Evaluation of the Safety and Efficacy of Treatment w/High Dose Melphalan Given Directly Into the Liver Followed by Treatment w/Approved Cancer Treatment or Approved Cancer Treatment Alone in Patients w/ Metastatic Colorectal Cancer w/Liver Dominant Disease (DEL-LIVER)

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

The goal of this clinical trial is to learn if using a liver-directed therapy with high dose chemotherapy followed by approved cancer treatment to treat patients with colorectal cancer that has spread to the liver is safe and tolerable. The clinical trial will also learn if the liver-directed therapy with high dose chemotherapy works on the disease in the liver. Investigators will compare the use of the liver-directed therapy with high dose chemotherapy followed by approved cancer treatment or approved cancer treatment alone.

Participants will:

• Undergo up to two liver-directed therapy with high dose chemotherapy procedures followed by approved cancer treatment or take approved cancer treatment alone
• Visit clinic at least every two weeks for checkups and tests
• Complete scans approximately every two months

Study Overview

• Status: Recruiting
• Conditions: Refractory Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Melphalan/HDS Followed by Consolidation Treatment with Trifluridine-tipiracil plus Bevacizumab; Drug: Trifluridine-tipiracil plus Bevacizumab Alone

Detailed Description

This is an open-label, randomized, multi-center study in which patients with liver dominant refractory mCRC will be randomized 2:1 to receive melphalan/HDS (2 cycles) followed by trifluridine-tipiracil plus bevacizumab treatment (Arm A) or trifluridine-tipiracil plus bevacizumab alone (Arm B).

Approximately 90 patients will be randomized 2:1 to the two treatment arms (Arm A, n=60; Arm B, n=30). Patients will receive one of the following treatments:

• Arm A: Patients will be treated with melphalan/HDS 3.0 mg/kg ideal body weight (IBW) for two treatment cycles. The second melphalan/HDS treatment will be administered 8 weeks after the first treatment with an acceptable delay of up to 2 weeks (10 weeks total) to allow for recovery of melphalan-related toxicity, if needed. Tumor response will be assessed every 8 weeks (± 3 days) during melphalan/HDS treatment, i.e., prior to Cycle 2 of melphalan/HDS and prior to the start of trifluridine-tipiracil plus bevacizumab treatment.
• Arm B: Patients will be treated with standard regimen of trifluridine-tipiracil and bevacizumab.

In both treatment arms, treatment with trifluridine-tipiracil plus bevacizumab will continue until disease progression, death, intolerable adverse events, consent withdrawal, principal investigator decision, or termination of study by Sponsor.

Cross-over: There will be no cross-over between the two arms of the study. Efficacy and Safety Assessment: Evaluation of tumor response will be determined by the local principal investigator using RECIST 1.1 criteria. Tumor response evaluation and patient management will be according to the principal investigator assessment of images and patients' clinical needs. Patients with progressive disease (PD) will be discontinued from study treatment and will be followed for survival until withdrawal of consent or death.

Study treatment will be discontinued if recovery from treatment related toxicity requires more than 2 weeks from the end of the treatment cycle during melphalan/HDS cycles (Arm A only), or more than a 28-day delay in the start of the next cycle of trifluridine-tipiracil plus bevacizumab; the end of treatment (EOT) visit will be conducted at that time or within 4 weeks.

Safety will be monitored continuously by documentation of AEs, SAEs, clinical laboratory measurements, vital signs, and physical examination.

Data Safety Monitoring Board (DSMB): A DSMB including independent (non-investigator) clinicians will oversee the emerging patient safety profile during the study. The DSMB will review study data on a regular basis according to the DSMB Charter.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Matthew Cooney, MD; Phone Number: 216-374-8221; Email: MedicalMonitoring@delcath.com

Study Locations

• Czechia
  • Prague, Czechia
    • Recruiting
    • Czech Republic - University Hospital
• Germany
  • Hanover, Germany
    • Recruiting
    • Medizinische Hochschule Hannover
  • Leipzig, Germany
    • Recruiting
    • Helios Park-Klinikum Leipzig
• Italy
  • Milan, Italy
    • Recruiting
    • Instiuto Europeo de Oncologia
• Netherlands
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center (LUMC)
• Serbia
  • Belgrade, Serbia, 11080
    • Recruiting
    • Clinical Hospital Center "Bezanijska Kosa"
• Spain
  • Barcelona, Spain
    • Recruiting
    • Hospital Clinic Barcelona
• Turkey (Türkiye)
  • Izmir, Turkey (Türkiye)
    • Recruiting
    • Izmir Ekonomi
• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope
    • Santa Monica, California, United States, 90404
      • Recruiting
      • UCLA Hematology/Oncology-Santa Monica
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
  • Kansas
    • Fairway, Kansas, United States, 66205
      • Recruiting
      • The University of Kansas Clinical Research Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Recruiting
      • Ochsner Clinic Foundation
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute, University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melphalan/HDS followed by Consolidation Treatment with Trifluridine-tipiracil plus Bevacizumab; Melphalan/HDS is given as an infusion of Melphalan into the hepatic artery under general anesthesia. This treatment is administered twice, 8 weeks apart. Following 2 treatments with Melphalan/HDS, Trifluridine-tipiracil is given 35 mg/m2 up to a maximum of 80 mg per dose orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle; and intravenous (IV) bevacizumab 5 mg/kg body weight on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity	Drug: Melphalan/HDS Followed by Consolidation Treatment with Trifluridine-tipiracil plus Bevacizumab; Trifluridine-tipiracil plus Bevacizumab Alone; Other Names: Melphalan; HDS; Trifluridine-tipiracil plus Bevacizumab; Trifluridine-tipiracil; Melphalan/HDS
Active Comparator: Trifluridine-tipiracil plus Bevacizumab Alone; Trifluridine-tipiracil plus Bevacizumab is the standard of care for patients with metastatic colorectal cancer. Trifluridine-tipiracil is given 35 mg/m2 up to a maximum of 80 mg per dose orally twice daily with food on Days 1 through 5 and Days 8 through 12 of each 28-day cycle; and intravenous (IV) bevacizumab 5 mg/kg body weight on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity	Drug: Trifluridine-tipiracil plus Bevacizumab Alone; Trifluridine-tipiracil plus Bevacizumab Alone; Other Names: Bevacizumab; Trifluridine-tipiracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hPFS	Hepatic Progression Free Survival	time from randomization to the first occurrence of hepatic disease progression, assessed over 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progression Free Survival	time from randomization to the first occurrence of progression, assessed up to 24 months
OS	Overall Survival	time from randomization date to the date of death due to any cause, assessed up to 36 months
ORR	Overall Response Rate complete response [CR] + partial response [PR]	Baseline through completion of treatment, assessed up to 24 months
hORR	Hepatic Overall Response Rate	assessed from Baseline until there is evidence of disease progression in the liver, assessed up to 24 months
DOR	Duration of Response	assessed from Baseline until there is evidence of disease progression, assessed up to 24 months
DCR	Disease Control Rate	complete response of any duration, partial response of any duration, or stable disease for a minimum of 12 weeks from randomization date, assessed up to 24 months
hDOR	Hepatic Duration of Response	assessed from Baseline until there is evidence of hepatic disease progression, assessed up to 24 months
hDCR	Hepatic Disease Control Rate	complete hepatic response of any duration, partial response of any duration, or stable disease for a minimum of 12 weeks from randomization date, assessed up to 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) Changes from baseline in physical examination findings, vital signs, clinical laboratory parameters, electrocardiogram (ECG) and echocardiogram (ECHO) parameters	assessed from signed informed consent form until study completion

Collaborators and Investigators

• Sponsor: Delcath Systems Inc.
• Investigators: Principal Investigator: Marwan Fakih, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: September 14, 2024
• First Submitted That Met QC Criteria: September 18, 2024
• First Posted (Actual): September 23, 2024

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: colorectal cancer; rectal cancer; metastatic colorectal cancer; melphalan; refractory metastatic colorectal cancer; melphalan/HDS; melphalan/hepatic delivery system; trifluridine-tipiracil; trifluridine-tipiracil (FTD-TPI); trifluridine-tipiracil (FTD-TPI) plus bevacizumab; trifluridine-tipiracil plus bevacizumab; hepatic delivery system; liver dominant disease
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Rectal Neoplasms; Colorectal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Amino Acids; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Bevacizumab; Melphalan; trifluridine tipiracil drug combination
• Other Study ID Numbers: PHP-CRC-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Delcath does not currently have a plan to share IPD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No