Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Transitional Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Pembrolizumab

Cisplatin

Antimetabolites

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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).

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.

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.

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.

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.

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

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.

Consolidative Surgery

Jason R. Brown, M.D.,PhD

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.

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

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

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

To assess safety and tolerability of pembrolizumab in combination with gemcitabine and cisplatin in patients with urothelial cancer per CTCAE v4 criteria.

To assess PaIR rate, i.e., ypT0, Tis, Ta, T1 ypN0, per RECIST 1.1 criteria, at radical cystectomy, following combination therapy.

Determine relapse free survival (RFS) 18 months post completion of therapy, per RECIST 1.1 criteria

After 18 months, patients will be followed for survival every 6 months for 5 years from end of treatment.

To compare the radical cystectomy (RC) rates in subjects who are cisplatin-eligible with those who are cisplatin-ineligible.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects	NCT02365766	Urothelial Carc... Bladder Cancer	Pembrolizumab Gemcitabine Cisplatin Consolidative S...	18 Years -	Hoosier Cancer Research Network
Neoadjuvant Pembrolizumab in Combination With Gemcitabine Therapy in Cis-eligible/Ineligible UC Subjects	NCT02365766	Urothelial Carc... Bladder Cancer	Pembrolizumab Gemcitabine Cisplatin Consolidative S...	18 Years -	Hoosier Cancer Research Network

Spots Global Cancer Trial Database for consolidative surgery