Clinical Trials /

Phase 2 Study of Pembrolizumab in Combination With Gemcitabine and Cisplatin as Neoadjuvant Therapy

NCT02690558

Description:

The purpose of this study is to evaluate whether adding pembrolizumab (Keytruda) to the combination of gemcitabine and cisplatin will improve shrinkage of the tumor before having a cystectomy, for people with muscle-invasive bladder cancer (MIBC).

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 2 Study of Pembrolizumab in Combination With Gemcitabine and Cisplatin as Neoadjuvant Therapy
  • Official Title: Phase II Single Arm Study of Gemcitabine and Cisplatin Plus Pembrolizumab as Neoadjuvant Therapy Prior to Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1520
  • NCT ID: NCT02690558

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
pembrolizumab, gemcitabine and cisplatinKeytruda, MK-3475pembrolizumab, gemcitabine and cisplatin

Purpose

The purpose of this study is to look at whether adding pembrolizumab (keytruda) to the combination of gemcitabine and cisplatin will improve shrinkage of the tumor before having a cystectomy, for people with muscle-invasive bladder cancer (MIBC).

Detailed Description

      Primary Objective To estimate the proportion of patients with pathological downstaging to
      <pT2 after neoadjuvant therapy with pembrolizumab when administered prior to and with
      gemcitabine and cisplatin in patients with MIBC

      Hypothesis: The rate of pathologic downstaging to <pT2 will improve compared to historical
      controls

      Secondary Objectives To estimate the proportion of patients with pT0 after neoadjuvant
      therapy with pembrolizumab when administered prior to and with gemcitabine and cisplatin in
      patients with MIBC

      Hypothesis: The rate of pathologic downstaging to pT0 will improve compared to historical
      controls

      To estimate event free survival (EFS) Hypothesis: EFS will be improved compared to
      historical controls

      To estimate overall survival (OS) Hypothesis: OS will be improved compared to historical
      controls

      To estimate the proportion of patients who are alive at 3 years (OS at 3 years) Hypothesis:
      OS at 3 years will be improved compared to historical controls

      To characterize the toxicity profile for the combination of pembrolizumab, gemcitabine, and
      cisplatin Hypothesis: Pembrolizumab, gemcitabine, and cisplatin will be a safe combination
      with acceptable toxicity rates

      Exploratory Objectives To explore the association of biological markers including PD-L1
      expression and immune gene expression signatures with pathological downstaging to <pT2, pT0,
      EFS, and OS

      To explore associations between BASE47 "basal," "claudin-low," and "luminal" subtypes of
      MIBC and pathological downstaging to <pT2, pT0, EFS, and OS

      To characterize the change in phenotype of TILs, including delineation of effector and
      regulatory T cells, before and after neoadjuvant treatment

      To define T cell receptor (TCR) and B cell receptor (BCR) repertoire profiles that are
      associated with pathological downstaging to <pT2, pT0, EFS, and OS

      First the participant will receive a dose of pembrolizumab alone. Two weeks after this dose,
      then s/he will receive all 3 study drugs (pembrolizumab, gemcitabine and cisplatin) on the
      first day of a 3 week "cycle". S/he will then receive 1 or 2 of these drugs on the 8th day
      of the cycle. The participant will receive the study drugs for 4 cycles for a total of 12
      weeks.

      Participants are followed for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
pembrolizumab, gemcitabine and cisplatinExperimentalThere is one arm in this study. Subjects will receive Pembrolizumab 200 mg IV as a single dose and then on day 1 every 3 weeks for 4 cycles (each cycle is 21 days) plus Gemcitabine 1000 mg/m2 IV on day 1 and day 8 every 3 weeks for 4 cycles and Cisplatin 70mg/m2 IV on Day 1 every 3 weeks for 4 cycles
  • pembrolizumab, gemcitabine and cisplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Be able to give written IRB approved informed consent and be able to follow protocol
             requirements.

          -  Be greater than or equal to 18 years of age on day of signing informed consent.

          -  Has a performance status of 0 or 1 on the ECOG Performance Scale

          -  Has histologically confirmed urothelial carcinoma of the bladder; those with mixed
             histology, including a component of urothelial carcinoma, are eligible. Pure small
             cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma are excluded.

          -  Has clinical stage T2-T4a N0/X M0 urothelial carcinoma. Clinical T stage is based on
             the pre-study standard of care transurethral resection of the bladder tumor (TURBT)
             sample and imaging studies.

          -  Has staging scans with abdominal/pelvic CT or MRI scan and CT scan or x-ray of the
             chest within 4 weeks prior to treatment initiation

          -  Be a medically appropriate candidate for radical cystectomy as determined by an
             attending urologist and be planning to receive cystectomy.

          -  Has had no prior systemic cytotoxic chemotherapy for urothelial carcinoma (prior
             intravesicular chemotherapies are permitted)

          -  Patients must have tumor tissue from transurethral resection of the bladder tumor
             (TURBT) available for submission that is sufficient for correlative testing, and
             agree to submission of a paraffin block or 20 formalin-fixed paraffin embedded (FFPE)
             slides of 5-10 microns in thickness. Patients must also agree to submission of tissue
             from cystectomy.

          -  Demonstrate adequate organ function as defined in the table below; all screening labs
             should be performed within 10 days of treatment initiation.

        Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL
        Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of
        assessment) Renal Serum creatinine OR Measured or calculateda creatinine clearance (CrCL;
        GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR

        ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum
        total bilirubin ≤ 1.5 X ULN (≤ 3 X ULN if Gilbert's Syndrome) OR Direct bilirubin ≤ ULN
        for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
        Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT)

        Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
        anticoagulant therapy. If subject receiving anticoagulants, PT or PTT should be within
        therapeutic range of intended use of anticoagulants

        aCreatinine clearance should be calculated per institutional standard.

          -  Female subjects of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of pembrolizumab.

          -  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. The two birth control methods can be composed
             of: two barrier methods or a barrier method plus a hormonal method to prevent
             pregnancy. Subjects should start using birth control from the screening visit and
             continue throughout the study period up to 120 days after the last dose of study
             therapy.

        The following are considered adequate barrier methods of contraception: diaphragm, condom
        (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal
        contraceptives will include any registered and marketed contraceptive agent that contains
        an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or
        intramuscular agents).

          -  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.

          -  Life expectancy greater than 3 months

          -  Consents to whole blood collection prior to initiating therapy and at cystectomy for
             support of correlative research studies

        Exclusion Criteria:

        The subject must be excluded from participating in the trial if the subject meets any of
        the following:

          -  Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             pembrolizumab.

          -  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. NOTE: see exception to use of systemic steroid as prophylactic
             anti-emetic prior to cisplatin in section 4.2.2. Inhaled and topical steroids are
             allowed.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Has had a prior monoclonal antibody 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.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

             • Note: If subject received major surgery, they must have recovered adequately from
             the toxicity and/or complications from the intervention prior to starting therapy.

          -  Has 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.

          -  Has 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.

          -  Has evidence of interstitial lung disease or 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, 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)

          -  Has received prior radiation therapy to the bladder for the purpose of treating
             urothelial carcinoma

          -  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 clinically relevant hearing impairment > Grade 2

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of subjects that reach pathological downstaging to <pT2 defined as pT0-T1N0M0 at the time of cystectomy
Time Frame:14 weeks of treatment plus cystectomy within 70 days after treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of subjects that reach complete pathologic response (pT0) defined as pT0N0M0 at the time of cystectomy
Time Frame:14 weeks of treatment plus cystectomy within 70 days of treatment
Safety Issue:
Description:
Measure:Event Free Survival
Time Frame:14 weeks of treatment plus 5 years of followup
Safety Issue:
Description:defined from D1 of neoadjuvant treatment until progression (in those who progress prior to surgery) or until recurrence (post-surgery) or until death as a result of any cause.
Measure:Overall survival
Time Frame:14 weeks of treatment plus 3 years or until death
Safety Issue:
Description:OS at 3 years is defined from D1 of treatment until 3 years or death as a result of any cause
Measure:Number of adverse events and severity by grade (CTCAE).
Time Frame:14 weeks of treatment plus 30 days for toxicity followup
Safety Issue:
Description:• Safety and toxicity will be characterized according to the reported adverse event (AE) profile using NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0, as well as a patient questionnaire derived from the Patient Reported Outcomes (PRO)-CTCAE and Patient Reported Outcomes Measurement Information System (PROMIS).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • muscle-invasive

Last Updated

March 10, 2017