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

Study Overview
=================
Brief Summary
-----------------
Background: The drug IL-15 activates the immune system. The drugs nivolumab and ipilimumab unblock immune cells. The drugs together may allow immune cells to recognize and attack cancer cells, causing tumors to shrink. Objective: To test the effects and maximum dose of IL-15, nivolumab, and ipilimumab. Eligibility: People ages 18 and older who have cancer that does not respond to treatment Design: Participants will be screened with: Medical history Physical exam Heart, blood, and urine tests Scans Tumor biopsy: A small needle removes a tumor sample. Participants will be in 1 of 3 treatment groups: IL-15 with nivolumab IL-15 with ipilimumab IL-15 with nivolumab and ipilimumab Participants will take the drugs in four 6-week cycles. IL-15 is injected under the skin. The other two drugs are injected into an arm vein over 60-90 minutes. Participants may need to stay at the hospital 2-3 hours after the first dose of any drug to watch for side effects. Each cycle will include: Weekly blood and urine tests 5 IL-15 injections 1 ipilimumab injection if applicable 3 nivolumab injections if applicable Scans and a tumor biopsy on day 42 After cycle 4, participants will stop taking IL-15. They will continue the other drugs until they can no longer tolerate the side effects or their cancer gets worse. Those cycles will include: Blood tests on 3-4 days Urine tests on 1 day 1 ipilimumab injection if applicable 3 nivolumab injections if applicable Scans every other cycle After participants stop treatment, their doctor will monitor their side effects for 4 months or until they go away.

Detailed Description
-----------------
BACKGROUND: IL-15 is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and NK cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating CD8+T cells and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity. Immune checkpoint inhibitors, including nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4), block the engagement of specific T-cell signaling pathways by tumor cells. These regulatory pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response. The combination of rhIL-15 with two checkpoint inhibitor therapies has potential to lead to enhanced immune activation, resulting in anti-tumor T cell responses that are effective in refractory cancers. PRIMARY OBJECTIVE: - Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated doses (MTD) of subcutaneous administration of 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. EXPLORATORY OBJECTIVE: Assess the clinical activity of rhIL-15, ipilimumab, and nivolumab combination therapy as characterized by RECIST 1.1 and immune RECIST (iRECIST) response rate of patients treated in this trial. 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 tissue. ELIGIBILITY: - Patients greater than or equal to 18 years of age with histologically confirmed solid tumor malignancy that is metastatic or treatment-refractory cancers. STUDY DESIGN: The first 4-6 patients enrolling in the study will be placed into lead-in doublets with a combination of rhIL-15 and either nivolumab OR ipilimumab; once toxicity is cleared in both doublets (i.e., 2 patients enrolled on each doublet remain free of DLTs for 6 weeks) and a safety analysis is reviewed and approved by the IRB, new patients will be enrolled directly onto the triple agent combination. For the first four 42-day cycles on the triplet, patients will receive SC rhIL-15 on days 1-8 and 22-29, intravenous (IV) nivolumab on days 8, 22, and 36, and IV ipilimumab on day 8. Cycles 5 and onwards will not include treatment with rhIL-15. Patients will be encouraged to report any and all adverse events, given the high likelihood of toxicities with the triplet combination therapy. Blood for PD endpoints will be collected throughout the study and tumor biopsies will be collected pretreatment and on C1D42 (optional during the doublets and triplet escalation phase, mandatory during the triplet expansion phase)

Official Title
-----------------
Phase I Study of Recombinant Interleukin 15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in Subjects With Refractory Cancers

Conditions
-----------------
Metastatic Solid Tumors, Treatment-Refractory Cancers

Intervention / Treatment
-----------------
* Drug: rhIL-15
* Drug: Ipilimumab
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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. 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) AST/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 m2 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 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 greater than or equal to3 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 PI. 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 HIV infection or positive serology. Since rhIL-15 treatment stimulates the subjects 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lead-in doublet A<br>lead-in doublet for initial safety evaluation: rhIL-15 given SC days 1-8 and 22- 29 + ipilimumab (anti- CTLA-4) given IV on day 8 (IL-15 doses are limited to first 4 cycles only) | Drug: rhIL-15<br>* IL-15 is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and NK cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating CD8+T cells and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.<br>Drug: Ipilimumab<br>* Ipilimumab is a fully human monoclonal antibody against CTLA-4, a receptor present on the surface of activated T cells that functions as an immune checkpoint. Immune checkpoints pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response. Blocking the engagement of CTLA-4 with ipilimumab allows infiltrating T cells to mount an anti-tumor response. Ipilimumab is approved by the FDA for the treatment of certain patients with melanoma and has shown clinical activity in other tumor types as well.<br>|
| Experimental: lead-in doublet B<br>lead-in doublet for initial safety evaluation: rhIL-15 given SC days 1-8 and 22- 29 + nivolumab (anti-PD1) given IV on days 8, 22, and 36 (IL-15 doses are limited to first 4 cycles only) | Drug: rhIL-15<br>* IL-15 is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and NK cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating CD8+T cells and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.<br>Drug: Nivolumab<br>* Nivolumab is a humanized monoclonal antibody against programmed death 1 (PD-1), a receptor present on the surface of activated T cells that functions as an immune checkpoint. One of the ligands for PD-1, PD-L1, is commonly expressed by tumor cells. Similar to inhibition of the CTLA-4 pathway by ipilimumab, blocking of PD-1/PD-L1 signaling by nivolumab allows infiltrating T cells to mount an an immune response against the tumor. Nivolumab is approved as a single agent for several cancer types, as well as for the treatment of advanced melanoma in combination with ipilimumab.<br>|
| Experimental: triplet<br>triplet combination | Drug: rhIL-15<br>* IL-15 is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and NK cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating CD8+T cells and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.<br>Drug: Ipilimumab<br>* Ipilimumab is a fully human monoclonal antibody against CTLA-4, a receptor present on the surface of activated T cells that functions as an immune checkpoint. Immune checkpoints pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response. Blocking the engagement of CTLA-4 with ipilimumab allows infiltrating T cells to mount an anti-tumor response. Ipilimumab is approved by the FDA for the treatment of certain patients with melanoma and has shown clinical activity in other tumor types as well.<br>Drug: Nivolumab<br>* Nivolumab is a humanized monoclonal antibody against programmed death 1 (PD-1), a receptor present on the surface of activated T cells that functions as an immune checkpoint. One of the ligands for PD-1, PD-L1, is commonly expressed by tumor cells. Similar to inhibition of the CTLA-4 pathway by ipilimumab, blocking of PD-1/PD-L1 signaling by nivolumab allows infiltrating T cells to mount an an immune response against the tumor. Nivolumab is approved as a single agent for several cancer types, as well as for the treatment of advanced melanoma in combination with ipilimumab.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, toxicity profile, dose-limiting toxicity (DLT), and maximum tolerated doses (MTD) | Determine the safety, toxicity profile, DLTs, and MTD of rhIL-15 administered subcutaneously for 8 consecutive days in combination with anti-CTLA-4 and anti-PD1 monoclonal antibodies, 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. | Cycle 1 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Immunotherapy, T Cells, Checkpoint Inhibitor, IL-15, Combination Therapy