Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma
Condition: Recurrent Melanoma; Stage IV Melanoma; Tumors Metastatic to Brain
MeSH terms: Melanoma
Intervention: Ipilimumab; Whole-Brain Radiation Therapy (WBRT); Stereotactic Radiosurgery (SRS)
Intervention description: Given IV; Undergo WBRT; Undergo SRS
Intervention MeSH terms: Ipilimumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 17.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase I trial studies the side effects and best dose of ipilimumab when given together
      with whole brain radiation therapy or stereotactic radiosurgery in treating patients with
      melanoma with brain metastases. Monoclonal antibodies, such as ipilimumab, can block tumor
      growth in different ways. Some block the ability of the tumor to grow and spread. Others find
      Tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy,
      such uses high-energy x-rays and other types of radiation to kill tumor cells. Giving
      radiation therapy in different ways may kill more tumor cells. Giving ipilimumab together
      with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient age is >= 18 years

          2. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, or
             1.

          3. Ability to provide written informed consent obtained prior to participation in the
             study and any related procedures being performed

          4. 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 <= 2.5 x ULN for patients without liver metastasis

               -  AST/ALT <= 5 times for liver metastases

               -  Bilirubin <= 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a
                  total bilirubin less than 3.0 mg/dL)

               -  Serum creatinine <= 2.0 x ULN or 24-hour creatinine clearance >= 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

          5. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.

          6. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone
             supplements to treat underlying hypothyroidism.

          7. 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.

          8. 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.

          9. A pathological diagnosis of melanoma is required, from either the primary or a
             metastasis. This also includes uveal melanoma.

         10. A radiological diagnosis (CT or MRI) of one or more brain metastases is required.

         11. Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or
             surgical procedures to NCI CTCAE Version 4.0 grade <= 1.

         12. Specific eligibility criteria for the two arms

               -  Arm A WBRT and Ipilimumab:

                    -  Patients have 5 or more brain metastases, or patients have any brain
                       metastases exceeding the limit for SRS (maximum diameter is > 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 <= 4
                       cm in diameter.

                    -  Patients have only one brain metastasis and completely resected, the
                       resection cavity is <= 4 cm in diameter.

                    -  OR If a patient is found to have progression of brain metastases that exceed
                       4 cm in diameter based on the MRI scan on the time of SRS procedure, the
                       patient should be re-assigned to WBRT arm or withdrawn from the study. The
                       study PI should be notified.

                    -  OR If a patient is found to have progression of brain metastases that exceed
                       4 lesions based on the MRI scan on the time of the SRS procedure, the
                       patient can either be treated with SRS to all the lesions (up to 10
                       lesions), re-assigned to WBRT arm, or withdrawn from the study per the
                       treating physician. The study PI should be notified.

        Exclusion Criteria:

          1. Patient with leptomeningeal carcinomatosis.

          2. 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).

          3. Major surgery or radiation therapy within 2 weeks of starting the study treatment.

          4. If patients are receiving chemotherapy or other investigational drugs, they must be
             discontinued 4 weeks prior to enrollment.

          5. NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.

          6. Any of the following within the 6 months prior to study drug administration:

             myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
             graft, symptomatic congestive heart failure, cerebrovascular accident or transient
             ischemic attack, or pulmonary embolism. Patients with known cardiac disease will be
             required to have an ECHO or MUGA scan at baseline and at the completion of study.

          7. Ongoing cardiac dysrhythmias of NCI CTCAE grade >= 2.

          8. Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal
             medical therapy).

          9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in
             the normal range with medication.

         10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
             (AIDS)-related illness or other active infection.

         11. 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.

         12. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration, or may interfere with the interpretation of study results, and in
             the judgment of the investigator would make the subject inappropriate for entry into
             this study.

         13. Concomitant therapy with any of the following: IL-2, interferon, or other non-study
             immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents,
             vermurafenib, or other investigational therapies.

         14. All efforts need to be taken to avoid/minimize the use of cortical steroid during
             radiation period (1 week prior to start radiation, during radiation, and 1 week after
             finishing radiation). Any steroid used considered necessary by the treating physician
             should be closely documented, including medication, route of administration, dose, and
             duration.

         15. Active infection with hepatitis B, or hepatitis C.

         16. Patients who had prior brain radiation treatment.

         17. Patients are excluded if they have a history of any other malignancy from which the
             patient has been disease-free for less than 2 years, with the exception of adequately
             treated basal or squamous cell carcinoma of skin, superficial bladder cancer or
             carcinoma in situ of cervix, AJCC (version 7.0) stage 0 or I breast cancer, AJCC
             (version 7.0) stage I, or II prostate cancer.

         18. Patients are excluded if they have a history of autoimmune disease, as follows:
             Patients with a history of inflammatory bowel disease are excluded from this study as
             are patients with a history of symptomatic disease (e.g., rheumatoid arthritis,
             systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune
             vasculitis [e.g., Wegener's Granulomatosis]). Patients with motor neuropathy
             considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis)
             are excluded. Patients with a history of autoimmune thyroiditis are eligible if their
             current thyroid disorder is treated and stable with replacement or other medical
             therapy.

         19. Patients who are allergic to Ipilimumab.

         20. Patients who received ipilimumab before.

         21. Patients who are allergic to MRI contrast agent or have contraindication for MRI.