Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Phase II Study of Nivolumab in Combination With Ipilimumab for Uveal Melanoma

Summary: The goal of this clinical research study is to learn if ipilimumab and nivolumab can help to control uveal melanoma.
  Ipilimumab is designed to increase the immune system's ability to fight cancer.
  Nivolumab is an antibody (a protein that attacks foreign cells) that is designed to allow the body's immune system to work against tumor cells.

Detailed description: Study Drug Administration:
  If you are found to be eligible to take part in this study, you will receive ipilimumab by vein over 90 minutes (+/- 15 minutes) each time. You will receive nivolumab by vein over 60 minutes (+/- 15 minutes) each time.
  You will receive ipilimumab and nivolumab every 3 weeks (+/- 7 days) for a total of 4 doses (Weeks 1, 4, 7, and 10). You will continue to receive nivolumab every 2 weeks after that.
  Study Visits:
  At Weeks 1, 4, 7, 10, 13, and every 6 weeks after that:
  -  You will have a physical exam, including measurement of your vital signs and weight. If your screening visit occurred within 14 days of your first on-study visit, it will not need to be repeated on Day 1 of Cycle 1.
  -  You will be asked about any symptoms or side effects you may have had and any drugs you may be taking.
  -  Your performance status will be recorded.
  -  Blood (about 1 tablespoon) will be drawn for routine tests and to check your liver and thyroid function.
  -  At Weeks 1, 4, 7, and 10 only, if you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine pregnancy test.
  Sometime during Cycles 2-4, you will have a core or excisional biopsy of the tumor for biomarker testing, including genetic biomarkers. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug. To perform a core biopsy, a sample of tissue is removed using a hollow core needle that has a cutting edge. To perform an excisional biopsy, the area of abnormal skin, including a portion of normal skin area is removed by cutting it out. You may receive stitches after an excisional biopsy.
  At Week 12 and every 6 weeks after that, you will have scans such as a CT scan to check the status of the disease.
  Length of Treatment:
  You may receive up to 4 doses of ipilimumab and may continue taking nivolumab for as long as the doctor thinks it is in your best interest.
  You may no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
  Your participation on the study will be over once you have completed the end-of-treatment visit, and follow-up.
  End-of-Treatment Visit:
  After you are finished taking the study drugs:
  -  You will have a physical exam, including measurement of your vital signs.
  -  You will be asked about any symptoms or side effects you may have had and any side drugs you may be taking.
  -  Blood (about 1 tablespoon) will be drawn for routine tests and to check your liver and thyroid function.
  Follow-Up:
  For at least 60 days after you are finished taking the study drugs, you will have follow-up by phone or at the clinic. You will be asked how you are doing.
  This is an investigational study. Ipilimumab is FDA approved and commercially available to treat metastatic melanoma, including uveal melanoma. Nivolumab is FDA approved and commercially available to treat metastatic melanoma, including uveal melanoma, that has gotten worse while taking ipilimumab. Combining these 2 drugs to treat of uveal melanoma is investigational.
  Up to 52 patients will take part in this study. All will be enrolled at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Willing and able to give written informed consent.
  2. History of uveal melanoma and documented metastatic disease with at least one measurable lesion is required. which is >/= 1 cm x 1 cm (on spiral CT or equivalent).
  3. Any number of prior therapies is allowed.
  4. Required values for initial laboratory tests: WBC >/= 2000/uL, ANC >/= 1500/uL, Platelets >/= 100 x 10^3/uL, Hemoglobin >/= 9 g/dL, Creatinine </= 1.5 x ULN or creatinine clearance (CrCl) > 40 mL/min (using the Cockcroft-Gault formula): Female CrCl = (140 - age in years) x weight in kg x 0.85, 72 x serum creatinine in mg/dL, Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL, AST/ALT</= 3 x ULN for patients without liver metastasis,</= 5 x ULN for liver metastases, Bilirubin </= 1.5 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  5. In suspected patients no active or chronic infection with HIV, Hepatitis B, or Hepatitis C.
  6. Performance status ECOG 0-1.
  7. Men and women, >/= 18 years of age. Because no dosing or adverse event data are currently available on the use of ipilimumab in patients </= 18 years of age, minors are excluded from this study.
  8. Baseline imaging in the form of CT chest, abdomen, pelvis with oral and intravenous contrast within 28 days of study entry. For patients with a contrast allergy, choice of alternative body imaging will be at the discretion of the investigator or his designee. MRI of the brain is only needed if clinically indicated.
  9. Prior to start of treatment must be more than 21 days elapsed from surgery, radiation therapy, or prior chemotherapy. More than 42 days elapsed from prior immune therapy including vaccines.
  10. Women of childbearing potential (WOCBP) and fertile men with partners of childbearing potential 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.
  Exclusion Criteria:
  1. Untreated primary uveal melanoma except in cases where metastatic disease is diagnosed at the time of primary disease.
  2. Metastatic uveal melanoma patients with bone-only disease.
  3. Any other malignancy from which the patient has been disease-free for less than 2 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, breast, or prostate.
  4. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment,
  5. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
  6. Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
  7. A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist.
  8. Concomitant therapy with any of the following: tamoxifen, toremifene, IL 2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids greater than physiologic replacement doses. Ocular steroid use is acceptable.
  9. Women of childbearing potential (WOCBP)who: (a.) are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for up to 26 weeks after cessation of study drug, or (b.) have a positive pregnancy test at baseline, or (c.) are pregnant or breastfeeding.
  10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.

Relevance to patient case: not relevant