Aldesleukin and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability of IL-2 when given in combination with pembrolizumab to patients with advanced melanoma. Aldesleukin may stimulate white blood cells to melanoma cells. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving aldesleukin and pembrolizumab may kill more tumor cells. There are two parts to this study: Phase Ib: To determine the safety and side effects of increasing doses of IL-2 in combination with pembrolizumab Phase II: Once the maximum tolerated dose of IL-2 is determined, additional patients will be treated to determine if it is effective against the cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine an optimal tolerated dose (OTD) of aldesleukin (interleukin [IL]-2) that is effective and tolerable in combination with pembrolizumab. II. To characterize the efficacy of the OTD of IL-2 in combination with pembrolizumab. SECONDARY OBJECTIVES: I. To characterize the safety of IL-2 in doses ranging up to the Food and Drug Administration (FDA)- approved dose when administered in combination with pembrolizumab. II. To characterize clinical endpoints, including overall survival, progression-free survival, and complete response rate. TERTIARY OBJECTIVES: I. To characterize immune parameters in the blood and tumor microenvironment and cellular and molecular features of the tumor tissue that correlate with response to combination therapy for study as potential predictive biomarkers. OUTLINE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 every 3 weeks and aldesleukin IV every 8 hours for up to 14 doses at weeks 4, 7, 16, 19, 28, and 31 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months up to 10 years.

Official Title
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Trial of Interleukin-2 in Combination With Pembrolizumab for Patients With Unresectable or Metastatic Melanoma

Conditions
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Metastatic Melanoma, Stage III Mucosal Melanoma of the Head and Neck, Stage IIIA Skin Melanoma, Stage IIIB Skin Melanoma, Stage IIIC Skin Melanoma, Stage IV Skin Melanoma, Stage IVA Mucosal Melanoma of the Head and Neck, Stage IVB Mucosal Melanoma of the Head and Neck, Stage IVC Mucosal Melanoma of the Head and Neck

Intervention / Treatment
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* Biological: Aldesleukin
* Other: Laboratory Biomarker Analysis
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic diagnosis of cutaneous melanoma, mucosal melanoma, or melanoma of unknown primary that is considered unresectable (stage III) or metastatic (stage IV) Be willing and able to provide written informed consent/assent for the trial Have measurable disease evident on radiographs (preferred) or clinical examination; for this protocol, measurable disease is defined as at least one evaluable tumor that is at least 10 mm in longest dimension Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale Patients must have a brain magnetic resonance imaging (MRI) or computed tomography (CT) (with and without contrast) that is free of active metastases; metastases that have been treated with radiation or surgical resection, are stable for at least 4 weeks and do not require steroids are eligible Normal cardiac function; patients who have a history of heart disease, or who are over the age of 50 years must have a normal cardiac stress test within the prior 90 days Normal lung function; patients who have extensive pulmonary metastases or any chronic pulmonary disease history must have pulmonary function testing demonstrating forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) > 65% of predicted values Absolute neutrophil count (ANC) >= 1,500 /mcL Platelets >= 100,000 / mcL Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases Albumin >= 2.5 mg/dL International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Subject meets institutional requirements for IL-2 therapy Exclusion Criteria: Has primary ocular melanoma Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive steroid therapy or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment; exception: physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency is not considered systemic immunosuppressive steroid therapy Has received previous high dose IL-2 therapy, any programmed death (PD)-1 blocking antibody (e.g. pembrolizumab, nivolumab), or any programmed death ligand (PD-L)1 blocking antibody in the metastatic setting; prior therapy with any PD-1 blocking antibody is allowed if given in the adjuvant setting and the last dose was > 6 months prior to study entry; prior therapy with ipilimumab is allowed (in the adjuvant or metastatic setting); other prior therapy (in the adjuvant or the metastatic setting) is allowed, including targeted therapy, chemotherapy, or experimental therapy Has a history of significant congestive heart failure or significant pulmonary disease Has a known history of active TB (bacillus tuberculosis) Hypersensitivity to pembrolizumab or any of its excipients Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent Note: subjects with =< grade 2 neuropathy and/or alopecia are exceptions to this criterion and may qualify for the study Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment Has known history of, or any evidence of active, non-infectious pneumonitis Has an active infection requiring systemic therapy Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) Has received a live vaccine within 30 days of planned start of study therapy Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

Ages Eligible for Study
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Minimum Age: 15 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: Sequential Assignment
Interventional Model Description: Dose escalation study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pembrolizumab, aldesleukin)<br>Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks and aldesleukin IV every 8 hours for up to 14 doses at weeks 4, 7, 16, 19, 28, and 31 in the absence of disease progression or unacceptable toxicity. | Biological: Aldesleukin<br>* Given IV<br>* Other names: Recombinant Human Interleukin-2;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate as Assessed by Response (BORR) Evaluation Criteria in Solid Tumors Version 1.1, With the Modification That Progressive Disease Must be Confirmed on a Subsequent Scan | Estimated using OTD of IL-2 and pembrolizumab assessed by Response Evaluation Criteria in Solid Tumors version 1.1,for target lesions and assessed by CT or MRI imaging: Complete response (CR) - disappearance of all target lesions; Partial response (PR) - >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) - At least a 20% increase in the sum of the longest diameter of target lesions; or Stable Disease (SD) - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. By testing increasing doses up to 600,000 IU. Receive IL-2 6,000 International Units per kilogram (IU/kg);in cycles 2, 3, 6,7,10 and 11, with follow up thirty days after the last dose of study drug | Four to six weeks later up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Participants are treated with pembrolizumab and the MTD of IL-2. Will be measured using the RECIST v 1.1. For all participants who experience a complete response, the date noted for disease response is the time of the scan when it was originally determined, and not the later date of the confirmatory scan. | Four to six weeks later, up to three years | 
| Number of Adverse Effects (AE) as Evaluated by National Cancer Institute Common Terminology Criteria for AE's, Version 4.0 | Each participant will be assessed for potential or new worsening AE's. AE's will be graded and recorded through the study and during follow-up period according to National Cancer Institute Common Terminology Criteria for AE's, version 4.0. Grade 1-5 with grade 5 being the most severe. | Thirty days after last dose of treatment, up to three years | 
| Overall Survival Estimated Using Kaplan-Meier Curves | Assess for survival status until death. Time to death measured in months. | Baseline to end of follow-up, up to 3 years | 
| Progressive Free Survival Retaining Progression-free Survival Status up to 36 Months | As measured by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for targeted lesions; Partial response (PR) - >= 30% increase in the sum of the longest diameter of target lesions; or stable (SD) - neither sufficient shrinkage to quality for PR nor Sufficient increase to quality PD. Descriptive statistical will be used. Continuous variables will be presented by summary statistics (such as mean, median, standard error and 90% CI) and the categorical variables by frequency distributions (i.e., frequency counts, percentages and 90% CI). | Up to three years |