Clinical Trials /

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

NCT02621151

Description:

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.

Related Conditions:
  • Bladder Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 15-00220
  • NCT ID: NCT02621151

Conditions

  • Muscle-invasive Urothelial Cancer of the Bladder

Interventions

DrugSynonymsArms
PembrolizumabMK3475, KeytrudaPembrolizumab, Gemcitabine, and RT
GemcitabineGemzarPembrolizumab, Gemcitabine, and RT

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab, Gemcitabine, and RTExperimentalLead-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
  • Pembrolizumab
  • Gemcitabine

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Two-year bladder-intact disease-free survival rate
Time Frame:2 years
Safety Issue:
Description: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

Measure:Safety (adverse events) of the protocol therapy
Time Frame:From beginning of protocol therapy to 90 days after the end of radiation therapy
Safety Issue:
Description:The adverse events are evaluated per Common Terminology Criteria for Adverse Events (CTCAE) 4.
Measure:Complete response (CR) rate
Time Frame:up to 21 weeks
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:up to 5 years
Safety Issue:
Description:Defined as time to death from beginning of protocol therapy.
Measure:Metastasis-free survival
Time Frame:up to 5 years
Safety Issue:
Description:Defined as time to the development of radiographic distant metastases from beginning of protocol therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NYU Langone Health

Trial Keywords

  • combination therapy
  • immunotherapy
  • immune checkpoint inhibition

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