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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Muscle-invasive Urothelial Cancer of the Bladder
• Intervention / Treatment: Drug: Gemcitabine; Biological: Pembrolizumab; Procedure: Transurethral Resection of Bladder Tumor; Radiation: External Beam Radiation Therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering
    • New York, New York, United States, 10016
      • NYU Perlmutter Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7305
      • University of North Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

Drug: Gemcitabine; Other Names: Gemzar; Biological: Pembrolizumab; Other Names: Keytruda; MK3475; Procedure: Transurethral Resection of Bladder Tumor; Radiation: External Beam Radiation Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Two-year Bladder-intact Disease-free Survival	Bladder-intact disease-free survival is defined as the time from initiation of protocol therapy until the first occurrence of muscle-invasive bladder cancer recurrence, regional pelvic recurrence, distant metastases, bladder cancer-related death, or cystectomy.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response (CR) Rate	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.	up to 21 weeks
Percentage of Participants Who Survived at Study Completion		up to 5 years
Percentage of Participants Who Achieved Metastasis-free Survival at Study Completion	Metastasis-free survival is defined as not having developed radiographic distant metastases.	up to 5 years

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Minas Economides, MD, NYU Langone Health

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2016
• Primary Completion (Actual): November 10, 2022
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: December 1, 2015
• First Submitted That Met QC Criteria: December 2, 2015
• First Posted (Estimated): December 3, 2015

Study Record Updates

• Last Update Posted (Estimated): October 7, 2025
• Last Update Submitted That Met QC Criteria: September 17, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: immunotherapy; combination therapy; immune checkpoint inhibition
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urologic Neoplasms; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Surgical Procedures, Operative; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Urologic Surgical Procedures; Urogenital Surgical Procedures; Gemcitabine; pembrolizumab; Transurethral Resection of Bladder
• Other Study ID Numbers: 15-00220

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The de-identified participant data from the final research dataset will be shared upon reasonable request beginning 9 to 36 months after publication or as required by a condition of awards or supporting agreements, provided the requesting investigator executes a data use agreement with NYU Langone Health. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's Data Sharing Strategy Board (DSSB). Requests should be directed to: [contact information for PI or designee]. The protocol and statistical analysis plan will be posted on Clinicaltrials.gov only as required by federal regulation or supporting awards and agreements.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• IPD Sharing Access Criteria: The investigator who proposed to use the data will be granted access upon reasonable request. Requests should be directed to minas.economides@nyulangone.org. To gain access, data requestors will need to sign a data access agreement. This instance of data sharing will also require separate IRB review as well as review from NYU Langone's DSSB.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No