A Phase II Study of High Dose Bolus IL2 in Patients With Inoperable Stage III or Stage IV Melanoma Who Have Failed Prior Anti-PD1 Immunotherapy: Efficacy and Biomarker Study
Condition: Melanoma
MeSH terms: Melanoma
Intervention: High dose bolus interleukin-2 (HD IL2)
Intervention description: Each course consists of 2 cycles of HD IL2 as follows: high-dose IL2 at 600,000 IU/kg is given intravenously (IV) every 8 hours for up to 14 doses (one cycle), followed by a rest period of 1-2 weeks and readmission for a second HD IL2 cycle for up to 14 doses (second cycle).
The planned treatment consists of 3 courses (6 cycles) of HD IL-2.
Intervention MeSH terms: Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This study is for patients with advanced stage III or stage IV melanoma not adequately
      treated by surgery who have progressed after treatment with nivolumab or pembrolizumab. The
      purpose of this study is to see if giving high dose interleukin-2 (IL-2) after progression on
      nivolumab or pembrolizumab is effective in treating metastatic melanoma. This study is also
      being done to look at the severity of side effects of IL-2 in patients.

      IL-2 is approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced
      melanoma.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have 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.

          -  Patients must have measurable disease, according to RECIST version 1.1

          -  Patients 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.

          -  A patient must have previously received anti-PD1 immunotherapy (nivolumab or
             pembrolizumab) and later experienced disease progression, within 3 months of
             registration on this study.

          -  Patients must not have received systemic therapy or radiotherapy within the preceding
             3 weeks. Patients must have recovered from adverse events from previous therapy by the
             time registration.

          -  Patients must be at least 4 weeks from major surgery and have fully recovered from any
             effects of surgery, and be free of significant detectable infection prior to
             registration.

          -  For patients who have received prior anti-CTLA4 monoclonal antibody therapy
             (ipilimumab or tremelimumab), there is a risk of bowel perforation with IL-2 therapy.
             Therefore, for these patients if they have a history of colitis or diarrhea during
             anti-CTLA4 monoclonal antibody therapy, it is recommended that they have a formal
             evaluation by a gastroenterologist and a colonoscopy/endoscopy should be considered to
             demonstrate the absence of active bowel inflammation before initiating IL-2 therapy on
             this protocol.

          -  Life expectancy of greater than 3 months in the opinion of the investigator.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >/=70%)

          -  Patients must have normal organ and marrow function as defined in the clinical trial
             protocol.

          -  Patients on full-dose anticoagulants (e.g., warfarin) with prothrombin time (PT)/
             international normalized ratio (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 one 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.

          -  Cardiac: 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 (MUGA), stress echo or exercise stress test) for cardiac ischemia within 8
             weeks prior to registration.

          -  Central Nervous System (CNS): 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 week of registration in the study.

          -  Ability to understand and the willingness to sign a written informed consent document.

        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, adrenal insufficiency, hypopituitarism) are
             eligible if they are stable on hormone replacement therapy.

          -  Patients may not be receiving any other investigational agents.

          -  Patients with active brain metastases should be excluded from this clinical trial
             except as noted above.

          -  Patients with clinically significant cardiovascular or cerebrovascular disease:

               1. history of cerebrovascular accident or transient ischemic attack within past 6
                  months from registration.

               2. myocardial infarction, coronary artery bypass grafting (CABG) or unstable angina
                  within the past 6 Months from registration.

               3. New York Heart Association grade III or greater congestive heart failure, serious
                  cardiac arrhythmia requiring medication, unstable angina pectoris within past 6
                  months from registration.

               4. clinically significant peripheral vascular disease within past 6 months from
                  registration.

          -  PT INR >1.5 unless the patient is on full-dose warfarin.

          -  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. Patients stable on physiologic replacement doses of
             steroids or other forms of hormone replacement therapy are eligible.