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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Melanoma; In-Transit Metastasis
• Intervention / Treatment: Drug: Nivolumab; Procedure: Isolated limb perfusion (ILP)

• Study Type: Interventional
• Enrollment (Estimated): 74
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Roger Olofsson Bagge, MD, PhD; Phone Number: +46 31 3428207; Email: roger.olofsson.bagge@gu.se
• Study Contact Backup: Name: Therese Bengtsson; Phone Number: +46 31 3420000; Email: therese.bengtsson@vgregion.se

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Netherlands Cancer Institute
    • Contact: Winan van Houdt, MD, PhD
    • Principal Investigator: Winan van Houdt, MD, PhD
  • Groningen, Netherlands
    • Not yet recruiting
    • Erasmus MC Cancer Institute
    • Contact: Lukas Been
    • Principal Investigator: Lukas Been, Md, PhD
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Erasmus MC Cancer Institute
    • Contact: Dirk Grünhagen
    • Principal Investigator: Dirk Grünhagen, MD, PhD
• Sweden
  • Gothenburg, Sweden, 413 45
    • Recruiting
    • Sahlgrenska University Hospital
    • Contact: Roger Olofsson Bagge, Dr; Phone Number: +46 31 3428207; Email: roger.olofsson.bagge@gu.se
    • Principal Investigator: Roger Olofsson Bagge, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Male or female aged above 18 years.
2. Signed and dated written informed consent before the start of specific protocol procedures.
3. Histologically or cytologically proven in-transit metastases of malignant melanoma with or without regional lymph node metastases (AJCC v8 stage N1c, N2c and N3c).
4. Measurable disease with at least 1 metastasis measuring at least 5mm
5. ECOG performance status of 0-2

Exclusion Criteria

1. 1. Life expectancy of less than 6 months
2. Inability to understand given information or undergo study procedures according to protocol.
3. Pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed within 24 hours before the administration of study drug.
4. Patients must agree to follow instructions for method of contraception for 5 months (women) and 7 months (males) after treatment.
5. Active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), significant arrhythmias and severe valvular disease that precludes general anaesthesia.
6. History or evidence of clinically significant pulmonary disease e.g., severe COPD that precludes general anesthesia.
7. Reduced renal function defined as S-Creatinine >=1.5xULN
8. 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.
9. Reduced blood leukocytes or platelets defined as a leucocyte count < 2.0x109/L and thrombocyte count <100x109/L.
10. Active, 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.
11. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
12. 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.
13. Has an active infection requiring systemic therapy.
14. Has received a live vaccine within 30 days prior to the first dose of trial treatment and 3 months after treatment.
15. Concomitant therapy with any of the following: IL 2 or other non-study immunotherapy regimens; cytotoxic chemotherapy except melphalan (ILP); other investigational therapies within 30 days before trial treatment and 3 months after trial treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ILP + Nivolumab; The day before planned ILP, the patient will receive one infusion of nivolumab 480mg	Drug: Nivolumab; One infusion of nivolumab (Opdivo®) 480mg (flat dose) in NaCl (Natriumklorid Baxter Viaflo, 9 mg/ml) during 60 minutes; Procedure: Isolated limb perfusion (ILP); 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.
Placebo Comparator: ILP + Placebo; The day before planned ILP, the patient will receive one infusion of placebo	Procedure: Isolated limb perfusion (ILP); 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.

What is the study measuring?

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 3 months after treatment in melanoma patients with in-transit metastasis.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Time to local progression (TTLP)	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
Distant metastases-free survival (DMFS)	Evaluation of DMFS, defined as the number of months from the date of ILP to the date of the first documented distant disease recurrence.	36 months
Progression-free survival (PFS)	Evaluation of PFS, defined as the number of months from the date of ILP to the date of the first documented disease recurrence or progression at any site.	36 months

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region

Publications and helpful links

General Publications

• Tulokas SKA, Kohtamaki LM, Makela SP, Juteau S, Alback A, Vikatmaa PJ, Mattila KE, Skytta TK, Koivunen JP, Tyynela-Korhonen K, Hernberg MM. Isolated limb perfusion with melphalan as treatment for regionally advanced melanoma of the limbs: results of 60 patients treated in Finland during 2007-2018. Melanoma Res. 2021 Oct 1;31(5):456-463. doi: 10.1097/CMR.0000000000000755.
• Holmberg CJ, Zijlker LP, Katsarelias D, Huibers AE, Wouters MWJM, Schrage Y, Reijers SJM, van Thienen JV, Grunhagen DJ, Martner A, Nilsson JA, van Akkooi ACJ, Ny L, van Houdt WJ, Olofsson Bagge R. The effect of a single dose of nivolumab prior to isolated limb perfusion for patients with in-transit melanoma metastases: An interim analysis of a phase Ib/II randomized double-blind placebo-controlled trial (NivoILP trial). Eur J Surg Oncol. 2024 Mar 12;50(6):108265. doi: 10.1016/j.ejso.2024.108265. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: September 23, 2018
• First Submitted That Met QC Criteria: September 24, 2018
• First Posted (Actual): September 26, 2018

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Neoplasm Metastasis; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: SUGBG-KIR-2018-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes