Clinical Trials in Metastatic Uveal Melanoma: Current Status Review Article Ocul Oncol Pathol 2020;6:381–387 Clinical Trials in Metastatic Uveal Melanoma: Current Status Tamara A. Sussman a Pauline Funchain a Arun Singh b a Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA; b Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA Received: March 2, 2020 Accepted: May 3, 2020 Published online: September 10, 2020 Arun Singh Department of Ophthalmic Oncology, Cole Eye Institute Cleveland Clinic Foundation 9500 Euclid Avenue, Cleveland, OH 44195 (USA) singha @ ccf.org © 2020 S. Karger AG, Baselkarger@karger.com www.karger.com/oop DOI: 10.1159/000508383 Keywords Uveal melanoma · Metastasis · Oncology · Clinical trials · Liver-directed therapy Abstract Background: Uveal melanoma is a rare subtype of melano- ma. Prognosis and survival rates for patients with metastatic uveal melanoma remain poor. No current FDA-approved standard of care therapy is available for patients with meta- static uveal melanoma. Thus, clinical trials are essential for the development of new therapies and to provide patients hope for improved survival and outcomes. Summary: In this article, we review clinical trials identified on the database https://clinicaltrials.gov that are open and enrolling patients with metastatic uveal melanoma as of November 26, 2019. This search produced 17 active trials involving liver-directed therapy, CNS-directed therapy, and systemic therapy with immunotherapy, targeted therapy, or oncolytic virus thera- py. Here, we discuss liver and CNS-directed therapy as well as systemic targeted therapy and oncolytic virus therapy. Im- munotherapy clinical trials are discussed in a companion re- view article by Dr. Marlana Orloff. Key Messages: Various novel therapeutic targets and immunomodulatory ap- proaches are on the horizon for patients with metastatic uveal melanoma and may yield incremental therapeutic benefit. Selecting a clinical trial must be individualized and made jointly with the patient and his/her oncologist. © 2020 S. Karger AG, Basel Introduction Uveal melanoma is the most common intraocular tu- mor in adults. The overall incidence of uveal melanoma has remained stable from 1973 to 2013, with about 5 pa- tients per million affected, which comprises 3% of all mel- anomas [1, 2]. For all stages, the 5-year overall survival (OS) remains about 80.9% [1]. While about 5% of patients present with metastatic disease, up to 50% develop meta- static disease with subsequently worse prognosis [3]. Of patients who develop metastatic disease, liver is the most common site (89%) [4]. Historically, median OS for met- astatic uveal melanoma ranges from 3 to 12 months, with a 1-year OS of 20% [4, 5]. However, more recent data from clinical trial patients suggests a median progression- free survival (PFS) and OS of 3.3 months and 10.2 months, and 1-year OS of 43% [6]. Prognosis and survival rates for metastatic uveal melanoma remain poor, and there is cur- rently no FDA approved therapy in the metastatic setting. Clinical trials are essential for the development of new therapies and to provide patients hope for improved sur- vival and outcomes. Methods We conducted a search for active clinical trials available world- wide for metastatic uveal melanoma on November 26, 2019, through the clinical trial database available at https://clinicaltrials. gov. ClinicalTrials.gov is run by the National Library of Medicine Sussman/Funchain/SinghOcul Oncol Pathol 2020;6:381–387382 DOI: 10.1159/000508383 at the National Institutes of Health, and is the largest clinical trials registry, currently holding registrations from over 818,000 trials from 209 countries. Our search produced 146 available trials for uveal melanoma (Fig. 1), with a significant proportion (80%, n = 117) of trials not accruing patients due to status of completed, ter- minated, withdrawn, suspended, active – not recruiting, or un- known status. Once removed, 29 currently recruiting trials re- mained. Of these trials, 12 were excluded: 4 nontherapeutic trials, 5 localized eye therapy trials, and 3 trials for neoadjuvant or adju- vant therapy for resectable disease. A final 17 trials were identified for treatment of metastatic uveal melanoma; including 5 trials uti- lizing liver-directed therapy, 1 trial with CNS-directed therapy, and 11 trials with systemic immunotherapy or targeted therapy used in combination or as single agent. Trials including immuno- logical checkpoint inhibitors with liver-directed therapies are cat- egorized as liver-directed therapy trials. Similarly, a trial including an immunological checkpoint inhibitor in combination with CNS- directed therapy is categorized as CNS-directed therapy trial. All clinical trials for metastatic uveal melanoma discussed in this re- view are summarized in Table 1. Clinical Trials for Patients with Metastatic Uveal Melanoma Systemic Therapy Clinical Trials No current standard of care therapy exists for meta- static uveal melanoma. Response rates with checkpoint inhibitor therapy with single agent anti-CTLA4 (ipilim- umab) or anti-PD1 (nivolumab) or combination anti- CTLA4/anti-PD1 inhibition have been disappointing, As of November 26, 2019 146 Clinical trials identified for uveal melanoma ClinicalTrials.gov 117 trials excluded on basis of trial status: 62 Completed 17 Terminated 3 Withdrawn 2 Suspended 16 Active, not recruiting 1 Not yet recruiting (Questionnaire) 1 Enrolling by invitation (Observational) 11 Unknown* 29 clinical trials in uveal melanoma with status of recruiting 9 trials excluded on basis of description, objective or outcome: 1 New imaging technique 3 Biomarker analysis 5 Localized eye therapy 20 clinical trials in high risk or stage III-IV uveal melanoma 3 trials excluded on basis of treatment type: 2 Adjuvant 1 Neoadjuvant 17 clinical trials in metastatic or unresectable uveal melanoma: 11 Systemic therapy 5 Immunotherapy 4 Targeted therapy 2 Oncolytic virus therapy 5 Liver directed therapy 1 CNS directed therapy *Study has passed its completion date and status has not been verified in more than 2 years Fig. 1. Flow diagram of clinical trials for uveal melanoma. Clinical Trials in Metastatic Uveal Melanoma 383Ocul Oncol Pathol 2020;6:381–387 DOI: 10.1159/000508383 with response rates of 3.6% with single agent, and 12–17% with combination therapy [7–9]. PFS and OS with immu- notherapy are 2.8 months and 8.9 months, respectively. Similarly, PFS and OS with targeted (kinase) therapy are 2.8 months and 9.1 months [6]. Currently, 11 clinical tri- als with systemic therapy are available, specifically 5 trials with immunological checkpoint inhibitors, 4 trials with targeted therapy, and 2 trials with oncolytic virus therapy. The 5 trials with systemic immunotherapy are discussed separately in the companion review article by Marlana Orloff, MD. The remaining systemic therapy trials will be discussed in this review. Trials with agents targeting spe- Table 1. Clinical trials in metastatic uveal melanoma NCT number Trial Status Phase Locations NCT02768766 Intermittent selumetinib for uveal melanoma recruiting I Columbia University Medical Center; Memorial Sloan Kettering Cancer Center; MD Anderson Cancer Center NCT03947385 IDE196 in patients with solid tumors harboring GNAQ/11 mutations or PRKC fusions recruiting I/II Columbia University Medical Center; Thomas Jefferson University; Sarah Cannon Research Institute/Tenessee Oncology; MD Anderson Cancer Center; Westmead Hospital (Sydney, Australia) NCT03207347 Niraparib in BAP1 and other DNA damage response deficient neoplasms recruiting II University of Florida NCT04187833 Nivolumab in combination with talazoparib in melanoma and mutations in BRCA or BRCA-ness genes active, not yet recruiting II Cleveland Clinic NCT03297424 PLX2853 in advanced malignancies recruiting I/II Honor Health (Arizona); Sylvester Comprehensive Cancer Center/University of Miami Miller School of Medicine; Columbia University; South Texas Accelerated Research Therapeutics; Virginia Cancer Specialist NCT02831933 Radiation and gene therapy before nivolumab for metastatic non-small cell carcinoma and uveal melanoma recruiting II Houston Methodist Hospital NCT03865212 Modified virus VSV-IFNbetaTYRP1 in treating patients with stage III-IV melanoma recruiting I Mayo Clinic in Florida; Mayo Clinic in Rochester NCT02913417 Yttrium90, ipilimumab, & nivolumab for uveal melanoma with liver metastases recruiting I/II California Pacific Medical Center; University of Chicago; Thomas Jefferson University NCT03472586 Ipilimumab and nivolumab with immunoembolization in treating participants with metastatic uveal melanoma in the liver recruiting II Thomas Jefferson University NCT01785316 The Scandinavian randomized controlled trial of isolated hepatic perfusion for uveal melanoma liver metastases recruiting III Sahlgrenska University Hospital (Sweden) NCT00986661 A study to assess PV-10 chemoablation of cancer of the liver recruiting I Sharp Memorial Hospital (San Diego, California); Florida Hospital Tampa; St. Luke’s University Health Network (Bethlehem, Pennsylvania); Vanderbilt University Medical Center; MD Anderson Cancer Center NCT02678572 Percutaneous hepatic perfusion in patients with hepatic-dominant ocular melanoma (FOCUS) recruiting III Stanford University; Moffit Cancer Center; Emory University; University of Chicago; University of Maryland Cancer Center; Atlantic Melanoma Center at Morristonwn Medical Center (NJ); Roswell Park Cancer Institute; Duke University Medical Center; Ohio State University; St. Luke’s University Hospital Cancer Center; Thomas Jefferson University; University of Tennesee; MD Anderson Cancer Center; sites in Austria, Belgium, France, Germany, Italy, Spain, Switzerland, UK NCT03025256 Intravenous and intrathecal nivolumab in treating patients with leptomeningeal disease recruiting I MD Anderson Cancer Center Sussman/Funchain/SinghOcul Oncol Pathol 2020;6:381–387384 DOI: 10.1159/000508383 cific pathways alone or in combination with immuno- logical checkpoint inhibitors are categorized as targeted therapy clinical trials. Similarly, trials with oncolytic viral therapies alone or in combination with immunological checkpoint inhibitors are categorized as oncolytic virus therapy trials. Details of the targeted therapy and onco- lytic virus therapy trials are presented in Table 1. Targeted Therapy Clinical Trials The current landscape of systemic therapy for cutane- ous melanoma is largely driven by immunotherapy. Al- though effective in treating patients with cutaneous mel- anoma, response rates have been disappointing in uveal melanoma. Different approaches, including targeted should also be explored in this field. Four clinical trials are currently available utilizing targeted therapy. A phase 1 trial of intermittent dosing of the mitogen-activated pro- tein kinase kinase (MEK) enzyme inhibitor, selumetinib, in metastatic uveal melanoma patients who have not re- ceived prior MEK inhibitor therapy (NCT02768766), tar- gets the mitogen-activated protein kinase (MAPK) path- way, regardless of tumor mutational status. Oncogenic mutations in GNAQ or GNA11 are observed in more than 80% of primary uveal melanomas and activate signaling pathways primarily including the MAPK pathway, which leads to cell proliferation and survival [10, 11]. A prior randomized phase 2 trial compared selumetinib to che- motherapy in 101 metastatic uveal melanoma patients and found a modest benefit in PFS (15.9 vs. 7 weeks) and in objective response rate (14 vs. 0%) for those treated with selumetinib [12]. However, treatment-related ad- verse events were observed in 97% of patients treated with selumetinib. With this trial, an intermittent dosing sched- ule may achieve a better toxicity profile and response rate if higher doses of selumetinib can be achieved. Mutations in GNAQ or GNA11 also activate the pro- tein kinase C pathway, which also leads to cell prolifera- tion and survival and thus serves as another target for cancer-directed therapy. A current phase 1/2 basket trial is available to metastatic uveal melanoma patients and other solid tumors, which uses the drug IDE196 in pa- tients harboring GNAQ/11 mutations or protein kinase C fusions (NCT03947385). A recent phase 1 study of IDE196 in patients with metastatic uveal melanoma dem- onstrated encouraging clinical activity with 6/66 patients achieving a partial response and 45/66 with stable disease [13]. The toxicity profile was tolerable, with 25% of pa- tients developing grade 3–4 adverse events, namely hypo- tension. While two dosing strategies were employed in this trial (once daily dosing and twice daily dosing), twice daily dosing was better tolerated and potentially exhibited longer duration of response. All patients (n = 38) in the daily dosing regimen discontinued treatment due to pro- gressive disease, whereas 5 patients in the twice-daily dos- ing regimen (n = 30) remained on treatment for greater than 13 months. Of these 5 patients, 2 maintained a par- tial response and 3 had stable disease [13]. For this reason, the study design for IDE196 includes a dose escalation phase for twice daily dosing to determine the recom- mended phase 2 dose in patients with metastatic uveal melanoma, cutaneous melanoma, colorectal cancer, and other solid tumors. Another target for clinical trials is double stranded DNA damage repair genes. Germline and somatic muta- tions in the double-stranded DNA damage repair gene BAP1 have been found in patients with uveal melanoma. PARP1/2 enzymes are responsible for repairing single- stranded DNA breaks. Inhibition by a PARP inhibitor, along with a deficient DNA damage repair gene, ultimate- ly leads to truncation of DNA replication, transcription, and cell death, also known as synthetic lethality [14]. Sev- eral trials in other tumor types, specifically breast, ovari- an, and prostate cancers that target the BRCA1/2 genes have successfully shown improved response rates and PFS with PARP inhibitor therapy [15–17]. A current clin- ical trial is evaluating niraparib in BAP1 and other DNA damage response deficient neoplasms in metastatic uveal melanoma, mesothelioma, and renal cell carcinoma (NCT03207347). Similarly, another phase 2 trial that is active, but not yet recruiting patients, is using the combi- nation of talazoparib (PARP inhibitor) and nivolumab (anti-PD-1 immunotherapy) in metastatic uveal or cuta- neous melanoma patients that harbor a mutation in a DNA damage repair gene (NCT04187833). The DNA damage repair genes included in this study are BRCA1/2 and BRCAness genes, which are specifically responsible for homologous recombination repair of DNA. In cuta- neous melanoma, the combination of PARP and PD-1 inhibition has shown to increase the immunogenicity of tumor cells by promoting T cell and natural killer cell in- filtration, and increasing tumor expression of PD-L1 in vitro and in vivo [18–20]. Lastly, a phase 1/2 trial evaluates PLX2853 in advanced malignancies (NCT03297424). PLX2853 is an inhibitor of bromodomain-containing protein 4 (BRD4), a BET family member, an epigenetic regulator that is known to exert key roles involved in chromatin remodeling and transcriptional regulation. BRD4 is significantly upregu- lated in melanoma tissue; treatment with BRD4 or BET inhibitors have shown to impair melanoma cell prolifera- Clinical Trials in Metastatic Uveal Melanoma 385Ocul Oncol Pathol 2020;6:381–387 DOI: 10.1159/000508383 tion and tumor growth in vitro and in vivo [21]. Simi- larly, BRD4 inhibition demonstrated cytotoxic activity in uveal melanoma cell lines and mouse xenograft models carrying GNAQ/11 mutations [22]. Oncolytic Virus Therapy Clinical Trials Oncolytic viruses are also an alternate approach in treating metastatic uveal melanoma patients. Oncolytic virus therapy has been utilized in cutaneous melanoma with the development of talimogene laher- parepvec (TVEC), approved by the FDA in October 2015. TVEC is currently being studied in combination to ex- pand its use and synergize with other interventions, in- cluding immune checkpoint inhibitor therapy. However, oncolytic virus therapy has not yet been introduced in the field of uveal melanoma. Currently, two clinical trials are available for intratumoral injection of oncolytic virus therapy. One is a phase 2 trial for anti-PD-1 naïve patients to receive gene therapy with intralesional injection of ad- enovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) with valacyclovir and stereotactic body radiation therapy followed by nivolum- ab administration on day 17 (NCT02831933). This thera- peutic combination builds on the concept of “suicide gene therapy,” where a therapeutic gene-encoding en- zyme (ADV/HSV-tk) is capable of transforming a non- toxic prodrug (valacyclovir) into a cell toxin that enhanc- es the cytotoxic effect within cancer cells and protects the healthy cells [23]. Another clinical trial using a modified virus is a phase 1 study of VSV-IFNbetaTYRP1 in pa- tients with metastatic uveal or cutaneous melanoma (NCT03865212). The vesicular stomatitis virus (VSV) is altered to include two extra genes: human interferon beta (hIFN-β), which may protect normal healthy cells from becoming infected with the virus, and TYRP1, which is expressed mainly in melanocytes and melanoma tumor cells. TYRP1 can trigger a strong immune response to kill the melanoma tumor cells. VSV has been shown to have a rapid replication rate within the tumor and to be cyto- toxic in melanoma xenograft models. Targeting TYRP1 antigen has been shown to increase CD4 T cells and IL-17 in vitro and in vivo, resulting in increased immune cell infiltration into the tumor microenvironment [24–26]. Liver-Directed Therapy Clinical Trials As up to 89% of patients with metastatic uveal mela- noma develop metastatic disease to the liver, recent stud- ies have suggested statistically significant improved pro- gression-free survival (PFS) and OS with liver-directed therapy when compared to systemic therapy (median PFS 5.2 vs. 2.8 months; mOS 14.6 vs. 9.3 months) [6]. How- ever, when controlling for key patient characteristics, the OS benefit for liver-directed therapies is no longer seen. Five studies are currently available for metastatic uveal melanoma patients with significant liver disease burden and limited extrahepatic disease, which include: a phase 1/2 study of combination immunotherapy with ipilim- umab/nivolumab with SirSpheres Yttrium-90 internal hepatic radiation (NCT02913417); combination ipilim- umab/nivolumab with immunoembolization (phase 2) to liver metastases (NCT03472586); phase 3 isolated hepat- ic perfusion study where high concentration chemother- apy is perfused through the liver with minimal systemic exposure (NCT01785316); a phase 1 study of intralesion- al injection of PV-10 (10% rose bengal disodium), which has an expansion cohort of patients that can receive im- mune checkpoint inhibitor therapy (NCT00986661); and a phase 3 study of percutaneous hepatic perfusion with melphalan (NCT02678572). This study (also known as the FOCUS trial) delivers melphalan 3 mg/kg using the Delcath Hepatic Delivery System via percutaneous cath- eterization of the femoral artery to access the hepatic ar- tery to infuse the chemotherapeutic agent, and in the in- ferior caval vein to aspirate the chemosaturated blood re- turning through the hepatic veins, which is perfused through an extracorporeal filtration system, and then re- turned to systemic circulation. Patients can receive up to six treatments at 6-week intervals. In another phase 3 tri- al, percutaneous hepatic perfusion of melphalan was compared with best alternative care in 93 patients with melanoma liver metastases. Eighty-three patients in this study had uveal melanoma. Hepatic PFS was significant- ly prolonged with melphalan infusion (median 7.0 vs. 1.6 months); however, no difference was observed in OS (median 10.6 vs. 10.0 months) [27]. CNS-Directed Therapy Clinical Trial While uveal melanoma does not typically metastasize to the central nervous system, several case reports and case series have demonstrated leptomeningeal involve- ment [28, 29]. Data from metastatic cutaneous melanoma patients with leptomeningeal disease has shown a median OS of only 1.8 months [30]. Limited treatment options are available for cutaneous and uveal melanoma patients with leptomeningeal disease with limited evidence of long-term clinical benefit from them [31]. A current phase 1 clinical trial available for uveal melanoma pa- tients with leptomeningeal disease involves the adminis- tration of intrathecal nivolumab with intravenous nivolumab beginning in cycle 2 (NCT03025256). Sussman/Funchain/SinghOcul Oncol Pathol 2020;6:381–387386 DOI: 10.1159/000508383 Conclusions The current landscape of clinical trials available for treatment of metastatic uveal melanoma is comprised of 17 active trials that encompass a range of modalities, in- cluding immunotherapy, targeted therapy, oncolytic vi- rus therapy, as well as liver-directed therapy, and CNS- directed therapy. While informative, our review of avail- able clinical trials has limitations. While our search criteria were broad in order to encompass all clinical trials available for metastatic uveal melanoma, trials were large- ly limited to “recruiting” status. Therefore, trials that opened or started recruiting after the search date of No- vember 26, 2019, were not included in this review. As uve- al melanoma is a rare disease, we would expect a few trials may have opened after the search was performed. As no current standard of care therapy exists for metastatic uve- al melanoma, clinical trials are essential for developing new therapies and offering patients hope for improved outcomes. Various novel therapeutic targets and immu- nomodulatory approaches are on the horizon and may yield incremental therapeutic benefit. Selecting an appro- priate clinical trial can be overwhelming and should be made with a patient’s oncologist. Oncologists and their clinical trial team can discuss with patients the details of a trial, eligibility criteria, and expected toxicity. Addition- ally, oncologists can compare available clinical trials to standard of care therapy in the context of a patient’s co- morbidities, location, and burden of metastatic disease. Conflict of Interest Statement Tamara Sussman has no conflicts of interest to declare. Pauline Funchain receives consultant fees from Eisai and research funding from Pfizer. Arun Singh receives consulting fees from Eckert and Zeigler, and Isoaid; advisory board meeting with Immunocore; and stock options with Aura. Funding Sources No funding was received for the preparation of the manuscript. Author Contributions T.A.S. collected data, performed search, and wrote manuscript. A.S. designed concept and revised manuscript. P.F. revised manu- script. All authors approve the final version of the manuscript. References 1 Aronow ME, Topham AK, Singh AD. Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival (SEER 1973-2013) [Internet]. Ocul Oncol Pathol. 2018 Apr; 4(3): 145–51. [cited 2019 Aug 14] Available from: h t t p : / / w w w . n c b i . n l m . n i h . g o v / p u b m e d / 29765944 2 Singh AD, Turell ME, Topham AK. Uveal melanoma: trends in incidence, treatment, and survival [Internet]. Ophthalmology. 2011 Sep; 118(9): 1881–5. [cited 2019 Aug 14] Available from: https://linkinghub. elsevier. com/retrieve/pii/S016164201100073X 3 Kujala E, Mäkitie T, Kivelä T. Very Long- Term Prognosis of Patients with Malignant Uveal Melanoma [Internet]. Invest Opthal- mol Vis Sci. 2003 Nov 1 [cited 2019 Aug 14]; 44(11): 4651. Available from: http://www. ncbi.nlm.nih.gov/pubmed/14578381 https:// doi.org/10.1167/iovs.03-0538. 4 Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, et al. De- velopment of metastatic disease after enroll- ment in the COMS trials for treatment of cho- roidal melanoma: Collaborative Ocular Mela- noma Study Group Report No. 26 [Internet]. Arch Ophthalmol. 2005 Dec 1 [cited 2019 Aug 14]; 123(12): 1639–43. Available from: http://archopht.jamanetwork.com/article. aspx?doi=10.1001/archopht.123.12.1639 5 Augsburger JJ, Corrêa ZM, Shaikh AH. Effec- tiveness of treatments for metastatic uveal melanoma [Internet]. Am J Ophthalmol. 2009 Jul; 148(1): 119–27. [cited 2019 Aug 14] Available from: http://www.ncbi.nlm.nih. gov/pubmed/19375060 6 Khoja L, Atenafu EG, Suciu S, Leyvraz S, Sato T, Marshall E, et al. Meta-Analysis in Metastatic Uveal Melanoma to Determine Progression-Free and Overall Survival Benchmarks: an International Rare Cancers Initiative (IRCI) Ocular Melanoma study [Internet]. Ann Oncol. 2019 May 31 [cited 2019 Aug 14]; 30(8): 1370–80. Available from: https://academic.oup.com/annonc/ article/30/8/1370/5509502 7 Algazi AP, Tsai KK, Shoushtari AN, Munhoz RR, Eroglu Z, Piulats JM, et al. Clinical out- comes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016 Nov; 122(21): 3344–53. 8 Pelster M, Gruschkus SK, Bassett R, Gombos DS, Shephard M, Posada L, et al. Phase II study of ipilimumab and nivolum- ab (ipi/nivo) in metastatic uveal melanoma (UM). J Clin Oncol. 2019 May; 37(15_sup- pl): 9522. 9 Piulats Rodriguez JM, De La Cruz Merino L, Espinosa E, Alonso Carrión L, Martin Algarra S, López-Castro R, et al. Phase II multicenter, single arm, open label study of Nivolumab in combination with Ipilimumab in untreated patients with metastatic uveal melanoma. Ann Oncol. 2018 Oct (suppl_8):viii442- viii466. 10 Onken MD, Worley LA, Long MD, Duan S, Council ML, Bowcock AM, et al. Oncogenic mutations in GNAQ occur early in uveal mel- anoma. Invest Ophthalmol Vis Sci. 2008 Dec; 49(12): 5230–4. 11 Van Raamsdonk CD, Griewank KG, Cros- by MB, Garrido MC, Vemula S, Wiesner T, et al. Mutations in GNA11 in uveal mela- noma. N Engl J Med. 2010 Dec; 363(23): 2191–9. 12 Carvajal RD, Sosman JA, Quevedo JF, Mil- hem MM, Joshua AM, Kudchadkar RR, et al. Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA. 2014 Jun; 311(23): 2397–405. 13 Kapiteijn E, Carlino M, Boni V, Loirat D, Speetjens F, Park J, et al. Abstract CT068: A Phase I trial of LXS196, a novel PKC inhibitor for metastatic uveal melanoma. Cancer Res. 2019 Jul; 79(13 suppl):CT068. 14 Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Can- cer Res. 2012 Nov; 72(21): 5588–99. https://www.karger.com/Article/FullText/508383?ref=1#ref1 https://www.karger.com/Article/FullText/508383?ref=2#ref2 https://www.karger.com/Article/FullText/508383?ref=3#ref3 https://www.karger.com/Article/FullText/508383?ref=3#ref3 https://www.karger.com/Article/FullText/508383?ref=4#ref4 https://www.karger.com/Article/FullText/508383?ref=5#ref5 https://www.karger.com/Article/FullText/508383?ref=6#ref6 https://www.karger.com/Article/FullText/508383?ref=7#ref7 https://www.karger.com/Article/FullText/508383?ref=8#ref8 https://www.karger.com/Article/FullText/508383?ref=9#ref9 https://www.karger.com/Article/FullText/508383?ref=10#ref10 https://www.karger.com/Article/FullText/508383?ref=11#ref11 https://www.karger.com/Article/FullText/508383?ref=12#ref12 https://www.karger.com/Article/FullText/508383?ref=13#ref13 https://www.karger.com/Article/FullText/508383?ref=14#ref14 https://www.karger.com/Article/FullText/508383?ref=14#ref14 Clinical Trials in Metastatic Uveal Melanoma 387Ocul Oncol Pathol 2020;6:381–387 DOI: 10.1159/000508383 15 Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gon- çalves A, Lee KH, et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation [Internet]. N Engl J Med. 2018 Aug; 379(8): 753–63. [cited 2019 Feb 27] Available from: http://www.nejm.org/ doi/10.1056/NEJMoa1802905 16 Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer [Internet]. N Engl J Med. 2015 Oct; 373(18): 1697–708. [cited 2019 Feb 26] Avail- able from: http://www.nejm.org/doi/10.1056/ NEJMoa1506859 17 Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, et al. Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer [Internet]. JAMA Oncol. 2019 Jun; 5(8): 1132. [cited 2019 Sep 4] Available from: https://ja- manetwork.com/journals/jamaoncology/ful- larticle/2735888 18 Huang J, Wang L, Cong Z, Amoozgar Z, Kin- er E, Xing D, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer [Internet]. Biochem Biophys Res Commun. 2015 Aug; 463(4): 551–6. [cited 2019 Feb 26] Available from: https://linkinghub.elsevier. com/retrieve/pii/S0006291X15010116 19 Jiao S, Xia W, Yamaguchi H, Wei Y, Chen MK, Hsu JM, et al. PARP Inhibitor Upregu- lates PD-L1 Expression and Enhances Can- cer-Associated Immunosuppression [Inter- net]. Clin Cancer Res. 2017 Jul; 23(14): 3711– 20. [cited 2019 Feb 26] Available from: http:// clincancerres.aacrjournals.org/lookup/ doi/10.1158/1078-0432.CCR-16-3215 20 Pantelidou C, Sonzogni O, De Oliveria Tavei- ra M, Mehta AK, Kothari A, Wang D, et al. PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Mod- els of Triple-Negative Breast Cancer [Inter- net]. Cancer Discov. 2019 Jun; 9(6): 722–37. [cited 2019 Jul 30] Available from: http:// www.ncbi.nlm.nih.gov/pubmed/31015319 21 Segura MF, Fontanals-Cirera B, Gaziel- Sovran A, Guijarro MV, Hanniford D, Zhang G, et al. BRD4 sustains melanoma prolifera- tion and represents a new target for epigenetic therapy. Cancer Res. 2013 Oct; 73(20): 6264– 76. 22 Ambrosini G, Sawle AD, Musi E, Schwartz GK. BRD4-targeted therapy induces Myc-in- dependent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells [Internet]. Oncotarget. 2015 Oct; 6(32): 33397–409. [cited 2019 Dec 2] Available from: http://www.ncbi.nlm.nih. gov/pubmed/26397223 23 Sakkas A, Zarogoulidis P, Domvri K, Hohen- forst-Schmidt W, Bougiouklis D, Kakolyris S, et al. Safety and efficacy of suicide gene ther- apy with adenosine deaminase 5-fluorocyto- sine silmutaneously in in vitro cultures of melanoma and retinal cell lines. J Cancer. 2014 Apr; 5(5): 368–81. 24 Stojdl DF, Lichty B, Knowles S, Marius R, At- kins H, Sonenberg N, et al. Exploiting tumor- specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med. 2000 Jul; 6(7): 821–5. 25 Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, et al. Using virally expressed melanoma cDNA libraries to iden- tify tumor-associated antigens that cure mela- noma [Internet]. Nat Biotechnol. 2012 Mar; 30(4): 337–43. [cited 2019 Nov 27] Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 22426030 26 Hastie E, Grdzelishvili VZ. Vesicular stomati- tis virus as a flexible platform for oncolytic vi- rotherapy against cancer [Internet]. J Gen Vi- rol. 2012 Dec; 93(Pt_12): 2529–45. [cited 2019 Nov 27] Available from: http://www.ncbi. nlm.nih.gov/pubmed/23052398 27 Hughes MS, Zager J, Faries M, Richard Alex- ander H, Royal RE, Wood B, et al. Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Pa- tients with Melanoma Liver Metastases. Ann Surg Oncol. 2016 Apr; 23(4): 1309–1319. 28 Fedorenko IV, Evernden B, Kenchappa RS, Sahebjam S, Ryzhova E, Puskas J, et al. A rare case of leptomeningeal carcinomatosis in a patient with uveal melanoma: case report and review of literature. Melanoma Res. 2016 Oct; 26(5): 481–6. 29 Glitza IC, Reddy ST, Patel SP. Leptomenin- geal disease in uveal melanoma: a case series. J Neurooncol 2018 Sep; 139(2): 503–505. 30 Davies MA, Liu P, McIntyre S, Kim KB, Papa- dopoulos N, Hwu WJ, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011 Apr; 117(8): 1687–96. 31 Groves MD. Leptomeningeal disease. Neuro- surg Clin N Am. 2011 Jan; 22(1): 67–78. https://www.karger.com/Article/FullText/508383?ref=15#ref15 https://www.karger.com/Article/FullText/508383?ref=16#ref16 https://www.karger.com/Article/FullText/508383?ref=17#ref17 https://www.karger.com/Article/FullText/508383?ref=18#ref18 https://www.karger.com/Article/FullText/508383?ref=19#ref19 https://www.karger.com/Article/FullText/508383?ref=20#ref20 https://www.karger.com/Article/FullText/508383?ref=21#ref21 https://www.karger.com/Article/FullText/508383?ref=22#ref22 https://www.karger.com/Article/FullText/508383?ref=23#ref23 https://www.karger.com/Article/FullText/508383?ref=24#ref24 https://www.karger.com/Article/FullText/508383?ref=24#ref24 https://www.karger.com/Article/FullText/508383?ref=25#ref25 https://www.karger.com/Article/FullText/508383?ref=26#ref26 https://www.karger.com/Article/FullText/508383?ref=26#ref26 https://www.karger.com/Article/FullText/508383?ref=27#ref27 https://www.karger.com/Article/FullText/508383?ref=27#ref27 https://www.karger.com/Article/FullText/508383?ref=28#ref28 https://www.karger.com/Article/FullText/508383?ref=29#ref29 https://www.karger.com/Article/FullText/508383?ref=30#ref30 https://www.karger.com/Article/FullText/508383?ref=31#ref31 https://www.karger.com/Article/FullText/508383?ref=31#ref31 TabellenTitel