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Pembrolizumab (MK3475), Gemcitabine, and Concurrent Hypofractionated Radiation Therapy for Muscle-Invasive Urothelial Cancer of the Bladder

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ClinicalTrials.gov Identifier: NCT02621151
Recruitment Status : Active, not recruiting
First Posted : December 3, 2015
Last Update Posted : December 5, 2022
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
NYU Langone Health

Brief Summary:
This trial is to assess the efficacy of pembrolizumab (MK3475) added to concurrent radiation and gemcitabine in the management of patients with muscle-invasive urothelial cancer who are not candidates for or decline radical cystectomy.

Condition or disease Intervention/treatment Phase
Muscle-invasive Urothelial Cancer of the Bladder Biological: Pembrolizumab Procedure: Transurethral Resection of Bladder Tumor Drug: Gemcitabine Radiation: External Beam Radiation Therapy Phase 2

Detailed Description:

The investigators hypothesize that the addition of immune checkpoint inhibition with pembrolizumab, an anti-PD-1 inhibitor, to chemo-radiation therapy to the bladder may work to both increase eradication of local tumor as well as distant micrometastases through heightened immune surveillance.

Due to the lack of a previous phase I trial establishing the safety of this combination (pembrolizumab, gemcitabine, and radiation therapy (RT)), an initial safety lead-in cohort of 3 to 6 patients is enrolled for assessing dose-limiting toxicities. Similar to the Phase I 3+3 design, if there is no or only one patient in that cohort experiencing a dose-limiting toxicity, the trial continues to the Phase II part to enroll additional 48 patients for efficacy evaluation.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of MK3475 in Combination With Gemcitabine and Concurrent Hypofractionated Radiation Therapy as Bladder Sparing Treatment for Muscle-Invasive Urothelial Cancer of the Bladder
Actual Study Start Date : August 11, 2016
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Experimental: Pembrolizumab, Gemcitabine, and RT
  • Lead-in single dose Pembrolizumab 200 mg, intravenously (IV)
  • Transurethral Resection of Bladder Tumor (TURBT) at pre-RT (maximal) and completion of therapy (diagnostic)
  • External Beam Radiation Therapy (EBRT) - 52 Gy in 20 fractions over 4 weeks (1 fraction = 2.6 Gy)
  • Gemcitabine 27 mg/m^2 IV twice weekly for 4 weeks concurrent with EBRT
  • Pembrolizumab 200 mg IV every 3 weeks for total 3 doses starting day 1 of EBRT
Biological: Pembrolizumab
Other Names:
  • MK3475
  • Keytruda

Procedure: Transurethral Resection of Bladder Tumor
Drug: Gemcitabine
Other Name: Gemzar

Radiation: External Beam Radiation Therapy

Primary Outcome Measures :
  1. Two-year bladder-intact disease-free survival rate [ Time Frame: 2 years ]
    Bladder-intact disease-free survival is defined as time from initiation of protocol therapy until the development of muscle-invasive bladder cancer recurrence, regional pelvic recurrence, distant metastases, bladder cancer-related death, or cystectomy.

Secondary Outcome Measures :
  1. Safety (adverse events) of the protocol therapy [ Time Frame: From beginning of protocol therapy to 90 days after the end of radiation therapy ]
    The adverse events are evaluated per Common Terminology Criteria for Adverse Events (CTCAE) 4.

  2. Complete response (CR) rate [ Time Frame: up to 21 weeks ]
    The CR rate is the percentage of patients who have achieved CR. At the completion of protocol therapy, patients undergo standard cystoscopy, exam under anesthesia and transurethral resection of bladder tumor to document pathologic response. CR requires no tumor palpable on bimanual examination under anesthesia, no tumor visible on cystoscopy, negative tumor site biopsy, and negative urine cytology.

  3. Overall survival [ Time Frame: up to 5 years ]
    Defined as time to death from beginning of protocol therapy.

  4. Metastasis-free survival [ Time Frame: up to 5 years ]
    Defined as time to the development of radiographic distant metastases from beginning of protocol therapy.

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

Inclusion Criteria:

  • Histologically confirmed muscle-invasive urothelial cancer of the bladder within 60 days of study enrollment. Patients must be willing to provide a TURBT specimen during screening and prior to enrollment if adequate specimen (FFPE tissue block or 20 unstained slides) from initial TURBT documenting muscle-invasive urothelial bladder cancer is not available.
  • Clinical stage T2-T4a, N0, M0 urothelial bladder cancer.
  • Deemed to not be a candidate for radical cystectomy by attending urologic oncologist or refuse radical cystectomy.
  • Be willing and able to provide written informed consent/assent for the trial.
  • Be ≥ 18 years of age on day of signing informed consent.
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Scale.
  • Demonstrate adequate organ function as defined below, all screening labs should be performed within 10 days of protocol enrollment.

    • Absolute neutrophil count >= 1,500 /mcL;
    • Platelets >= 100,000 /mcL;
    • Hemoglobin >= 9.0 g/dL;
    • Serum creatinine <=1.5 x upper limit of normal (ULN) or calculated creatinine clearance >= 30 mL/min as calculated by Cockcrof-Gault formaulae or by 24 hour urine collection;
    • Serum total bilirubin <=1.5 x ULN or direct bilirubin <= ULN for subjects with total bilirubin levels > 1.5 x ULN;
    • Aspartate aminotransferase and alanine aminotransferase <= 1.5 x ULN;
    • Albumin >= 2.5 mg/dL;
    • International normalized ratio or prothrombin time (PT) <= 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial prothrombin 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.
  • 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:

  • Has received prior targeted small molecule therapy, radiation therapy or systemic chemotherapy for urothelial bladder cancer including neoadjuvant chemotherapy. Prior intravesical chemotherapy or intravesical immunotherapy is permissible, however, no prior intravesical therapy is permitted within 4 weeks of study enrollment; adjuvant therapy is not permitted.
  • Has received prior pelvic radiation therapy.
  • Has a history of inflammatory bowel disease or history of scleroderma.
  • 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 (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  • If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  • Any prior history of invasive malignancy within the past 5 years except non-melanoma skin cancer, carcinoma in-situ, localized prostate cancer without biochemical recurrence following definitive treatment.
  • Has any history of inflammatory bowel disease or scleroderma.
  • Has other 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.
  • History of Guillain-Barre Syndrome or Stevens-Johnson Syndrome
  • 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.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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): NCT02621151

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United States, Illinois
University of Chicago
Chicago, Illinois, United States, 60637
United States, Michigan
University of Michigan Health System
Ann Arbor, Michigan, United States, 48109
United States, New York
NYU Perlmutter Cancer Center
New York, New York, United States, 10016
Memorial Sloan Kettering
New York, New York, United States, 10065
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599-7305
Sponsors and Collaborators
NYU Langone Health
Merck Sharp & Dohme LLC
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Principal Investigator: Victor Adorno, MD NYU Perlmutter Cancer Center
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Responsible Party: NYU Langone Health
ClinicalTrials.gov Identifier: NCT02621151    
Other Study ID Numbers: 15-00220
First Posted: December 3, 2015    Key Record Dates
Last Update Posted: December 5, 2022
Last Verified: December 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NYU Langone Health:
combination therapy
immune checkpoint inhibition
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological