Aldesleukin With or Without Ziv-Aflibercept in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2015 by National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: December 10, 2010
Last updated: September 2, 2015
Last verified: September 2015

This randomized phase II trial studies how well aldesleukin with or without ziv-aflibercept works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Aldesleukin may stimulate the white blood cells to kill cancer. Ziv-aflibercept may stop the growth of melanoma by blocking blood flow to the tumor. It is not yet known whether aldesleukin is more effective with or without ziv-aflibercept in treating melanoma.

Condition Intervention Phase
Recurrent Melanoma
Stage IIIA Skin Melanoma
Stage IIIB Skin Melanoma
Stage IIIC Skin Melanoma
Stage IV Skin Melanoma
Biological: Aldesleukin
Other: Laboratory Biomarker Analysis
Biological: Ziv-Aflibercept
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Sequential Biotherapy With Aflibercept and High Dose IL-2 Versus High Dose IL-2 Alone in Patients With Inoperable Stage III or Stage IV Melanoma: Efficacy and Biomarker Study

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: The time from the date of randomization until date of progression, death, or recurrence, assessed up to 5 years ] [ Designated as safety issue: No ]
    The primary comparison will be based on the log-rank test for comparison of progression-free survival, which will be estimated by the Kaplan-Meier method. Cox regression will also be conducted for progression-free survival.

Secondary Outcome Measures:
  • 1-year survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Cox regression will be conducted for survival.

  • Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Toxicity will be primarily be evaluated by examining the number of doses of aldesleukin administered during the first course of combination therapy; the percentage of patients who receive all 56 doses will also be summarized. The toxicity after the scheduled 10th dose of aldesleukin, the frequency of grade III and IV toxicities, and unusual toxicities will also be summarized.

  • Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Cox regression will be conducted for survival. Survival endpoints will be evaluated from data of randomization and will be also reported on the as-treated populations for comparison.

  • Response rate, evaluated using the RECIST v1.1 [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Response rate will be estimated and a 95% confidence interval (CI) provided for each arm.

Other Outcome Measures:
  • Changes in VEGF levels [ Time Frame: Baseline up to 5 years ] [ Designated as safety issue: No ]
    Explored using multivariate Cox regression.

Estimated Enrollment: 105
Study Start Date: January 2011
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (ziv-aflibercept and aldesleukin)
Patients receive ziv-aflibercept IV over at least 1 hour in weeks 1, 3, 5, and 7 (and in week 9 of course 1 only) and high-dose aldesleukin IV over 15 minutes every 8 hours for 5 days in weeks 1 and 3 (and in weeks 3 and 5 of course 1 only). Treatment repeats every 8 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising ziv-aflibercept IV on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Biological: Aldesleukin
Given IV
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Ziv-Aflibercept
Given IV
Other Names:
  • AVE0005
  • Eylea
  • Vascular Endothelial Growth Factor Trap
  • VEGF Trap
  • VEGF Trap R1R2
  • VEGF-Trap
  • Zaltrap
Experimental: Arm II (aldesleukin)
Patients receive high-dose aldesleukin IV over 15 minutes every 8 hours for 5 days in weeks 1 and 3. Treatment repeats every 4 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Biological: Aldesleukin
Given IV
Other Names:
  • 125-L-Serine-2-133-interleukin 2
  • Proleukin
  • r-serHuIL-2
  • Recombinant Human IL-2
  • Recombinant Human Interleukin-2
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:


I. Test the hypothesis that combination biotherapy with aflibercept (ziv-aflibercept) and high-dose (HD) interleukin (IL)-2 (aldesleukin) will improve the progression-free survival compared to HD IL-2 alone.


I. Evaluate the response rate (complete response [CR] + partial response [PR]) of aflibercept and HD IL-2 as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 and compare to results of HD IL-2 alone.

II. Evaluate the toxicities and tolerance of combination biotherapy with aflibercept and HD IL-2 and maintenance aflibercept alone in this patient population and compare to HD-IL2 alone.

III. Test the hypotheses related to the laboratory correlative studies. IV. Evaluate the overall survival of patients treated with aflibercept and HD IL-2 and HD IL-2 alone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive ziv-aflibercept intravenously (IV) over at least 1 hour on day 1 of weeks 1, 3, 5, and 7 (and in week 9 of course 1 only) and high-dose aldesleukin IV over 15 minutes every 8 hours for 5 days in weeks 1 and 3 (and in weeks 3 and 5 of course 1 only). Treatment repeats every 8 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising ziv-aflibercept IV on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive high-dose aldesleukin IV over 15 minutes every 8 hours for 5 days in weeks 1 and 3. Treatment repeats every 4 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-4 months for 5 years.


Ages Eligible for Study:   17 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed metastatic melanoma (includes American Joint Committee on Cancer [AJCC] stage IV or advanced/inoperable stage III; 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, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 10 mm with computed tomography (CT) scan or clinically (must be measurable with calipers) according to RECIST version 1.1
  • Patients must be free of brain metastasis by contrast-enhanced CT/magnetic resonance imaging (MRI) scans within 4 weeks prior to enrollment; if known to have prior brain metastases, must not have evidence of active brain disease after definitive therapy (surgery, radiation therapy, or stereotactic radiosurgery) on two successive MRI evaluations at least 3 months apart (one of which is =< 4 weeks prior to starting the study drugs)
  • A patient may be treatment naïve; however, up to two prior regimens for metastatic melanoma are allowed; prior adjuvant interferon (IFN)-alpha is allowed; no prior therapy with bevacizumab, aflibercept or interleukin-2 (IL-2)
  • Patients must not have received systemic therapy or radiotherapy within the preceding 4 weeks; patients must have recovered from adverse events due to agents administered more than 4 weeks earlier
  • 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
  • For patients who have received prior anti-cytotoxic T-lymphocyte antigen (CTLA)4 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, they should have a formal evaluation by a gastroenterologist and a colonoscopy 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%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within 1.5 x institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  • Creatinine within 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine level above institutional normal
  • Urine protein should be screened by urinalysis for urine protein creatinine ratio (UPCR); for UPCR > 1, a 24-hour urine protein should be obtained and the level should be < 500 mg
  • 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:

    • 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
    • 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)
  • Forced expiratory volume (FEV) 1 > 2.0 liters or > 75% of predicted for height and age (pulmonary function test [PFTs] are required for patients over 50 years old or with significant pulmonary or smoking history)
  • 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 (coronary artery disease [CAD] or serious arrhythmias) will be required to have a negative or low probability cardiac stress test (for example, thallium stress test, stress multi-gated acquisition scan [MUGA], stress echocardiography [echo], or exercise stress test) for cardiac ischemia within 8 weeks prior to registration
    • An echocardiogram should be performed at baseline in all patients; ejection fraction (EF) from baseline echocardiogram must be within the institutional limits of normal as determined by the reading cardiologist; if the baseline cardiac stress test incorporates an echocardiogram, then this will not need to be done again at baseline
  • No history of cerebrovascular accident or transient ischemic attacks within the past 6 months
  • 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 (beta-human chorionic gonadotropin [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 chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • Patients may not be receiving any other investigational agents
  • Patients with brain metastases should be excluded from this clinical trial except as noted above
  • Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies, and patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to other agents used in the study
  • Serious or non-healing wound, ulcer, or bone fracture
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days of treatment
  • Patients with the following invasive procedures:

    • Major surgical procedures, open biopsy or significant traumatic injury within 28 days prior to day 1 therapy
    • Anticipation of need for major surgical procedures during the course of the study
    • Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 1 of therapy; central venous catheter placements are permitted to be completed 7 or more days prior to day 1 of therapy; however, peripherally inserted central catheter (peripherally inserted central catheter [PICC] or PIC line) may be placed at any time prior to or during therapy
  • Patients with clinically significant cardiovascular or cerebrovascular disease:

    • History of cerebrovascular accident or transient ischemic attack within past 6 months
    • Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg or systolic blood pressure (BP) > 180 mm Hg if diastolic blood pressure < 90 mm Hg, on at least 2 repeated determinations on separate days within past 3 months
    • Myocardial infarction, coronary artery bypass graft (CABG) or unstable angina within the past 6 Months
    • New York Heart Association grade III or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris within past 6 months
    • Clinically significant peripheral vascular disease within past 6 months
    • Pulmonary embolism, deep vein thrombosis (DVT), or other thromboembolic event within past 6 months
  • History of tumor-related or other serious hemorrhage, bleeding diathesis, or underlying coagulopathy
  • 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
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Patients who have other current malignancies are not eligible; patients with other malignancies are eligible if they have been continuously disease free for > 5 years prior to the time of randomization; 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 a prior history of basal cell or squamous cell 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01258855

United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Sanjay Awasthi    626-359-8111 ext 69200   
Principal Investigator: Sanjay Awasthi         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Heinz-Josef Lenz    323-865-3955   
Principal Investigator: Heinz-Josef Lenz         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Scott D. Christensen    916-734-3772   
Principal Investigator: Scott D. Christensen         
City of Hope South Pasadena Recruiting
South Pasadena, California, United States, 91030
Contact: Stephen C. Koehler    626-396-2900   
Principal Investigator: Stephen C. Koehler         
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion Recruiting
Aurora, Colorado, United States, 80045
Contact: Karl D. Lewis    720-848-0584   
Principal Investigator: Karl D. Lewis         
United States, Georgia
Emory University/Winship Cancer Institute Recruiting
Atlanta, Georgia, United States, 30322
Contact: David H. Lawson    404-778-1900   
Principal Investigator: David H. Lawson         
United States, Illinois
Lurie Children's Hospital-Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Timothy M. Kuzel    312-695-4518   
Principal Investigator: Timothy M. Kuzel         
United States, Indiana
IU Health Methodist Hospital Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Theodore F. Logan    317-948-7576   
Principal Investigator: Theodore F. Logan         
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center Recruiting
Iowa City, Iowa, United States, 52242
Contact: Mohammed M. Milhem    319-356-2324   
Principal Investigator: Mohammed M. Milhem         
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Lawrence E. Flaherty    313-576-8725   
Principal Investigator: Lawrence E. Flaherty         
United States, Minnesota
Metro-Minnesota NCI Community Oncology Research Program Recruiting
Saint Louis Park, Minnesota, United States, 55416
Contact: Patrick J. Flynn    612-863-8585   
Principal Investigator: Patrick J. Flynn         
United States, New Hampshire
Dartmouth Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Lionel D. Lewis    603-650-8685   
Principal Investigator: Lionel D. Lewis         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Saby George    716-845-8387   
Sub-Investigator: Saby George         
United States, Ohio
Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Henry B. Koon    216-368-1175   
Principal Investigator: Henry B. Koon         
Cleveland Clinic Foundation Recruiting
Cleveland, Ohio, United States, 44195
Contact: Marc S. Ernstoff    216-444-0888   
Principal Investigator: Marc S. Ernstoff         
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Thomas E. Olencki    614-293-4680   
Principal Investigator: Thomas E. Olencki         
United States, Pennsylvania
Penn State Milton S Hershey Medical Center Recruiting
Hershey, Pennsylvania, United States, 17033-0850
Contact: Chandra P. Belani    717-531-1078   
Principal Investigator: Chandra P. Belani         
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Ahmad A. Tarhini    412-648-6507   
Principal Investigator: Ahmad A. Tarhini         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Igor Puzanov    615-936-6938   
Principal Investigator: Igor Puzanov         
United States, Virginia
University of Virginia Cancer Center Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Geoffrey R. Weiss    434-243-0066   
Principal Investigator: Geoffrey R. Weiss         
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Ahmad Tarhini Beckman Research Institute
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01258855     History of Changes
Other Study ID Numbers: NCI-2011-02498, NCI-2011-02498, CHNMC-PHII-107, CDR0000690654, PhII-107, 8628, N01CM00038, N01CM00070, N01CM00071, N01CM62209, P30CA033572, UM1CA186705
Study First Received: December 10, 2010
Last Updated: September 2, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Nevi and Melanomas
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Endothelial Growth Factors
Analgesics, Non-Narcotic
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antineoplastic Agents
Antiviral Agents
Central Nervous System Agents
Growth Substances
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses processed this record on October 08, 2015