Radiation and Combination Immunotherapy for Melanoma
Condition: Metastatic Melanoma
MeSH terms: Melanoma
Intervention: Aldesleukin: All Patients; Nivolumab: Cohort 1 (Cutaneous); Nivolumab: Cohort 2 (Ocular); Ipilimumab: Cohort 2 (Ocular)
Intervention description: Cycle 1:
(600,000 U/kg/dose) given as a bolus infusion once every 8 to 12 hours over 5 days or until no longer tolerated (to a maximum of 10 doses). Administered as an inpatient.
Days 1-5 and Days 15-19 (all patients); Cycle 1: 6 Week Duration Nivolumab 240 mg IV
Cycle 2: 6 Week Duration Nivolumab 240 mg IV on Day 1, 15 and 29
Cycle 3: 4 Week Duration Nivolumab 240 mg IV on Day 1 and 15
Patients may continue maintenance nivolumab 240 mg IV every 2 weeks OR nivolumab 480 mg IV every 4 weeks per 2018 FDA approval at discretion of the treating physician and independent of this study; Cycle 1: 6 Week Duration Nivolumab 3 mg/kg IV on Day 29
OR for a high risk patient with an excellent performance status, the following regimen may be given at the discretion of the treating investigator:
Nivolumab 1 mg/kg IV on Day 29
Cycle 2: 6 Week Duration Nivolumab on Day 8 and on Day 29 using the same dose regimen as used Cycle 1 Day 29
Cycle 3: 4 Week Duration Nivolumab on Day 8 using the same dose regimen as used Cycle 1 Day 29.
Patients may continue maintenance nivolumab 240 mg IV every 2 weeks OR nivolumab 480 mg IV every 4 weeks per 2018 FDA approval at discretion of the treating physician and independent of this study; Cycle 1: 6 Week Duration Ipilimumab 1 mg/kg IV on Day 29
OR for a high risk patient with an excellent performance status, the following regimen may be given at the discretion of the treating investigator:
Ipilimumab 3 mg/kg IV on Day 29
Cycle 2: 6 Week Duration Ipilimumab on Day 8 and on Day 29 using the same dose regimen as used Cycle 1 Day 29
Cycle 3: 4 Week Duration Ipilimumab on Day 8 using the same dose regimen as used Cycle 1 Day 29
Intervention MeSH terms: Aldesleukin; Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: MM

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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
             Investigator.

          -  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%
                  predicted

               -  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
                  females.

          -  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
             therapy).

          -  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

        Exclusion Criteria:

          -  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
             enrollment.

          -  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.