This is a Phase 2 study designed to evaluate the combination of checkpoint blockade and
aldesleukin (IL-2) therapy after a course of standard of care palliative radiation in the
management of unresectable metastatic melanoma. To be eligible, a patient must have a minimum
of 3 (preferably >5) radiographically distinct, measurable (>1.5 cm) lesions based on RECIST
1.1. Metastatic cutaneous melanoma must be refractory to standard immunotherapy drugs,
molecular targeted agents and/or chemotherapy. Patients with ocular melanoma subtypes may
enroll in this study without prior therapy, as there is no standard front-line therapy for
this subset of patients.
- Biopsy-proven unresectable, metastatic melanoma refractory to standard immunotherapy
drugs or regimens, including prior treatment with Aldesleukin (IL-2), GM-CSF,
Ipilimumab, Nivolumab, Pembrolizumab, and/or Imlygic (T- VEC).
- Prior clinical trial participation or treatment with molecularly targeted agents
(i.e. Vemurafenib/Cobimetinib, Dabrafenib/Trametinib) or chemotherapy (i.e.
Temozolomide, Dacarbazine, Platinum, or Taxanes) is permitted.
- Patients with ocular melanoma may enroll (Cohort 2) without prior therapy as
there is no standard 1st line therapy for this subset of melanoma.
- Must have a minimum of 3 radiographically distinct (>1.5 cm) lesions measurable by
RECIST 1.1 at time of study enrollment (>5 preferred).
- A maximum of 2 metastases per treated organ may be targeted for palliative
radiation, but must be separated by more than 5 cm of normal tissue
- At least 2 non-irradiated lesions are required for systemic response assessments
- Pulmonary metastases: Pulmonary metastasis permissible. Appropriate candidates with
lung lesions may be considered for ablative hypofractionation using SBRT.
- Hepatic metastases: Hepatic metastasis permissible. Appropriate candidates with
metastasis to liver may be considered for ablative hypofractionation using SBRT .
- Brain metastases: Brain metastases may be treated using Gamma Knife Radiosurgery (GKR)
or whole brain radiation therapy (WBRT) per the treating radiation oncologist. Total
radiation dose and number of fractions will be determined by the treating radiation
oncologist based on anatomic and dosing constraints. MRI of the vertebral column is
required for all patients with suspected epidural tumor extension.
- Must have sufficient archival tissue block material (1.5 x 1.5 x 1.5 cm) and/or newly
obtained core or excisional biopsy of tumor tissue; minimum of 2 cores.
- ECOG performance status 0 or 1 (Appendix 2)
- Age 18 through 80 years of age; > 80 years of age must be approved by Principal
- Adequate organ function within 14 days of enrollment (30 days for pulmonary and
cardiac assessments) defined as:
- Hematologic: leukocytes ≥ 2,000/mcL, ANC ≥ 1,000/mcL, hemoglobin ≥ 9.0 g/dL,
platelets ≥ 100,000/mcL unsupported by transfusions
- Renal: Serum creatinine ≤ 1.8 mg/dL; for patients with a creatinine > 1.5 mg/dL
or a history of renal dysfunction, an estimated glomerular filtration rate ≥ 35
mL/min/1.73 m2 is required
- Hepatic: AST, ALT, and alkaline phosphatase ≤ 5 x upper limit of normal and total
bilirubin ≤ 2.0 mg/dL
- Pulmonary: oxygen saturation ≥90% on room air; corrected DLCO and FEV1, ≥ 60%
- Cardiac: Absence of clinical decompensated congestive heart failure or
uncontrolled arrhythmia; left ventricular ejection fraction (echocardiogram
within 6 months permitted) ≥ 40%. QTc must be < 450 ms in males and < 470 ms in
- A minimum of 1 week between last anti-tumor treatment if given, and 1st dose of
radiation therapy (not applicable for patients enrolling after palliative radiation
- Recovery from previous cancer treatment if applicable defined as ≤ Grade 1 (by CTCAE
5.0 criteria) at enrollment
- Women of childbearing potential and males with partners of childbearing potential must
agree to the use of barrier methods of contraception, hormonal contraceptives, or
abstain from heterosexual activity for the duration of study treatment and for 3
months after the last dose of study drug.
- Ability to understand and provide voluntary written consent
- Pregnant or breast feeding. The agents used in this study have the potential to harm a
fetus. Radiation is a known teratogen. There is insufficient information regarding
potential for fetal harm during immunotherapy at this time. Biological females of
childbearing potential must have a negative pregnancy test within 14 days of
- Concurrent use of high dose steroids; chronic steroid use of < 2 mg dexamethasone or
equivalent per day is permissible
- Concurrent malignancy requiring active treatment, except basal cell carcinoma of the
skin, squamous cell carcinoma of the skin or carcinoma in situ
- Severe and active autoimmune diseases requiring systemic immunosuppression
- Prior organ allograft or allogeneic transplantation
- Other contraindication to IL-2, nivolumab, ipilimumab, or combination immunotherapy
per treating medical oncologist
- Live vaccines within 30 days prior to the first dose of IL-2 and while participating
in the trial. Examples of live vaccines include, but are not limited to, measles,
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.
Seasonal influenza vaccines for injection are generally inactivated virus vaccines and
are allowed. Intranasal influenza vaccine (eg, Flu - Mist®) is a live attenuated
vaccine, and is not allowed.