melphalan delivered into the liver followed by trifluridine‑tipiracil plus bevacizumab versus trifluridine‑tipiracil plus bevacizumab alone for liver‑dominant metastatic colorectal cancer

An Open-label, Randomized, Multi-Center Study to Evaluate the Efficacy and Safety of Induction Treatment With Melphalan/HDS Followed by Consolidation Treatment With Trifluridine-Tipiracil Plus Bevacizumab Versus Trifluridine-Tipiracil Plus Bevacizumab Alone in Patients With Refractory Metastatic Colorectal Cancer With Liver Dominant Disease

This test sees if giving high‑dose melphalan directly into the liver followed by trifluridine‑tipiracil plus bevacizumab helps people with liver‑dominant metastatic colorectal cancer more than the drugs alone.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 90 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Delcath Systems Inc. (industry)
• Drugs / interventions: bevacizumab, chemotherapy
• Locations: 10 sites (Duarte, California and 9 other locations)
• Trial ID: NCT06607458 on ClinicalTrials.gov

What this trial studies

This open‑label, randomized Phase 2 trial will enroll about 90 patients with liver‑dominant, refractory metastatic colorectal cancer and randomize them 2:1 to melphalan/HDS (two liver‑directed high‑dose melphalan procedures) followed by trifluridine‑tipiracil plus bevacizumab (Arm A) or to trifluridine‑tipiracil plus bevacizumab alone (Arm B). Melphalan/HDS is dosed at 3.0 mg/kg ideal body weight for up to two cycles given about eight weeks apart, with imaging every eight weeks to monitor tumor response in the liver. Systemic trifluridine‑tipiracil plus bevacizumab continues in both arms until progression or unacceptable toxicity. The trial collects safety, tolerability, and liver response outcomes and does not allow crossover between arms.

Who should consider this trial

Good fit: Adults with histologically confirmed metastatic colorectal cancer that is liver‑dominant (liver lesions occupying ≤50% of liver parenchyma), measurable by CT/MRI, not suitable for curative resection or ablation, and who meet protocol performance and organ‑function criteria.

Not a fit: Patients with extensive extrahepatic disease, more than 50% liver involvement, resectable liver metastases, poor liver function, or contraindications to melphalan or bevacizumab are unlikely to benefit or may be ineligible.

Why it matters

Potential benefit: If successful, this approach could improve control of liver metastases and delay disease progression, potentially prolonging the benefit of therapy for patients with liver‑dominant disease.

How similar studies have performed: Smaller studies of hepatic‑directed melphalan or percutaneous hepatic perfusion have shown activity against liver metastases, but combining liver‑directed melphalan with trifluridine‑tipiracil plus bevacizumab remains investigational.

Eligibility criteria

Inclusion Criteria:

* Histologically confirmed diagnosis of metastatic colorectal cancer and histologically or cytologically proven CRC metastases that occupy 50% or less of the liver parenchyma.
* Patient has liver-dominant metastatic disease. Liver-dominant is defined as the majority of total tumor burden is located in the liver, and the liver lesions are not resectable or treatable with ablation or are associated with extrahepatic disease that makes surgical intervention non-curative.
* Disease in the liver must be measurable (per RECIST v.1.1 guidelines) by computed tomography (CT) and/or magnetic resonance imaging (MRI).
* If there is evidence of extrahepatic metastatic disease, it is limited, and the life-threatening component of disease is in the liver. Limited extrahepatic disease is defined in this protocol as follows: up to 5 tumor lesions in the lung with longest diameter not greater than 2 cm and/or up to 5 lymph nodes that measure 2 cm or less per lesion; solitary lesions definitively treated with no sign of progression in the last 6 months.
* Scans used to determine eligibility (CT scan of the chest/abdomen/pelvis and MRI of the liver) must be performed within 28 days prior to randomization.
* Previous treatment and progressed on or following, or intolerant to, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and/or an anti-EGFR therapy if RAS wild-type.
* ECOG PS of 0-1 within 14 days prior to randomization.

Exclusion Criteria:

* Child-Pugh Class B or C cirrhosis or evidence of clinically significant portal hypertension by history, endoscopy, or radiologic studies (large abdominal varices, prior history of varices by endoscopy).
* New York Heart Association functional classification II, III or IV or active cardiac condition(s), including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), worsening or new-onset congestive heart failure, significant arrhythmias, or severe valvular disease that create(s) undue risks of undergoing general anesthesia.
* History or evidence of clinically significant pulmonary disease that precludes the use of general anesthesia.
* History of bleeding disorders, presence of brain metastases, or other intracranial abnormalities found on baseline radiologic imaging that would put them at risk for bleeding with anti-coagulation.
* Known varices at risk of bleeding, including medium or large esophageal or gastric varices, active peptic ulcer, or history of recent hemoptysis.
* Active second malignancy, or has history of recently definitively treated invasive cancer in the past 2 years prior to enrolment with the exception of non-melanoma skin cancer.
* Peritoneal lesions or large abdominal masses.
* Use of immunosuppressive drugs.
* Inability to temporarily stop chronic anti-coagulation therapy.
* Active bacterial infections with systemic manifestations.
* Active viral infection, including Hepatitis B and Hepatitis C infection. NOTE: Patients with anti-hepatitis B core antibody (HBc) positive, or hepatitis B surface antigen (HBsAg) but DNA negative are allowed exception(s).
* Severe allergic reaction to iodine contrast that cannot be controlled by premedication with antihistamines and steroids.
* History of or known hypersensitivity to melphalan or the components of the melphalan/HDS system.
* History of known hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
* Uncontrolled endocrine disorder including diabetes mellitus, hypothyroidism, or hyperthyroidism.
* Received anti-cancer therapy including radiotherapy or investigational agent for any indication ≤ 30 days prior to randomization
* Previous treatment with trifluridine-tipiracil.
* History of allergic reactions attributed to compounds of similar composition to trifluridine/tipiracil or any of its excipients.
* Hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption.
* History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients.
* History of hypersensitivity to Chinese Hamster Ovary cell products or other recombinant human or humanized antibodies.
* Contraindications to bevacizumab, including uncontrolled hypertension, history of active fistula or bowel perforation (unless in the setting of a resected primary), history of CVA or arterial thrombotic event in the last 1 year, or history of venous thrombotic event in the last 30 days.
* Evidence of hepatic vein or portal vein thrombosis
* Prior chemoembolization or radioembolization to the liver or prior hepatic arterial infusion therapy

Where this trial is running

Duarte, California and 9 other locations

• City of Hope — Duarte, California, United States (RECRUITING)
• UCLA Hematology/Oncology-Santa Monica — Santa Monica, California, United States (RECRUITING)
• Moffitt Cancer Center — Tampa, Florida, United States (RECRUITING)
• The University of Kansas Clinical Research Center — Fairway, Kansas, United States (RECRUITING)
• Huntsman Cancer Institute, University of Utah — Salt Lake City, Utah, United States (RECRUITING)
• Czech Republic - University Hospital — Prague, Czechia (RECRUITING)
• Helios Park-Klinikum Leipzig — Leipzig, Germany (RECRUITING)
• Instiuto Europeo de Oncologia — Milan, Italy (RECRUITING)
• Clinical Hospital Center "Bezanijska Kosa" — Belgrade, Serbia (RECRUITING)
• Hospital Clinic Barcelona — Barcelona, Spain (RECRUITING)

Study contacts

• Principal investigator: Marwan Fakih, MD — City of Hope Medical Center
• Study coordinator: Matthew Cooney, MD

Conditions: Refractory Metastatic Colorectal Cancer, melphalan/HDS, melphalan/hepatic delivery system, trifluridine-tipiracil, trifluridine-tipiracil plus bevacizumab, hepatic delivery system, melphalan, liver dominant disease