PHP in Combination With IPI1/NIVO3 Compared to IPI3/NIVO1 Only in Patients With Uveal Melanoma Liver Metastases

Official title

A Phase III Randomized Controlled Multicentre Trial of Percutaneous Hepatic Perfusion in Combination With Ipilimumab and Nivolumab Compared to Ipilimumab and Nivolumab Only in Patients With Uveal Melanoma Liver Metastases

Overview

Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will develop in approximately 35%-50% of the patients within 10 years. The liver is the most common site for metastases, and about 50% of the patients will have isolated liver metastases. These metastases are generally refractory to systemic chemotherapy and the median survival for patients with liver metastases is about 6 months. Regardless of treatment, the mortality rate is approximately 90% at 2 years with only about 1% of the patients surviving more than 5 years. The primary objective with this study is to evaluate progression-free survival in patients with uveal melanoma liver metastases randomized to either percutaneous hepatic perfusion (PHP) in combination with ipilimumab and nivolumab or ipilimumab and nivolumab only. Secondary objectives include further efficacy and safety analysis, as well as biomarker discovery.

Interventions

• Device PHP
  Patients will be treated with 2 cycles of PHP (CHEMOSAT® Hepatic Delivery System for Melphalan) six weeks apart
• Drug IPI1/NIVO3
  Patients will be treated with 2 cycles of i.v. ipilimumab 1mg/kg and nivolumab 3mg/kg q3w, followed by continued i.v. nivolumab 480mg q4w up to 1 year.
• Drug IPI3/NIVO1
  Patients will be treated with 4 cycles of intravenous (i.v.) infusion with ipilimumab 3mg/kg and nivolumab 1mg/kg q3w followed by continued i.v. nivolumab 480mg q4w up to 1 year.

Primary outcome measures

• Progression-free survival (PFS) [Time frame: 24 month]

Secondary outcome measures (9)

• Adverse events [Time frame: 24 month]
• Overall response rate [Time frame: 24 month]
• Clinical benefit rate [Time frame: 24 month]
• Hepatic progression-free survival [Time frame: 24 month]
• Overall survival [Time frame: 24 month]
• Melanoma-specific survival [Time frame: 24 month]
• Duration of response [Time frame: 24 month]
• Quality of Life as assessed by FACT-G [Time frame: 24 month]
• Quality of Life as assessed by EQ-5D-5L [Time frame: 24 month]

Eligibility 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, rheumatoid 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Sweden · 6 centers

• Sahlgrenska University Hospital — Gothenburg
• Linköping University Hospital — Linköping
• Skåne University Hospital — Lund
• Karolinska University Hospital, — Stockholm
• Norrland University Hospital — Umeå
• Uppsala University Hospital — Uppsala

Identifiers

NCT: NCT06519266 · 2023-508156-20-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗