Bladder Cancer, Urothelial Carcinoma
Conditions
Keywords
MK-3475, Gemcitabine, Cisplatin, Pembrolizumab, Neoadjuvant Bladder Cancer
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.
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
Interventions
DRUGPembrolizumab
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.
DRUGGemcitabine
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.
DRUGCisplatin
For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles.
PROCEDUREConsolidative 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.
Sponsors
Hoosier Cancer Research Network
Merck Sharp & Dohme LLC
Jason R. Brown
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. * 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. * 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. * 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 * AST(SGOT) and 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Safety of Pembrolizumab in Combination With Gemcitabine-Cisplatin | Up to 4 weeks | 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. |
| Rate of Pathologic Muscle Invasive Response (PaIR) | Within 2-7 weeks post last dose of pembrolizumab (up to 6 months) | Pathologic muscle invasion response (PaIR), or ≤ypT1N0M0, rate is assessed from the consolidative surgery (radical cystectomy (RC) / nephroureterectomy (NU) - lymph node dissection (LND)) specimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-Free Survival (RFS) at 18 Months | 18 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Relapse-Free Survival is defined by the date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs. |
| Overall Survival (OS) at 5 Years | 5 years | Determine the Overall survival at 5 years. OS is defined by the date of randomization to date of death from any cause. |
| Radical Cystectomy (RC) Rate | 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. |
Countries
United States
Participant flow
Pre-assignment details
All participants in Phase 1b received same dose (Pembrolizumab 200 mg).
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg Arm A: Cisplatin-eligible subjects were received pembrolizumab at starting dose of 200mg (dose level 0) in combination with gemcitabine and cisplatin. 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: In this dose-finding cohort, pembrolizumab (MK-3475) were 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.
Gemcitabine: For cisplatin-eligible patients on phase Ib, gemcitabine 1000mg/m2 IV, D1 and D8 every 21 days for 4 cycles.
Cisplatin: For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles. | 6 |
| Phase II Cohort I: Cisplatin-eligible- Pembrolizumab 200 mg Arm B: 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.
Pembrolizumab: 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.
Gemcitabine: For cisplatin-eligible patients on phase II cohort 1, gemcitabine 1000mg/m2 IV, D1 and D8 every 21 days for 4 cycles.
Cisplatin: For cisplatin-eligible patients, cisplatin 70mg/m2 IV will be administered D1 every 21 days for 4 cycles. | 37 |
| Phase II Cohort II: Cisplatin-ineligible -Pembrolizumab 200 mg Arm C: 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.
Pembrolizumab: 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.
Gemcitabine: 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. | 38 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Eligibility Criteria Not Met | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Phase II Cohort II: Cisplatin-ineligible -Pembrolizumab 200 mg | Phase II Cohort I: Cisplatin-eligible- Pembrolizumab 200 mg | Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg |
|---|---|---|---|---|
| Age, Continuous | 68 years | 73 years | 63 years | 66 years |
| ECOG performance status ECOG = 0 | 54 Participants | 22 Participants | 26 Participants | 6 Participants |
| ECOG performance status ECOG = 1 | 23 Participants | 12 Participants | 11 Participants | 0 Participants |
| ECOG performance status ECOG = 2 | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 36 Participants | 35 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 3 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 35 Participants | 31 Participants | 5 Participants |
| Region of Enrollment United States | 81 participants | 38 participants | 37 participants | 6 participants |
| Sex: Female, Male Female | 22 Participants | 11 Participants | 10 Participants | 1 Participants |
| Sex: Female, Male Male | 59 Participants | 27 Participants | 27 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 11 / 37 | 16 / 38 |
| other Total, other adverse events | 6 / 6 | 37 / 37 | 38 / 38 |
| serious Total, serious adverse events | 1 / 6 | 17 / 37 | 17 / 38 |
Outcome results
Primary
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.
Time frame: Up to 4 weeks
Population: All participants in Phase 1b received same dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg | Phase Ib: Safety of Pembrolizumab in Combination With Gemcitabine-Cisplatin | 0 Participants |
Primary
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.
Time frame: Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint PaIR Rate was defined as all Cisplatin-eligible treated at the MTD, which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2 + cisplatin 70mg/m2; and all Cisplatin-ineligible treated at the MTD which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2.~38 out of 43 Cisplatin eligible patients and 33 out of 38 Cisplatin ineligible patients had data of pathological response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg | Rate of Pathologic Muscle Invasive Response (PaIR) | 61 Percentage of participants |
| Cohort II: Cisplatin Ineligible - Pembrolizumab 200 mg | Rate of Pathologic Muscle Invasive Response (PaIR) | 51.5 Percentage of participants |
Secondary
Overall Survival (OS) at 5 Years
Determine the Overall survival at 5 years. OS is defined by the date of randomization to date of death from any cause.
Time frame: 5 years
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Overall Survival was defined as all Cisplatin-eligible patients treated at the MTD, which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2 + cisplatin 70mg/m2; and all Cisplatin-ineligible patients treated at the MTD which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg | Overall Survival (OS) at 5 Years | 71.9 Percentage of participants |
| Cohort II: Cisplatin Ineligible - Pembrolizumab 200 mg | Overall Survival (OS) at 5 Years | 56.6 Percentage of participants |
Secondary
Radical Cystectomy (RC) Rate
To compare the radical cystectomy (RC) rates in subjects who are cisplatin-eligible with those who are cisplatin-ineligible.
Time frame: Within 2-7 weeks post last dose of pembrolizumab (up to 6 months)
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Radical Cystectomy Rate was defined as all Cisplatin-eligible patients treated at the MTD, which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2 + cisplatin 70mg/m2; and all Cisplatin-ineligible patients treated at the MTD which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2.~37 out of 38 Cisplatin ineligible patients were evaluable for Radical Cystectomy Rate.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg | Radical Cystectomy (RC) Rate | 86 Percentage of participants |
| Cohort II: Cisplatin Ineligible - Pembrolizumab 200 mg | Radical Cystectomy (RC) Rate | 89 Percentage of participants |
Secondary
Relapse-Free Survival (RFS) at 18 Months
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Relapse-Free Survival is defined by the date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death occurs.
Time frame: 18 months
Population: In accordance with the Statistical Analysis Plan, the analysis population for the endpoint Relapse-Free Survival was defined as all Cisplatin-eligible patients treated at the MTD, which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2 + cisplatin 70mg/m2; and all Cisplatin-ineligible patients treated at the MTD which was determined to be pembrolizumab 200 mg + gemcitabine 1000mg/m2.~37 out of 38 Cisplatin ineligible patients were evaluable for RFS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Cohort I: Cisplatin-eligible - Pembrolizumab 200 mg | Relapse-Free Survival (RFS) at 18 Months | 83 Percentage of participants |
| Cohort II: Cisplatin Ineligible - Pembrolizumab 200 mg | Relapse-Free Survival (RFS) at 18 Months | 57.4 Percentage of participants |