Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers

* INCLUSION CRITERIA:

Subjects must have histologically confirmed solid tumor malignancy that is metastatic or treatment refractory cancers which are not curable or do not have known measures or treatments that are associated with a survival advantage (as defined by the subject or the physician investigator). Enrollment of subjects with tumors that can be safely biopsied is encouraged.

Subjects must have evaluable, or measurable disease defined as greater than or equal to 1 lesion that can be accurately measured in greater than or equal to 1 dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with a spiral computed tomography (CT) scan.

Subjects must have recovered to less than or equal to grade 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) or stabilized from toxicity of prior chemotherapy or biologic therapy administered more than 4 weeks or 5 half-lives earlier, whichever is shorter.

Subjects on bisphosphonates/denosumab for any cancer or on hormone therapy for prostate cancer may continue this therapy. However, subjects with prostate cancer must have confirmed metastatic disease that has progressed despite hormonal therapy or refused or is intolerant of hormonal therapy.

Age greater than or equal to 18 years.

Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky or Lansky greater than or equal to 70%.

Subjects must have normal organ and marrow function as defined below:

* Leukocytes greater than or equal to 2,000/mm\^3
* Absolute neutrophil count (ANC) greater than or equal 1,500/mm\^3
* Platelets greater than or equal to 100,000/mm\^3
* Total bilirubin less than or equal to 1.5 times institutional upper limit of normal (ULN)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than or equal to 1.5 times institutional upper limit of normal (ULN) or if liver metastasis, less than or equal to 2.5 times ULN
* Serum creatinine less than or equal to 1.5 times institutional ULN, OR Creatinine clearance greater than or equal to 50 mL/min/1.73 m\^2 for subjects with serum creatinine levels greater than 1.5 times higher than institutional normal
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

Subjects with inactive central nervous system (CNS) metastasis are eligible. Inactive CNS metastasis is defined as: no symptoms of brain metastases after successful definitive treatment of brain metastases (surgical resection, whole brain irradiation, stereotactic radiation therapy, or a combination of these) with stable or improved radiographic appearance on magnetic resonance imaging (MRI) scan at least 1 month after completion of treatment.

Subjects may have previously progressed on treatment with one of the 3 agents being used in this trial or treatment with other checkpoint inhibitors, as long as they have recovered from previous toxicity. Subjects that previously progressed on treatment with a combination of any 2 of the 3 agents being used in this trial are eligible for the triplet cohort only.

The effects of ipilimumab, nivolumab, and rhIL-15 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during the treatment portion of the study, and for a minimum for 5 months (women) and 7 months (men) after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Ability to understand and the willingness to sign a written informed consent document.

Willingness to provide blood and biopsy samples for research purposes if on the expansion phase of the study.

EXCLUSION CRITERIA:

Subjects who have received any prior cytotoxic therapy, immunotherapy, major surgery, antitumor vaccines or monoclonal antibodies in the 4 weeks or 5 half-lives, whichever is shorter, prior to cycle 1, day 1 (C1D1) (6 weeks prior for checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) and for nitrosoureas or mitomycin C). Subjects must not have received radiotherapy in the 2 weeks prior to C1D1. Subjects who had grade greater than or equal to 3 immune-related adverse events (irAE) (excluding endocrinopathies) during previous treatment with one of the checkpoint inhibitors are excluded from the trial; subjects who had grade 1 or 2 irAE (including serious AEs) that have resolved to grade 1 are eligible at the discretion of the principal investigator (PI).

Subjects with primary brain cancers or active central nervous system (CNS) metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the agents on this trial.

Concurrent anticancer therapy (including other investigational agents) with the exception of hormone therapy for breast or prostate cancer. Patients that have received treatment for a different cancer previously and have been disease-free for less than one year are excluded.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, cognitive impairment, active substance abuse, or psychiatric illness/social situations that, in the view of the Investigator, would preclude safe treatment or the ability to give informed consent and limit compliance with study requirements.

Inability or refusal to practice effective contraception during therapy or the presence of pregnancy or active breastfeeding. Because there is no significant preclinical information regarding the risk to a fetus or newborn infant, pregnant or breastfeeding women will be excluded from participation in this trial.

Documented human immunodeficiency virus (HIV) infection or positive serology. Since rhIL-15 treatment stimulates the subject's immune system to attack their tumor, the defective immune systems of subjects with HIV makes responses to this treatment much less likely to provide benefit and these subjects are not eligible for this trial.

History of severe asthma (subjects with a history of mild asthma that are on or can be switched to non-corticosteroid bronchodilator regimens are eligible).

Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. The use of inhaled corticosteroids is allowed.