Bladder Cancer
Conditions
Keywords
muscle-invasive
Brief summary
This is a phase 2 trial seeking to define the safety and activity of gemcitabine, cisplatin, plus nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer and to define the role of clinical complete response in predicting benefit in patients opting to avoid cystectomy.
Interventions
DRUGNivolumab
Nivolumab 360mg will be administered on Day 1 of each 21 day cycle for four 21-day cycles. Based on response and a balanced patient-physician discussion, subjects may receive nivolumab 240 mg for 8 cycles (cycle = 14 days).
DRUGGemcitabine
Gemcitabine 1000mg/m\^2 will be administered on Days 1 and 8 for four 21-day cycles.
DRUGCisplatin
Cisplatin 70mg\^m2 will be administered on Day 1 for four 21-day cycles.
Sponsors
Bristol-Myers Squibb
Icahn School of Medicine at Mount Sinai
Matthew Galsky
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ECOG Performance Status of ≤ 1 within 28 days prior to registration. * Histological evidence of clinically localized muscle-invasive urothelial cancer of the bladder (i.e., ct2-4n0m0). candidate for cystectomy as per treating physician. * Demonstrate adequate organ function per listed criteria: * Absolute Neutrophil Count (ANC): ≥ 1.5 x 10\^9/L * Hemoglobin (Hgb): ≥ 9 g/dL * Platelets: ≥ 100 x 10\^9/L * Calculated creatinine clearance: Creatinine ≤ 1.5 or creatinine clearance ≥ 60 mL/min * Bilirubin: ≤ 1.5 × upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) * Aspartate aminotransferase (AST) : ≤ 3 × ULN * Alanine aminotransferase (ALT) : ≤ 3 × ULN * All subjects must have adequate archival tissue identified at screening (i.e., at least 15 unstained slides or paraffin block). Subjects without available archival tissue must be discussed with the sponsor-investigator. * Women of childbearing potential must have a negative serum or urine pregnancy within 7 days prior to C1D1. NOTE: Women of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL. NOTE: Women of childbearing potential (WOCBP) receiving nivolumab must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent to 5 months after the last dose of nivolumab or for the timeframe outlined per package insert for chemotherapy. This timeframe also applies to breastfeeding. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Male subjects capable of fathering a child that are sexually active with partners of childbearing potential must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent to the timeframe outlined per package insert for chemotherapy. Contraception is not required for nivolumab. The timeframes described in the previous 2 sentences apply to sperm donation. Two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
Exclusion criteria
* Prior treatment with systemic chemotherapy for muscle-invasive urothelial cancer of the bladder * Active infection requiring systemic therapy * Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). * Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. * Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured. * Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. * Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. * Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways. * Grade ≥ 2 neuropathy (NCI CTCAE version 4). * Prior radiation therapy for bladder cancer * Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (RNA) or hepatitis C antibody (HCV antibody) indicating acute or chronic infection. * Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). * Evidence of interstitial lung disease or active, non-infectious pneumonitis. * Solid organ or allogeneic stem cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response (CCR) Rate | 24 months | Clinical complete response rate will be defined as the percentage of patients who achieved cT0 or cTa disease after gemcitabine, cisplatin, plus nivolumab. |
| Predict Benefit From Treatment | 24 months | Determine the ability of clinical complete response (cT0 or cTa) to predict benefit from treatment.Benefit will be defined as a pathologic complete response (\<pT1) in patients undergoing cystectomy and 2 year metastasis-free in patients pursuing surveillance. The positive predictive value of CCR with 95% confidence interval are presented in Outcome Measure Data Table. Positive predictive value is the ratio of patients truly diagnosed as positive to all those who had positive test results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free Survival | Up to a maximum of 60 months | Recurrence-free survival is defined as the time from initiation of treatment to death or recurrence, depending on which occurs first |
| Pathologic Complete Response Rate in Patients Undergoing Cystectomy | Up to a maximum of 53 months | Pathologic complete response rate in patients undergoing radical cystectomy is defined as the proportion of patients with \<pT1 |
| Adverse Events | AE had been recorded from time of signed informed consent until 100 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 13 months. | The frequency and severity of all grade 3+ treatment-emergent adverse events occurring in at least 10% of patients are reported by CTCAEv4 term and grade. |
| Overall Survival | Up to a maximum of 60 months | Overall survival is defined as the time from initiation of treatment to death. |
| Association Between a Prespecified Panel of Genomic Biomarkers and Benefit From Treatment in Patients Achieving a Clinical Complete Response. | 24 months | Benefit will be defined as a pathologic complete response (p\<T1) in patients undergoing cystectomy and 2 years metastasis-free in patients pursuing surveillance. The positive predictive value of CCR with or without genomic alterations in baseline TURBT tissue for a composite outcome measure of 2-year bladder-intact survival in patients forgoing immediate cystectomy or \<ypT1N0 in patients undergoing immediate cystectomy are presented with 95% confidence interval in Outcome Measure Data Table. Positive predictive value is the ratio of patients truly diagnosed as positive to all those who had positive test results. |
| Bladder Intact Overall Survival | Up to a maximum of 60 months | Bladder-intact overall survival is defined as the time from initiation of treatment until death or cystectomy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine, Cisplatin and Nivolumab Combination Therapy: Nivolumab 360mg IV, Gemcitabine 100mg/m\^2 IV ,Cisplatin 70mg/m\^2 IV for four 21-day cycles. At restaging, subjects with cT0 or cTa status may undergo cystectomy or continue maintenance Nivolumab 240mg IV for up to 8 14-day cycles. Subjects with \> cTa status will undergo cystectomy.
Nivolumab: Nivolumab 360mg will be administered on Day 1 of each 21 day cycle for four 21-day cycles. Based on response and a balanced patient-physician discussion, subjects may receive nivolumab 240 mg for 8 cycles (cycle = 14 days).
Gemcitabine: Gemcitabine 1000mg/m\^2 will be administered on Days 1 and 8 for four 21-day cycles.
Cisplatin: Cisplatin 70mg\^m2 will be administered on Day 1 for four 21-day cycles. | 76 |
| Total | 76 |
Baseline characteristics
| Characteristic | Gemcitabine, Cisplatin and Nivolumab |
|---|---|
| Age, Continuous | 69 years |
| Clinical stage cT2N0M0 | 43 Participants |
| Clinical stage cT3N0M0 | 24 Participants |
| Clinical stage cT4N0M0 | 9 Participants |
| Histology UC with glandular | 2 Participants |
| Histology UC with micropapillary | 6 Participants |
| Histology UC with other variant | 4 Participants |
| Histology UC with squamous | 7 Participants |
| Histology Urothelial Cancer (UC) | 57 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants |
| Race (NIH/OMB) White | 58 Participants |
| Region of Enrollment United States | 76 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 76 |
| other Total, other adverse events | 76 / 76 |
| serious Total, serious adverse events | 40 / 76 |
Outcome results
Primary
Clinical Complete Response (CCR) Rate
Clinical complete response rate will be defined as the percentage of patients who achieved cT0 or cTa disease after gemcitabine, cisplatin, plus nivolumab.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Clinical Complete Response (CCR) Rate | 43 Percentage of participants |
Primary
Predict Benefit From Treatment
Determine the ability of clinical complete response (cT0 or cTa) to predict benefit from treatment.Benefit will be defined as a pathologic complete response (\<pT1) in patients undergoing cystectomy and 2 year metastasis-free in patients pursuing surveillance. The positive predictive value of CCR with 95% confidence interval are presented in Outcome Measure Data Table. Positive predictive value is the ratio of patients truly diagnosed as positive to all those who had positive test results.
Time frame: 24 months
Population: Among the 33 patients achieving a CCR, only one opted for immediate cystectomy with surgical pathology, revealing a low-grade ypTaN0 urothelial cancer (UC). Therefore 32 patients were used for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Predict Benefit From Treatment | 0.97 Proportion of CCR patients |
Secondary
Adverse Events
The frequency and severity of all grade 3+ treatment-emergent adverse events occurring in at least 10% of patients are reported by CTCAEv4 term and grade.
Time frame: AE had been recorded from time of signed informed consent until 100 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 13 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | PAIN | 1 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | ASPARTATE AMINOTRANSFERASE INCREASED | 1 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | DEPRESSION | 1 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | ANEMIA | 12 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | NEUTROPHIL COUNT DECREASED | 26 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | URINARY TRACT INFECTION | 13 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | HYPONATREMIA | 5 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | HYPERTENSION | 4 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | WHITE BLOOD CELL DECREASED | 3 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | PLATELET COUNT DECREASED | 4 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | HEMATURIA | 3 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | DYSPNEA | 1 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | VOMITING | 1 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | ABDOMINAL PAIN | 2 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | HYPOKALEMIA | 3 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | ANXIETY | 1 participants |
| Gemcitabine, Cisplatin and Nivolumab | Adverse Events | HYPERGLYCEMIA | 2 participants |
Secondary
Association Between a Prespecified Panel of Genomic Biomarkers and Benefit From Treatment in Patients Achieving a Clinical Complete Response.
Benefit will be defined as a pathologic complete response (p\<T1) in patients undergoing cystectomy and 2 years metastasis-free in patients pursuing surveillance. The positive predictive value of CCR with or without genomic alterations in baseline TURBT tissue for a composite outcome measure of 2-year bladder-intact survival in patients forgoing immediate cystectomy or \<ypT1N0 in patients undergoing immediate cystectomy are presented with 95% confidence interval in Outcome Measure Data Table. Positive predictive value is the ratio of patients truly diagnosed as positive to all those who had positive test results.
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Association Between a Prespecified Panel of Genomic Biomarkers and Benefit From Treatment in Patients Achieving a Clinical Complete Response. | 0.72 Proportion of CCR patients |
Secondary
Bladder Intact Overall Survival
Bladder-intact overall survival is defined as the time from initiation of treatment until death or cystectomy.
Time frame: Up to a maximum of 60 months
Population: Bladder-intact overall survival results are showing in accordance with CCR status. Out of 76 patients, 33 patients achieved a clinical complete response, and 43 patients did not achieve a clinical complete response.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Bladder Intact Overall Survival | CCR Patients | NA Months |
| Gemcitabine, Cisplatin and Nivolumab | Bladder Intact Overall Survival | Non-CCR Patients | 4.53 Months |
Secondary
Overall Survival
Overall survival is defined as the time from initiation of treatment to death.
Time frame: Up to a maximum of 60 months
Population: Overall survival results are showing in accordance with CCR status. Out of 76 patients, 33 patients achieved a clinical complete response, and 43 patients did not achieve a clinical complete response.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Overall Survival | CCR Patients | NA Months |
| Gemcitabine, Cisplatin and Nivolumab | Overall Survival | Non-CCR Patients | NA Months |
Secondary
Pathologic Complete Response Rate in Patients Undergoing Cystectomy
Pathologic complete response rate in patients undergoing radical cystectomy is defined as the proportion of patients with \<pT1
Time frame: Up to a maximum of 53 months
Population: Only 8 patients achieving a clinical complete response (CCR) later underwent cystectomy, and 34 patients not achieving a CCR underwent cystectomy.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Pathologic Complete Response Rate in Patients Undergoing Cystectomy | CCR Patients | 1 Participants |
| Gemcitabine, Cisplatin and Nivolumab | Pathologic Complete Response Rate in Patients Undergoing Cystectomy | Non-CCR Patients | 3 Participants |
Secondary
Recurrence-free Survival
Recurrence-free survival is defined as the time from initiation of treatment to death or recurrence, depending on which occurs first
Time frame: Up to a maximum of 60 months
Population: Recurrence-free survival results are showing in accordance with CCR status. Out of 76 patients, 33 patients achieved a clinical complete response, and 43 patients did not achieve a clinical complete response.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gemcitabine, Cisplatin and Nivolumab | Recurrence-free Survival | CCR Patients | 51.52 Months |
| Gemcitabine, Cisplatin and Nivolumab | Recurrence-free Survival | Non-CCR Patients | NA Months |