Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma

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Brief Title

Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma

Official Title

Phase II Multicenter, Non Randomized, Open Label Trial of Nivolumab in Combination With Ipilimumab in Subjects With Previously Untreated Metastatic Uveal Melanoma

Brief 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall Survival at 12 months

Secondary Outcome

 Overall survival at 24 months.

Condition

Uveal Melanoma

Intervention

ipilimumab

Study Arms / Comparison Groups

 Nivolumab and Ipilimumab
Description:  Nivolumab and Ipilimumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

48

Start Date

April 2016

Completion Date

December 2021

Primary Completion Date

May 2017

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent must be provided;

          2. Patients must have a histological diagnosis of uveal melanoma;

          3. Progressive metastatic disease at baseline. Progressive disease is defined as new or
             progressive lesions on cross-sectional imaging;

          4. Age>18 years;

          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1;

          6. Measurable disease by CT or MRI per RECIST 1.1 criteria;

        Exclusion Criteria:

          1. Prior systemic treatment for metastatic uveal melanoma.

          2. Prior malignancy active within the previous 3 years except for locally curable cancers
             that have been apparently cured, such as basal or squamous cell skin cancer,
             superficial bladder cancer, carcinoma in situ of cervix or breast, or incidental
             prostate cancer.

          3. Autoimmune disease: Patients with a history of inflammatory bowel disease, including
             ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients
             with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive
             sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg,
             Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g.
             Guillain-Barre Syndrome and Myasthenia Gravis). Subjects with 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 are permitted to enroll.

          4. Any underlying medical or psychiatric condition, which in the opinion of the
             investigator will make the administration of nivolumab and ipilimumab hazardous or
             obscure the interpretation of Advers Events (AEs), such as a condition associated with
             frequent diarrhea.

          5. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to
             1 month before or after any dose of nivolumab and ipilimumab).

          6. A history of prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4
             antibody, or any other antibody or drug specifically targeting T-cell costimulation or
             immune checkpoint pathways.

          7. Concomitant therapy with any of the following: Interleukin (IL) -2, interferon, or
             other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
             agents; other investigation therapies; or chronic use of systemic corticosteroids,
             defined as >10mg daily prednisone equivalents. Inhaled or topical steroids, and
             adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the
             absence of active autoimmune disease.

          8. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases
             are eligible if these have been treated and there is no magnetic resonance imaging
             (MRI) evidence of progression for at least 8 weeks after treatment is complete and
             within 28 days prior to first dose of study drug administration. There must also be no
             requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
             prednisone equivalents) for at least 2 weeks prior to study drug administration.

          9. Women of childbearing potential (WOCBP) as defined below, who:

               -  are unwilling or unable to use an acceptable method of contraception to avoid
                  pregnancy for their entire study period and for at least 8 weeks after cessation
                  of study drug, or

               -  have a positive pregnancy test at baseline, or

               -  are pregnant or breastfeeding.
      

Gender

All

Ages

18 Years - 99 Years

Accepts Healthy Volunteers

No

Contacts

Josep Maria Piulats, MD, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT02626962

Organization ID

GEM-1402

Secondary IDs

2015-004429-15

Responsible Party

Sponsor

Study Sponsor

Grupo Español Multidisciplinar de Melanoma

Collaborators

 Bristol-Myers Squibb

Study Sponsor

Josep Maria Piulats, MD, Study Chair, ICO Hospitalet


Verification Date

June 2021