Clinical Trials /

Combination Therapy With Pembrolizumab and sEphB4-HSA in Previously Treated Urothelial Carcinoma

NCT02717156

Description:

This phase II trial studies how well recombinant EphB4-HSA fusion protein and pembrolizumab work in treating patients with urothelial (bladder) cancer that has spread from the primary site to other places in the body or has come back and does not respond to certain chemotherapy drugs. Combinations of biological substances in recombinant EphB4-HSA fusion protein may be able to carry tumor-killing substances directly to urothelial cancer cells. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Giving recombinant EphB4-HSA fusion protein and pembrolizumab together may be a better treatment for patients with urothelial cancer.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Therapy With Pembrolizumab and sEphB4-HSA in Previously Treated Urothelial Carcinoma
  • Official Title: A Phase II Trial of sEphB4-HSA in Combination With Anti PD1 Antibody Pembrolizumab (MK-7435) for Metastatic Urothelial Cancer Refractory to Platinum

Clinical Trial IDs

  • ORG STUDY ID: 4B-15-11
  • SECONDARY ID: NCI-2016-00147
  • SECONDARY ID: 4B-15-11
  • SECONDARY ID: P30CA014089
  • NCT ID: NCT02717156

Conditions

  • Stage IV Bladder Urothelial Carcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (EphB4-HSA and pembrolizumab)
Recombinant EphB4-HSA Fusion ProteinsEphB4-HSATreatment (EphB4-HSA and pembrolizumab)

Purpose

This phase II trial studies how well recombinant EphB4-HSA fusion protein and pembrolizumab work in treating patients with urothelial (bladder) cancer that has spread from the primary site to other places in the body or has come back and does not respond to certain chemotherapy drugs. Combinations of biological substances in recombinant EphB4-HSA fusion protein may be able to carry tumor-killing substances directly to urothelial cancer cells. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of cancer cells to grow and spread. Giving recombinant EphB4-HSA fusion protein and pembrolizumab together may be a better treatment for patients with urothelial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the feasibility of using pembrolizumab-recombinant EphB4-HSA fusion protein
      (sEphB4-HSA) combination in patients with advanced urothelial carcinoma.

      II. To measure the overall survival (OS).

      SECONDARY OBJECTIVES:

      I. To measure the progression-free survival (PFS). II. To measure the objective response
      rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

      TERTIARY OBJECTIVES:

      I. To examine programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1),
      programmed cell death 1 ligand 2 (PD-L2) and EPH receptor B4 (EphB4) expression by tumor
      cells (TC) as well as immune cells (IC)- macrophages and T cells- in tumor tissue and
      correlate them with ORR, PFS and OS.

      II. To examine the tumor tissue T cell frequency (counts), tumor tissue T cell clonality
      using T cell receptor (TCR) sequencing, and peripheral blood T cell clonality, pre-treatment
      and post-treatment and correlate these with ORR, PFS and OS.

      III. To measure the phenotype of lymphocytes and myeloid derived suppressor cells (MDSC), in
      pre and post-treatment blood samples and correlate these with ORR, PFS and OS; an extra
      blood sample for future studies will also be collected and banked.

      IV. To examine peripheral blood circulating tumor cells (CTCs) for enumeration and molecular
      analysis in pre and post-treatment blood samples, and correlate these with ORR, PFS and OS.

      V. To collect and bank tumor tissue. VI. To examine the role of adding positron emission
      tomography (PET) to a contrast computed tomography (CT) for evaluation of response to
      treatment.

      OUTLINE:

      Patients receive recombinant EphB4-HSA fusion protein intravenously (IV) over 60 minutes on
      days 1, 8, and 15 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3
      weeks in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 6-12
      weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (EphB4-HSA and pembrolizumab)ExperimentalPatients receive recombinant EphB4-HSA fusion protein IV over 60 minutes on days 1, 8, and 15 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Be willing and able to provide written informed consent/assent for the trial
    
              -  Advanced (metastatic or recurrent) pathologically proven urothelial carcinoma which
                 is refractory to platinum based due to disease progression on a platinum containing
                 regimen; patients progressing within 12 months of their last dose of platinum-based
                 neoadjuvant or adjuvant chemotherapy will be considered platinum refractory
    
              -  Have measurable disease based on RECIST 1.1
    
              -  Be willing to provide tissue from a newly obtained core or excisional biopsy of a
                 tumor lesion; newly-obtained is defined as a specimen obtained for up to 6 weeks (42
                 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained
                 samples cannot be provided (e.g. inaccessible or subject safety concern) may submit
                 an archived specimen only upon agreement from the Sponsor; an optional core biopsy
                 will be requested from an accessible metastatic site after 2 cycles of treatment
    
              -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
                 performance scale
    
              -  Absolute neutrophil count (ANC) >= 1,500/mcL
    
              -  Platelets >= 100,000/mcL
    
              -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
                 dependency (within 7 days of assessment)
    
              -  Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can
                 also be used in place of creatinine or creatinine clearance [CrCl]) >= 30mL/min for
                 subject with creatinine levels > 1.5 X institutional upper limit of normal (ULN)
    
              -  Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total
                 bilirubin levels > 1.5 ULN
    
              -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
                 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
                 X ULN or =< 5 X ULN for subjects with liver metastases
    
              -  Albumin >= 2.5 mg/dL
    
              -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
                 subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
                 time (PTT) is within therapeutic range of intended use of anticoagulants
    
              -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
                 anticoagulant therapy as long as PT or PTT is within therapeutic range of intended
                 use of anticoagulants
    
              -  Recovered to grade 1 from the effects (excluding alopecia) of any prior therapy for
                 their malignancies
    
              -  Female subject of childbearing potential should have a negative urine or serum
                 pregnancy within 72 hours prior to receiving the first dose of study medication; if
                 the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
                 will be required
    
              -  Female subjects of childbearing potential should be willing to use 2 methods of birth
                 control or be surgically sterile, or abstain from heterosexual activity for the
                 course of the study through 120 days after the last dose of study medication;
                 subjects of childbearing potential are those who have not been surgically sterilized
                 or have not been free from menses for > 1 year
    
              -  Male subjects should agree to use an adequate method of contraception starting with
                 the first dose of study therapy through 120 days after the last dose of study therapy
    
            Exclusion Criteria:
    
              -  Is currently participating and receiving study therapy or has participated in a study
                 of an investigational agent and received study therapy or used an investigational
                 device within 4 weeks of the first dose of treatment
    
              -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
                 other form of immunosuppressive therapy within 7 days prior to the first dose of
                 trial treatment
    
              -  Has a known history of active TB (bacillus tuberculosis)
    
              -  Hypersensitivity to pembrolizumab or any of its excipients
    
              -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
                 day 1 or who has not recovered (ie, =< grade 1 or at baseline) from adverse events
                 due to agents administered more than 4 weeks earlier
    
              -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
                 within 2 weeks prior to study day 1 or who has not recovered (ie, =< grade 1 or at
                 baseline) from adverse events due to a previously administered agent; Note: subjects
                 with =< grade 2 neuropathy are an exception to this criterion and may qualify for the
                 study; Note: if subject received major surgery, they must have recovered adequately
                 from the toxicity and/or complications from the intervention prior to starting
                 therapy
    
              -  Has a known additional malignancy that is progressing or requires active treatment;
                 exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
                 skin or early stage carcinoma of the cervix that has undergone potentially curative
                 therapy or in situ cervical cancer; patients with incidental prostate cancer
                 diagnosed at cystectomy or deemed appropriate for surveillance based on national
                 guidelines will be allowed to enroll
    
              -  Has known active central nervous system (CNS) metastases and/or carcinomatous
                 meningitis; subjects with previously treated brain metastases may participate
                 provided they are stable (without evidence of progression by imaging for at least
                 four weeks prior to the first dose of trial treatment and any neurologic symptoms
                 have returned to baseline), have no evidence of new or enlarging brain metastases,
                 and are not using steroids for at least 7 days prior to trial treatment; this
                 exception does not include carcinomatous meningitis which is excluded regardless of
                 clinical stability
    
              -  Has active autoimmune disease that has required systemic treatment in the past 2
                 years (i.e. with use of disease modifying agents, corticosteroids or
                 immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or
                 physiologic corticosteroid replacement therapy for adrenal or pituitary
                 insufficiency, etc) is not considered a form of systemic treatment
    
              -  Has known history of, or any evidence of active, non-infectious pneumonitis
    
              -  Has an active infection requiring systemic therapy
    
              -  Has a history or current evidence of any condition, therapy, or laboratory
                 abnormality that might confound the results of the trial, interfere with the
                 subject's participation for the full duration of the trial, or is not in the best
                 interest of the subject to participate, in the opinion of the treating investigator
    
              -  Has known psychiatric or substance abuse disorders that would interfere with
                 cooperation with the requirements of the trial
    
              -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
                 projected duration of the trial, starting with the pre-screening or screening visit
                 through 120 days after the last dose of trial treatment
    
              -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or
                 sEsphB4-HSA
    
              -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
    
              -  Has known active Hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or
                 Hepatitis C (eg, hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
                 detected)
    
              -  Major systemic infection requiring antibiotics 72 hours or less prior to first dose
                 of study drug
    
              -  Has New York Heart Association (NYHA) class 3 or 4, myocardial infarction, acute
                 coronary syndrome, 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 sEphB4HSA or
                 pembrolizumab (MK-3475) or places the patient at undue risk for treatment related
                 complications
    
              -  Any other condition, including mental illness or substance abuse, deemed by the
                 investigator to be likely to interfere with a patient's ability to sign informed
                 consent, cooperate and participate in the study, or interferes with the
                 interpretation of the results
    
              -  Any active bleeding in the last =< 4 weeks or have an otherwise known bleeding
                 diathesis
    
              -  Has received a live vaccine within 30 days of planned start of study therapy; Note:
                 seasonal influenza vaccines for injection are generally inactivated flu vaccines and
                 are allowed; however intranasal influenza vaccines (eg, flu-mist) are live attenuated
                 vaccines, and are not allowed
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of toxicities and adverse events classified according to the Common Terminology Criteria for Adverse Events v4.03
    Time Frame:Up to 30 days
    Safety Issue:
    Description:All observed toxicities will be summarized in terms of type (organ affected or laboratory determination, severity, and time of onset. Tables will be created to summarize these toxicities and side effects, overall and by course. The proportion of patients who are eligible to begin the 3rd planned cycle will be calculated, using the number of eligible patients who began treatment as the denominator; 95% confidence intervals will be constructed.

    Secondary Outcome Measures

    Measure:OR defined as complete response or partial response according to RECIST v 1.1
    Time Frame:Up to 3 years
    Safety Issue:
    Description:The proportion of patients who experience an overall objective response (CR or PR will be calculated as the ratio of the number of eligible patients who experienced the response, divided by the total number of eligible patients who began treatment; 95% confidence intervals will be constructed.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:University of Southern California

    Last Updated

    April 19, 2017