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

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 of the 3 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)

- 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

DLCO/VA and FEV1 greater than or equal to 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 halflives, 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 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 HIV infection or positive serology, active bacterial infections, serologic or
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 or absolute requirement for chronic inhaled corticosteroid
medications (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.