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

NCT02365766 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: HCRN GU14-188
• Study Type: interventional
• Target: 83
• Locations: 1 country
• Sites: 9

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.

Conditions

Urothelial Carcinoma; Bladder Cancer

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Phase Ib: Safety of Pembrolizumab in Combination With Gemcitabine-Cisplatin

  Number of patients with experienced Dose-Limiting Toxicities (DLTs) will be monitored as a safety and tolerability of pembrolizumab in combination with gemcitabine and cisplatin . The Pembrolizumab DLT is defined as a drug-related adverse events (AEs) per Common Terminology Criteria for Adverse Events (CTCAE) V4 criteria that occurs in the first 4 weeks of treatment of pembrolizumab (C1D8 - C2D14) and meets the DLT definition per protocol.

  Up to 4 weeks

• Rate of Pathologic Muscle Invasive Response (PaIR)

  Pathologic muscle invasion response (PaIR), or ≤ypT1N0M0, rate is assessed from the consolidative surgery (radical cystectomy (RC) / nephroureterectomy (NU) - lymph node dissection (LND)) specimen.

  Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)

Secondary Outcomes (3)

• Relapse-Free Survival (RFS) at 18 Months

  18 months

• Overall Survival (OS) at 5 Years

  5 years

• Radical Cystectomy (RC) Rate

  Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)

Study Arms (3)

Arm A - Phase 1b Dose Finding Cohort:

EXPERIMENTAL

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; Drug: Gemcitabine; Drug: Cisplatin

Arm B - Phase II Cohort I:

EXPERIMENTAL

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; Drug: Gemcitabine; Drug: Cisplatin; Procedure: Consolidative Surgery

Arm C - Phase II Cohort II:

EXPERIMENTAL

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; Drug: Gemcitabine; Procedure: Consolidative Surgery

Interventions

Pembrolizumab DRUG

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.

Also known as: MK-3475

Arm A - Phase 1b Dose Finding Cohort:; Arm B - Phase II Cohort I:; Arm C - Phase II Cohort II:

Gemcitabine DRUG

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.

Also known as: Gemzar

Arm A - Phase 1b Dose Finding Cohort:; Arm B - Phase II Cohort I:; Arm C - Phase II Cohort II:

Cisplatin DRUG

For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles.

Also known as: Platinol

Arm A - Phase 1b Dose Finding Cohort:; Arm B - Phase II Cohort I:

Consolidative Surgery PROCEDURE

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.

Arm B - Phase II Cohort I:; Arm C - Phase II Cohort II:

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be willing and able to provide written informed consent for the trial.
• Over 18 years of age on day of signing informed consent.
• ECOG PS ≤ 2; please see protocol for specific details regarding ECOG PS for each cohort.
• Have histologically confirmed muscle invasive disease of the urinary bladder. For subjects who have tumors limited to the upper tract including renal pelvis or ureters, muscle invasive disease does not need to be pathologically proven, and a CT urogram must be performed (MRI is not acceptable to meet this criterion). To be eligible, subjects with upper tract tumors of the renal pelvis and ureter(s) must meet a high risk assessment defined as: tumor ≥ 1cm and/or hydronephrosis and/or high grade pathology and/or multifocal disease, where a radical NU approach to treat localized disease is warranted.
• Histology must be urothelial carcinoma (transitional cell carcinoma) or urothelial carcinoma with mixed histology/features.

You may not qualify if:

• 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.
• Having an archived tumor block available to submit 11 unstained slides for PD-L1 expression, basal and luminal subtype analysis is MANDATORY for subjects with bladder cancer (optional for those with tumors limited to the upper tract if sufficient tissue is not available). If slides are not available, a biopsy is strongly encouraged to obtain tissue for submission (See Study Procedures Manual for collection, labeling and shipping instructions).
• Subjects on full dose anticoagulants must be on a stable regimen of warfarin or low molecular weight heparin (LMWH) for at least two weeks.
• Demonstrate adequate organ function as defined below: All screening labs should be performed within 28 days of study registration.
• System
• Hematological
• Absolute neutrophil count (ANC): ≥1500 / 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 ≤2.5xULN for subjects with Gilbert's disease

Sponsors & Collaborators

• Jason R. Brown: lead
• Hoosier Cancer Research Network: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (9)

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

IU Health Central Indiana Cancer Center

Indianapolis, Indiana, 46219, United States

Location

Community Regional Cancer Care

Indianapolis, Indiana, 46256, United States

Location

St. Vincent Hospital

Indianapolis, Indiana, 46260, United States

Location

Washington University: Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

University of New Mexico Cancer Center

Albuquerque, New Mexico, 87106, United States

Location

University Hospitals Seidman Cancer Center

Cleveland, Ohio, 44106, United States

Location

Thomas Jefferson University: Kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

Location

Virginia Oncology Associates

Norfolk, Virginia, 23502, United States

Location

Related Links

• Hoosier Cancer Research Network Website

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms

Interventions

pembrolizumab; Gemcitabine; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: Fauzia Sharmin
• Organization: Hoosier Cancer Research Network

fsharmin@hoosiercancer.org

317-921-2050

Study Officials

• Jason R. Brown, M.D.,PhD

  Hoosier Cancer Research Network

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: February 11, 2015
• First Posted: February 19, 2015
• Study Start: May 27, 2015
• Primary Completion: August 1, 2020
• Study Completion: February 23, 2024
• Last Updated: March 18, 2025
• Results First Posted: March 18, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)