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

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ClinicalTrials.gov Identifier: NCT02365766
Recruitment Status : Recruiting
First Posted : February 19, 2015
Last Update Posted : February 8, 2018
Sponsor:
Collaborators:
Hoosier Cancer Research Network
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Christopher Hoimes, M.D., Hoosier Cancer Research Network

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Bladder Cancer Drug: Pembrolizumab Drug: Gemcitabine Drug: Cisplatin Procedure: Consolidative Surgery Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : May 2015
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : December 2018


Arm Intervention/treatment
Experimental: Arm A - Phase 1b Dose Finding Cohort:
Cisplatin-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).
Drug: Pembrolizumab
In this dose-finding cohort, pembrolizumab (MK-3475) will be administered (cisplatin-eligible patients only) at starting dose 200mg IV every 21 days for 4 cycles to determine RP2D. Once MTD is established in phase Ib, pembrolizumab will be administered on phase II cohorts I and II at RP2D every 21 days for 5 cycles.
Other Name: MK-3475

Drug: Gemcitabine
For cisplatin-eligible patients on phase Ib and phase II cohort 1, gemcitabine 1000mg/m2 IV, D1 and D8 every 21 days for 4 cycles. For cisplatin-ineligible patients on phase II cohort II, gemcitabine 1000mg/m2 will be administered D1, D8 and D15 every 28 days for 3 cycles.
Other Name: Gemzar

Drug: Cisplatin
For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles.
Other Name: Platinol

Experimental: Arm B - Phase II Cohort I:
Cisplatin-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.
Drug: Pembrolizumab
In this dose-finding cohort, pembrolizumab (MK-3475) will be administered (cisplatin-eligible patients only) at starting dose 200mg IV every 21 days for 4 cycles to determine RP2D. Once MTD is established in phase Ib, pembrolizumab will be administered on phase II cohorts I and II at RP2D every 21 days for 5 cycles.
Other Name: MK-3475

Drug: Gemcitabine
For cisplatin-eligible patients on phase Ib and phase II cohort 1, gemcitabine 1000mg/m2 IV, D1 and D8 every 21 days for 4 cycles. For cisplatin-ineligible patients on phase II cohort II, gemcitabine 1000mg/m2 will be administered D1, D8 and D15 every 28 days for 3 cycles.
Other Name: Gemzar

Drug: Cisplatin
For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles.
Other Name: Platinol

Procedure: Consolidative Surgery
Following completion of treatment, subjects will then have surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.

Experimental: Arm C - Phase II Cohort II:
Cisplatin-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.
Drug: Pembrolizumab
In this dose-finding cohort, pembrolizumab (MK-3475) will be administered (cisplatin-eligible patients only) at starting dose 200mg IV every 21 days for 4 cycles to determine RP2D. Once MTD is established in phase Ib, pembrolizumab will be administered on phase II cohorts I and II at RP2D every 21 days for 5 cycles.
Other Name: MK-3475

Drug: Gemcitabine
For cisplatin-eligible patients on phase Ib and phase II cohort 1, gemcitabine 1000mg/m2 IV, D1 and D8 every 21 days for 4 cycles. For cisplatin-ineligible patients on phase II cohort II, gemcitabine 1000mg/m2 will be administered D1, D8 and D15 every 28 days for 3 cycles.
Other Name: Gemzar

Procedure: Consolidative Surgery
Following completion of treatment, subjects will then have surgery to remove their primary tumor within 2-7 weeks after their last dose of neoadjuvant therapy.




Primary Outcome Measures :
  1. 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) ]
    To assess safety and tolerability of pembrolizumab in combination with gemcitabine and cisplatin in patients with urothelial cancer per CTCAE v4 criteria.

  2. Phase II: Rate of Pathologic Muscle Invasive Response (PaIR) [ Time Frame: Within 2-7 weeks post last dose of pembrolizumab (up to 6 months) ]
    To assess PaIR rate, i.e., ypT0, Tis, Ta, T1 ypN0, per RECIST 1.1 criteria, at radical cystectomy, following combination therapy.


Secondary Outcome Measures :
  1. Relapse-Free Survival (RFS) [ Time Frame: Up to 18 months ]
    Determine relapse free survival (RFS) 18 months post completion of therapy, per RECIST 1.1 criteria

  2. Overall Survival (OS) [ Time Frame: From date of registration to date of death (up to 5 years) ]
    After 18 months, patients will be followed for survival every 6 months for 5 years from end of treatment.

  3. Radical Cystectomy (RC) Rate [ Time Frame: Within 2-7 weeks post last dose of pembrolizumab (up to 6 months) ]
    To compare the radical cystectomy (RC) rates in subjects who are cisplatin-eligible with those who are cisplatin-ineligible.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02365766


Contacts
Contact: Christopher Hoimes, M.D. (216) 844-3951 cjh122@case.edu
Contact: Michael Nunley 317.634.5842 ext 17 mnunley@hoosiercancer.org

Locations
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Costantine Albany, M.D.    317-278-1711    calbany@iu.edu   
Contact: Marietta Moore    317-274-7477    marlmoor@iupui.edu   
IU Health Central Indiana Cancer Center Recruiting
Indianapolis, Indiana, United States, 46219
Contact: Deborah McCullough    317-948-1921    dmccullough2@iuhealth.org   
Principal Investigator: Andrew Greenspan, MD         
Community Regional Cancer Care Recruiting
Indianapolis, Indiana, United States, 46256
Contact: Kelly Verel    317-497-2836    KVerel@ecommunity.com   
Principal Investigator: Radhika Walling, MD         
St. Vincent Hospital Recruiting
Indianapolis, Indiana, United States, 46260
Contact: Deborah Estes    317-338-6594    deborah.estes@ascension.org   
Principal Investigator: Niraj Gupta, MD         
United States, Missouri
Washington University: Siteman Cancer Center Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Joel Picus, M.D.    314-362-5740    jpicus@dom.wustl.edu   
Contact: Amber Smith, R.N.    314-508-7249    asmith1@wustl.edu   
United States, New Mexico
University of New Mexico Cancer Center Recruiting
Albuquerque, New Mexico, United States, 87106
Contact: Mollie Geske    505-925-0377    mgeske@nmcca.org   
Principal Investigator: Richard Lauer, MD         
United States, Ohio
University Hospitals Seidman Cancer Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Christopher Hoimes, D.O.    216-844-3951    cjh122@case.edu   
Contact: Cheryl Eitman    216-844-5393    cheryl.eitman2@uhhospitals.org   
United States, Pennsylvania
Thomas Jefferson University: Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Jean Hoffman-Censits, M.D.    215-955-8874    jean.hoffman-censits@jefferson.edu   
Contact: Monica Byrnes    215.503.0552    monica.byrnes@jefferson.edu   
United States, Virginia
Virginia Oncology Associates Recruiting
Norfolk, Virginia, United States, 23502
Contact: Mark Fleming, M.D.    757-213-5813    mark.fleming@usoncology.com   
Contact: Wendi Gobhart    757.213.5813    wendi.gobhart@usoncology.com   
Sponsors and Collaborators
Christopher Hoimes, M.D.
Hoosier Cancer Research Network
Merck Sharp & Dohme Corp.
Investigators
Study Chair: Christopher Hoimes, M.D. Hoosier Cancer Research Network

Additional Information:
Responsible Party: Christopher Hoimes, M.D., Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT02365766     History of Changes
Other Study ID Numbers: HCRN GU14-188
First Posted: February 19, 2015    Key Record Dates
Last Update Posted: February 8, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Christopher Hoimes, M.D., Hoosier Cancer Research Network:
MK-3475
Gemcitabine
Cisplatin
Pembrolizumab
Neoadjuvant Bladder Cancer

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gemcitabine
Pembrolizumab
Cisplatin
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs