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


Condition: Urothelial Carcinoma, Bladder Cancer

Intervention:

  • Other: Placebo
  • Drug: Pembrolizumab

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.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02500121

Sponsor: Matthew Galsky

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:

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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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:

Estimated Enrollment: 200

Study Start Date: November 2015

Phase: Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

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.

Contact:

  • Matthew Galsky, M.D.
  • 212.241.6756

Locations:

  • University of Arizona at Dignity Health St. Joseph's
  • Phoenix Arizona 85004 United States
  • City of Hope Comprehensive Cancer Center
  • Duarte California 91010 United States
  • University of Southern California
  • Los Angeles California 90033 United States
  • Georgetown University
  • Washington District of Columbia 20057 United States
  • University of Florida
  • Gainesville Florida 32610 United States
  • IU Health Goshen Center for Cancer Care
  • Goshen Indiana 46526 United States
  • Indiana University Melvin and Bren Simon Cancer Center
  • Indianapolis Indiana 46202 United States
  • IU Health Central Indiana Cancer Center
  • Indianapolis Indiana 46219 United States
  • Community Regional Cancer Care
  • Indianapolis Indiana 46256 United States
  • Community Healthcare System
  • Munster Indiana 46321 United States
  • University of Maryland
  • Baltimore Maryland 21201 United States
  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Baltimore Maryland 21231 United States
  • Henry Ford Health System
  • Detroit Michigan 48202 United States
  • University of Minnesota
  • Minneapolis Minnesota 55455 United States
  • Washington University: Siteman Cancer Center
  • Saint Louis Missouri 63110 United States
  • GU Cancer Research Network, LLC
  • Omaha Nebraska 68130 United States
  • The John Theuer Cancer Center at Hackensack University Medical Center
  • Hackensack New Jersey 07601 United States
  • University of New Mexico Cancer Center
  • Albuquerque New Mexico 87106 United States
  • Roswell Park Cancer Institute
  • Buffalo New York 14263 United States
  • Tisch Cancer Institute at Mount Sinai Medical Center
  • New York New York 10029 United States
  • University of Rochester Medical Center
  • Rochester New York 14642 United States
  • University of North Carolina at Chapel Hill
  • Chapel Hill North Carolina 27514 United States
  • Ohio State University Comprehensive Cancer Center
  • Columbus Ohio 43210 United States
  • Fox Chase Cancer Center
  • Philadelphia Pennsylvania 19111 United States
  • Medical University of South Carolina
  • Charleston South Carolina 29425 United States
  • Vanderbilt-Ingram Cancer Center
  • Nashville Tennessee 37232 United States
  • Huntsman Cancer Institute University of Utah
  • Salt Lake City Utah 84112 United States
  • Virginia Oncology Associates
  • Norfolk Virginia 23502 United States

View trial on ClinicalTrials.gov


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