Clinical Trials /

Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects

NCT02365766

Description:

This is a pre-surgical study involving subjects with muscle invasive bladder cancer, or urothelial cancer, who are candidates for neoadjuvant therapy. It is is a two-part trial with a one-arm phase Ib portion followed by a two-arm phase II portion. The study treatment is stratified into two cohorts based on cisplatin eligibility.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects
  • Official Title: Phase Ib/II Study of Neoadjuvant Pembrolizumab With Gemcitabine-Cisplatin (Cisplatin-Eligible) or Gemcitabine (Cisplatin-Ineligible) in Subjects With T2-4aN0M0 Urothelial Cancer: HCRN GU14-188

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU14-188
  • NCT ID: NCT02365766

Conditions

  • Urothelial Carcinoma
  • Bladder Cancer

Interventions

DrugSynonymsArms
PembrolizumabMK-3475Arm A - Phase 1b Dose Finding Cohort:
GemcitabineGemzarArm A - Phase 1b Dose Finding Cohort:
CisplatinPlatinolArm A - Phase 1b Dose Finding Cohort:

Purpose

This is a pre-surgical study involving subjects with muscle invasive bladder cancer, or urothelial cancer, who are candidates for neoadjuvant therapy. It is is a two-part trial with a one-arm phase Ib portion followed by a two-arm phase II portion. The study treatment is stratified into two cohorts based on cisplatin eligibility.

Detailed Description

      OUTLINE: This is a multi-center study.

      INVESTIGATIONAL TREATMENT:

      Phase Ib Dose-Finding Cohort I Cisplatin-Eligible:

      Phase Ib is a 3+3 design for the cisplatin-eligible group only. Cisplatin-eligible subjects
      receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days repeated for 4 cycles; cisplatin
      70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min
      must follow split dosing of cisplatin over two days). Pembrolizumab will be given every 3
      weeks for 5 doses, with a starting dose of 200 mg. NOTE: the last dose of pembrolizumab falls
      on what would be D8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN.

      Phase II Arm A: Cohort I Cisplatin-Eligible:

      Cisplatin-eligible subjects receive: gemcitabine 1000mg/m2 IV D1 and D8 every 21 days
      repeated for 4 cycles; cisplatin 70mg/m2 IV D1 and D8 every 21 days, repeated for 4 cycles.
      (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days).
      Pembrolizumab at recommended phase II dose (RP2D) is given every 3 weeks for 5 doses starting
      with C1D8. NOTE: the last dose of pembrolizumab falls on what would be day 8 of a 5th 'chemo'
      cycle, however gemcitabine/cisplatin is NOT GIVEN. Cohort I treatment with gemcitabine and
      cisplatin will continue for a maximum of 4 cycles (cycle = 21days).

      Phase II Arm B: Cohort II:

      Cisplatin-ineligible subjects receive gemcitabine 1000mg/m2 IV D1, D8 and D15 every 28 days,
      repeated for 3 cycles. Pembrolizumab at RP2D is given every 3 weeks for 5 doses starting with
      C1D8. NOTE: due to the timing of gemcitabine cycles every 4 weeks, and every three week
      dosing of pembrolizumab, there are two doses of pembrolizumab given during cycle 2: D1 and
      D22. Additionally, the last dose of pembrolizumab falls on what would be D8 of a 4th 'chemo'
      cycle; however gemcitabine is NOT GIVEN. Cohort II treatment with gemcitabine will continue
      for a maximum of 3 cycles (cycle = 28 days)

      Subjects will then have surgery to remove their primary tumor within 2-7 weeks after their
      last dose of neoadjuvant therapy.

      Eastern Cooperative Oncology Group (ECOC) performance status: 0-1 for cisplatin-eligible
      subjects; 0-2 for cisplatin-ineligible subjects.

      Demonstrate adequate organ function as defined by the following laboratory values at study
      entry. All screening labs should be performed within 28 days of C1D1.

      Hematopoetic:

        -  Absolute neutrophil count (ANC) ≥1,500 /mcL

        -  Absolute lymphocyte count ≥350 mcL

        -  Platelets ≥100,000 / mcL

        -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

      Renal:

        -  Measured or calculated creatinine clearance ≥30 mL/min

      Hepatic:

        -  Serum total bilirubin ≤ 1.25 X ULN OR ≤ 2.5 x ULN for subjects with Gilbert's disease

        -  Aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤ 2 X
           ULN

      Coagulation:

        -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤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

        -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
           anticoagulant therapy and as long as PT or PTT is within therapeutic range of intended
           use of anticoagulants
    

Trial Arms

NameTypeDescriptionInterventions
Arm A - Phase 1b Dose Finding Cohort:ExperimentalCisplatin-eligible subjects will receive pembrolizumab at starting dose of 200mg (dose level 0), and/or 120mg (dose level -1) in combination with gemcitabine and cisplatin. The MTD will be the highest pembrolizumab dose level in combination with gemcitabine/cisplatin every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days). Once the MTD is established, this portion of the study will close and the phase II will open to cohorts I and II at the recommended phase II dose (RP2D).
  • Pembrolizumab
  • Gemcitabine
  • Cisplatin
Arm B - Phase II Cohort I:ExperimentalCisplatin-eligible subjects receive gemcitabine/cisplatin every 21 days, repeated for 4 cycles. (Subjects with Ccr of 50-59 mL/min must follow split dosing of cisplatin over two days) . Pembrolizumab at RP2D is given every 21 days for 5 doses starting C1D8. Note: the last dose of pembrolizumab falls on what would be day 8 of a 5th 'chemo' cycle, however gemcitabine/cisplatin is NOT GIVEN. Subjects will then have consolidative surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.
  • Pembrolizumab
  • Gemcitabine
  • Cisplatin
Arm C - Phase II Cohort II:ExperimentalCisplatin-ineligible subjects receive gemcitabine every week every 28 days for 3 cycles. Pembrolizumab at RP2D is given every 21 days for 5 doses starting C1D8. NOTE: due to the timing of gemcitabine cycles every 4 weeks, and every 3-week dosing of pembrolizumab, there are two doses of pembrolizumab given during cycle 2: D1 and D22. Additionally, the last dose of pembrolizumab falls on what would be D8 of a 4th 'chemo' cycle; however gemcitabine is NOT GIVEN. Subjects will then have consolidative surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.
  • Pembrolizumab
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent for the trial.

          -  Over 18 years of age on day of signing informed consent.

          -  Have histologically confirmed muscle invasive disease of the urinary bladder, renal
             pelvis, or ureters.

          -  Histology must be urothelial carcinoma (transitional cell carcinoma) or urothelial
             carcinoma with mixed histology/features.

          -  Clinical stage cT2-4aN0M0. Please see exclusion criteria for acceptable N0
             determination/lymph node size.

          -  Have a surgical evaluation that documents the plan for multimodality therapy with a
             consolidative radical cystectomy or nephroureterectomy.

        NOTE on surgical intent: Criteria for acceptable surgical risk are not defined and per
        treating urologist. Minimum guidance on surgical intent includes subjects who do not have
        significant cardiovascular disease such as NHYA class III or IV heart failure, unstable
        arrhythmias or angina, active CAD, and/or EF<25%. Specific diagnostic testing to determine
        surgical intent is not required and per treating urologist or oncologist discretion.

          -  Have an archived tumor block available to submit unstained slides for PD-L1
             expression, basal and luminal subtype analysis; MANDATORY. If slides are not
             available, a biopsy is strongly encouraged to obtain tissue for submission

          -  Subjects on full dose anticoagulants must be on a stable regimen of warfarin or low
             molecular weight heparin (LMWH) for at least two weeks.

          -  Female subjects of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to study registration. If the urine test is
             positive or cannot be confirmed as negative, a serum pregnancy test is required.

          -  Female subjects of childbearing potential must be willing to use 2 methods of birth
             control, be surgically sterile, or abstain from heterosexual intercourse for the
             course of the study and through 120 days after the last dose of study medication.
             NOTE: Subjects of childbearing potential are those who have not been surgically
             sterilized or have not been free from menses for > 1 year.

          -  Male subjects must agree to use a barrier method of male contraception starting with
             the first dose of study therapy and through 120 days after the last dose of study
             therapy.

        COHORT I - CISPLATIN-ELIGIBLE:

        In addition to the inclusion criteria listed above, Cohort I subjects must satisfy all of
        the following criteria:

          -  Glomerular filtration rate (GFR) or creatinine clearance (Ccr) ≥ 50 mL/min. (24 hour
             urine preferred). The cisplatin dose will be split over two days for values between
             50-59 mL/min

          -  ECOG PS 0, 1 (and not 2)

          -  Hearing impaired ≤ grade 1 (may or may not be enrolled in a monitoring program)

          -  Peripheral neuropathy ≤grade 1

        COHORT II - CISPLATIN-INELIGIBLE:

        In addition to the inclusion criteria listed above, Cohort II subjects must also meet any
        ONE of the following criteria:

          -  GFR or Ccr: 30-49 (24 hour urine preferred).

          -  ECOG PS 2

          -  Hearing impaired ≥grade 2 as assessed by treating physician (may or may not be
             enrolled in a monitoring program).

          -  Peripheral neuropathy of Grade 2-4

        Exclusion Criteria:

        Subjects may not have any of the following:

          -  A non-surgical approach recommended by the treating urologist due to any reason.
             Criteria for surgical intent are not defined and, rather, suitability is determined
             and documented by the subject's treating urologist. Minimum guidance on surgical
             intent includes subjects who do not have significant cardiovascular disease such as
             NHYA class III or IV heart failure, unstable arrhythmias or angina, active CAD, and/or
             EF<25%. Specific cardiopulmonary diagnostic testing to determine surgical intent is
             not required and per treating urologist or oncologist discretion.

          -  Has abdomino-pelvic short axis lymph node of ≥15mm without biopsy. NOTE: A subject
             with a staging biopsy proving a non-neoplastic process/N0 will meet inclusion.

          -  Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 28 days prior to study registration.

          -  Has a diagnosis of immunodeficiency or received systemic steroid therapy or any other
             form of immunosuppressive therapy within 7 days prior to study registration. Subjects
             on steroids for physiologic replacement due to a non-cancer related cause would not be
             excluded.

          -  Has had a prior monoclonal antibody ≤ 28 days prior to study registration or who has
             not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents
             administered more than 28 days earlier.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy for
             urothelial carcinoma.

          -  Has a known additional malignancy that is progressing or required treatment ≤ 48
             months of study registration. Exceptions include basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, in situ cervical cancer that has undergone
             potentially curative therapy, stable (as defined by PSA change, checked within 30
             days) and untreated very low-risk or low-risk prostate cancer defined by current NCCN
             guidelines.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Brain imaging is not required and per discretion of treating physician.

          -  Has an active autoimmune disease requiring systemic treatment within the past 3 months
             or a documented history of clinically severe autoimmune disease, or a syndrome that
             requires systemic steroids or immunosuppressive agents. NOTE: Subjects with vitiligo
             or resolved childhood asthma/atopy would be an exception. Subjects that require
             intermittent use of bronchodilators or local steroid injections would not be excluded
             from the study. Subjects with hypothyroidism stable on hormone replacement or
             Sjogren's syndrome will not be excluded from the study.

          -  Has known 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 therapy with hematopoietic growth factor such as G-CSF or GM-CSF in the
             14 days prior to registration.

          -  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 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 prior to the first dose of trial treatment.
             NOTE: Examples of live vaccines include, but are not limited to, the following:
             measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral)
             vaccines. Seasonal influenza vaccines for injection are generally killed virus
             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:Phase Ib: Number of Patients with Adverse Events as a Measure of Safety and Tolerability
Time Frame:C1D1 and every 21 days thereafter while on treatment (up to 4 months)
Safety Issue:
Description:To assess safety and tolerability of pembrolizumab in combination with gemcitabine and cisplatin in patients with urothelial cancer per CTCAE v4 criteria.

Secondary Outcome Measures

Measure:Relapse-Free Survival (RFS)
Time Frame:Up to 18 months
Safety Issue:
Description:Determine relapse free survival (RFS) 18 months post completion of therapy, per RECIST 1.1 criteria
Measure:Overall Survival (OS)
Time Frame:From date of registration to date of death (up to 5 years)
Safety Issue:
Description:After 18 months, patients will be followed for survival every 6 months for 5 years from end of treatment.
Measure:Radical Cystectomy (RC) Rate
Time Frame:Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)
Safety Issue:
Description:To compare the radical cystectomy (RC) rates in subjects who are cisplatin-eligible with those who are cisplatin-ineligible.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Christopher Hoimes, M.D.

Trial Keywords

  • MK-3475
  • Gemcitabine
  • Cisplatin
  • Pembrolizumab
  • Neoadjuvant Bladder Cancer

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