Clinical Trials /

sEphB4-HSA in Treating Patients With Kaposi Sarcoma

NCT02799485

Description:

This phase II trial studies recombinant EphB4-HSA fusion protein (EphB4-HSA) in treating patients with Kaposi sarcoma. Recombinant EphB4-HSA fusion protein may block the growth of blood vessels that provide blood to the cancer, and may also prevent cancer cells from growing.

Related Conditions:
  • Kaposi Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: sEphB4-HSA in Treating Patients With Kaposi Sarcoma
  • Official Title: A Phase II Study of sEphB4-HSA in Kaposi Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: AMC-096
  • SECONDARY ID: NCI-2015-00052
  • SECONDARY ID: 096
  • SECONDARY ID: AMC 096
  • SECONDARY ID: U01CA121947
  • NCT ID: NCT02799485

Conditions

  • Skin Kaposi Sarcoma

Interventions

DrugSynonymsArms
Recombinant EphB4-HSA Fusion ProteinsEphB4-HSATreatment (recombinant EphB4-HSA fusion protein)

Purpose

This phase II trial studies recombinant EphB4-HSA fusion protein (EphB4-HSA) in treating patients with Kaposi sarcoma. Recombinant EphB4-HSA fusion protein may block the growth of blood vessels that provide blood to the cancer, and may also prevent cancer cells from growing.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the clinical response and toxicity of recombinant EphB4-HSA fusion protein
      (sEphB4-HSA) (at initial dosing of 15 mg/kg every 2 weeks) in participants with Kaposi
      sarcoma.

      SECONDARY OBJECTIVES:

      I. To assess the safety of sEphB4-HSA in participants with Kaposi sarcoma (KS). II. To
      determine trough level exposure of sEphB4-HSA and correlate with tumor response.

      III. To characterize the pharmacodynamics of sEphB4-HSA and correlate these effects with
      clinical response.

      IV. Effects on viral replication and gene expression of human herpes virus-8 (HHV-8).

      V. Changes in vascular endothelial growth factor (VEGF)-Notch-EphrinB2 angiogenic pathway.

      VI. Effects on immune response and modulation. VII. Effects on tumor cell apoptosis and
      proliferation. VIII. Effects on sEphB4-HSA on human immunodeficiency virus (HIV) plasma
      viral loads in participants with HIV.

      IX. To archive peripheral blood mononuclear cells (PBMCs) and tissue samples to be used in
      conjunction with samples collected in subsequent trials of sEphB4-HSA for future studies
      including identification of biomarkers predictive of response.

      X. To evaluate the clinical response and toxicity of sEphB4-HSA (at increased dosing of 10
      mg/kg every week) in participants with KS.

      TERTIARY OBJECTIVES:

      I. Describe baseline quality of life (QOL) scores, using the functional assessment of HIV
      Infection (FAHI) + Kaposi sarcoma (KS) questionnaire, in participants with KS, and explore
      changes in QOL of participants on treatment with sEphB4-HSA.

      OUTLINE:

      Patients receive recombinant EphB4-HSA fusion protein intravenously (IV) over 1 hour on days
      1 and 15. Patients with disease progression after 2 or more courses who have not experienced
      toxicity may receive recombinant EphB4-HSA fusion protein IV over 1 hour on days 1, 8, 15,
      and 22. Treatment repeats every 28 days for up to 12 courses in the absence of further
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 1 month; patients with
      partial response or better are followed up every 3 months for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (recombinant EphB4-HSA fusion protein)ExperimentalPatients receive recombinant EphB4-HSA fusion protein IV over 1 hour on days 1 and 15. Patients with disease progression after 2 or more courses who have not experienced toxicity may receive recombinant EphB4-HSA fusion protein IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the absence of further disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Participants may be treatment naïve, refractory to or intolerant of one or more prior
                 therapies, or treated with prior systemic treatment including but not limited to
                 liposomal doxorubicin
    
              -  Participants must have biopsy-proven KS involving skin with or without visceral
                 involvement
    
              -  If HIV-positive, any cluster of differentiation (CD)4 count will be allowed on study
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky
                 performance score (KPS) >= 60%
    
              -  Life expectancy of greater than 3 months
    
              -  Absolute neutrophil count >= 1,500/mcL*
    
                   -  Participants may be receiving growth factor support to meet these criteria
    
              -  Platelets >= 100,000/mcL
    
              -  Total bilirubin =< 1.5 x upper limit of normal (ULN)
    
              -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
                 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
                 =< 2.5 x ULN
    
              -  Creatinine within normal institutional limit for the reference lab OR creatinine
                 clearance >= 60 mL/min/1.73 m^2 as calculated by Cockcroft-Gault formula for
                 participants with creatinine levels above institutional normal
    
              -  Participants must have cutaneous lesion(s) amenable to four (4) 5-mm tumor biopsies
                 during the study (either 4 separate lesions measuring >= 5 mm each OR 2 separate
                 lesions measuring >= 10 mm each) and at least five additional lesions measurable for
                 assessment with no improvement over the past month
    
              -  Females of childbearing potential (FCBP)* must have a negative serum or urine
                 pregnancy test with a sensitivity of at least 25 mIU/mL within 14 days prior to
                 enrollment and again within 24 hours prior to starting cycle 1 of sEphB4-HSA;
                 further, they must either commit to continued abstinence from heterosexual
                 intercourse or begin TWO acceptable methods of birth control: one highly effective
                 method and one additional effective method AT THE SAME TIME during receipt of
                 sEphB4-HSA, and 12 weeks after discontinuation of sEphB4-HSA; FCBP must also agree to
                 ongoing pregnancy testing; men must agree to use a latex condom during sexual contact
                 with a FCBP even if they have had a successful vasectomy
    
                   -  A female of childbearing potential is a sexually mature woman who: 1) has not
                      undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
                      postmenopausal for at least 24 consecutive months (i.e., has had menses at any
                      time in the preceding 24 consecutive months)
    
              -  Documentation of HIV status; if participant is HIV positive, HIV-1 infection, as
                 documented by any federally approved, licensed HIV rapid test performed in
                 conjunction with screening (or enzyme-linked immunosorbent assay [ELISA], test kit,
                 and confirmed by Western blot or other approved test); alternatively, this
                 documentation may include a record demonstrating that another physician has
                 documented the participant's HIV status based on either: 1) approved diagnostic
                 tests, or 2) the referring physician's written record that HIV infection was
                 documented, with supporting information on the participant's relevant medical history
                 and/or current management of HIV infection
    
                   -  If the participant is HIV negative, documentation of a negative result for any
                      federally approved, licensed HIV rapid test within 4 weeks prior to study
                      enrollment will suffice; if the initial rapid test is positive, further approved
                      confirmatory test results must be present to document the subject's HIV status
    
              -  If participant is HIV positive, participants must be on a stable antiretroviral
                 regimen for at least 12 weeks prior to study enrollment
    
              -  There should be no evidence for improvement in KS in the 3 months prior to study
                 enrollment, unless there is evidence for progression of KS in the 4 weeks immediately
                 prior to study enrollment
    
              -  Participants must, in the opinion of the investigator, be capable of complying with
                 the protocol
    
            Exclusion Criteria:
    
              -  Inability to understand and inability to provide informed consent
    
              -  Participants who are receiving any other investigational agents
    
              -  Participants who have had anti-neoplastic treatment for KS (including chemotherapy,
                 radiotherapy, local treatment including topical fluorouracil [5-FU], biological
                 therapy or investigational therapy) 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
    
              -  Participants with known brain metastases should be excluded from this clinical trial
    
              -  History of allergic reactions attributed to compounds of similar chemical or biologic
                 composition to sEphB4-HSA or other agents used in study
    
              -  Participants who refuse antiretroviral therapy for HIV, if HIV positive
    
              -  Concurrent, acute, active infection, or treatment for infection, other than oral
                 thrush or genital herpes, within 14 days of enrollment
    
              -  Participants for whom front-line cytotoxic therapy is indicated (i.e. symptomatic
                 visceral or pulmonary KS or symptomatic KS impairing functional status)
    
              -  Concurrent neoplasia requiring cytotoxic therapy
    
              -  Participant is =< 2 years free of another primary malignancy; exceptions include the
                 following:
    
                   -  Basal cell skin cancer
    
                   -  Cervical carcinoma in situ
    
                   -  Anal carcinoma in situ
    
              -  Any steroid treatment except for that required for replacement therapy in adrenal
                 insufficiency, topical or injected testosterone for hypogonadism, or inhaled steroids
                 for the treatment of asthma
    
              -  Previous local therapy of any KS-indicator lesion unless the lesion has clearly
                 progressed since that local treatment; any prior local treatment to indicator lesions
                 regardless of the elapsed time should not be allowed unless there is evidence of
                 clear-cut progression of said lesion
    
              -  Female participants who are pregnant, lactating, or breast-feeding
    
              -  Breastfeeding should be discontinued if the mother is treated with sEphB4-HSA
    
              -  Participants with a recent history (< 6 months) of a major infarct including but not
                 inclusive to bowel ischemia, cerebral vascular accident, transient ischemic attack,
                 myocardial infarction, limb ischemia, or skin necrosis
    
              -  Participants with a QTcF (Fridericia correction formula) > 480 ms on 2 out of 3
                 electrocardiograms (EKGs) (if first EKG is < 480, no need to repeat, if first EKG is
                 > 480 repeat twice for a total of 3 EKGs)
    
              -  Participants with uncontrolled sustained hypertension which will be defined as
                 systolic blood pressure > 140, and diastolic blood pressure > 90, even with use of
                 anti-hypertensive medications
    
              -  Participants with a recent history (< 6 months) of a major bleed which will be
                 defined as a symptomatic bleeding in a critical area or organ, such as intracranial,
                 intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or
                 intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin
                 level 2 grams/dL or more, or leading to transfusion of two or more units of whole
                 blood or packed red cells
    
              -  Participants on any dose of warfarin or are on full dose anticoagulation with other
                 agents including low molecular weight heparin, antithrombin agents, antiplatelet
                 agents and full dose aspirin within 7 days prior to study enrollment; participants on
                 prophylactic doses of low molecular weight heparin are allowed
    
              -  Cardiac related illnesses including, but not limited to:
    
                   -  Symptomatic congestive heart failure including participants with grade III/IV
                      cardiac disease as defined by the New York Heart Association functional criteria
    
                   -  Unstable angina pectoris
    
                   -  Cardiac arrhythmia
    
              -  Proteinuria as defined as > 2+ on urine dipstick; if dipstick urinalysis shows >= 2+
                 proteinuria, 24-hour urine for protein must be < 2 grams
    
              -  Participants with diabetes mellitus with ketoacidosis or chronic obstructive
                 pulmonary disease (COPD) requiring hospitalization in the preceding 6 months, or any
                 other intercurrent medical condition that contraindicates treatment with sEphB4-HSA
                 or places the participant at undue risk for treatment related complications
    
              -  Physical or psychiatric illness/social situations that in the estimation of the
                 investigator would limit compliance with study requirements or place the participant
                 at high risk of toxicity or non-compliance
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Proportion of participants experiencing clinical response
    Time Frame:4 weeks (after 2 courses) and up to 12 months (end of follow-up)
    Safety Issue:
    Description:The observed proportions of participants experiencing clinical response and unacceptable toxicity will be calculated with 95% confidence intervals. For clinical response, the Kaplan-Meier method will be used to estimate the distribution for time to death assessed for up to 1 month after treatment completion; for time to progression assessed from chemotherapy initiation to first documented progression up to 1 month after treatment completion; and for time to response assessed from the first dose until first documented response up to 1 month after completion of treatment. The Kaplan-Meier method will then be used to estimate the distribution of time to response, time to relapse, and time to death. Time to response is the time from the first dose until documented first response. Time to progression is the time from first dose to first documented progression. Response duration is the time from first documented response to first documented progression.

    Secondary Outcome Measures

    Measure:Pharmacodynamic parameters of recombinant EphB4-HSA fusion protein
    Time Frame:Days 1 and 15 of courses 1 and 2; days 1, 8, 15, and 22 of 1st 2 courses at escalated dose
    Safety Issue:
    Description:Descriptive statistics and graphical displays will be used to evaluate correlation between response and pharmacodynamics of EphB4-HSA. Depending on the number enrolled, the association between clinical response and changes in trough levels, pharmacodynamic endpoints, viral copy number, protein expression and activation status, and finally immune cell counts and activation status will be investigated using the nonparametric Wilcoxon rank sum test.
    Measure:Trough levels of recombinant EphB4-HSA fusion protein
    Time Frame:Days 1 and 15 of courses 1 and 2; days 1, 8, 15, and 22 of 1st 2 courses at escalated dose
    Safety Issue:
    Description:Descriptive statistics and graphical displays will be used to evaluate correlation between response and trough levels of EphB4-HSA. Depending on the number enrolled, the association between clinical response and changes in trough levels, pharmacodynamic endpoints, viral copy number, protein expression and activation status, and finally immune cell counts and activation status will be investigated using the nonparametric Wilcoxon rank sum test.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:AIDS Malignancy Consortium

    Last Updated

    January 10, 2017