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

Официальное название

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

Обзор

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.

Вмешательства

• Препарат Nivolumab
  One infusion of nivolumab (Opdivo®) 480mg (flat dose) in NaCl (Natriumklorid Baxter Viaflo, 9 mg/ml) during 60 minutes
• Процедура 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 perf

Первичные конечные точки

• Complete response rate (CR) [Срок оценки: 3 months]

Вторичные конечные точки (7)

• Time to local progression (TTLP) [Срок оценки: 36 months]
• Distant metastases-free survival (DMFS) [Срок оценки: 36 months]
• Progression-free survival (PFS) [Срок оценки: 36 months]
• Melanoma specific survival (MSS) [Срок оценки: 36 months]
• Overall survival (OS) [Срок оценки: 36 months]
• Quality of life measured by FACT-M [Срок оценки: 36 months]
• Quality of life measured by EQ-5D [Срок оценки: 36 months]

Критерии участия

Критерии включения

• 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 metastasis measuring at least 5mm
• ECOG performance status of 0-2

Критерии исключения

• 1\. 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.
• Active cardiac conditions, including unstable coronary syndromes (unstable or severe angina, recent myocardial infarction), significant arrhythmias and severe valvular disease that precludes general anaesthesia.
• History or evidence of clinically significant pulmonary disease e.g., severe COPD that precludes general anesthesia.
• Reduced renal function defined as S-Creatinine >=1.5xULN
• 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, 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.
• 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 within 30 days before trial treatment and 3 months after trial treatment.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Нидерланды · 3 центра

• Netherlands Cancer Institute — Amsterdam
• Erasmus MC Cancer Institute — Groningen
• Erasmus MC Cancer Institute — Rotterdam

Швеция · 1 центр

• Sahlgrenska University Hospital — Gothenburg

Публикации

• 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 PMID 38493679
• Constantinescu A, Olofsson Bagge R, Huibers A. Immunological phenotype as a predictor for response after isolated limb perfusion for patients with melanoma in-transit metastasis. Eur J Surg Oncol. 2026 Mar;52(3):111424. doi: 10.1016/j.ejso.2026.111424. Epub 2026 Jan 23. PMID 41616426
• 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. PMID 34132224

Идентификаторы

NCT: NCT03685890 · SUGBG-KIR-2018-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗