This is a Phase II study of high dose bolus interleukin-2 (HD IL2) in combination with low
dose ipilimumab followed sequentially by nivolumab in patients with advanced inoperable stage
III or stage IV melanoma who have failed prior anti-PD1 immunotherapy.
The planned treatment consists of up to 3 courses (One cycle is 21 days and one course is 4
cycles). HD IL2 will be given during week 1 of the 2 initial cycles or each course.
Ipilimumab will be given concurrently at the low dose of 1 mg/kg on Day 1 of the 2 initial
cycles of each course for up to 2 doses, total. Nivolumab will be given on Day 1 of the 3rd
cycle of each course. No systemic treatment will be administered during the 4th cycle.
Response assessment will occur at the end of the 4th cycle. Patients without evidence of
disease progression (RECIST v.1.1) or limiting toxicities will be offered additional courses
of treatment for up to a maximum of 3 courses, total
Inclusion Criteria:
- Histologically or cytologically confirmed metastatic melanoma. This includes American
Joint Committee on Cancer (AJCC) stage IV or advanced/inoperable stage III. This also
includes patients with a history of lower stage melanoma and subsequent recurrent
metastatic disease that is either locally/regionally advanced/inoperable disease or
distant metastases
- Measurable disease, according to RECIST version 1.1
- Must be free of active brain metastasis by contrast-enhanced CT/MRI scans within 4
weeks prior to enrollment. If known to have prior brain metastases, these must have
been adequately managed with standard of care radiation therapy, stereotactic
radiosurgery or surgery prior to registration on the study.
- Must have previously received anti-PD1 immunotherapy (nivolumab or pembrolizumab) and
later experienced disease progression.
- Must not have received systemic therapy or radiotherapy (including SRS) within the
preceding 3 weeks. Patients must have recovered from adverse events from previous
therapy by the time registration.
- Must be at least 4 weeks from major surgery and have fully recovered from any effects
of surgery, and must be free of significant detectable infection prior to
registration.
- Patients who have received prior anti-CTLA4 monoclonal antibody therapy (ipilimumab or
tremelimumab) are eligible.
- Patients who have previously experienced prior high-grade (grade 3 or 4 by CTCAE
criteria) immune related adverse events with immune checkpoint inhibitors must be
discussed with the study PI and cleared prior to enrollment on this study in order to
ensure patient safety.
- Patients with BRAF V600 mutant melanoma must have previously received BRAF targeted
therapy for metastatic melanoma and later experienced disease progression. Patients
who refuse or decline to receive BRAF targeted therapy or were intolerant of BRAF
targeted therapy are eligible.
- Life expectancy of greater than 3 months in the opinion of the investigator
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Must have normal organ and marrow function as specified per protocol.
- Patients on full-dose anticoagulants with Prothrombin Time Test International
Normalized Ratio (PT INR) >1.5 are eligible provided that both of the following
criteria are met: (a) The patient has an in-range INR (usually between 2 and 3) on a
stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin.
(b) The patient has no active bleeding or pathological condition that carries a high
risk of bleeding (e.g., tumor involving major vessels or known varices).
- Pulmonary: Forced Expiratory Volume at 1 second (FEV1) > 2.0 liters or > 75% of
predicted for height and age. Pulmonary function tests (PFTs) are required for
patients over 50 years old or with significant pulmonary or smoking history
- No evidence of congestive heart failure, symptoms of coronary artery disease,
myocardial infarction less than 6 months prior to entry, serious cardiac arrhythmias,
or unstable angina.
- Patients who are over 40 years old or have had previous myocardial infarction greater
than 6 months prior to study entry or have significant cardiac family history (CAD or
serious arrhythmias) will be required to have a negative or low probability cardiac
stress test (for example, thallium stress test, stress multigated acquisition scan
(MUGA), stress echo or exercise stress test) for cardiac ischemia within 8 weeks prior
to registration.
- No history of cerebrovascular accident or transient ischemic attacks within the past 6
months from registration.
- 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, for
the duration of study participation, and for at least 6 months after completion of
study therapy. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.
- Women should not be lactating and, if of childbearing age, should have a negative
pregnancy test (b-HCG test; serum or urine, minimum sensitivity 25 IU/L or equivalent
units of b-HCG) within two weeks of registration in the study.
Exclusion Criteria:
- Patients who have had systemic therapy for melanoma or radiotherapy within 3 weeks
prior to registering on the study or those who have not recovered from adverse events
due to agents administered more than 3 weeks earlier. Patients with a history of
endocrinopathies (e.g. hypothyroidism) are eligible if they are stable on hormone
replacement therapy. Patients with a history of adrenal insufficiency are not
eligible.
- Patients may not be receiving any other investigational agents.
- Patients with active brain metastasis are excluded
- Patients with clinically significant cardiovascular or cerebrovascular disease
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements.
- Patients who have other current malignancies are not eligible. Patients with other
malignancies are eligible if they have been continuously disease free for > 2 years
prior to the time of registration. Patients with prior history at any time of any in
situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ,
atypical melanocytic hyperplasia or melanoma in situ are eligible. Patients with prior
history of basal or squamous skin cancer are eligible. Patients who have had multiple
primary melanomas are eligible.
- Patients must not have autoimmune disorders or conditions of immunosuppression that
require current ongoing treatment with systemic corticosteroids (or other systemic
immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or
continuous use of topical steroid creams or ointments or ophthalmologic steroids or
steroid inhalers. If a patient had been taking steroids, at least 2 weeks must have
passed since the last dose.
