GEM STUDY: Radiation And Yervoy in Patients With Melanoma and Brain Metastases
Condition: Melanoma; Brain Metastases
MeSH terms: Melanoma; Neoplasm Metastasis; Neoplasms, Second Primary; Brain Neoplasms
Intervention: Ipilimumab
Intervention description: Ipilimumab 3mg/Kg iv q 3 weeks for 4 cycles
Intervention MeSH terms: Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: melanoma; brain; metastases; Patients with melanoma and brain metastases

Summary:

      Ipilimumab adds a clinical benefit to radiation therapy in patients with melanoma metastatic
      to the brain.

      Melanoma is the third most common cancer causing brain metastases, after cancers of the lung
      and breast, which appears to reflect the relative propensity of melanoma to metastasize to
      the central nervous system (CNS). Brain metastases are responsible for 20 to 54 percent of
      deaths in patients with melanoma, and among those with documented brain metastases, these
      lesions contribute to death in up to 95 percent of cases, with an estimated median overall
      survival ranging between 1.8 and 10.5 months, depending upon other prognostic factors.

      Ipilimumab is an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA4) monoclonal antibody that
      has demonstrated a clinically relevant and statistically significant improvement in overall
      survival, either alone (second line) or in combination with dacarbazine (DTIC) in 1st line.

      Ipilimumab has shown activity against brain metastases.

      According to the European Medicines Agency (EMA) approved label for Yervoy®, the use of
      glucocorticoids at baseline (commonly prescribed when brain metastases are diagnosed) should
      be avoided before the administration of ipilimumab. Data show that the use of even high doses
      of glucocorticoids for the management of immune-related adverse events do not decrease the
      efficacy of Yervoy®. There is no documented experience on the efficacy of Yervoy® when given
      concomitantly with radiation therapy and glucocorticoids.

      In experimental models, radiation therapy is synergistic to anti-Cytotoxic T-Lymphocyte
      Antigen 4 (anti-CTLA4) strategies (abscopal effect).

      There are no published results from clinical trials on the interaction between radiation
      therapy and ipilimumab.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Willing and able to give written informed consent.

          2. Histologic diagnosis of melanoma.

          3. First episode of radiological evidence of brain metastases

          4. Be over the age of 18 years old

          5. Radiation Therapy Oncology Group-recursive partitioning analysis (RTOG-RPA) class 2

          6. Karnofsky performance status (PS) more than 70%

          7. Barthel Index of Activities of Daily Living more than 10

          8. Measurable disease (mWHO criteria).

          9. Adequate organ function as determine by the following criteria:

               -  White blood count (WBC) more or equal to 2000/ microliter (uL)

               -  Absolute neutrophil count (ANC) more than 1.5 x 109/L.

               -  Platelet count more than 75 x 109/L.

               -  Hemoglobin more than 9 g/dL. If the patient received a red blood count (RBC)
                  transfusion, the required value of hemoglobin should be met at least 1 week after
                  the most recent transfusion.

               -  Serum creatinine less or equal to 2.0 x upper limit of normal (ULN).

               -  Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT)
                  less or equal to 2.5 x ULN for patients without liver metastasis, or less or
                  equal to 5 times for liver metastases.

               -  Total bilirubin less or equal 2.0 x ULN, (except patients with Gilbert's
                  Syndrome, who must have a total bilirubin less than 3.0 mg/dL)

         10. Persons of reproductive potential must agree to use an adequate method of
             contraception throughout treatment and for at least 26 weeks after ipilimumab is
             stopped

        Exclusion Criteria:

          1. Patients with melanoma and brain metastases with any of the following disease-specific
             characteristics:

               -  Documented evidence of prior progression of melanoma to an ipilimumab-containing
                  regimen (i.e. received at least 2 doses of ipilimumab for either advanced disease
                  or in the adjuvant setting and the disease progressed/relapsed (according to mWHO
                  criteria) within 24 weeks since the first dose of ipilimumab)

               -  Prior radiation therapy to the brain

               -  Other prior antineoplastic therapies for brain metastases.

               -  Patients with cerebral metastases as the only location of the disease, for which
                  local therapy (neurosurgery, radiosurgery) could achieve a disease-free status

               -  Patients with a rapid clinical deterioration, or with risk of herniation, or who
                  require unstable ascending dosing of supportive medication in the last week
                  -including anti-convulsivants, steroids and analgesics-, or who require
                  dexamethasone more than 16 mg/d (or other glucocorticoid at an equipotent dose),
                  or with a high lactate dehydrogenase (LDH) more than 2 x ULN.

          2. Any other malignancy form which the patient has been disease-free for less than 5
             years, with the exception of adequately treated and cured basal or squamous cell skin
             cancer, superficial bladder cancer or carcinoma in situ of the cervix, or incidental
             prostate cancer.

          3. Uncontrolled diabetes mellitus (HbA1c more than 9 %)

          4. Autoimmune disease other than vitiligo or past thyroiditis under substitutive hormone
             therapy: 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).

          5. Other chronic intestinal diseases associated with diarrhea.

          6. Active infection or other serious illness or medical condition.

          7. Known active or chronic infection with HIV, Hepatitis B, or Hepatitis C.

          8. Concomitant therapy with any of the following: interleukin-2 (IL-2), interferon, or
             other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
             agents; other investigation therapies; or chronic use of systemic corticosteroids
             (used for the management of non-cancer related illnesses), either concomitantly or
             during the last 30 days prior to the beginning of the treatment.

          9. Any experimental therapy administered in the past 30 days prior to the beginning of
             the treatment.

         10. Any non-oncology vaccine therapy used for the prevention of infectious diseases (for
             up to 4 weeks prior to or after any dose of blinded study drug) (see definitions in
             protocol text)

         11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (eg, infectious) illness.

         12. Any other general, medical or psychological conditions which in the opinion of the
             investigator will make the administration of ipilimumab hazardous, or that would
             preclude appropriate informed consent or compliance with the protocol, or obscure the
             interpretation of eventual adverse events (AEs).