Percutaneous Hepatic Perfusion with Melphalan Plus Ipilimumab and Nivolumab Versus Ipilimumab and Nivolumab in Uveal Melanoma Liver Metastases
- Trial ID
- 2023-508156-20-00
- Sponsor
- Vaestra Goetalandsregionen
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III randomized controlled multicentre trial is to evaluate **progression-free survival** in patients with **uveal melanoma liver metastases**. Participants are randomized to receive either percutaneous hepatic perfusion (PHP) in combination with ipilimumab and nivolumab or ipilimumab and nivolumab only. This objective is clinically relevant as it aims to determine the efficacy of adding PHP to the standard immunotherapy regimen, potentially improving patient outcomes in this aggressive cancer type.
Secondary objectives include studying the efficacy and safety of the treatment regimens, as well as performing biomarker discovery analysis. These objectives are crucial for understanding the broader impact of the treatment on patient health and identifying potential biomarkers that could guide future therapeutic strategies.
Participants
The clinical trial focuses on patients with **uveal melanoma liver metastases**. The study population includes both male and female participants aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not involve a vulnerable population. Participants must have histologically or cytologically confirmed liver metastasis of uveal melanoma and measurable disease by computed tomography (CT) per RECIST 1.1 criteria, with at least one target lesion identified in the liver. The trial excludes individuals who have received previous treatment for uveal melanoma metastases, except those with confirmed progression on tebentafusp or after surgical resection or ablative treatments. The sponsor has not provided information on the total number of participants. Lifestyle considerations include the requirement for male and female participants of childbearing potential to use adequate contraception during the study and for a specified period after the last dose of study medication. Abstinence is considered acceptable if it is the usual lifestyle and preferred method of contraception for the subject. Participants must also provide signed informed consent to be eligible for the study.
Plans and Procedures
The clinical trial is a **Phase III randomized controlled multicentre trial** designed to evaluate the efficacy and safety of **percutaneous hepatic perfusion** (PHP) in combination with **ipilimumab** and **nivolumab** compared to ipilimumab and nivolumab alone in patients with **uveal melanoma liver metastases**. The primary objective is to assess progression-free survival, with secondary endpoints including the incidence and severity of adverse events, objective response rate, and overall survival, among others. The trial is expected to commence recruitment on April 1, 2024, and conclude by December 31, 2028.
Participants will be randomly assigned to one of the two treatment arms. The trial employs a double-blind design to ensure unbiased results. The study will involve multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, performance status, and disease characteristics. Eligible participants must be 18 years or older, have a confirmed diagnosis of liver metastasis from uveal melanoma, and meet other specific inclusion criteria. The screening visit will include assessments such as a pregnancy test for females of childbearing potential and a performance status evaluation.
Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety. These visits will include imaging studies to assess disease progression, laboratory tests, and clinical evaluations. The frequency and duration of these visits will be determined by the treatment protocol and the participant's response to therapy. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study.
The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period of 52 weeks for the combination therapy. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure their safety and well-being.
Treatment
The clinical trial involves the administration of **Alkeran** (melphalan), a pharmaceutical product provided in the form of a powder and liquid for solution for injection. The medication is administered via **intraarterial use** during a procedure known as Percutaneous Hepatic Perfusion (PHP). The dosage is calculated based on body weight, with a maximum dose of 220 mg per procedure. The PHP procedure involves isolating the liver from systemic circulation and infusing melphalan into the hepatic artery. The blood containing the chemotherapy is filtered and returned to the body. The treatment period for Alkeran is up to 12 weeks.
**OPDIVO** (nivolumab) is another experimental medication used in this trial. It is provided as a 10 mg/mL concentrate for solution for infusion. The administration route is **intravenous infusion**, with a maximum daily dose of 480 mg and a total dose of up to 6.24 grams over the treatment period. The maximum treatment duration for OPDIVO is 52 weeks. Nivolumab is a protein-based therapeutic agent, specifically a monoclonal antibody, and is used to modulate the immune response in cancer therapy.
**YERVOY** (ipilimumab) is also included in the trial, provided as a 5 mg/mL concentrate for solution for infusion. It is administered via **intravenous infusion**. The dosing is based on body weight, with a maximum daily dose of 3 mg/kg and a total dose of up to 12 mg/kg over the treatment period. The maximum treatment duration for YERVOY is 15 weeks. Ipilimumab is a monoclonal antibody that functions as an immune checkpoint inhibitor, enhancing the immune system's ability to target cancer cells.
In this trial, the combination of these medications is being evaluated for their efficacy in treating patients with uveal melanoma liver metastases. The trial compares the combination of PHP with ipilimumab and nivolumab against the administration of ipilimumab and nivolumab alone. Participant compliance is monitored through regular assessments and adherence to the dosing schedule is ensured by the clinical team.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)** in patients with uveal melanoma liver metastases. This primary endpoint will determine the length of time during and after the treatment that the patients live without the disease worsening. Secondary endpoints include the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), objective response rate (ORR), clinical benefit rate (CBR), hepatic progression-free survival (hPFS), extrahepatic progression-free survival (xhPFS), overall survival (OS), melanoma-specific survival (MSS), duration of response (DOR), quality of life (QoL), ctDNA zero-conversion rate at 24 weeks, and predictive and prognostic biomarker discovery.
The trial will compare two treatment regimens: percutaneous hepatic perfusion (PHP) in combination with ipilimumab and nivolumab versus ipilimumab and nivolumab alone. The efficacy parameters will be measured and collected at various timepoints throughout the study, with specific attention to the progression of the disease and patient survival rates. The use of validated scales and laboratory tests will be employed to ensure accurate and reliable data collection. The trial is designed to provide comprehensive insights into the efficacy of the treatment combinations, with a focus on improving patient outcomes in terms of survival and quality of life.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient is ≥18 years.
- Signed informed consent.
- ECOG performance status of 0 or 1.
- Histologically or cytologically confirmed liver metastasis of uveal melanoma.
- Measurable disease by computed tomography (CT) per RECIST 1.1 criteria with at least one target lesion identified in the liver.
- No previous treatment for uveal melanoma metastases, except patients that have confirmed progression on tebentafusp, or after surgical resection or ablative treatments (e.g., radiofrequency ablation or stereotactic body radiation therapy).
- Patient deemed suitable for percutaneous hepatic perfusion.
- Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- Female patients of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Male patients of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 150 days after the last dose of study therapy. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Exclusion Criteria
- Life expectancy of less than 6 months.
- More than 50% of the liver volume replaced by tumor as measured by CT.
- Extrahepatic disease as measured by CT of thorax and abdomen.
- History of congestive heart failure, active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), significant arrhythmias and severe valvular disease that precludes the use of general anesthesia.
- History or evidence of clinically significant pulmonary disease e.g. severe COPD that precludes the use of general anesthesia.
- Patients who are unable to undergo general anesthesia for any reason.
- Reduced renal function defined as S-Creatinine >=1.5xULN or Creatinine Clearance < 40 mL/min, calculated using the Cockroft and Gault formula.
- Reduced hepatic function (defined as AST, ALT, bilirubin>2.5*ULN and PK-INR>1.5) or medical history of liver cirrhosis (Child-Pugh Class B or C) or evidence of portal hypertension by history, endoscopy or radiology.
- Hemoglobin <90 g/L or platelets <100x109/L or neutrophils <1.5x109/L
- Use of live vaccines four weeks before or after the last study treatment.
- History of severe reactions to monoclonal antibodies, melphalan, heparin or iodine contrast.
- Known human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C.
- Active autoimmune disease or a documented history of autoimmune disease requiring systemic immunomodulatory treatment. Diabetes, rematoid arthritis, psoriasis, atopic dermatitis and hypothyroidism are excepted.
- A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
- Concomitant therapy with any other anti-cancer therapy, concurrent medical conditions requiring use of immunosuppressive medications or use of other investigational drugs.
- Has a known additional malignancy that is progressing or requires active treatment.
- Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 150 days after the last dose of study drug.
- A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate in the opinion of the treating investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Norway | Recruiting | 01 Apr 2024 | 10 |
 Sweden | Recruiting | 01 Apr 2024 | 40 |
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 |
|---|---|---|---|---|---|---|
Alkeran 50 mg pulver och vätska till injektionsvätska, lösning | Test | PULVER OCH VÄTSKA TILL INJEKTIONSVÄTSKA, LÖSNING | INTRAARTERIAL USE | 220 | 12 | PRD1575934 |
YERVOY 5 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 3 | 15 | PRD2341715 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 480 | 52 | PRD2941372 |