Yttrium90, Ipilimumab, & Nivolumab for Uveal Melanoma With Liver Metastases

Despite rapid improvements in the treatment of cutaneous melanoma, there has been little
advance in therapy for uveal melanoma with hepatic metastases, an fatal orphan disease with
no established therapy. Studies by Dr. Sato and others have described some activity for
selective internal radiation with Yttrium90 microspheres (SIR-Spheres).There is limited
activity as single agents for both the immunotherapy drugs ipilimumab (anti-CTLA-4) and
nivolumab (anti-PD-1). In cutaneous melanoma the combination of ipilimumab and nivolumab is
clearly synergistic with improvement in response rates and progression-free survival over
single agents; however this has yet to be established for uveal melanoma.

Recent experimental and clinical evidence suggests additional synergy between radiation
therapy and immunotherapy. This synergy seems most evident when radiation is given through
large fraction stereotactic treatments or brachytherapy. The investigators will explore this
synergy with a feasibility study of 18 patients who will receive SirSpheres Yttrium-90
selective internal radiation given through the hepatic artery in two treatments followed by
immunotherapy with the combination of ipilimumab and nivolumab. The immunotherapy will be
given with the dose and schedule that has been established and FDA-approved for cutaneous
melanoma. Because of the generally low toxicity of Yttrium-90 selective internal radiation
therapy the investigators feel it can be given in full dosage prior to full dosage of
immunotherapy.

Inclusion Criteria:

1. Histologic diagnosis of metastatic uveal melanoma.

2. Patients must have measurable disease as defined by RECIST (see Section 6).

3. Patients must have liver metastasis

4. Patients must have no more than one prior systemic therapeutic regimen. This includes
chemotherapy, biologic therapy, biochemotherapy, or investigational treatment. This
does not include any therapies given in the adjuvant setting. No prior anti-CTLA4
therapy. Prior anti PD-1 or anti-PDL-1 antibody therapy is acceptable.

5. No concomitant therapy with any of the following: IL-2, interferon or other non-study
immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
investigation therapies; or chronic use of systemic corticosteroids.

6. Patients with prior selective internal radiation are candidates are eligible as long
as they are candidates for repeat procedures and they have demonstrated progressive
disease.

7. Age ≥ 18 years.

8. No known infection with HIV. Due to the mechanism of action of ipilimumab, activity
and side effects in an immune compromised patient are unknown.

9. No active infection with Hepatitis B.

10. No active infection with Hepatitis C.

11. ECOG performance status 0 or 1.

12. Women must not be pregnant or breast-feeding due to unknown effects of treatments on
the unborn fetus. All women of childbearing potential must have a blood test within 72
hours prior to randomization to rule out pregnancy. Women of childbearing potential
and sexually active males must be strongly advised to use an accepted and effective
method of contraception. Women of childbearing potential (WOCBP) must be using an
adequate method of contraception to avoid pregnancy throughout the study and for up to
12 weeks after the last dose of investigational product, in such a manner that the
risk of pregnancy is minimized. Sexually mature females who have not undergone a
hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive
months (i.e., who have had menses at some time in the preceding 24 consecutive months)
are considered to be of childbearing potential. 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 (e.g.,vasectomy) should be
considered to be of childbearing potential.

13. Patients must have the following lab values obtained < 4 weeks prior to starting
treatment:

- WBC ≥2000/uL

- ANC ≥1500/mcL

- Platelets ≥ 100,000/mcL

- Hemoglobin ≥ 8g/dL

- Creatinine ≤ 3.0 xULN

- AST and ALT < 2.5 x ULN

- Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a
total bilirubin less than 3.0 mg/dL)

- Albumin ≥ 3g/dL

Exclusion Criteria

1. Patients are excluded if they have liver tumor volume > 50%

2. Patients are excluded if they have active CNS metastases. Patients with history of CNS
metastases must have MRI scans that show stability of brain metastases for 8 weeks.

3. 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 and cured basal or squamous cell skin cancer, superficial bladder cancer or
carcinoma in situ of the cervix, or stage 1 or 2 cutaneous melanoma

4. 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 a history of
Guillain-Barre Syndrome are excluded but myasthenia gravis or psoriasis is acceptable.

5. Patients are excluded for any underlying medical or psychiatric condition which, in
the opinion of the investigator, will make treatment hazardous or obscure the
interpretation of adverse events, such as a condition associated with frequent
diarrhea.

6. Patients are excluded if they have a history of prior treatment with ipilimumab or
CTLA-4 inhibitor.

7. Patients are excluded if they have any concurrent medical condition requiring the use
of systemic steroids (the use of inhaled or topical steroids is permitted).

8. Patients are excluded if they have had prior hepatic arterial embolization therapy