Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma

Inclusion Criteria

• Patient age is >= 18 years
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1.
• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• Patients must meet the following laboratory criteria:
• WBC >= 2000/uL
• ANC >= 1000/uL
• Platelets >= 75 x 10^3/uL
• Hemoglobin >= 9 g/dL (>= 80 g/L; may be transfused)
• AST/ALT = 50 ml/min
• Total serum calcium (corrected for serum albumin) or ionized calcium >= lower limit of normal (LLN)
• Serum potassium >= LLN
• Serum sodium >= LLN
• Serum albumin >= LLN or 3g/dl
• Patients with any elevated Alkaline Phosphatase due to bone metastases can be enrolled
• No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
• Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 26 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as:
• Amenorrhea >= 12 consecutive months without another cause, or
• For women with irregular menstrual periods and taking hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >= 35 mIU/mL.
• Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab.
• Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized.
• A pathological diagnosis of melanoma is required, from either the primary or a metastasis. This also includes uveal melanoma.
• A radiological diagnosis (CT or MRI) of one or more brain metastases is required.
• Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or surgical procedures to NCI CTCAE Version 4.0 grade 4 cm).
• OR Patient has only one brain metastasis and completely resected, the resection cavity is > 4 cm in diameter.
• Arm B SRS and Ipilimumab:
• Patients have 4 or fewer brain metastases. All the brain metastases are = 2.
• Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal medical therapy).
• Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication.
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness or other active infection.
• Pregnancy or breastfeeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.
• Other severe acute or c