Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma
Condition: Uveal Melanoma
MeSH terms: Melanoma; Uveal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a Phase 2, single-arm study of nivolumab combined with ipilimumab in subjects with
      previously untreated, unresectable or metastatic uveal melanoma. Previous studies with
      immunotherapy have shown promising results and this synergistic combination was very
      effective in other tumors. This study will allow for further characterization of the safety
      and clinical activity of nivolumab combined with ipilimumab in subjects with uveal melanoma.
    

Detailed description: 
      Uveal melanoma is a rare disease, accounting for 0.1% of all cancer deaths. This disease
      arises from melanocytes of the uveal tract and is the most common primary intraocular tumor
      in adults, with an incidence estimated at 0.6 per 100,000 persons/year in the Western
      population and seems to have remained stable over time.

      Metastases in uveal melanoma appear in 6.5%-35% of the patients during the first decade. The
      clinical and metastatic behavior differs from cutaneous melanoma because of its initially
      purely hematogenous dissemination and its tendency to metastasize to the liver. Furthermore,
      the liver is almost a "sentinel lymph node" for uveal melanoma, because it is affected in 95%
      of patients and it is the sole site of metastasis in most cases. This specific ocular-hepatic
      tropism remains unexplained. When liver metastases develop, the prognosis is poor and life
      expectancy is reduced to less than 6 months in the absence of treatment. Only few prognostic
      factors for survival have been identified. Age, short time interval to metastases
      development, and tumor burden in the liver have shown a negative impact on survival, whereas
      patients diagnosed at regular follow-up survive significantly longer, probably due to the
      earlier diagnosis. Several loco-regional treatment options can be considered if metastases
      are confined to the liver, including partial hepatic resection or radiofrequency ablation.
      Curative resection is possible in only a small fraction of patients due to the number,
      location or size of the metastases.

      Systemic chemotherapy is usually unsuccessful in metastatic uveal melanoma and results were
      recently reviewed showing an Overall Response Rate of 4,6 %with 95% CI 3.3-6.3%. There is no
      proof that conventional chemotherapy prolongs survival with most studies reporting OS between
      5 and 12 months. Most therapies are derived from the experience extrapolated from cutaneous
      melanoma. Only few chemotherapeutic regimens have been studied in phase II trials such as
      bleomycin /vincristine/ lomustine /dacarbazine (BOLD), fotemustine,9-nitrocamptothecin,
      temozolomide, bendamustine, gemcitabine/treosulfan, cisplatin/gemcitabine/treosulfan, and
      dacarbazine/treosulfan with poor results that range from 0 to 15% response rate and less than
      12 months overall survival with first line therapy. A phase III trial randomizing patients to
      chemotherapy or Best Suportive Care (BSC) is not expected to be performed because of
      difficulty in recruiting due to the low incidence of disease.

      In the other hand, the best understanding of the biology of cancer disease has allowed us to
      identify pathways that are important in mechanisms of proliferation, survival or
      dissemination. Recently Guanine Nucleotide-Binding Protein G (GNAQ) gene oncogenic mutation
      has been identified in close to 50% of primary uveal melanomas. The emergence of newer agents
      that target this or other pathways (such as selumetinib, sunitinib, imatinib, vorinostat,
      antiangiogenics) have resulted in multiple small studies that up to date have failed to show
      a clear superiority against chemotherapy. To summarize, patients with metastatic uveal
      melanoma should be included in clinical trials evaluating other options with newer agents
      with potentially less toxicity and greater efficacy than conventional chemotherapy.
    

Intervention name(s): ipilimumab; Nivolumab
Intervention type(s): Drug; Drug
Intervention description(s): Ipilimumab every 3 weeks for a total of four doses (Cycles 1 and 2); Nivolumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks
Other intervention name(s): Yervoy; Opdivo
Intervention MeSH terms: Nivolumab; Ipilimumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: melanoma