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Recombinant Human Interleukin-15, Nivolumab, and Ipilimumab in Treating Patients with Metastatic or Refractory Solid Tumors

Trial Status: Active

This phase I trial studies the side effects and best dose of recombinant human interleukin-15 when given in combination with nivolumab and ipilimumab in treating patients with solid tumors that have spread to other places in the body (metastatic) or do not respond to treatment (refractory). Biological therapies, such as recombinant human interleukin-15, use substances made from living organisms that may activate the immune system. 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 recombinant human interleukin-15 together with nivolumab and ipilimumab may work better by allowing immune cells to recognize and then attack tumor cells, causing the tumor to shrink.

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 >= 1 lesion that can be accurately measured in >= 1 dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with a spiral computed tomography (CT) scan
  • Subjects must have recovered 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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky or Lansky >= 70%)
  • Leukocytes >= 2,000/mm^3
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelets >= 100,000/mm^3
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 1.5 x institutional upper limit of normal (ULN) or if liver metastasis, =< 2.5 x ULN
  • Serum creatinine =< 1.5 x institutional ULN, OR creatinine clearance >= 50 mL/min/1.73 m^2 for subjects with serum creatinine levels > 1.5 x higher than institutional normal
  • Diffusion capacity of the lung for carbon monoxide/alveolar volume ratio (DLCO/VA) and forced expiratory volume in 1 second (FEV1) >= 50% of predicted on pulmonary function tests (subjects must have pulmonary function tests performed to be eligible)
  • 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-CTLA-4 or anti-PD1/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 >= 3 immune-related adverse event (irAE) during previous treatment with one of the checkpoint inhibitors are excluded from the trial; subjects who had grade 1 or 2 irAE that have resolved to grade 1 are eligible
  • Subjects with primary brain cancers or active 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, active bacterial infections, serologic or polymerase chain reaction (PCR) evidence for active or chronic hepatitis B or hepatitis C; since rhIL-15 treatment stimulates the subjects’ immune system to attack their tumor, the defective immune systems of subjects with HIV or hepatitis B or hepatitis C 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


National Cancer Institute Developmental Therapeutics Clinic
Contact: Site Public Contact
Phone: 800-411-1222
National Institutes of Health Clinical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-411-1222


I. Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated doses (MTD) of subcutaneous (SC) recombinant human interleukin-15 (rhIL-15 [rhIL-15]), given in combination with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibody nivolumab in patients with metastatic or treatment-refractory cancers which are not curable or do not have known measures or treatments that are associated with a survival advantage.


I. Assess the clinical activity of rhIL-15, ipilimumab, and nivolumab combination therapy as characterized by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune RECIST (iRECIST) response rate of patients treated in this trial.

II. Investigate the biological effects of this combination on circulating T cell subsets and on PD-1/PD-L1 expression and immune cell activation in tumor biopsies.

III. Perform genomic analysis on tumor biopsies in order to identify genomic alterations and gene expression changes associated with clinical response to rhIL-15, ipilimumab, and nivolumab combination therapy.

OUTLINE: This is a dose-escalation study of recombinant human interleukin-15.

Patients receive recombinant human interleukin-15 SC on days 1-8 and 22-29, nivolumab intravenously (IV) over 30 minutes on days 8, 22, and 36, and ipilimumab IV over 90 minutes on day 8. Treatment repeats every 42 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After a 1-week break (Transition Period), patients then receive nivolumab IV over 30 minutes on days 1, 15, and 29, and ipilimumab IV over 90 minutes on day 1. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 120 days and then periodically.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Geraldine O'Sullivan Coyne

  • Primary ID 10080
  • Secondary IDs NCI-2017-01238, 18-C-0033, CC 18-C-0033
  • ID NCT03388632