Evaluation of Melphalan/HDS Induction Followed by Trifluridine-Tipiracil and Bevacizumab Versus Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer
- Trial ID
- 2024-520356-24-00
- Protocol
- PHP-CRC-201
- Sponsor
- Delcath Systems Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **Melphalan/HDS** followed by **trifluridine–tipiracil** plus **bevacizumab** on hepatic progression-free survival (hPFS) compared to trifluridine–tipiracil plus bevacizumab alone in patients with liver dominant metastatic colorectal cancer (mCRC). This is clinically relevant as improving hPFS can potentially enhance patient outcomes by delaying disease progression in a population with limited treatment options.
Secondary objectives include: - Further evaluation of the anti-tumor efficacy of Melphalan/HDS followed by trifluridine–tipiracil plus bevacizumab compared to trifluridine–tipiracil plus bevacizumab alone in patients with liver dominant mCRC. - Evaluation of the safety and tolerability of Melphalan/HDS followed by trifluridine–tipiracil plus bevacizumab compared to trifluridine–tipiracil plus bevacizumab alone. - Characterization of the local and systemic exposure of melphalan administered by the HDS.
Participants
The clinical trial involves a total of **61 participants** diagnosed with **refractory metastatic colorectal cancer with liver dominant disease**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have previously been treated and progressed on specific chemotherapy and biological therapies. Participants were selected based on their diagnosis of liver-dominant metastatic disease, where the majority of the tumor burden is located in the liver, and the disease is measurable by imaging techniques. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified, but participants must meet specific health criteria, including a weight of at least 35 kg. The trial population is not limited by gender, and both vulnerable and non-vulnerable populations are included. Key inclusion criteria require participants to have a histologically confirmed diagnosis of metastatic colorectal cancer and to have progressed on or developed intolerance to prior treatments.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, 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 primary objective is to assess the effect on hepatic progression-free survival (hPFS) compared to the control group. The trial is expected to commence recruitment on June 2, 2025, and conclude by February 1, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histologically confirmed diagnosis, and measurable disease in the liver. The trial will include follow-up visits to monitor treatment response and safety, with assessments conducted according to RECIST v1.1 guidelines. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced by participants.
The expected length of participant involvement is determined by the treatment regimen, with a maximum treatment period of 16 weeks for Melphalan and 4 weeks for trifluridine–tipiracil plus bevacizumab. Participants may be subject to early termination from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The study will adhere to rigorous ethical standards, ensuring informed consent and the use of highly effective contraception for participants of childbearing potential.
Treatment
The clinical trial involves the administration of several treatments, including **Zirabev**, **Lonsurf**, and **Melphalan Hikma**. **Zirabev** is a **concentrate for solution for infusion** containing the active substance **bevacizumab**. It is administered as a solution for infusion, with a maximum daily dose of 10 mg/kg and a maximum treatment period of 3 weeks. The pharmaceutical form is a concentrate for solution for infusion, and it is not a pediatric formulation. The administration route is intravenous, and participant compliance is monitored through infusion records.
**Lonsurf** is available in two formulations: 20 mg/8.19 mg and 15 mg/6.14 mg film-coated tablets. The active substances in Lonsurf are **trifluridine** and **tipiracil hydrochloride**. The tablets are administered orally, with a maximum daily dose of 80 mg and a maximum treatment period of 4 weeks. The pharmaceutical form is a film-coated tablet, and it is not a pediatric formulation. Compliance is monitored through pill counts and patient diaries.
**Melphalan Hikma** is provided as a **powder and solvent for solution for injection/infusion**. The active substance is **melphalan**, and it is administered via intrabursal use. The maximum daily dose is 1 mg/kg, with a total maximum dose of 220 mg over a treatment period of 16 weeks. The pharmaceutical form is a powder and solvent for solution for injection/infusion, and it is not a pediatric formulation. Compliance is monitored through infusion records and patient follow-up visits.
The trial also includes a comparator treatment consisting of **trifluridine–tipiracil plus bevacizumab** alone, which serves as the standard-of-care therapy. This comparator treatment is administered in the same manner as the experimental treatments, with similar dosing schedules and compliance monitoring methods. The trial aims to evaluate the efficacy and safety of these treatments in patients with refractory metastatic colorectal cancer with liver dominant disease.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **hepatic progression-free survival (hPFS)**, defined as the time from randomization to the first occurrence of hepatic disease progression or death due to any cause. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR) which encompasses complete response (CR) and partial response (PR), hepatic ORR (hORR), duration of response (DOR), hepatic DOR (hDOR), disease control rate (DCR), hepatic DCR (hDCR), and overall survival (OS).
These efficacy parameters will be measured and collected at specified timepoints throughout the trial. The assessment of disease progression and response will be conducted using imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI), following the RECIST v1.1 guidelines. The trial aims to evaluate the effect of Melphalan/HDS followed by trifluridine–tipiracil plus bevacizumab compared to trifluridine–tipiracil plus bevacizumab alone in patients with liver-dominant metastatic colorectal cancer. The trial is designed to provide a comprehensive evaluation of the treatment's impact on both hepatic and overall disease progression and survival outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient is ≥ 18 years of age on day of consent.
- Histologically confirmed diagnosis of mCRC 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 v1.1 guidelines) by computed tomography (CT) and/or magnetic resonance imaging (MRI).
- Patient weighs ≥ 35 kg (due to possible size limitations with respect to percutaneous catheterization of the femoral artery and vein required with Melphalan/HDS).
- 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
- 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.
- Patient was previously treated and progressed on, or following, or developed intolerance to, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and/or an anti-EGFR therapy if RAS wild-type. Patient with MSI-H/dMMR CRC was previously treated and progressed on or following, or developed intolerance to, immune checkpoint inhibitor (ICPI) therapy, if eligible.
- Patient has an ECOG PS of 0-1 within 14 days prior to randomization
- If patient is a woman of childbearing potential (WOCBP) (i.e., fertile meaning not permanently sterilized and having had a menstrual period within the past 12 months), has a negative serum pregnancy test (β-human chorionic gonadotropin β-HCG) within 7 days prior to randomization.
- If patient is a WOCBP or fertile male (not permanently sterile by bilateral orchiectomy), they or their partner must be willing to use a highly effective contraception method (e.g., combined hormonal contraception; progestogen-only hormonal contraception; intrauterine device, intrauterine hormone-releasing system; bilateral tubal occlusion, vasectomized partner or sexual abstinence) from consent to at least 6 months after the last administration of study treatment.
- Signed informed consent.
Exclusion Criteria
- Patient has 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).
- Patient has New York Heart Association functional classification II, III or IV 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.
- Patient has history or evidence of clinically significant pulmonary disease or any other condition that precludes the use of general anesthesia.
- Patient has a history of bleeding disorders, presence of brain metastases, or other intracranial abnormalities that would put them at risk for bleeding with anti-coagulation.
- Patient has known varices at risk of bleeding, including medium or large esophageal or gastric varices, active peptic ulcer, or history of recent hemoptysis.
- Patient has an active second malignancy or has a history of recent definitively treated invasive cancer within 2 years prior to enrolment, with the exception of non-melanoma skin cancer.
- Patient has peritoneal lesions or large abdominal masses.
- Patient is pregnant or breastfeeding.
- Patient is a WOCBP (i.e., fertile meaning not permanently sterilized and having had a menstrual period within the past 12 months) who is unable to undergo hormonal suppression to avoid menstruation during treatment.
- Patient is taking immunosuppressive drugs. NOTE: Oral corticosteroids ≤ 10 mg/day are allowed.
- Patient is unable to be temporarily removed from chronic anti-coagulation therapy.
- Patient has active bacterial infection(s) with systemic manifestations (malaise, fever, leucocytosis).
- Patient has an active 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).
- Patient has known severe allergic reaction to iodine contrast that cannot be controlled by premedication with antihistamines and steroids.
- Patient has a history of or known hypersensitivity to melphalan or the components of the Melphalan/HDS system.
- Patient has known latex allergy.
- Patient has a history of known hypersensitivity to heparin or the presence of heparin-induced thrombocytopenia.
- Patient has an uncontrolled endocrine disorder including diabetes mellitus, hypothyroidism, or hyperthyroidism.
- Patient received anti-cancer therapy including radiotherapy or investigational agent for any indication ≤ 30 days prior to randomization.
- Patients should have recovered to Grade 1 or less for AEs related to prior treatment unless deemed clinically not significant, such as lymphopenia, anemia or Grade 2 neuropathy due to prior oxaliplatin treatment. NOTE: Certain side effects that are unlikely to develop into serious or life–threatening events (e.g., alopecia) are allowed at ≥ Grade 1.
- Patient is less than 28 days after surgery and surgical wound is not fully healed.
- Patient is currently under treatment for cancer other than mCRC or is not deemed to be cancer free.
- Patient was previously treated with trifluridine–tipiracil.
- Patient has history of allergic reactions attributed to compounds of similar composition to trifluridine/tipiracil or any of its excipients.
- Patient has hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
- Patient has history of allergic reactions or hypersensitivity to bevacizumab or any of its excipients.
- Patient has 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 cerebrovascular accident 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.
- Albumin level < 3.0 g/dL.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 02 Jun 2025 | 3 |
 Germany | Recruiting | 02 Jun 2025 | 20 |
 Italy | Recruiting | 02 Jun 2025 | 3 |
 The Netherlands | Recruiting | 02 Jun 2025 | — |
 Spain | Recruiting | 02 Jun 2025 | 6 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lonsurf 15 mg/6.14 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 80 | 4 | PRD4106910 |
Zirabev 25 mg/ml concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 10 | 3 | PRD7082676 |
MELPHALAN HIKMA 50 mg/10ml, poudre et solvant pour solution injectable / pour perfusion | Test | POUDRE ET SOLVANT POUR SOLUTION INJECTABLE / POUR PERFUSION | INTRABURSAL USE | 1 | 16 | PRD10822966 |
Zirabev 25 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | SOLUTION FOR INFUSION | 10 | 3 | PRD7082677 |
Lonsurf 20 mg/8.19 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL USE | 80 | 4 | PRD4021876 |