scholarly journals Combining Hepatic Percutaneous Perfusion With Lpilimumab Plus Nivolumab In Advanced Uveal Melanoma (CHOPIN): Study Protocol For A Phase Lb/Randomized Phase II Trial.

2021 ◽  
Author(s):  
Thaïs M.L. Tong ◽  
Monique K. van der Kooij ◽  
Frank M. Speetjens ◽  
Arian R. van Erkel ◽  
Rutger W. van der Meer ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Hepatic Metastases ◽  
Maximum Tolerated Dose ◽  
Extrahepatic Disease ◽  
Combination Regimen ◽  
Randomized Phase Ii ◽  
Registration Number

Abstract Background: While immune checkpoint inhibition (ICI) has revolutionized the treatment of metastatic cutaneous melanoma, no standard treatments are available for patients with metastatic uveal melanoma (UM). Several locoregional therapies are effective in the treatment of liver metastases, such as percutaneous hepatic perfusion with melphalan (M-PHP). The available literature suggests that treatment with ICI following locoregional treatment of liver UM metastases can result in clinical response. We hypothesize that combining M-PHP with ICI will lead to enhanced antigen presentation and increased immunomodulatory effect, improving control of both hepatic and extrahepatic disease. Methods: Open-label, single center, phase Ib/randomized phase II trial, evaluating the safety and efficacy of the combination of M-PHP with ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) in patients with unresectable hepatic metastases of UM in first line treatment, with or without limited extrahepatic disease. Primary objective is to determine safety, toxicity and efficacy of the combination regimen, defined by maximum tolerated dose (MTD) and progression-free survival (PFS) at one year. Secondary objectives include overall survival (OS) and overall response rate (ORR). A maximum of 88 patients will be treated in phase I and phase II combined. Baseline characteristics will be described with descriptive statistics (t-test, Chi-square test). To study the association between risk factors and toxicity a logistic regression model will be applied. PFS and OS will be summarized using Kaplan-Meier curves.Discussion: This is the first trial to evaluate this treatment combination by establishing the maximum tolerated dose and evaluating the efficacy of the combination treatment. M-PHP has shown to be a safe and effective treatment for UM patients with liver metastases and became the standard treatment option in our center. The combination of ICI with M-PHP is investigated in the currently described trial which might lead to a better treatment response both in and outside the liver. Trial Registration: This trial was registered in the U.S. National Library of Medicine with identifier NCT04283890. Registered as per February 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04283890. EudraCT registration number: 2018-004248-49.Local MREC registration number: NL60508.058.19.

scholarly journals A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma

2006 ◽  
Vol 17 (12) ◽  
pp. 1826-1829 ◽  
Author(s):  
A. Schmittel ◽  
M. Schmidt-Hieber ◽  
P. Martus ◽  
N.E. Bechrakis ◽  
R. Schuster ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Randomized Phase Ii

Phase Ib/randomized phase II study combining hepatic percutaneous perfusion with ipilimumab plus nivolumab in advanced uveal melanoma: The CHOPIN trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9595-TPS9595
Author(s):  
Thaïs M.L. Tong ◽  
Mark C. Burgmans ◽  
Monique Van der Kooij ◽  
Frank M. Speetjens ◽  
Arian R. van Erkel ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Primary Objective ◽  
High Dose ◽  
Phase Ii Trials ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Recist 1.1 ◽  
Randomized Phase Ii

TPS9595 Background: Uveal Melanoma (UM), although rare, is the most common intraocular malignant tumor in adults. Despite successful treatment of the primary tumor, approximately half of all patients will develop metastatic disease, mainly in the liver. Prognosis of metastatic UM is poor and overall survival (OS) has not improved over the last 30 years. Effective systemic therapies are lacking but recent literature suggests an improved effect of the combination of immunotherapy with ipilimumab/nivolumab (IPI/NIVO) as opposed to monotherapy. Percutaneous hepatic perfusion (PHP) is a liver-directed therapy that allows delivery of a high dose of melphalan to the liver with limited systemic toxicity. Efficacy of PHP has been demonstrated in phase II trials including patients with liver-dominant or liver-only metastases. In this study we combine PHP with IPI/NIVO with the goal of inducing a synergistic effect and improving disease control. The aim of the phase 1b is to establish the maximum tolerated dose (MTD) of IPI/NIVO when combined with PHP. The following randomized phase II trial aims to determine the efficacy of IPI/NIVO combined with PHP, compared to PHP alone. Methods: We initiated a prospective, single center, phase Ib and randomized phase II trial with a maximum of 88 patients in total. Patients with confirmed measurable hepatic UM metastases according to RECIST 1.1 and WHO performance score of 0-1 are included. Exclusion criteria are age > 75 years, treatment with systemic immunosuppressive medication and prior systemic treatment for metastasic UM. Phase Ib is a dose-escalation study consisting of two cohorts. The dose of IPI and NIVO is increased from 1mg/kg and 1mg/kg in cohort 1, to 1mg/kg and 3mg/kg, in cohort 2, respectively. The melphalan dose for the PHP is 3mg/kg (maximum dose of 220mg) in both cohorts. Treatment duration is 12 weeks consisting of 4 courses of IPI/NIVO with 2 PHP's in week 1 and 7. In phase II, the same treatment scheme as phase Ib is used in the treatment arm combining IPI/NIVO with PHP at the established MTD. The second treatment arm consists of 2 PHP's performed at a 6 week interval. Follow-up includes laboratory tests, CT-chest/abdomen and MRI-liver. Safety and toxicity are assessed according to the CTCAE V5.0. Radiological response is assessed according to RECIST 1.1 and irRECIST. Primary objective of phase Ib is to determine safety of the combination of IPI/NIVO with PHP defined by the MTD. In phase II the primary objective is the efficacy of combination treatment of IPI/NIVO with PHP defined by progression-free survival at one year. Secondary objectives include OS and overall response rate. Cohort 1 and 2 of phase Ib have been completed without dose limiting toxicities and the MTD is defined as IPI 1 mg/kg and NIVO 3 mg/kg. Accrual to phase II started in December 2020. An update will be presented at ASCO 2021. Clinical trial information: NCT04283890.

scholarly journals Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial

2017 ◽  
Vol 109 (9) ◽  
Author(s):  
Theo Ruers ◽  
Frits Van Coevorden ◽  
Cornelis J. A. Punt ◽  
Jean-Pierre E. N. Pierie ◽  
Inne Borel-Rinkes ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Phase Ii ◽  
Colorectal Liver Metastases ◽  
Phase Ii Trial ◽  
Local Treatment ◽  
Randomized Phase Ii ◽  
Unresectable Colorectal Liver Metastases

A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8018-8018
Author(s):  
A. H. Schmittel ◽  
M. Schmidt-Hieber ◽  
N. E. Bechrakis ◽  
R. Schuster ◽  
J. M. Siehl ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Phase Ii ◽  
Randomized Trials ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Free Survival ◽  
Randomized Phase Ii ◽  
Melanoma Patients ◽  
To Receive

8018 Background: In-vitro studies have suggested synergy of gemcitabine and treosulfan against uveal melanoma cells, and the combination of both drugs in the GeT regimen has shown activity in metastatic uveal melanoma patients. This first randomized phase II trial in this rare disease compared the efficacy of the gemcitabine/treosulfan (GeT) combination versus treosulfan alone. Methods: Chemotherapy-naïve patients with proven metastatic uveal melanoma were randomly assigned to receive 1000mg/m2 gemcitabine plus 3500mg/m2 of treosulfan (GeT) or 3500mg/m2 of treosulfan (T) alone. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. In the absence of disease progression a maximum of 6 cycles were administered. Results: Forty-eight patients were randomized. Seven confirmed stable diseases and one partial remission were observed in 24 patients (PR+SD=33%) treated with the GeT regimen, whereas no PR and only 3 SD (13%) were observed in the treosulfan alone arm (p=0.08). Median progression free survival was 3 months (95% CI 1.1–4.9) in the GeT arm and 2 months (95% CI interval 1.7–2.3) in the treosulfan arm (p=0.008, log-rank). Six and 12 months progression free survival was 34.8% and 17.9% and 16.7% and 0% always favouring the GeT arm. Conclusions: This first prospectively randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over treosulfan alone. Therefore GeT will further be investigated in randomized trials. No significant financial relationships to disclose.

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