Isolated Hepatic Perfusion in Combination With Ipilimumab and Nivolumab in Patients With Uveal Melanoma Metastases (SCANDIUM II)

January 25, 2024 updated by: Roger Olofsson Bagge, Vastra Gotaland Region

SCANDIUM II Trial - A Phase I Randomized Controlled Multicentre Trial of Isolated Hepatic Perfusion in Combination With Ipilimumab and Nivolumab in Patients With Uveal Melanoma Metastases

Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumour, 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. Isolated hepatic perfusion is a regional treatment where the liver is completely isolated from the systemic circulation, allowing a high concentration of chemotherapy to be perfused through the liver with minimal systemic exposure. The introduction of modern immunotherapy in the treatment arsenal for cutaneous melanoma also creates hope for patients with uveal melanoma metastases. However, the results of immunotherapy have so far been disappointing. The reason for the low efficacy could be that uveal melanoma develops in the immune privileged eye.

The hypothesis in this trial is that isolated hepatic perfusion with melphalan causes an immunogenic type of cell death by local tumour destruction while leaving the immune-system intact. This will cause an activation of the immune-system and the addition of ipilimumab and nivolumab will enhance this effect, ultimately increasing the treatment efficacy.

The primary objective of this trial is to evaluate the safety and tolerability of isolated hepatic perfusion together with ipilimumab and nivolumab when given at the same time or as a sequenced regimen. The study design is a phase I randomized controlled, multicentre, open-label trial. Active follow-up will be performed for 2 years. Patients will be randomized after diagnoses of metastatic disease to one of the following treatment arms:

Arm A. Patients will be treated with IHP followed by 4 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.

Arm B. Patients will be treated with 1 course of ipilimumab 3mg/kg and nivolumab 1mg/kg followed by IHP after 3 weeks and then another 3 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.

Study Overview

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Gothenburg, Sweden, 413 45
        • Sahlgrenska University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

  1. Patient is ≥18 years of age on the day of signing informed consent
  2. Patient is willing and able to provide written informed consent and comply with study procedures. Written informed consent must be signed and dated before the start of specific protocol procedures
  3. Patient must have a histologically confirmed diagnosis of stage IV uveal melanoma. If tissue biopsy is judged not feasible by the investigator, cytological diagnosis from fine needle aspiration (FNA) will be accepted
  4. Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria with at least one target lesion identified in the liver.
  5. ECOG performance status of 0 or 1
  6. No previous immunotherapy for uveal melanoma metastases.
  7. 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
  8. Female patients of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  9. Male patients of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 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

  1. Life expectancy of less than 3 months
  2. Body mass index above 35
  3. More than 50% of the liver volume replaced by tumor as measured by CT or MRI
  4. Known congestive heart failure with an LVEF <40%
  5. COPD or other chronic pulmonary disease with PFT's indicating an FEV< 50% predicted for age
  6. Interstitial lung disease (ILD) or (non-infectious) pneumonitis
  7. Reduced renal function defined as S-Creatinine >=1.5xULN or Creatinine Clearance < 40 mL/min, calculated using the Cockroft and Gault formula
  8. Reduced hepatic function (defined as AST, ALT, bilirubin>3*ULN and PK-INR>1.5) or medical history of liver cirrhosis or portal hypertension
  9. Hemoglobin <90 g/L or platelets <100x109/L or neutrophils <1.5x109/L
  10. Use of live vaccines four weeks before or after the last study treatment
  11. History of severe hypersensitivity reactions to mAbs
  12. Known human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), hepatitis B or hepatitis C
  13. Active autoimmune disease or a history of known or suspected autoimmune disease
  14. 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.
  15. Concomitant therapy with any other anti-cancer therapy, concurrent medical conditions requiring use of immunosuppressive medications or use of other investigational drugs
  16. Has a known additional malignancy that is progressing or requires active treatment.
  17. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
  18. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A
Patients will be treated with IHP followed by 4 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.
The procedure is performed under general anaesthesia. The caval vein is isolated infrahepatically above the renal veins and suprahepatically between the diaphragm and the pericardium. A catheter is placed in the retrohepatic portion of the caval vein for perfusion outflow. The portal vein is clamped and the proper hepatic artery is cannulated via the gastroduodenal artery. The liver perfusion is performed at a rate of 8- 9 ml/kg/min with a target liver temperature of 40 degrees Celsius. The leakage from the system was continuously recorded using Technetium labelled albumin (Vasculosis) injected into the perfusion circuit. Melphalan (1 mg/kg bodyweight divided into two doses, given 30 minutes apart) is added to the perfusion system. The perfusion is then continued for 60 minutes, after which the perfusion was discontinued.
4 courses of ipilimumab 3mg/kg every third week
4 courses of nivolumab 1mg/kg every third week
Experimental: Arm B
Patients will be treated with 1 course of ipilimumab 3mg/kg and nivolumab 1mg/kg followed by IHP after 3 weeks and then another 3 courses of ipilimumab 3mg/kg and nivolumab 1mg/kg every third week followed by continued nivolumab 480mg q4w up to 1 year.
The procedure is performed under general anaesthesia. The caval vein is isolated infrahepatically above the renal veins and suprahepatically between the diaphragm and the pericardium. A catheter is placed in the retrohepatic portion of the caval vein for perfusion outflow. The portal vein is clamped and the proper hepatic artery is cannulated via the gastroduodenal artery. The liver perfusion is performed at a rate of 8- 9 ml/kg/min with a target liver temperature of 40 degrees Celsius. The leakage from the system was continuously recorded using Technetium labelled albumin (Vasculosis) injected into the perfusion circuit. Melphalan (1 mg/kg bodyweight divided into two doses, given 30 minutes apart) is added to the perfusion system. The perfusion is then continued for 60 minutes, after which the perfusion was discontinued.
4 courses of ipilimumab 3mg/kg every third week
4 courses of nivolumab 1mg/kg every third week

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
Time Frame: 1 year
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate (ORR)
Time Frame: 2 years
Evaluation of objective response rate (ORR)
2 years
Clinical benefit rate (CBR)
Time Frame: 2 years
Evaluation of clinical benefit rate (CBR)
2 years
Progression-free survival (PFS)
Time Frame: 2 years
Evaluation of progression-free survival (PFS)
2 years
Hepatic progression-free survival (hPFS)
Time Frame: 2 years
Evaluation of hepatic progression-free survival (hPFS)
2 years
Overall survival (OS)
Time Frame: 2 years
Evaluation of overall survival (OS)
2 years
Time to response (TTR)
Time Frame: 2 years
Evaluation of time to response (TTR)
2 years
Duration of response (DOR)
Time Frame: 2 years
Evaluation of duration of response (DOR)
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 8, 2021

Primary Completion (Estimated)

August 4, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

July 5, 2020

First Submitted That Met QC Criteria

July 5, 2020

First Posted (Actual)

July 9, 2020

Study Record Updates

Last Update Posted (Estimated)

January 26, 2024

Last Update Submitted That Met QC Criteria

January 25, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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