Clinical Trials /

Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer

NCT02500121

Description:

This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer who have achieved at least stable disease on first-line chemotherapy.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer
  • Official Title: A Randomized, Double-blinded, Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer: Hoosier Cancer Research Network GU14-182

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU14-182
  • NCT ID: NCT02500121

Conditions

  • Urothelial Carcinoma
  • Bladder Cancer

Interventions

DrugSynonymsArms
PembrolizumabExperimental Arm B

Purpose

This is a multi-institutional, randomized, placebo controlled, double-blinded phase II trial of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer who have achieved at least stable disease on first-line chemotherapy.

Detailed Description

      OUTLINE: This is a multi-center trial.

      Eligible subjects will be 1:1 randomized to placebo (Control Arm A) and pembrolizumab
      (Experimental Arm B). Stratification factors for randomization: presence of visceral
      metastatic disease (lung, liver, or bone or other organs vs. lymph node only) at the time of
      initiation of first-line chemotherapy, and response to first-line chemotherapy (CR/PR vs. SD.
      Subjects who progress on placebo will be assessed to determine if they are eligible to cross
      over to unblinded treatment with pembrolizumab.

      INVESTIGATIONAL TREATMENT:

      For Control Arm A, commercially available normal saline will be used as the placebo. No
      active placebo drug will be mixed with the normal saline.

      For Experimental Arm B, pembrolizumab (or placebo), 200 mg intravenous infusion (IV) every 3
      weeks for up to 12 months, or until progressive disease (PD) or unacceptable toxicity.

      The following required laboratory values must be obtained within fourteen days prior to
      registration for protocol therapy:

      Hematopoietic:

        -  Absolute neutrophil count (ANC) ≥1,500 /mcL

        -  Platelets ≥100,000 / mcL

        -  Hemoglobin ≥8.5 g/dL

      Renal:

        -  Creatinine ≤1.5x ULN OR

        -  Measured or calculated creatinine clearance ≥30 mL/min for subject with creatinine
           levels >1.5x institutional ULN

        -  GFR can also be used in place of creatinine or CrCl

      Hepatic:

        -  Serum total bilirubin ≤ 1.5 X ULN OR

        -  Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

        -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subject with liver metastases

      Coagulation:

        -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN. If subject is
           on anticoagulant therapy, PT or PTT must be within therapeutic range of intended use of
           anticoagulants.
    

Trial Arms

NameTypeDescriptionInterventions
Control Arm APlacebo ComparatorCommercially available normal saline will be used as the placebo. No active placebo drug will be mixed with the normal saline. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.
    Experimental Arm BExperimentalPembrolizumab, 200mg IV every 3 weeks. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.
    • Pembrolizumab

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Written informed consent and HIPAA authorization for release of personal health
                 information. NOTE: HIPAA authorization may be included in the informed consent or
                 obtained separately.
    
              -  Age ≥ 18 years at the time of consent.
    
              -  ECOG Performance Status (PS) of ≤ 1 within fourteen days of registration for protocol
                 therapy.
    
              -  Histological or cytological evidence of urothelial cancer of the bladder, urethra,
                 ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell
                 differentiated) will be permitted provided that the predominant histology is
                 urothelial carcinoma.
    
              -  Metastatic and/or unresectable (cT4b) disease
    
              -  Must have achieved an objective response (CR/PR) or stable disease (SD) after 4 to 6
                 cycles of standard first-line platinum-based chemotherapy for mUC (e.g., as per NCCN
                 guidelines). Able to commence study treatment within 2 to 6 weeks of receiving last
                 dose of first-line chemotherapy.
    
              -  All subjects must have adequate archival tissue available prior to registration (i.e.,
                 at least 20 unstained slides or paraffin block). If acceptable archival tissue is not
                 available, the subject must be willing to consent to providing a core or excisional
                 biopsy for research prior to registration for protocol therapy. If archival tissue is
                 not available and there are no sites amenable to biopsy, enrollment must be discussed
                 with the sponsor-investigator on a case by case basis.
    
              -  Female subjects of childbearing potential must have a negative serum pregnancy within
                 three days prior to registration for protocol therapy
    
              -  Sexually active, pre-menopausal women of childbearing potential must be willing to use
                 an adequate method of contraception or be surgically sterile, or abstain from
                 heterosexual activity for the course of the study through 120 days after the last dose
                 of study drug. Subjects of childbearing potential are those who have not been
                 surgically sterilized or have not been free from menses for > one year.
    
              -  Male subjects of childbearing potential must agree to use an adequate method of
                 contraception starting with the first dose of study drug through 120 days after the
                 last dose of study drug.
    
            Exclusion Criteria:
    
              -  More than one line of prior chemotherapy for metastatic or locally advanced disease,
                 with the following exception:
    
                   -  Prior neoadjuvant/adjuvant chemotherapy will not count as line of therapy if
                      completed greater than 12 months prior to initiation of chemotherapy regimen for
                      metastatic or unresectable disease.
    
              -  Current or past participation in a study of an investigational agent or using an
                 investigational device within four weeks of registration for protocol therapy.
    
              -  A diagnosis of immunodeficiency or is receiving treatment with systemic steroid
                 therapy or any other form of immunosuppressive therapy within seven days prior to
                 registration for protocol therapy.
    
              -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within two
                 weeks prior to registration for protocol therapy. Note: If the subjects have undergone
                 major surgery, they must have recovered adequately from the toxicity and/or
                 complications from the intervention prior to starting protocol therapy.
    
              -  A known additional malignancy that is progressing or requires active treatment.
                 Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
                 skin, or in situ cervical cancer that has undergone potentially curative therapy.
    
              -  A 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 registration for protocol therapy 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 seven days prior to registration for protocol therapy.
    
              -  Active autoimmune disease that has required systemic treatment in 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 evidence of active, non-infectious pneumonitis.
    
              -  Has a history of interstitial lung disease.
    
              -  An active infection requiring systemic therapy.
    
              -  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.
    
              -  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 screening period through 120 days
                 after the last dose of protocol therapy.
    
              -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic
                 T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other
                 antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
                 Examples include nivolumab, MPDL3280, etc.
    
              -  A known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    
              -  A known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
                 [qualitative] is detected).
    
              -  Receipt of a live vaccine within 30 days prior to registration for protocol therapy.
    
              -  Unresolved toxicity (i.e., > Grade 1 or above baseline) due to previously administered
                 agents. Exception includes: subjects with ≤ Grade 2 neuropathy are eligible for the
                 study.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Six-month progression-free survival (PFS) disease assessment among subjects treated with pembrolizumab versus placebo as maintenance therapy after up to 8 cycles of first-line chemotherapy.
    Time Frame:Assessed at six months, calculated from the date of randomization
    Safety Issue:
    Description:Percentage of subjects still alive and progression-free at six months, as per immune-related RECIST (irRECIST).

    Secondary Outcome Measures

    Measure:Six-month PFS rates among the subsets of subjects with PD-L1 positive and PD-L1 negative tumors treated with pembrolizumab versus placebo.
    Time Frame:Assessed at six months, calculated from the date of randomization
    Safety Issue:
    Description:Percentage of subjects in these subsets still alive and progression-free, as per immune-related RECIST (irRECIST).
    Measure:PFS rates among subjects treated with pembrolizumab versus placebo
    Time Frame:Every 3 weeks beginning with C1D1 for up to 24 months
    Safety Issue:
    Description:Percentage of subjects still alive and progression-free, as per immune-related RECIST (irRECIST).
    Measure:PFS rates among the subsets of subjects with PD-L1 positive and PD-L1 negative tumors treated with pembrolizumab versus placebo.
    Time Frame:Every 3 weeks beginning with C1D1 for up to 24 months
    Safety Issue:
    Description:Percentage of subjects still alive and progression-free, as per immune-related RECIST (irRECIST).
    Measure:PFS rates among subjects with metastatic urothelial cancer, treated with pembrolizumab versus placebo as maintenance therapy, after up to 8 cycles of first-line therapy
    Time Frame:Every 3 weeks beginning with C1D1, assessed for up to 6 months
    Safety Issue:
    Description:Percentage of subjects still alive and progression-free, as per RECIST 1.1
    Measure:Number of subjects with adverse events as a measure of the safety and tolerability of pembrolizumab
    Time Frame:Every 3 weeks beginning with C1D1 for up to 24 months
    Safety Issue:
    Description:Proportion of subjects with treatment-related toxicities, as per Common Terminology Criteria for Adverse Events (CTCAE) v 4.0
    Measure:Objective response rate (ORR) assessment of subjects on maintenance pembrolizumab vs placebo with measurable
    Time Frame:Every 12 weeks from the date of randomization to the date of documented disease progression or date of death, whichever occurs first, assessed for up to 104 weeks (24 months)
    Safety Issue:
    Description:ORR as per irRECIST and RECIST 1.1
    Measure:ORR assessment of subjects receiving pembrolizumab after progressing on placebo
    Time Frame:Every 12 weeks from the date of randomization to the date of documented disease progression, per irRECIST and RECIST 1.1, assessed for up to 104 weeks (24 months)
    Safety Issue:
    Description:ORR per irRECIST and RECIST 1.1
    Measure:Overall survival (OS) rates in subjects treated with pembrolizumab vs placebo
    Time Frame:Every 12 weeks from the date of randomization to the date of death, assessed for up to 24 months
    Safety Issue:
    Description:Proportion of subjects still alive at the end of study treatment
    Measure:Hazard ratios (HR) with respect to both PFS and OS, comparing subjects treated with pembrolizumab vs placebo
    Time Frame:From the date of randomization to documented progression or death, whichever occurs first, assessed for up to 24 months
    Safety Issue:
    Description:HRs will be evaluated using Cox proportional hazard models
    Measure:Restricted mean survival time (RMST) of subjects treated with pembrolizumab vs placebo
    Time Frame:Every 12 weeks from the date of randomization to the date of death or documented disease progression, whichever occurs first, assessed for up to 24 months
    Safety Issue:
    Description:RMST in subjects treated with pembrolizumab versus placebo using Kaplan-Meier estimates of survival functions
    Measure:Durations of response in subjects treated with pembrolizumab versus placebo
    Time Frame:Every 12 weeks from date of randomization to the date of documented disease progression or date of death, whichever occurs first, assessed for up to 24 months
    Safety Issue:
    Description:Durations of response will be summarized by median and compared using Wilcoxon rank sum test

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Matthew Galsky

    Trial Keywords

    • Pembrolizumab
    • PD-1 Inhibitor

    Last Updated

    February 7, 2018