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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01258855
Collaborator
(none)
84
Enrollment
21
Locations
2
Arms
86.3
Actual Duration (Months)
4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
  • Biological: Aldesleukin
  • Other: Laboratory Biomarker Analysis
  • Biological: Ziv-Aflibercept
 Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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.
SECONDARY OBJECTIVES:

  1. 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.

  2. 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.

  3. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
84 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (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
Actual Study Start Date :
Jan 18, 2011
Actual Primary Completion Date :
Mar 29, 2018
Actual Study Completion Date :
Mar 29, 2018

Arms and Interventions

Arm Intervention/Treatment
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:
  • AFLIBERCEPT
  • 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

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free Survival [The time from the date of randomization until date of progression, death, or recurrence, assessed up to 5 years]

      Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    Secondary Outcome Measures

    1. Overall Survival [Until Death from any cause, up to 5 years]

      Estimated using the product-limit method of Kaplan and Meier.

    2. Response Rate [Up to 5 years]

      Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (RR) = CR + PR.

    3. Count of Participants With Adverse Events [Up to 5 years]

      Count of the number of participants with grade 3 & 4 adverse events attributed to treatment agents. Events are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

    4. Progression-free Survival for Patients With High Vascular Endothelial Growth Factor (VEGF) Levels [Up to 5 years]

      Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median baseline measure for VEGF were used as the cut point for "low" vs "high" VEGF groups.

    5. Progression-free Survival for Patients With Low VEGF Levels [Up to 5 years]

      Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median baseline measure for VEGF were used as the cut point for "low" vs "high" VEGF groups.

    Other Outcome Measures

    1. 1-year Overall Survival Rate [Until Death from any cause, up to 1 year]

      Estimated using the product-limit method of Kaplan and Meier.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    17 Years and Older
    Sexes Eligible for Study:
    All
    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

    Locations

    Site City State Country Postal Code
    1 City of Hope Comprehensive Cancer Center Duarte California United States 91010
    2 University of California Davis Comprehensive Cancer Center Sacramento California United States 95817
    3 City of Hope South Pasadena South Pasadena California United States 91030
    4 Emory University Hospital/Winship Cancer Institute Atlanta Georgia United States 30322
    5 Lurie Children's Hospital-Chicago Chicago Illinois United States 60611
    6 Northwestern University Chicago Illinois United States 60611
    7 University of Chicago Comprehensive Cancer Center Chicago Illinois United States 60637
    8 Indiana University/Melvin and Bren Simon Cancer Center Indianapolis Indiana United States 46202
    9 IU Health Methodist Hospital Indianapolis Indiana United States 46202
    10 University of Iowa/Holden Comprehensive Cancer Center Iowa City Iowa United States 52242
    11 Wayne State University/Karmanos Cancer Institute Detroit Michigan United States 48201
    12 Metro Minnesota Community Oncology Research Consortium Saint Louis Park Minnesota United States 55416
    13 Dartmouth Hitchcock Medical Center Lebanon New Hampshire United States 03756
    14 Roswell Park Cancer Institute Buffalo New York United States 14263
    15 Case Western Reserve University Cleveland Ohio United States 44106
    16 Cleveland Clinic Foundation Cleveland Ohio United States 44195
    17 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    18 Penn State Milton S Hershey Medical Center Hershey Pennsylvania United States 17033-0850
    19 University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania United States 15232
    20 Vanderbilt University/Ingram Cancer Center Nashville Tennessee United States 37232
    21 University of Virginia Cancer Center Charlottesville Virginia United States 22908

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Ahmad Tarhini, City of Hope Comprehensive Cancer Center

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01258855
    Other Study ID Numbers:
    • NCI-2011-02498
    • NCI-2011-02498
    • PHII-107
    • CHNMC-PHII-107
    • CDR0000690654
    • 8628
    • 8628
    • N01CM00038
    • N01CM00070
    • N01CM00071
    • N01CM62209
    • P30CA033572
    • UM1CA186705
    First Posted:
    Dec 13, 2010
    Last Update Posted:
    May 10, 2019
    Last Verified:
    May 1, 2019
    Additional relevant MeSH terms:
    Melanoma
    Skin Neoplasms
    Aldesleukin
    Aflibercept
    Interleukin-2
    Endothelial Growth Factors

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Period Title: Overall Study
    STARTED 55 29
    COMPLETED 55 29
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone) Total
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles) Total of all reporting groups
    Overall Participants 55 29 84
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    55
    55
    55
    Sex: Female, Male (Count of Participants)
    Female
    22
    40%
    11
    37.9%
    33
    39.3%
    Male
    33
    60%
    18
    62.1%
    51
    60.7%
    Race/Ethnicity, Customized (Count of Participants)
    Caucasian
    54
    98.2%
    28
    96.6%
    82
    97.6%
    African American
    1
    1.8%
    0
    0%
    1
    1.2%
    Hispanic
    0
    0%
    1
    3.4%
    1
    1.2%
    Region of Enrollment (Count of Participants)
    United States
    55
    100%
    29
    100%
    84
    100%

    Outcome Measures

    1. Primary Outcome
    Title Progression-free Survival
    Description Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    Time Frame The time from the date of randomization until date of progression, death, or recurrence, assessed up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 55 29
    Median (95% Confidence Interval) [months]
    6.9
    2.3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combination Arm (Ziv-Afilbercept+HD IL2), Mono-therapy Arm (HD IL2 Alone)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments
    Method Log Rank
    Comments
    2. Secondary Outcome
    Title Overall Survival
    Description Estimated using the product-limit method of Kaplan and Meier.
    Time Frame Until Death from any cause, up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 55 29
    Median (95% Confidence Interval) [months]
    26.9
    24.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combination Arm (Ziv-Afilbercept+HD IL2), Mono-therapy Arm (HD IL2 Alone)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.43
    Comments
    Method Log Rank
    Comments
    3. Secondary Outcome
    Title Response Rate
    Description Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (RR) = CR + PR.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 55 29
    Number [percentage of participants]
    22
    40%
    17
    58.6%
    4. Secondary Outcome
    Title Count of Participants With Adverse Events
    Description Count of the number of participants with grade 3 & 4 adverse events attributed to treatment agents. Events are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 55 29
    Anemia
    2
    3.6%
    0
    0%
    Leukocytosis
    1
    1.8%
    0
    0%
    Lymphocyte count decreased
    41
    74.5%
    20
    69%
    Neutrophil count decreased
    2
    3.6%
    0
    0%
    Platelet count decreased
    11
    20%
    9
    31%
    Left ventricular systolic
    1
    1.8%
    0
    0%
    Sinus tachycardia
    0
    0%
    1
    3.4%
    Supraventricular tachycardia
    1
    1.8%
    1
    3.4%
    Hypertension
    14
    25.5%
    0
    0%
    Hypotension
    1
    1.8%
    4
    13.8%
    Thromboembolic event
    2
    3.6%
    1
    3.4%
    Fatigue
    5
    9.1%
    3
    10.3%
    Fever and chills
    1
    1.8%
    1
    3.4%
    Diarrhea
    0
    0%
    1
    3.4%
    Oral mucositis
    0
    0%
    1
    3.4%
    Nausea and vomiting
    2
    3.6%
    2
    6.9%
    LFTs increased
    13
    23.6%
    9
    31%
    Lipase increased
    0
    0%
    2
    6.9%
    Confusion
    3
    5.5%
    0
    0%
    Creatinine increased
    2
    3.6%
    0
    0%
    Proteinuria
    6
    10.9%
    0
    0%
    Urine output decreased
    8
    14.5%
    7
    24.1%
    Dyspnea
    1
    1.8%
    4
    13.8%
    Maculopapular rash
    1
    1.8%
    0
    0%
    5. Secondary Outcome
    Title Progression-free Survival for Patients With High Vascular Endothelial Growth Factor (VEGF) Levels
    Description Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median baseline measure for VEGF were used as the cut point for "low" vs "high" VEGF groups.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 21 7
    Median (95% Confidence Interval) [months]
    8.7
    3.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combination Arm (Ziv-Afilbercept+HD IL2), Mono-therapy Arm (HD IL2 Alone)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.003
    Comments
    Method Log Rank
    Comments
    6. Secondary Outcome
    Title Progression-free Survival for Patients With Low VEGF Levels
    Description Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Median baseline measure for VEGF were used as the cut point for "low" vs "high" VEGF groups.
    Time Frame Up to 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 23 6
    Median (95% Confidence Interval) [months]
    6.9
    4.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Combination Arm (Ziv-Afilbercept+HD IL2), Mono-therapy Arm (HD IL2 Alone)
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.02
    Comments
    Method Log Rank
    Comments
    7. Other Pre-specified Outcome
    Title 1-year Overall Survival Rate
    Description Estimated using the product-limit method of Kaplan and Meier.
    Time Frame Until Death from any cause, up to 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    Measure Participants 55 29
    Number (95% Confidence Interval) [percentage of participants]
    75.6
    137.5%
    66.8
    230.3%

    Adverse Events

    Time Frame Adverse events were recorded and graded throughout the study and until 30 days following the last dose of treatment agent.
    Adverse Event Reporting Description "Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
    Arm/Group Title Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Arm/Group Description Each course consisted of 2 cycles of HD IL2 at 600,000 IU/kg IV every 8 hours for up to 14 doses (1st cycle), followed by a period of 1 week rest and readmission for HD IL2 (2nd cycle). Ziv-aflibercept was given concurrently at 3 mg/kg IV every 2 weeks, starting 2 weeks prior to IL2 in course 1. In the absence of disease progression, maintenance ziv-aflibercept was given at 4 mg/kg every 2 weeks after completion of IL2 Patients received HD IL2 for a maximum of 3 courses (6 cycles)
    All Cause Mortality
    Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 37/55 (67.3%) 20/29 (69%)
    Serious Adverse Events
    Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 28/55 (50.9%) 7/29 (24.1%)
    Cardiac disorders
    Sinus bradycardia 1/55 (1.8%) 1 0/29 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 1/55 (1.8%) 1 0/29 (0%) 0
    Abdominal pain 1/55 (1.8%) 1 0/29 (0%) 0
    Colitis 1/55 (1.8%) 1 0/29 (0%) 0
    Colonic hemorrhage 1/55 (1.8%) 1 0/29 (0%) 0
    Nausea 1/55 (1.8%) 1 2/29 (6.9%) 2
    Oral pain 2/55 (3.6%) 2 0/29 (0%) 0
    Vomiting 1/55 (1.8%) 1 1/29 (3.4%) 1
    General disorders
    Fatigue 0/55 (0%) 0 1/29 (3.4%) 1
    Fever 1/55 (1.8%) 1 0/29 (0%) 0
    Infusion related reaction 1/55 (1.8%) 1 0/29 (0%) 0
    Hepatobiliary disorders
    Choledocholithiasis 1/55 (1.8%) 1 0/29 (0%) 0
    Portal vein thrombosis 0/55 (0%) 0 1/29 (3.4%) 1
    Infections and infestations
    Skin infection 1/55 (1.8%) 1 0/29 (0%) 0
    Soft tissue infection 1/55 (1.8%) 1 0/29 (0%) 0
    Investigations
    Alanine aminotransferase increased 1/55 (1.8%) 1 0/29 (0%) 0
    Aspartate aminotransferase increased 1/55 (1.8%) 1 0/29 (0%) 0
    Blood bilirubin increased 1/55 (1.8%) 1 0/29 (0%) 0
    Lipase increased 2/55 (3.6%) 2 0/29 (0%) 0
    Lymphocyte count decreased 15/55 (27.3%) 17 3/29 (10.3%) 3
    Lymphocyte count increased 1/55 (1.8%) 12 0/29 (0%) 0
    Neutrophil count decreased 1/55 (1.8%) 1 0/29 (0%) 0
    Platelet count decreased 3/55 (5.5%) 4 0/29 (0%) 0
    Serum amylase increased 1/55 (1.8%) 1 0/29 (0%) 0
    Metabolism and nutrition disorders
    Hyperkalemia 1/55 (1.8%) 1 0/29 (0%) 0
    Hypermagnesemia 1/55 (1.8%) 1 0/29 (0%) 0
    Hypoalbuminemia 3/55 (5.5%) 3 0/29 (0%) 0
    Hypoglycemia 1/55 (1.8%) 1 0/29 (0%) 0
    Hypophosphatemia 7/55 (12.7%) 9 0/29 (0%) 0
    Nervous system disorders
    Encephalopathy 1/55 (1.8%) 1 0/29 (0%) 0
    Seizure 1/55 (1.8%) 1 0/29 (0%) 0
    Psychiatric disorders
    Confusion 0/55 (0%) 0 1/29 (3.4%) 1
    Delirium 1/55 (1.8%) 1 0/29 (0%) 0
    Renal and urinary disorders
    Urinary retention 1/55 (1.8%) 2 0/29 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary edema 1/55 (1.8%) 1 0/29 (0%) 0
    Respiratory failure 0/55 (0%) 0 1/29 (3.4%) 1
    Skin and subcutaneous tissue disorders
    Dry skin 2/55 (3.6%) 2 0/29 (0%) 0
    Skin ulceration 2/55 (3.6%) 2 0/29 (0%) 0
    Vascular disorders
    Hypertension 2/55 (3.6%) 2 0/29 (0%) 0
    Thromboembolic event 1/55 (1.8%) 1 0/29 (0%) 0
    splenic infarct 1/55 (1.8%) 1 0/29 (0%) 0
    Other (Not Including Serious) Adverse Events
    Combination Arm (Ziv-Afilbercept+HD IL2) Mono-therapy Arm (HD IL2 Alone)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 55/55 (100%) 29/29 (100%)
    Blood and lymphatic system disorders
    Anemia 40/55 (72.7%) 77 20/29 (69%) 39
    Leukocytosis 1/55 (1.8%) 1 0/29 (0%) 0
    hemoptysis 1/55 (1.8%) 1 0/29 (0%) 0
    low carbon dioxide 1/55 (1.8%) 1 0/29 (0%) 0
    red blood cells decreased 1/55 (1.8%) 1 0/29 (0%) 0
    white blood cells increased 7/55 (12.7%) 10 2/29 (6.9%) 2
    Cardiac disorders
    Atrial fibrillation 2/55 (3.6%) 2 3/29 (10.3%) 5
    Chest pain - cardiac 2/55 (3.6%) 2 1/29 (3.4%) 1
    Left ventricular systolic dysfunction 1/55 (1.8%) 1 0/29 (0%) 0
    Mobitz (type) II atrioventricular block 1/55 (1.8%) 1 0/29 (0%) 0
    Mobitz type I 2/55 (3.6%) 2 0/29 (0%) 0
    Palpitations 2/55 (3.6%) 2 0/29 (0%) 0
    Sinus bradycardia 3/55 (5.5%) 4 0/29 (0%) 0
    Sinus tachycardia 39/55 (70.9%) 71 19/29 (65.5%) 61
    Supraventricular tachycardia 1/55 (1.8%) 3 2/29 (6.9%) 3
    Ventricular arrhythmia 0/55 (0%) 0 1/29 (3.4%) 1
    Ventricular tachycardia 3/55 (5.5%) 3 2/29 (6.9%) 2
    bigeminy ventricular arrhythemia 0/55 (0%) 0 1/29 (3.4%) 1
    Ear and labyrinth disorders
    Ear pain 1/55 (1.8%) 1 0/29 (0%) 0
    Tinnitus 1/55 (1.8%) 2 0/29 (0%) 0
    Endocrine disorders
    Hyperthyroidism 0/55 (0%) 0 1/29 (3.4%) 1
    Hypothyroidism 1/55 (1.8%) 1 0/29 (0%) 0
    Eye disorders
    Blurred vision 3/55 (5.5%) 3 1/29 (3.4%) 1
    Dry eye 1/55 (1.8%) 1 0/29 (0%) 0
    Eye pain 1/55 (1.8%) 1 1/29 (3.4%) 1
    Flashing lights 1/55 (1.8%) 1 0/29 (0%) 0
    Floaters 1/55 (1.8%) 1 0/29 (0%) 0
    Photophobia 1/55 (1.8%) 1 0/29 (0%) 0
    diplopia 2/55 (3.6%) 2 0/29 (0%) 0
    double vision 1/55 (1.8%) 1 0/29 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 2/55 (3.6%) 2 2/29 (6.9%) 2
    Abdominal pain 12/55 (21.8%) 15 7/29 (24.1%) 9
    Anal mucositis 2/55 (3.6%) 2 0/29 (0%) 0
    Anal pain 1/55 (1.8%) 1 0/29 (0%) 0
    Bloating 1/55 (1.8%) 1 1/29 (3.4%) 1
    Colitis 1/55 (1.8%) 1 0/29 (0%) 0
    Colonic hemorrhage 1/55 (1.8%) 1 0/29 (0%) 0
    Constipation 12/55 (21.8%) 16 0/29 (0%) 0
    Diarrhea 40/55 (72.7%) 75 19/29 (65.5%) 31
    Dry mouth 5/55 (9.1%) 5 3/29 (10.3%) 3
    Dyspepsia 6/55 (10.9%) 8 2/29 (6.9%) 2
    Dysphagia 2/55 (3.6%) 2 0/29 (0%) 0
    Esophageal pain 1/55 (1.8%) 1 0/29 (0%) 0
    Esophagitis 1/55 (1.8%) 1 0/29 (0%) 0
    Flatulence 2/55 (3.6%) 2 0/29 (0%) 0
    Gastric hemorrhage 1/55 (1.8%) 1 0/29 (0%) 0
    Gastric varices 1/55 (1.8%) 1 0/29 (0%) 0
    Gastroesophageal reflux disease 4/55 (7.3%) 4 1/29 (3.4%) 1
    Gastrointestinal pain 1/55 (1.8%) 1 0/29 (0%) 0
    Hemorrhoids 1/55 (1.8%) 3 0/29 (0%) 0
    Lower gastrointestinal hemorrhage 1/55 (1.8%) 1 0/29 (0%) 0
    Mucositis nose 1/55 (1.8%) 1 0/29 (0%) 0
    Mucositis oral 21/55 (38.2%) 27 6/29 (20.7%) 6
    Nausea 41/55 (74.5%) 85 20/29 (69%) 44
    Oral hemorrhage 1/55 (1.8%) 1 0/29 (0%) 0
    Oral pain 7/55 (12.7%) 8 2/29 (6.9%) 2
    Pancreatitis 1/55 (1.8%) 1 0/29 (0%) 0
    Rectal hemorrhage 1/55 (1.8%) 3 0/29 (0%) 0
    Rectal mucositis 1/55 (1.8%) 2 0/29 (0%) 0
    Rectal pain 1/55 (1.8%) 1 0/29 (0%) 0
    Toothache 4/55 (7.3%) 4 0/29 (0%) 0
    Vomiting 30/55 (54.5%) 56 18/29 (62.1%) 40
    early satiety 1/55 (1.8%) 1 0/29 (0%) 0
    gum sensitivity 1/55 (1.8%) 1 0/29 (0%) 0
    mouth sores 1/55 (1.8%) 1 1/29 (3.4%) 1
    mouth ulcer 1/55 (1.8%) 1 0/29 (0%) 0
    mouth ulceration 1/55 (1.8%) 1 0/29 (0%) 0
    mouth ulcers 1/55 (1.8%) 1 0/29 (0%) 0
    mucosal edema 1/55 (1.8%) 1 0/29 (0%) 0
    oral mucosal tenderness 1/55 (1.8%) 1 0/29 (0%) 0
    tongue sensitivity 1/55 (1.8%) 1 0/29 (0%) 0
    General disorders
    Chills 40/55 (72.7%) 67 23/29 (79.3%) 44
    Edema face 6/55 (10.9%) 9 6/29 (20.7%) 7
    Edema limbs 25/55 (45.5%) 45 21/29 (72.4%) 30
    Edema trunk 1/55 (1.8%) 1 2/29 (6.9%) 2
    Facial pain 5/55 (9.1%) 5 0/29 (0%) 0
    Fatigue 39/55 (70.9%) 75 22/29 (75.9%) 33
    Fever 27/55 (49.1%) 46 19/29 (65.5%) 38
    Flu like symptoms 4/55 (7.3%) 7 1/29 (3.4%) 1
    Infusion related reaction 3/55 (5.5%) 3 0/29 (0%) 0
    Jaw Pain 1/55 (1.8%) 1 0/29 (0%) 0
    Malaise 8/55 (14.5%) 10 3/29 (10.3%) 4
    Non-cardiac chest pain 2/55 (3.6%) 2 3/29 (10.3%) 3
    Pain 5/55 (9.1%) 5 2/29 (6.9%) 4
    Rigors 1/55 (1.8%) 1 1/29 (3.4%) 1
    Swollen Lips 0/55 (0%) 0 1/29 (3.4%) 1
    edema LUE distal to PICC site 1/55 (1.8%) 1 0/29 (0%) 0
    failure to thrive 1/55 (1.8%) 1 0/29 (0%) 0
    night sweats 1/55 (1.8%) 1 1/29 (3.4%) 1
    tongue edema 0/55 (0%) 0 1/29 (3.4%) 1
    Hepatobiliary disorders
    intra and extrahepatic biliary duct dila 1/55 (1.8%) 1 0/29 (0%) 0
    Immune system disorders
    Allergic reaction 1/55 (1.8%) 1 0/29 (0%) 0
    seasonal allergies 1/55 (1.8%) 1 0/29 (0%) 0
    Infections and infestations
    Anorectal infection 1/55 (1.8%) 1 0/29 (0%) 0
    Catheter related infection 1/55 (1.8%) 1 0/29 (0%) 0
    Lung infection 0/55 (0%) 0 1/29 (3.4%) 1
    Mucosal infection 3/55 (5.5%) 3 3/29 (10.3%) 4
    Oral Yeast 1/55 (1.8%) 1 0/29 (0%) 0
    Pharyngitis 2/55 (3.6%) 2 0/29 (0%) 0
    Scrotal infection 2/55 (3.6%) 2 0/29 (0%) 0
    Sinusitis 4/55 (7.3%) 6 0/29 (0%) 0
    Skin infection 6/55 (10.9%) 6 1/29 (3.4%) 1
    Thrush 1/55 (1.8%) 1 0/29 (0%) 0
    Toe infection 1/55 (1.8%) 1 0/29 (0%) 0
    Tonsilar abscess 1/55 (1.8%) 1 0/29 (0%) 0
    Tooth infection 1/55 (1.8%) 1 0/29 (0%) 0
    Upper respiratory infection 2/55 (3.6%) 2 2/29 (6.9%) 2
    Urinary tract infection 6/55 (10.9%) 8 0/29 (0%) 0
    Vaginal infection 2/55 (3.6%) 2 1/29 (3.4%) 1
    cellulitis 1/55 (1.8%) 1 0/29 (0%) 0
    only noted as bacteremia 0/55 (0%) 0 1/29 (3.4%) 1
    throat 1/55 (1.8%) 1 0/29 (0%) 0
    thrush 2/55 (3.6%) 2 1/29 (3.4%) 1
    Injury, poisoning and procedural complications
    Bruising 2/55 (3.6%) 2 1/29 (3.4%) 1
    Fall 1/55 (1.8%) 1 0/29 (0%) 0
    Fracture 1/55 (1.8%) 1 0/29 (0%) 0
    Investigations
    Activated partial thromboplastin time pr 1/55 (1.8%) 1 2/29 (6.9%) 2
    Alanine aminotransferase increased 31/55 (56.4%) 72 14/29 (48.3%) 19
    Alkaline phosphatase increased 33/55 (60%) 84 16/29 (55.2%) 22
    Aspartate aminotransferase increased 42/55 (76.4%) 93 16/29 (55.2%) 32
    Blood bilirubin increased 37/55 (67.3%) 69 23/29 (79.3%) 42
    C Reactive Protein increased 1/55 (1.8%) 1 0/29 (0%) 0
    CD4 lymphocytes decreased 2/55 (3.6%) 2 1/29 (3.4%) 1
    Cardiac troponin I increased 1/55 (1.8%) 1 0/29 (0%) 0
    Cholesterol high 0/55 (0%) 0 1/29 (3.4%) 1
    Creatinine increased 25/55 (45.5%) 48 8/29 (27.6%) 10
    Ejection fraction decreased 1/55 (1.8%) 1 0/29 (0%) 0
    Elevated Lactate dehydrogenase 0/55 (0%) 0 1/29 (3.4%) 1
    Elevated lactate acid dehydrogenase 1/55 (1.8%) 1 1/29 (3.4%) 1
    Elevated lactate dehydrogenase 1/55 (1.8%) 1 0/29 (0%) 0
    Elevated neutrophil count 1/55 (1.8%) 1 0/29 (0%) 0
    Elevated white blood cells 1/55 (1.8%) 1 0/29 (0%) 0
    GGT increased 2/55 (3.6%) 2 1/29 (3.4%) 1
    Hemoglobin increased 2/55 (3.6%) 20 0/29 (0%) 0
    Hyperphosphatemia 5/55 (9.1%) 8 0/29 (0%) 0
    INR increased 4/55 (7.3%) 4 1/29 (3.4%) 1
    Increaesd LDH 1/55 (1.8%) 1 0/29 (0%) 0
    LDH 1/55 (1.8%) 1 0/29 (0%) 0
    LDH increased 8/55 (14.5%) 12 4/29 (13.8%) 4
    LDH serum high 1/55 (1.8%) 1 0/29 (0%) 0
    Lipase increased 2/55 (3.6%) 3 2/29 (6.9%) 4
    Lymphocyte count decreased 34/55 (61.8%) 69 18/29 (62.1%) 35
    Lymphocyte count increased 13/55 (23.6%) 19 2/29 (6.9%) 2
    Neutrophil count decreased 16/55 (29.1%) 39 12/29 (41.4%) 21
    Neutrophil count increased 1/55 (1.8%) 1 0/29 (0%) 0
    Neutrphil count increased 1/55 (1.8%) 1 0/29 (0%) 0
    Platelet count decreased 46/55 (83.6%) 90 23/29 (79.3%) 46
    Platelet count increased 4/55 (7.3%) 5 1/29 (3.4%) 1
    Serum amylase increased 3/55 (5.5%) 7 0/29 (0%) 0
    Urine output decreased 8/55 (14.5%) 10 7/29 (24.1%) 9
    Weight gain 32/55 (58.2%) 48 18/29 (62.1%) 23
    Weight loss 11/55 (20%) 40 3/29 (10.3%) 4
    White Blood Cells Increased 1/55 (1.8%) 1 0/29 (0%) 0
    White blood cell count increased 1/55 (1.8%) 1 0/29 (0%) 0
    White blood cell decreased 23/55 (41.8%) 37 13/29 (44.8%) 21
    White blood cell increased 3/55 (5.5%) 4 0/29 (0%) 0
    bicarbonate decreased 2/55 (3.6%) 2 3/29 (10.3%) 3
    chloride increased 0/55 (0%) 0 1/29 (3.4%) 1
    decreased appetite 1/55 (1.8%) 1 0/29 (0%) 0
    decreased folic acid 1/55 (1.8%) 1 0/29 (0%) 0
    decreased phosphorus 2/55 (3.6%) 2 0/29 (0%) 0
    ele3vated phosphorus 1/55 (1.8%) 1 0/29 (0%) 0
    elevated b natriuretic peptide 1/55 (1.8%) 1 0/29 (0%) 0
    elevated lactate dehydrogenase 9/55 (16.4%) 12 3/29 (10.3%) 3
    elevated platelet count 1/55 (1.8%) 1 0/29 (0%) 0
    elevated white blood cells 2/55 (3.6%) 2 1/29 (3.4%) 1
    generalized edema 1/55 (1.8%) 1 0/29 (0%) 0
    increased LDH 8/55 (14.5%) 8 0/29 (0%) 0
    increased PT 1/55 (1.8%) 1 0/29 (0%) 0
    increased basophils 0/55 (0%) 0 1/29 (3.4%) 1
    increased bilirubin, urine 1/55 (1.8%) 1 0/29 (0%) 0
    increased chloride 1/55 (1.8%) 1 0/29 (0%) 0
    increased eosinophils 1/55 (1.8%) 1 1/29 (3.4%) 1
    increased phosphorous 4/55 (7.3%) 5 0/29 (0%) 0
    increased phosphorus 1/55 (1.8%) 1 0/29 (0%) 0
    increased platelets 3/55 (5.5%) 3 0/29 (0%) 0
    increased thyroid stimulating hormone 1/55 (1.8%) 1 0/29 (0%) 0
    increased white blood cells 1/55 (1.8%) 1 0/29 (0%) 0
    lactate dehydrogenase 2/55 (3.6%) 2 0/29 (0%) 0
    lactate dehydrogenase elevated 4/55 (7.3%) 6 1/29 (3.4%) 1
    lactate dehydrogenase increased 3/55 (5.5%) 4 1/29 (3.4%) 1
    lymhocyte count increased 1/55 (1.8%) 1 0/29 (0%) 0
    neutrophil count increased 3/55 (5.5%) 3 1/29 (3.4%) 1
    oliguria 3/55 (5.5%) 5 2/29 (6.9%) 3
    platelet count increased 5/55 (9.1%) 7 0/29 (0%) 0
    rigors 1/55 (1.8%) 1 0/29 (0%) 0
    testosterone decreased 1/55 (1.8%) 1 0/29 (0%) 0
    white blood cell increased 1/55 (1.8%) 1 0/29 (0%) 0
    Metabolism and nutrition disorders
    Acidosis 3/55 (5.5%) 3 2/29 (6.9%) 2
    Anorexia 19/55 (34.5%) 28 10/29 (34.5%) 11
    Dehydration 3/55 (5.5%) 3 2/29 (6.9%) 2
    Hypercalcemia 3/55 (5.5%) 3 1/29 (3.4%) 2
    Hyperglycemia 6/55 (10.9%) 10 6/29 (20.7%) 11
    Hyperkalemia 22/55 (40%) 41 5/29 (17.2%) 7
    Hypermagnesemia 15/55 (27.3%) 22 5/29 (17.2%) 7
    Hypernatremia 1/55 (1.8%) 1 1/29 (3.4%) 2
    Hypertriglyceridemia 1/55 (1.8%) 4 2/29 (6.9%) 3
    Hyperuricemia 1/55 (1.8%) 1 0/29 (0%) 0
    Hypoalbuminemia 47/55 (85.5%) 106 24/29 (82.8%) 46
    Hypocalcemia 25/55 (45.5%) 42 13/29 (44.8%) 19
    Hypoglycemia 4/55 (7.3%) 19 1/29 (3.4%) 1
    Hypokalemia 22/55 (40%) 38 10/29 (34.5%) 10
    Hypomagnesemia 41/55 (74.5%) 81 21/29 (72.4%) 38
    Hyponatremia 42/55 (76.4%) 83 19/29 (65.5%) 30
    Hypophosphatemia 37/55 (67.3%) 83 22/29 (75.9%) 42
    LDH Serum Increased 1/55 (1.8%) 1 1/29 (3.4%) 1
    LDH Serum increased 1/55 (1.8%) 1 0/29 (0%) 0
    LDH serum increased 11/55 (20%) 23 5/29 (17.2%) 6
    Obesity 1/55 (1.8%) 7 0/29 (0%) 0
    Phosphorus Increased 1/55 (1.8%) 1 0/29 (0%) 0
    decreased bicarbonate 0/55 (0%) 0 1/29 (3.4%) 2
    elevated chloride 0/55 (0%) 0 1/29 (3.4%) 1
    hyperphosphatemia 6/55 (10.9%) 11 0/29 (0%) 0
    low CO2 1/55 (1.8%) 1 0/29 (0%) 0
    low hemoglobin 1/55 (1.8%) 1 0/29 (0%) 0
    phosphorus increasedf 1/55 (1.8%) 1 0/29 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 6/55 (10.9%) 16 3/29 (10.3%) 4
    Arthritis 0/55 (0%) 0 1/29 (3.4%) 1
    Back pain 3/55 (5.5%) 3 2/29 (6.9%) 2
    Chest wall pain 1/55 (1.8%) 1 0/29 (0%) 0
    Flank pain 1/55 (1.8%) 2 2/29 (6.9%) 2
    Generalized muscle weakness 3/55 (5.5%) 3 1/29 (3.4%) 1
    Joint range of motion decreased 3/55 (5.5%) 4 0/29 (0%) 0
    Muscle weakness lower limb 1/55 (1.8%) 1 0/29 (0%) 0
    Muscle weakness right-sided 1/55 (1.8%) 1 0/29 (0%) 0
    Myalgia 15/55 (27.3%) 18 4/29 (13.8%) 4
    Neck pain 1/55 (1.8%) 1 0/29 (0%) 0
    Pain in extremity 17/55 (30.9%) 19 2/29 (6.9%) 2
    Plantar fasciitis 1/55 (1.8%) 1 0/29 (0%) 0
    joint pain 1/55 (1.8%) 1 0/29 (0%) 0
    pain at left clavicle 1/55 (1.8%) 1 0/29 (0%) 0
    rib pain 1/55 (1.8%) 1 0/29 (0%) 0
    shoulder pain 1/55 (1.8%) 1 0/29 (0%) 0
    toe pain 1/55 (1.8%) 1 0/29 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain 1/55 (1.8%) 1 1/29 (3.4%) 1
    Nervous system disorders
    Cognitive disturbance 1/55 (1.8%) 1 0/29 (0%) 0
    Concentration impairment 0/55 (0%) 0 1/29 (3.4%) 1
    Dizziness 11/55 (20%) 12 6/29 (20.7%) 7
    Dysgeusia 6/55 (10.9%) 6 2/29 (6.9%) 2
    Headache 23/55 (41.8%) 45 5/29 (17.2%) 5
    Lethargy 3/55 (5.5%) 3 0/29 (0%) 0
    Memory impairment 0/55 (0%) 0 1/29 (3.4%) 1
    Nystagmus 1/55 (1.8%) 1 0/29 (0%) 0
    Paresthesia 2/55 (3.6%) 2 0/29 (0%) 0
    Peripheral sensory neuropathy 4/55 (7.3%) 4 2/29 (6.9%) 2
    Presyncope 0/55 (0%) 0 1/29 (3.4%) 1
    Sinus pain 4/55 (7.3%) 17 0/29 (0%) 0
    Somnolence 2/55 (3.6%) 4 1/29 (3.4%) 1
    Syncope 1/55 (1.8%) 1 0/29 (0%) 0
    Vasovagal reaction 1/55 (1.8%) 1 0/29 (0%) 0
    mental status changes 1/55 (1.8%) 1 0/29 (0%) 0
    neurological episode NOS 1/55 (1.8%) 1 0/29 (0%) 0
    paraesthesia 0/55 (0%) 0 1/29 (3.4%) 1
    sleep disturbance 1/55 (1.8%) 1 0/29 (0%) 0
    sleep disturbances 1/55 (1.8%) 1 1/29 (3.4%) 2
    tingling, left foot 0/55 (0%) 0 1/29 (3.4%) 1
    tingling, middle upper abdomen 0/55 (0%) 0 1/29 (3.4%) 1
    Psychiatric disorders
    Agitation 7/55 (12.7%) 7 4/29 (13.8%) 5
    Anxiety 26/55 (47.3%) 38 14/29 (48.3%) 18
    Confusion 11/55 (20%) 12 8/29 (27.6%) 11
    Delirium 2/55 (3.6%) 2 1/29 (3.4%) 1
    Depression 2/55 (3.6%) 2 3/29 (10.3%) 3
    Hallucinations 5/55 (9.1%) 5 4/29 (13.8%) 5
    Insomnia 10/55 (18.2%) 10 7/29 (24.1%) 7
    Restlessness 1/55 (1.8%) 2 1/29 (3.4%) 1
    Renal and urinary disorders
    Acute kidney injury 1/55 (1.8%) 3 3/29 (10.3%) 3
    Dysuria 1/55 (1.8%) 1 0/29 (0%) 0
    Hematuria 5/55 (9.1%) 5 1/29 (3.4%) 1
    Hemoglobinuria 2/55 (3.6%) 2 0/29 (0%) 0
    Proteinuria 25/55 (45.5%) 70 2/29 (6.9%) 2
    Urinary frequency 1/55 (1.8%) 1 1/29 (3.4%) 1
    Urinary incontinence 0/55 (0%) 0 1/29 (3.4%) 1
    Urinary retention 4/55 (7.3%) 9 2/29 (6.9%) 2
    Urinary tract pain 0/55 (0%) 0 1/29 (3.4%) 1
    Urinary urgency 1/55 (1.8%) 1 0/29 (0%) 0
    decreased urine output 1/55 (1.8%) 1 0/29 (0%) 0
    low urine output 1/55 (1.8%) 1 0/29 (0%) 0
    renal insufficiency 1/55 (1.8%) 1 0/29 (0%) 0
    urinary hesitancy 2/55 (3.6%) 2 0/29 (0%) 0
    urinary pressure 1/55 (1.8%) 1 0/29 (0%) 0
    Reproductive system and breast disorders
    Erectile dysfunction 1/55 (1.8%) 1 0/29 (0%) 0
    Genital edema 1/55 (1.8%) 1 0/29 (0%) 0
    Irregular menstruation 1/55 (1.8%) 1 0/29 (0%) 0
    Pelvic pain 1/55 (1.8%) 1 0/29 (0%) 0
    Vaginal pain 0/55 (0%) 0 1/29 (3.4%) 1
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 4/55 (7.3%) 5 0/29 (0%) 0
    Atelectasis 1/55 (1.8%) 1 0/29 (0%) 0
    CO2 Decreased 1/55 (1.8%) 1 0/29 (0%) 0
    Cough 14/55 (25.5%) 15 5/29 (17.2%) 8
    Dyspnea 22/55 (40%) 26 14/29 (48.3%) 16
    Epistaxis 7/55 (12.7%) 7 0/29 (0%) 0
    Hoarseness 20/55 (36.4%) 22 1/29 (3.4%) 1
    Hypoxia 3/55 (5.5%) 3 2/29 (6.9%) 2
    Laryngeal edema 1/55 (1.8%) 1 1/29 (3.4%) 1
    Nasal congestion 10/55 (18.2%) 17 2/29 (6.9%) 2
    Odynophagia 1/55 (1.8%) 1 0/29 (0%) 0
    Pharyngeal hemorrhage 1/55 (1.8%) 1 0/29 (0%) 0
    Pharyngolaryngeal pain 0/55 (0%) 0 1/29 (3.4%) 1
    Pleural effusion 4/55 (7.3%) 4 3/29 (10.3%) 3
    Postnasal drip 4/55 (7.3%) 4 0/29 (0%) 0
    Productive cough 1/55 (1.8%) 1 0/29 (0%) 0
    Pulmonary edema 3/55 (5.5%) 3 4/29 (13.8%) 4
    Sinus disorder 1/55 (1.8%) 1 0/29 (0%) 0
    Sore throat 15/55 (27.3%) 20 6/29 (20.7%) 6
    Tracheal mucositis 1/55 (1.8%) 1 0/29 (0%) 0
    Voice alteration 2/55 (3.6%) 3 0/29 (0%) 0
    Wheezing 5/55 (9.1%) 5 3/29 (10.3%) 3
    dry nostrils 1/55 (1.8%) 1 0/29 (0%) 0
    dry nostrils from O2 use 1/55 (1.8%) 1 0/29 (0%) 0
    tachypnea 0/55 (0%) 0 1/29 (3.4%) 1
    Skin and subcutaneous tissue disorders
    Alopecia 1/55 (1.8%) 1 1/29 (3.4%) 1
    Desquamation 1/55 (1.8%) 1 0/29 (0%) 0
    Dry skin 23/55 (41.8%) 26 15/29 (51.7%) 16
    Erythema multiforme 0/55 (0%) 0 1/29 (3.4%) 1
    Erythema: chest and face 1/55 (1.8%) 1 0/29 (0%) 0
    Erythroderma 1/55 (1.8%) 1 3/29 (10.3%) 3
    Hyperhidrosis 1/55 (1.8%) 1 0/29 (0%) 0
    Nail discoloration 1/55 (1.8%) 1 0/29 (0%) 0
    Onychomalacia 1/55 (1.8%) 1 0/29 (0%) 0
    Pain of skin 2/55 (3.6%) 2 0/29 (0%) 0
    Periorbital edema 2/55 (3.6%) 2 2/29 (6.9%) 2
    Pruritus 25/55 (45.5%) 30 17/29 (58.6%) 19
    Purpura 2/55 (3.6%) 3 0/29 (0%) 0
    Rash acneiform 2/55 (3.6%) 2 2/29 (6.9%) 2
    Rash maculo-papular 13/55 (23.6%) 41 6/29 (20.7%) 7
    Scalp pain 1/55 (1.8%) 1 0/29 (0%) 0
    Skin hypopigmentation 1/55 (1.8%) 2 1/29 (3.4%) 1
    Skin induration 1/55 (1.8%) 1 0/29 (0%) 0
    Urticaria 0/55 (0%) 0 1/29 (3.4%) 1
    callous, right hand 1/55 (1.8%) 1 0/29 (0%) 0
    dermatitis 1/55 (1.8%) 1 0/29 (0%) 0
    desquamation 0/55 (0%) 0 1/29 (3.4%) 1
    desquamation: hands, chest, foot, legs 1/55 (1.8%) 1 0/29 (0%) 0
    desquamation: head and neck 1/55 (1.8%) 1 0/29 (0%) 0
    erythema 1/55 (1.8%) 1 0/29 (0%) 0
    erythema: thighs, legs, arms 1/55 (1.8%) 1 0/29 (0%) 0
    excoriation 1/55 (1.8%) 1 0/29 (0%) 0
    excoriation, groin 1/55 (1.8%) 1 0/29 (0%) 0
    hypopigmentation 1/55 (1.8%) 1 0/29 (0%) 0
    peeling 1/55 (1.8%) 1 0/29 (0%) 0
    poison ivy 1/55 (1.8%) 1 0/29 (0%) 0
    ruddy color, whole body 1/55 (1.8%) 1 0/29 (0%) 0
    scrotal desquamation 1/55 (1.8%) 1 0/29 (0%) 0
    white papules, lip 1/55 (1.8%) 1 0/29 (0%) 0
    white spot on tonsil 1/55 (1.8%) 1 0/29 (0%) 0
    xanthelasma 1/55 (1.8%) 1 0/29 (0%) 0
    Vascular disorders
    Capillary leak syndrome 5/55 (9.1%) 5 1/29 (3.4%) 1
    Flushing 10/55 (18.2%) 17 8/29 (27.6%) 12
    Hot flashes 0/55 (0%) 0 1/29 (3.4%) 1
    Hypertension 29/55 (52.7%) 64 4/29 (13.8%) 6
    Hypotension 24/55 (43.6%) 40 22/29 (75.9%) 44
    Lymphedema 1/55 (1.8%) 1 0/29 (0%) 0
    Thromboembolic event 3/55 (5.5%) 3 2/29 (6.9%) 2

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Paul Frankel, Ph.D.
    Organization City of Hope
    Phone 626-218-5265
    Email pfrankel@coh.org
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01258855
    Other Study ID Numbers:
    • NCI-2011-02498
    • NCI-2011-02498
    • PHII-107
    • CHNMC-PHII-107
    • CDR0000690654
    • 8628
    • 8628
    • N01CM00038
    • N01CM00070
    • N01CM00071
    • N01CM62209
    • P30CA033572
    • UM1CA186705
    First Posted:
    Dec 13, 2010
    Last Update Posted:
    May 10, 2019
    Last Verified:
    May 1, 2019