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Clinical Trial
. 2015 Mar 11;10(3):e0118564.
doi: 10.1371/journal.pone.0118564. eCollection 2015.

Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma

Lisa Zimmer  1 , Julia Vaubel  1 , Peter Mohr  2 , Axel Hauschild  3 , Jochen Utikal  4 , Jan Simon  5 , Claus Garbe  6 , Rudolf Herbst  7 , Alexander Enk  8 , Eckhart Kämpgen  9 , Elisabeth Livingstone  1 , Leonie Bluhm  2 , Rainer Rompel  10 , Klaus G Griewank  1 , Michael Fluck  11 , Bastian Schilling  1 , Dirk Schadendorf  1
Affiliations
Clinical Trial

Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma

Lisa Zimmer et al. PLoS One. .

Abstract

Purpose: Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.

Patients and methods: We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months.

Results: Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed.

Conclusions: Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.

Trial registration: ClinicalTrials.gov NCT01355120.

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Conflict of interest statement

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Consultancy: LZ (Roche, Bristol-Myers Squibb, MSD Sharp and Dohme); JV (Roche); AH (Amgen, Bristol-Myers Squibb, Roche, EISAI, Celgene, GlaxoSmithKline, MedImmune, MelaScience, Merck Serono, MSD Sharp and Dohme, Novartis, Oncosec); RH (Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, Roche); AE (Biotest, Bristol-Myers Squibb, MSD Sharp and Dohme, Allergika); EL (Bristol-Myers Squibb, Boehringer-Ingelheim Pharma); DS (Bristol-Myers Squibb, Roche, Novartis, Amgen, GlaxoSmithKline); Board membership: PM (Bristol-Myers Squibb, Roche, MSD Sharp and Dohme, GlaxoSmithKline, Novartis, Merck); DS (Bristol-Myers Squibb, Roche, Novartis, Merck, Amgen, GlaxoSmithKline) Research grants: PM (Merck); AH (Amgen, Bristol-Myers Squibb, Roche, EISAI, Celgene, GlaxoSmithKline, MelaScience, Merck Serono, MSD Sharp and Dohme, Novartis, Oncosec); CG (Roche, Bristol-Myers Squibb, GlaxoSmithKline); AE (Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe); DS (Merck); Travel grants and honoraria for speaking or participation at meetings: LZ (Roche, Bristol-Myers Squibb, MSD Sharp and Dohme, GlaxoSmithKline, Novartis, Merck Serono, Teva), JV (Roche, Bristol-Myers Squibb, MSD Sharp and Dohme, GlaxoSmithKline, Novartis, Merck, Boehringer-Ingelheim Pharma, Galderma, Cephalon, Teva, Amgen); PM (Bristol-Myers Squibb, Roche, MSD Sharp and Dohme, GlaxoSmithKline, Novartis, Merck); AH (Amgen, Bristol-Myers Squibb, Roche, EISAI, Celgene, GlaxoSmithKline, MedImmune, MelaScience, Merck Serono, MSD Sharp and Dohme, Novartis, Oncosec); JU (Roche, Bristol-Myers Squibb, Roche, GlaxoSmithKline, MSD Sharp and Dohme, Leo Pharma); CG (Amgen, Roche, Bristol-Myers Squibb, GlaxoSmithKline, MSD Sharp and Dohme, Novartis); RH (Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, Roche); AE (Biotest, Bristol-Myers Squibb, MSD Sharp and Dohme, Janssen-Cilag, Roche, Allergika); EL (Bristol-Myers Squibb, Roche, Amgen, Boehringer-Ingelheim Pharma, MSD Sharp and Dohme, Merck); LB (Roche, Bristol-Myers Squibb, MSD Sharp and Dohme); MF (Bristol-Myers Squibb); BS (Bristol-Myers Squibb); DS (Bristol-Myers Squibb, Roche, Novartis, Merck, Amgen, GlaxoSmithKline); Relationship (paid or unpaid) with organizations and funding bodies including: CG (European Association of Dermatooncology); AE (Deutsche Forschungsgemeinschaft); Nongovernmental organizations, research institutions, or charities: CG (Deutsche Dermatologische Gesellschaft); AE (European Society for Dermatological Research). This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Consort Diagram for DeCOG-study.
Fig 2
Fig 2. Kaplan-Meier curves for overall survival (A) and progression-free survival (B) of treatment-naïve and pretreated patients with metastatic ocular melanoma who received ipilimumab 3 mg/kg.
Fig 3
Fig 3. Kaplan-Meier curves for overall survival stratified by the lactate dehydrogenase (LDH) level before the first dose of ipilimumab (A), the number of ipilimumab doses (B), and the absolute lymphocyte count (ALC) before the third dose (week 7) of ipilimumab (C).
(A) LDH level (<2-fold upper level norm (ULN) versus ≥ 2xULN). LDH < 2xULN: median OS: 9.3 months (95% CI 7.0–11.6); LDH ≥ 2xULN: median OS 2.5 months (95% CI 1.5–5.7). (B) the number of ipilimumab doses (<4 versus 4). 4 doses: median OS: 9.1 months (95% CI 6.7–13.9); < 4 doses: median OS: 2.8 monhts (95% CI 1.5–6.3). (C) ALC (<1000/μl versus ≥1000/μl). ALC ≥1000/μl: median OS: 8.6 (95% CI 7.0–14.5); ALC <1000/μl: median OS: 3.1 (95% CI 2.2–11.5).
See this image and copyright information in PMC

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