Testing the PD-1 Inhibitor Pembrolizumab as Maintenance Therapy After Initial Chemotherapy in Metastatic Bladder Cancer
Condition: Urothelial Carcinoma; Bladder Cancer
MeSH terms: Urinary Bladder Neoplasms
Intervention: Placebo; Pembrolizumab
Intervention description: Normal saline; Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 108.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pembrolizumab; PD-1 Inhibitor

Summary:

      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.
    

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.