The primary objective of this single arm phase 2 trial is to assess the response rate
[complete response (CR) + partial response (PR)] of sequential therapy of pembrolizumab
followed by HD IL-2 in subjects with stage IV malignant melanoma. Response assessment will be
performed after pembrolizumab therapy, and response reassessment will be performed after HD
IL-2 therapy using revised RECIST 1.1.
- Written informed consent and HIPAA authorization for release of personal health
information prior to registration. NOTE: HIPAA authorization may be included in the
informed consent or obtained separately.
- Age ≥ 18 years at the time of consent.
- ECOG Performance Status of 0-1 within 28 days prior to registration (Appendix 1).
- Life expectancy of 6 months or greater as determined by the site investigator.
- Histologically-confirmed diagnosis of unresectable stage IV or metastatic melanoma not
amenable to local therapy.
- Measurable disease, defined as at least 1 tumor that fulfills the criteria for a
target lesion according to RECIST 1.1 (Section 9), and obtained by imaging within 28
days prior to registration for protocol therapy.
- < 2 lines of prior therapy for metastatic melanoma. Cannot have received prior therapy
with HD IL-2. May have had one prior line of therapy that included a check point
- Prior systemic cancer treatment must be completed at least 21 days prior to first dose
of study drug and the subject must have recovered from all reversible acute toxic
effects of the regimen (other than alopecia or vitiligo) to Grade ≤ 1 or baseline.
- Not received radiation therapy within 21 days of initiation of study treatment, and
the measurable disease must have been outside of the radiation port.
- Demonstrate adequate organ function. All screening labs to be obtained within 28 days
prior to registration.
- WBC ≥ 3,000/L
- ANC ≥ 1,000/L
- Hgb ≥ 9g/dL
- Plt ≥ 100 × 10(9)/L
- Serum creatinine ≤ 1.5 mg/dL
- Calculated creatinine clearance ≥ 40 mL/min; if serum creatinine > 1.5 mg/dL
- Total Bilirubin ≤ 1.5 × upper limit of normal (ULN)
- Direct Bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT)≤ 2.5 × ULN or
≤ 5 x ULN for subjects with known hepatic metastasis
- International Normalized Ratio (INR) ≤ 1.5 × ULN; For subjects receiving warfarin
or LMWH, the subjects must, in the site 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
- Adequate baseline pulmonary function test (PFT) (FEV1 > 2 L or ≥ 75% of predicted for
height and age).
- Documented left ventricular ejection fraction (LVEF) of > 45%, testing is required in
- Age ≥ 60 years old
- Clinically significant atrial and or ventricular arrhythmias including but not
limited to: atrial fibrillation, ventricular tachycardia, second or third degree
- History of coronary revascularization or ischemic symptoms
- Archival tissue (from the primary tumor or metastases) is mandatory if available for
correlative studies. If archived tumor tissue is not available, the patient does not
need to undergo a biopsy to obtain tissue and is still eligible for study.
- Females of childbearing potential must have a negative serum pregnancy test within 3
days prior to registration. NOTE: Females are considered of child bearing potential
unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least
12 consecutive months
- Females of childbearing potential and males must be willing to abstain from
heterosexual activity or to use 2 forms of effective methods of contraception from the
time of informed consent until 120 days after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method.
- Male subjects who are not surgically sterile (vasectomy) must agree to use an adequate
method of contraception. Male subjects with female sexual partners who are pregnant,
possibly pregnant or who could become pregnant during the study must agree to use
condoms from the first dose of study drug through 120 days after the last dose of
study therapy. Total abstinence for the same study period is an acceptable
- As determined by the enrolling physician or protocol designee, ability of the subject
to understand and comply with study procedures for the entire length of the study
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.
- Active infection requiring systemic therapy
- Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the
mother is being treated on study.
- Known additional malignancy that is active and/or progressive requiring treatment;
exceptions include basal cell or squamous cell skin cancer, in situ cervical or
bladder cancer, or other cancer for which the subject has been disease-free for at
least five years.
- Active central nervous system (CNS) metastases. NOTE: if prior metastasis but treated
and clinically stable for 1 month after treatment are eligible. Subjects with 3 or
fewer brain metastases that are less than 1 cm in diameter and asymptomatic are
- Surgery within 4 weeks prior to study treatment except for minor procedures. NOTE:
Hepatic biliary stent placement is allowed.
- Uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mmHg
diastolic for > 4 weeks) despite standard medical management.
- Serious or non-healing wound, ulcer, or bone fracture within 28 days prior to
initiation of study treatment.
- Any Grade 3-4 GI bleeding within 3 months prior to initiation of study treatment.
- History of deep vein thrombosis, pulmonary embolism, or any other significant
thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis
are not considered "significant") during the 3 months prior to initiation of study
- 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.
- Gross hemoptysis within 2 months of initiation of study treatment.
- Has any condition that, in the opinion of the investigator, might jeopardize the
safety of the patient or interfere with protocol compliance.
- Has any mental or medical condition that prevents the patient from giving informed
consent or participating in the trial.
- Known hypersensitivity to pembrolizumab or IL-2 or any of their components.
- Known history of active tuberculosis.
- Concurrent systemic steroid therapy with doses above physiologic level.
- History of 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.
- Subjects with a history of autoimmune-related hypothyroidism on a stable dose of
thyroid replacement hormone may be eligible for this study.
- Subjects with controlled Type I diabetes mellitus on a stable dose of insulin
regimen may be eligible for this study.
- Subjects with a history of celiac disease may be eligible if controlled with
- 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
- Prior organ transplant including allogeneic transplantation.