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

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ClinicalTrials.gov Identifier: NCT02500121
Recruitment Status : Active, not recruiting
First Posted : July 16, 2015
Last Update Posted : December 10, 2018
Sponsor:
Collaborators:
Hoosier Cancer Research Network
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Matthew Galsky, Hoosier Cancer Research Network

Brief 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.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Bladder Cancer Other: Placebo Drug: Pembrolizumab Phase 2

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Study Start Date : November 2015
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Control Arm A
Commercially 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.
Other: Placebo
Normal saline

Experimental: Experimental Arm B
Pembrolizumab, 200mg IV every 3 weeks. Treatment will continue, in the absence of prohibitive toxicities or disease progression, for up to 24 months.
Drug: Pembrolizumab
Pembrolizumab, 200mg IV every 3 weeks until progressive disease, unacceptable toxicity, or for up to 24 months




Primary Outcome Measures :
  1. 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 ]
    Percentage of subjects still alive and progression-free at six months, as per immune-related RECIST (irRECIST).


Secondary Outcome Measures :
  1. 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 ]
    Percentage of subjects in these subsets still alive and progression-free, as per immune-related RECIST (irRECIST).

  2. PFS rates among subjects treated with pembrolizumab versus placebo [ Time Frame: Every 3 weeks beginning with C1D1 for up to 24 months ]
    Percentage of subjects still alive and progression-free, as per immune-related RECIST (irRECIST).

  3. 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 ]
    Percentage of subjects still alive and progression-free, as per immune-related RECIST (irRECIST).

  4. 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 ]
    Percentage of subjects still alive and progression-free, as per RECIST 1.1

  5. 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 ]
    Proportion of subjects with treatment-related toxicities, as per Common Terminology Criteria for Adverse Events (CTCAE) v 4.0

  6. 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) ]
    ORR as per irRECIST and RECIST 1.1

  7. 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) ]
    ORR per irRECIST and RECIST 1.1

  8. 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 ]
    Proportion of subjects still alive at the end of study treatment

  9. 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 ]
    HRs will be evaluated using Cox proportional hazard models

  10. 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 ]
    RMST in subjects treated with pembrolizumab versus placebo using Kaplan-Meier estimates of survival functions

  11. 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 ]
    Durations of response will be summarized by median and compared using Wilcoxon rank sum test



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02500121


  Show 28 Study Locations
Sponsors and Collaborators
Matthew Galsky
Hoosier Cancer Research Network
Merck Sharp & Dohme Corp.
Investigators
Study Chair: Matthew Galsky, M.D. Hoosier Cancer Research Network

Additional Information:
Responsible Party: Matthew Galsky, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT02500121     History of Changes
Other Study ID Numbers: HCRN GU14-182
First Posted: July 16, 2015    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Matthew Galsky, Hoosier Cancer Research Network:
Pembrolizumab
PD-1 Inhibitor

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Pembrolizumab
Antineoplastic Agents