Evaluating the Effect of Nivolumab for Patients With In-transit Metastases Treated With Isolated Limb Perfusion

Study Overview
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Brief Summary
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To evaluate safety and the effect of isolated limb perfusion together with nivolumab as a way to increase efficacy and give further insights in early immunological mechanisms. In the first phase Ib part, 20 patients will be enrolled and followed for a minimum of 3 months. An independent data safety monitoring board (DSMB) will continuously review safety and judge the seriousness of the events and also recommend the study to stop if necessary. If the DSMB do not find safety issues, the trial will continue as a phase II trial.

Official Title
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A Phase Ib/II Randomized Double-blind Placebo Controlled Trial Evaluating the Effect of Nivolumab for Patients With In-transit Melanoma Metastases Treated With Isolated Limb Perfusion - the NivoILP Trial

Conditions
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Melanoma, In-Transit Metastasis

Intervention / Treatment
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* Drug: Nivolumab
* Procedure: Isolated limb perfusion (ILP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female aged above 18 years. Signed and dated written informed consent before the start of specific protocol procedures. Histologically or cytologically proven in-transit metastases of malignant melanoma with or without regional lymph node metastases (AJCC v8 stage N1c, N2c and N3c). Measurable disease with at least 1 metastases measuring at least 5mm ECOG performance status of 0-2 Exclusion Criteria Life expectancy of less than 6 months Inability to understand given information or undergo study procedures according to protocol Pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed within 24 hours before the administration of study drug. Patients must agree to follow instructions for method of contraception for 5 months (women) and 7 months (males) after treatment described in section 8.4 History of ischemic cardiac disease or history of congestive heart failure with an LVEF < 40%. History of COPD or other chronic pulmonary disease with PFT's indicating an FEV< 50% predicted for age. 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 ASAT, ALAT, bilirubin >1.5 ULN and PK-INR >1.5) or a medical history of liver cirrhosis or portal hypertension Reduced blood leukocytes or platelets defined as a leucocyte count < 2.0x109/L and thrombocyte count <100x109/L Active, known or suspected autoimmune disease. Subjects are permitted to enrolment if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. A condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 30 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. Has an active infection requiring systemic therapy. Has received a live vaccine within 30 days prior to the first dose of trial treatment and 3 months after treatment. Concomitant therapy with any of the following: IL 2 or other non-study immunotherapy regimens; cytotoxic chemotherapy except melphalan (ILP); other investigational therapies 30 days before and after treatment in this trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is a randomized placebo controlled double blind trial. Patients will be randomized to ILP with nivolumab or ILP with placebo. Active follow-up for 3 years.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ILP + Nivolumab<br>The day before planned ILP, the patient will receive one infusion of nivolumab 480mg | Drug: Nivolumab<br>* One infusion of nivolumab (Opdivo®) 480mg (flat dose) in NaCl (Natriumklorid Baxter Viaflo, 9 mg/ml) during 60 minutes<br>Procedure: Isolated limb perfusion (ILP)<br>* Patients will be treated with ILP according to clinical routine at each separate site. The procedure is performed under general anaesthesia. The major artery and vein of the limb is catheterized, and a tourniquet is placed proximally on the limb. Continuous leakage monitoring is performed. The perfusate is heated to 40C and after ensuring steady state, melphalan (Alkeran®) at a dose of 13 mg/L (upper limb) or 10 mg/L (lower limb) is infused into the circulation during 20 minutes for a total perfusion time of 60 minutes. According to local routine tasonermin (Beromun®) will be added to the perfusate 30 minutes before the melphalan as a bolus dose of 1-4 mg.<br>|
| Placebo Comparator: ILP + Placebo<br>The day before planned ILP, the patient will receive one infusion of placebo | Procedure: Isolated limb perfusion (ILP)<br>* Patients will be treated with ILP according to clinical routine at each separate site. The procedure is performed under general anaesthesia. The major artery and vein of the limb is catheterized, and a tourniquet is placed proximally on the limb. Continuous leakage monitoring is performed. The perfusate is heated to 40C and after ensuring steady state, melphalan (Alkeran®) at a dose of 13 mg/L (upper limb) or 10 mg/L (lower limb) is infused into the circulation during 20 minutes for a total perfusion time of 60 minutes. According to local routine tasonermin (Beromun®) will be added to the perfusate 30 minutes before the melphalan as a bolus dose of 1-4 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate (CR) | To evaluate if melphalan based isolated limb perfusion (ILP) synergizes with nivolumab in inducing complete responses (CR) at 6 months after treatment in melanoma patients with in-transit metastasis. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local progression-free survival (LPFS) | Evaluation of local progression-free survival (LPFS). LPFS is defined as the number of months from the date of ILP to the date of the first documented disease recurrence or progression in the treated area (defined as the area below the tourniquet used for ILP). LPFS will be determined based on clinical assessments according to RECIST version 1.1 criteria. | 36 months | 
| Overall survival (OS) | Evaluation of overall survival (OS), OS is calculated as the time from date of treatment to date of death due to any cause. Both median OS and the per cent of patients alive at 36 months will be evaluated. | 36 months | 
| Melanoma specific survival (MSS) | Evaluation of melanoma specific survival (MSS), MSS is calculated as the time from date of treatment to date of death due to any cause. Both median MSS and the per cent of patients alive at 36 months will be evaluated. | 36 months | 
| Quality of life measured by FACT-M | Quality of life (QoL) by FACT-M. Change from baseline for all subscales as well as for the total scores. | 36 months | 
| Quality of life measured by EQ-5D | Quality of life (QoL) by EQ-5D measured as the change from baseline | 36 months |