The primary objective of this single arm phase 2 trial is to assess the response rate
[complete response (CR) + partial response (PR)] of combined nivolumab and HD IL-2 in
subjects with metastatic melanoma and renal cell carcinoma. Response will be performed after
each course of nivolumab and IL-2 using RECIST 1.1. Patients will be treated for one course
past best response for a maximum of 3 courses.
PrimaryObjective Determine the overall response rate (complete response and partial response)
for patients receiving anti-PD-1 (nivolumab) and high dose IL-2 (HD IL-2) in subjects with
metastatic melanoma or renal cell carcinoma who have previously progressed on anti-PD-1
therapy. Response assessment will be performed using revised RECIST guideline (v 1.1).
- Characterize safety, tolerability and adverse effects (AE) profile of nivolumab with HD
IL-2 in subjects with metastatic malignant melanoma or renal cell carcinoma
- Measure Progression-Free Survival (PFS) using RECIST 1.1 after completion of at least
one course of therapy (2 doses of nivolumab, 2 cycles of HD IL-2) for subjects enrolled
in the study.
- Correlate PD-L1 expression and tumor mutational burden (TMB) in archived diagnostic
tumor tissue with best clinical response for subjects with metastatic melanoma and renal
- Correlate myeloid-derived suppressor cells and T-cell subsets in peripheral blood during
therapy with best clinical response (RECIST criteria) and treatment outcome in subjects
with metastatic melanoma or renal cell carcinoma. Data will be collected prior to each
treatment and after each course of treatment.
Study Duration: 48 months Amount of Subjects: up to 25 subjects
- 1. Patient has the ability to understand and the willingness to sign a written
2. Age ≥ 18 years at the time of consent. 3. At least 6 weeks of prior anti-PD-1
therapy with documented clinical or radiographic progression. Last anti-PD-1 therapy
must be within 6 months of enrollment.
4. Histologically-confirmed diagnosis of unresectable stage III or metastatic (stage
IV) melanoma or renal cell carcinoma 5. Measurable disease, defined as at least 1
tumor that fulfills the criteria for a target lesion according to RECIST 1.1, and
obtained by imaging within 28 days prior registration for protocol therapy.
6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
within 28 days prior to registration for protocol therapy.
7. Adequate hepatic function within 28 days prior to registration for protocol therapy
defined as meeting all of the following criteria: i. total bilirubin ≤ 1.5 × upper
limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin
levels > 1.5 x ULN (except in patients with Gilbert's syndrome who must have a total
bilirubin less than 3.0 mg/dl.) ii. and aspartate aminotransferase (AST) ≤ 2.5 × ULN
or ≤ 5 × ULN for subjects with known hepatic metastases iii. and alanine
aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic
metastases 8. Adequate renal function within 28 days prior to registration for
protocol therapy defined by either of the following criteria: i. Serum creatinine ≤
1.5 mg/dL ii. OR if serum creatinine > 1.5 mg/dL, estimated glomerular filtration rate
(GFR) ≥ 50 mL/min 9. Adequate hematologic function within 28 days prior to
registration for protocol therapy defined as meeting all of the following criteria: i.
hemoglobin ≥ 9.0 g/dL ii. and absolute neutrophil count (ANC) ≥ 1000/L without the
support of filgrastim iii. white blood cells (WBC) ≥ 3000/L iv. and platelet count ≥
100 × 109/L 10. Adequate coagulation functioning within 28 days prior to registration
for protocol therapy defined by either of the following criteria: i. INR < 1.5 × ULN
ii. OR for subjects receiving warfarin or LMWH, the subjects must, in the
investigator's opinion, be clinically stable with no evidence of active bleeding while
receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if
that is the goal of anticoagulant therapy.
11. Adequate pulmonary and cardiac function for HD IL-2 (will be assessed clinically)
12. Female subjects of childbearing potential must have confirmed negative urine or
serum pregnancy test prior to drug administration and be willing to use two methods of
13. Male subjects who are not surgically sterile (vasectomy) must agree to use an
adequate method of contraception.
14. Subject's toxicities from prior treatments must have recovered to a grade 1 or
less (except for toxicities such as alopecia or vitiligo)
1. Active infection requiring systemic therapy
2. Women who are pregnant or breastfeeding.
3. Second active malignancy within the past 5 years with the exception of localized basal
or squamous cell skin cancer, in situ cervical or bladder cancer, or localized
prostate cancer under active surveillance.
4. Active symptomatic central nervous system (CNS) metastases. Prior treated metastases
or asymptomatic metastases are allowed. Patient can receive radiation between
treatments if deemed medically necessary.
5. Surgery within 4 weeks prior to study treatment except for minor procedures.
6. Uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mmHg
diastolic for > 4 weeks) despite standard medical management.
7. Serious or non-healing wounds, ulcers, or bone fractures within 28 days prior to
initiation of study treatment.
8. Any arterial thromboembolic events, including but not limited to myocardial
infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
within 6 months prior to initiation of study treatment.
9. Has any condition that, in the opinion of the investigator, might jeopardize the
safety of the patient or interfere with protocol compliance.
10. Has any mental or medical condition that prevents the patient from giving informed
consent or participating in the trial.
11. Known hypersensitivity to nivolumab or IL-2 or any of their components.
12. Known history of active tuberculosis.
13. Concurrent systemic steroid therapy with doses above physiologic level (more than 10
mg of prednisone daily).
14. Active autoimmune disease, including but not limited to myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,
granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis requiring treatment. Patients
cannot be on immunosuppressive medications other than physiologic replacement doses of
prednisone (less than 10 mg per day at enrollment) or equivalent steroid. Asymptomatic
patients or those stable on non-immunosuppressive medications are eligible.
15. Treatment with any investigational agent within 21 days prior to initiation of study
treatment and the subject must have recovered from the acute toxic effects of the
regimen with the exception of prior anti-PD-1.