Anti-PD-1 Antibody With HD IL-2 in Metastatic Melanoma

Study Overview
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Brief Summary
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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.

Official Title
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MMP-01: Pilot Study Evaluating Activity of the Combination of Anti-PD-1 Antibody With High Dose IL-2 in Metastatic Melanoma

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 inhibitor. 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 anticoagulant therapy. 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 patients with: Age ≥ 60 years old Clinically significant atrial and or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block 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 alternative. 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. Exclusion Criteria: 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 eligible. 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 treatment. 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 diet. 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. Prior organ transplant including allogeneic transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab and HD Interleukin 2<br>Pembrolizumab 200 mg IV over 30 minutes; Day 1 of each cycle 3 weeks (21 days) for 2 cycles. IL-2 600,000 IU/kg2 IV over 15 minutes every 8 hours for up to 14 doses over 5 days; Days 1-5 = Cycle 1; 9 days of rest in between; Days 15-19 = Cycle 2 | Drug: Pembrolizumab<br>* Subjects will receive 200 mg pembrolizumab every 3 weeks for two cycles. Cycle length is 21 days (i.e., 3 weeks). On the last day of Cycle 2 (+/- 3 days), disease status will be assessed via imaging.<br>* Other names: Keytruda;Drug: Interleukin-2<br>* Following the pembrolizumab treatment, HD IL-2 treatment will commence. After completing the 2 cycles of pembrolizumab, High Dose Interleukin-2 (HD IL-2) will be administered. This will require a hospital stay of at least 5 days for each treatment cycle. Established guidelines will be followed for safely administering HD-IL-2 and managing toxicities from this treatment. Two treatment cycles will be administered, Cycle 2 being separated from Cycle 1 by approximately 9 days after completion (assuming subject has recovered from Cycle 1 adequately to proceed with Cycle 2). Four weeks after completion of the 2 cycles (called a course of HD IL-2 therapy), disease status will be monitored via CT of the chest and abdomen/pelvis using revised RECIST guidelines<br>* Other names: High Dose IL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | 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 using revised RECIST 1.1 | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess Adverse Events | Assess adverse events via CTCAE v4.03 | 12 months | 
| Progression Free Survival (PFS) | Measure Progression-Free Survival (PFS) using revised RECIST guideline (version 1.1) after completion of 2 cycles of pembrolizumab and 2 cycles of HD IL-2 in all the subjects enrolled in the study. PFS is defined as the time from treatment initiation until objective tumor progression or death. | 12 months | 
| Overall Survival (OS) | Measure overall survival (OS) at 12 months in subjects with stage IV malignant melanoma who showed a response [stable disease (SD), complete response (CR) or partial response (PR)] following completion of 2 cycles of pembrolizumab and 2 cycles of HD IL-2. OS is defined as time from treatment initiation until death from any cause | 12 months |