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

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

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.

Study Overview

• Status: Terminated
• Conditions: Metastatic Melanoma; Stage IV Skin Melanoma; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IIIA Skin Melanoma; Stage III Mucosal Melanoma of the Head and Neck; 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: Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Biological: Aldesleukin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center
  • Indiana
    • Bloomington, Indiana, United States, 46996
      • Indiana University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Buffalo, New York, United States, 14203
      • Roswell Park Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (pembrolizumab, aldesleukin); 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475; Biological: Aldesleukin; Given IV; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Adam Berger, MD, Rutgers Cancer Institute of New Jersey

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2017
• Primary Completion (Actual): October 18, 2018
• Study Completion (Actual): June 5, 2023

Study Registration Dates

• First Submitted: April 19, 2016
• First Submitted That Met QC Criteria: April 21, 2016
• First Posted (Estimated): April 22, 2016

Study Record Updates

• Last Update Posted (Actual): August 3, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Skin Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Aldesleukin; Pembrolizumab; Interleukin-2
• Other Study ID Numbers: 091602 (Rutgers Cancer Institute of New Jersey); P30CA072720 (U.S. NIH Grant/Contract); Pro20160000394 (Other Identifier: Rutgers Cancer Institute of New Jersey); NCI-2016-00466 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No