Palliative Radiation Therapy, Aldesleukin, and Nivolumab with or without Ipilimumab in Treating Patients with Refractory Metastatic Melanoma
This phase II trial evaluates response rate and toxicity of standard palliative radiation therapy in combination with aldesleukin and nivolumab given with or without ipilimumab in treating patients with melanoma that has spread to places in the body (metastatic). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Aldesleukin stimulates white blood cells including T cells and natural killer cells to kill melanoma cells. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving radiation therapy may prime the immune system and make the cancer more susceptible to the immunotherapy drugs aldesleukin and nivolumab/ipilimumab given in sequential combination.
Inclusion Criteria
- Biopsy-proven unresectable, metastatic melanoma refractory to standard immunotherapy drugs or regimens, including prior treatment with aldesleukin (IL-2), granulocyte-macrophage colony stimulating factor (GM-CSF), ipilimumab, nivolumab, pembrolizumab, and/or imlygic (talimogene laherparepvec [TVEC]) * 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 Response Evaluation Criteria in Solid Tumors (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 metastasis permissible. Appropriate candidates with lung lesions may be considered for ablative hypofractionation using stereotactic body radiation therapy (SBRT)
- Hepatic metastasis permissible. Appropriate candidates with metastasis to liver may be considered for ablative hypofractionation using stereotactic body radiation therapy (SBRT)
- 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. Magnetic resonance imaging (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
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- > 80 years of age must be approved by the principal investigator
- Leukocytes >= 2,000/mcL (within 14 days of enrollment)
- Absolute neutrophil count (ANC) >= 1,000/mcL (within 14 days of enrollment)
- Hemoglobin >= 9.0 g/dL (within 14 days of enrollment)
- Platelets >= 100,000/mcL unsupported by transfusions (within 14 days of enrollment)
- 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 m^2 is required (within 14 days of enrollment)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) (=< 5 x ULN if known or suspected liver metastases [mets]) (within 14 days of enrollment)
- Alkaline phosphatase =< 3 x upper limit of normal (ULN) (=< 5 x ULN if known or suspected liver metastases [mets]) (within 14 days of enrollment)
- Total bilirubin =< 2.0 mg/dL (within 14 days of enrollment)
- Oxygen saturation >= 90% on room air; corrected carbon monoxide diffusing capability test (DLCO) and forced expiratory volume in one second (FEV1) >= 60% predicted (within 30 days of enrollment)
- Absence of clinical decompensated congestive heart failure or uncontrolled arrhythmia (within 30 days of enrollment)
- Left ventricular ejection fraction (echocardiogram within 6 months permitted) >= 40% (within 30 days of enrollment)
- Corrected QT interval (QTc) must be < 450 ms in males and < 470 ms in females (within 30 days of enrollment)
- A minimum of 1 week between last anti-tumor treatment and 1st dose of radiation therapy (not applicable for patients enrolling after palliative radiation therapy)
- Recovery from previous cancer treatment define as =< grade 1 (by Common Terminology Criteria for Adverse Events [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, Bacillus Calmette-Guerin (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
Additional locations may be listed on ClinicalTrials.gov for NCT03850691.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR) and confirm safety and tolerability of sequential combination immunotherapy in patients with metastatic melanoma after palliative radiation therapy.
SECONDARY OBJECTIVES:
I. Estimate 6-month progression-free survival (PFS).
II. Estimate 12-month overall survival (OS).
CORRELATIVE OBJECTIVES:
I. Assessment of tumor microenvironment changes and systemic immune parameters, identification of biomarkers of response, identification of autoimmune toxicities associated with therapy, and characterization of resistance and response mechanisms.
II. Assess the effect of natural genetic variation (single nucleotide polymorphisms [SNPs]) in selected genes including PD-1, PD-L1/L2, CTLA-4, TIM-3, LAG-3, OX40/OX40L as well as human leukocyte antigen (HLA), NKG2D and NKG2D ligand genes.
III. Evaluation of health related quality of life as assessed by the Functional Assessment of Cancer Therapy – Melanoma (FACT-M).
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I (CUTANEOUS MELANOMA): Patients undergo standard of care palliative radiation therapy over 3 weeks. Within 5 days of radiation therapy, patients receive aldesleukin intravenously (IV) over 15 minutes on days 1-5 and 15-19 for up to 10 doses. Patients also receive nivolumab IV over 30-60 minutes on day 29 of cycle 1, days 1, 15, and 29 of cycle 2, and days 1 and 15 of cycle 3. Treatment repeats every 2 weeks for up to 6 doses in the absence of disease progression or unacceptable toxicity. Patients may continue to receive nivolumab IV once every 2 or 4 weeks at the discretion of treating physician.
COHORT II (OCULAR MELANOMA): Patients undergo standard of care palliative radiation therapy and receive aldesleukin as in cohort I. Patients also receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes on day 29 of cycle 1, days 8 and 29 of cycle 2, and day 8 of cycle 3. Treatment repeats every 3 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity. Patients may continue to receive nivolumab IV once every 2 or 4 weeks at the discretion of treating physician.
After completion of study treatment, patients are followed up every 3 months for up to 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Minnesota/Masonic Cancer Center
Principal InvestigatorEvidio Domingo-Musibay
- Primary ID2018LS110
- Secondary IDsNCI-2019-02347
- ClinicalTrials.gov IDNCT03850691