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


Condition: Urothelial Carcinoma, Bladder Cancer

Intervention:

  • Drug: Pembrolizumab
  • Drug: Gemcitabine
  • Drug: Cisplatin
  • Procedure: Consolidative Surgery

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.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02365766

Sponsor: Christopher Hoimes, M.D.

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:
  • Measure: Phase II: Rate of Pathologic Muscle Invasive Response (PaIR)
  • Time Frame: Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: Relapse-Free Survival (RFS)
  • Time Frame: Up to 18 months
  • Safety Issue:
  • Measure: Overall Survival (OS)
  • Time Frame: From date of registration to date of death (up to 5 years)
  • Safety Issue:
  • Measure: Radical Cystectomy (RC) Rate
  • Time Frame: Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)
  • Safety Issue:

Estimated Enrollment: 81

Study Start Date: May 2015

Phase: Phase 1/Phase 2

Eligibility:

  • Age: minimum 18 Years maximum N/A
  • Gender: All

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:

  • 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.

Contact:

  • Christopher Hoimes, M.D.
  • (216) 844-3951

Locations:

  • Indiana University Melvin and Bren Simon Cancer Center
  • Indianapolis Indiana 46202 United States
  • IU Health Central Indiana Cancer Center
  • Indianapolis Indiana 46219 United States
  • Community Regional Cancer Care
  • Indianapolis Indiana 46256 United States
  • St. Vincent Hospital
  • Indianapolis Indiana 46260 United States
  • Washington University: Siteman Cancer Center
  • Saint Louis Missouri 63110 United States
  • University of New Mexico Cancer Center
  • Albuquerque New Mexico 87106 United States
  • University Hospitals Seidman Cancer Center
  • Cleveland Ohio 44106 United States
  • Thomas Jefferson University: Kimmel Cancer Center
  • Philadelphia Pennsylvania 19107 United States
  • Virginia Oncology Associates
  • Norfolk Virginia 23502 United States

View trial on ClinicalTrials.gov


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