Metastatic Urothelial Cancer
Conditions
Keywords
cisplatin-ineligible, gemcitabine, carboplatin, nivolumab, oxaliplatin
Brief summary
This is a randomized phase 2 trial of gemcitabine + carboplatin + nivolumab or gemcitabine + oxaliplatin + nivolumab for the treatment of cisplatin-ineligible patients with metastatic urothelial cancer. Randomization will be stratified on the lymph node only (and/or unresectable primary) metastatic status.
Detailed description
Patients will be randomized to Arm A: gemcitabine plus carboplatin plus nivolumab versus Arm B: gemcitabine plus oxaliplatin plus nivolumab. Randomization will be stratified on the metastasis status (lymph node only vs. the rest). Patients on both treatment arms will receive up to 6 cycles of combination therapy in the absence of prohibitive adverse effects or disease progression. Patients with at least stable disease at the completion of 6 cycles of treatment may continue maintenance single agent nivolumab for up to 12 cycles. Patients who require discontinuation of chemotherapy (i.e., gemcitabine plus carboplatin or gemcitabine plus oxaliplatin) prior to Cycle 6, but who have at least stable disease, may be considered for ongoing treatment with single-agent nivolumab on the maintenance phase after discussion with the sponsor-investigator.
Interventions
DRUGNivolumab
Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \ 2-4 weeks after completing combination chemotherapy plus nivolumab)
DRUGGemcitabine
1000 mg/m\^2
DRUGCarboplatin
AUC 4.5 (based on the Calvert formula)
DRUGOxaliplatin
130 mg/m\^2
Sponsors
Bristol-Myers Squibb
Hoosier Cancer Research Network
Matthew Galsky
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subject must meet all the following applicable inclusion criteria to participate in this study: * Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. * Age ≥ 18 years at the time of consent. * Eastern Cooperative Oncology Group (ECOG) performance status of = 2 * Able to comply with the study protocol, in the investigator's judgment. * Histologically documented, locally advanced (T4b, any N; or any T, N 2-3) or metastatic urothelial carcinoma (mUC) (M1, Stage IV) (also termed TCC or UCC of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra) Patients with mixed histologies are required to have a dominant transitional cell pattern. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical Stage T4b) or bulky nodal metastasis (N2-N3). * Measurable disease, as defined by RECIST v1.1 * Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (metastatic specimens preferable but if not available primary tumor specimens that are at least muscle-invasive are acceptable) in paraffin blocks (blocks preferred) or at least 15 unstained slides. If archival tissue is not available, subjects may be considered for enrollment on a case by case basis after discussion with the sponsor-investigator. * No prior chemotherapy for inoperable locally advanced or mUC. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval \> 12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment naive in the metastatic setting. * Cisplatin-ineligible as defined by at least one of the following: * Calculated creatinine clearance ≥ 30 (Cockroft-Gault) * ECOG performance status of 2 or greater * CTCAE v4 Grade ≥ 2 audiometric hearing loss * Demonstrate adequate organ function. All screening labs to be obtained within 28 days prior to registration: * Hematological: * Absolute Neutrophil Count (ANC) ≥ 1.5 x 10\^9/L * Hemoglobin (Hgb) ≥ 9 g/dL * Platelets ≥ 100 x 10\^9/L * Renal: • Calculated creatinine clearance ≥ 30 mL/min (Cockroft-Gault) * Hepatic: * 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 * Women of childbearing potential must have a negative serum or urine pregnancy. * Women of childbearing potential (WOCBP) and male subjects must use appropriate method(s) of contraception as stated for the timeline below. Male subjects are not required to use contraception as outlined in protocol.
Exclusion criteria
Subjects meeting any of the criteria below may not participate in the study: * 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 site 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). * Known positive result 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. Testing at screening is not required. * 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. * Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina. * Known left ventricular ejection fraction (LVEF) \< 40% Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF 40%-50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate. * Solid organ or tissue transplant including stem cell transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to a maximum of 50 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. ORR is defined as the percentage of patients who achieve a response (confirmed PR or CR) according to RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 19 months. | The frequency and severity of grade 3+ treatment emergent adverse events are reported by CTCAEv4 term and grade. |
| Duration of Response (DOR) | Up to a maximum of 50 months | DOR was defined as the period measured from the date that evaluation criteria were met for CR or PR (whichever status was recorded first) until the date that recurrence or PD was objectively documented. |
| Progression-Free Survival (PFS) | Up to maximum of 50 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. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause. |
| Overall Survival (OS) | Up to a maximum of 53 months | Overall survival is defined as the time from randomization until death or date of last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Gemcitabine plus carboplatin plus nivolumab
Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \
2-4 weeks after completing combination chemotherapy plus nivolumab)
Gemcitabine: 1000 mg/m\^2
Carboplatin: AUC 4.5 (based on the Calvert formula) | 23 |
| Arm B Gemcitabine plus oxaliplatin plus nivolumab
Nivolumab: Nivolumab 360mg (and/or) Maintenance Single Agent Nivolumab 480mg (starting \
2-4 weeks after completing combination chemotherapy plus nivolumab)
Gemcitabine: 1000 mg/m\^2
Oxaliplatin: 130 mg/m\^2 | 23 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unable to start treatment. | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A | Arm B | Total |
|---|---|---|---|
| Age, Continuous | 72 years | 72 years | 72 years |
| ECOG performance status ECOG = 0 | 8 Participants | 7 Participants | 15 Participants |
| ECOG performance status ECOG = 1 | 11 Participants | 8 Participants | 19 Participants |
| ECOG performance status ECOG = 2 | 4 Participants | 8 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 21 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Primary tumor site Bladder | 17 Participants | 18 Participants | 35 Participants |
| Primary tumor site Renal pelvis | 2 Participants | 2 Participants | 4 Participants |
| Primary tumor site Ureters | 1 Participants | 1 Participants | 2 Participants |
| Primary tumor site Urethra | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 19 Participants | 17 Participants | 36 Participants |
| Region of Enrollment United States | 23 participants | 23 participants | 46 participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 34 Participants |
| Tobacco use history Current | 1 Participants | 2 Participants | 3 Participants |
| Tobacco use history Former | 16 Participants | 11 Participants | 27 Participants |
| Tobacco use history Never | 6 Participants | 10 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 23 | 16 / 23 |
| other Total, other adverse events | 22 / 23 | 23 / 23 |
| serious Total, serious adverse events | 15 / 23 | 17 / 23 |
Outcome results
Primary
Objective Response Rate (ORR)
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. ORR is defined as the percentage of patients who achieve a response (confirmed PR or CR) according to RECIST 1.1.
Time frame: Up to a maximum of 50 months
Population: Out of 23 subjects in Arm B, two subjects were not evaluable for best response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Objective Response Rate (ORR) | 69.6 Percentage of participants |
| Arm B | Objective Response Rate (ORR) | 33.3 Percentage of participants |
Secondary
Adverse Events
The frequency and severity of grade 3+ treatment emergent adverse events are reported by CTCAEv4 term and grade.
Time frame: AE had been recorded from time of signed informed consent until 30 days after discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever occurs first, up to a maximum of 19 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Adverse Events | Hypophosphatemia | 1 Number of Participants |
| Arm A | Adverse Events | Febrile neutropenia | 2 Number of Participants |
| Arm A | Adverse Events | Muscle weakness left-sided | 1 Number of Participants |
| Arm A | Adverse Events | Alkaline phosphatase increased | 0 Number of Participants |
| Arm A | Adverse Events | Peripheral sensory neuropathy | 1 Number of Participants |
| Arm A | Adverse Events | Lung infection | 1 Number of Participants |
| Arm A | Adverse Events | Atrial fibrillation | 1 Number of Participants |
| Arm A | Adverse Events | Aspartate aminotransferase increased | 1 Number of Participants |
| Arm A | Adverse Events | Bladder spasm | 1 Number of Participants |
| Arm A | Adverse Events | Anemia | 8 Number of Participants |
| Arm A | Adverse Events | Dyspnea | 2 Number of Participants |
| Arm A | Adverse Events | Lipase increased | 3 Number of Participants |
| Arm A | Adverse Events | Other respiratory, thoracic and mediastinal disorders | 1 Number of Participants |
| Arm A | Adverse Events | Other infections and infestations | 1 Number of Participants |
| Arm A | Adverse Events | Other skin and subcutaneous tissue disorders | 2 Number of Participants |
| Arm A | Adverse Events | Lymphocyte count decreased | 3 Number of Participants |
| Arm A | Adverse Events | Rash maculo-papular | 2 Number of Participants |
| Arm A | Adverse Events | Hepatitis viral | 1 Number of Participants |
| Arm A | Adverse Events | Other surgical and medical procedures | 0 Number of Participants |
| Arm A | Adverse Events | Neutrophil count decreased | 12 Number of Participants |
| Arm A | Adverse Events | Hypertension | 1 Number of Participants |
| Arm A | Adverse Events | Skin infection | 1 Number of Participants |
| Arm A | Adverse Events | Hypotension | 1 Number of Participants |
| Arm A | Adverse Events | Platelet count decreased | 1 Number of Participants |
| Arm A | Adverse Events | Thromboembolic event | 2 Number of Participants |
| Arm A | Adverse Events | Pain | 2 Number of Participants |
| Arm A | Adverse Events | Hearing impaired | 1 Number of Participants |
| Arm A | Adverse Events | Serum amylase increased | 1 Number of Participants |
| Arm A | Adverse Events | Diarrhea | 0 Number of Participants |
| Arm A | Adverse Events | Urinary tract infection | 4 Number of Participants |
| Arm A | Adverse Events | Nausea | 0 Number of Participants |
| Arm A | Adverse Events | White blood cell decreased | 4 Number of Participants |
| Arm A | Adverse Events | Other gastrointestinal disorders | 0 Number of Participants |
| Arm A | Adverse Events | Kidney infection | 2 Number of Participants |
| Arm A | Adverse Events | Pancreatitis | 1 Number of Participants |
| Arm A | Adverse Events | Hyperglycemia | 0 Number of Participants |
| Arm A | Adverse Events | Upper gastrointestinal hemorrhage | 1 Number of Participants |
| Arm A | Adverse Events | Alanine aminotransferase increased | 1 Number of Participants |
| Arm A | Adverse Events | Vomiting | 0 Number of Participants |
| Arm A | Adverse Events | Hyponatremia | 1 Number of Participants |
| Arm A | Adverse Events | Fatigue | 1 Number of Participants |
| Arm A | Adverse Events | Other investigations | 1 Number of Participants |
| Arm B | Adverse Events | Pain | 1 Number of Participants |
| Arm B | Adverse Events | Other investigations | 0 Number of Participants |
| Arm B | Adverse Events | Anemia | 3 Number of Participants |
| Arm B | Adverse Events | Febrile neutropenia | 0 Number of Participants |
| Arm B | Adverse Events | Hepatitis viral | 0 Number of Participants |
| Arm B | Adverse Events | Kidney infection | 0 Number of Participants |
| Arm B | Adverse Events | Lung infection | 0 Number of Participants |
| Arm B | Adverse Events | Other infections and infestations | 0 Number of Participants |
| Arm B | Adverse Events | Skin infection | 2 Number of Participants |
| Arm B | Adverse Events | Urinary tract infection | 1 Number of Participants |
| Arm B | Adverse Events | Alanine aminotransferase increased | 1 Number of Participants |
| Arm B | Adverse Events | Alkaline phosphatase increased | 2 Number of Participants |
| Arm B | Adverse Events | Aspartate aminotransferase increased | 4 Number of Participants |
| Arm B | Adverse Events | Lipase increased | 7 Number of Participants |
| Arm B | Adverse Events | Lymphocyte count decreased | 1 Number of Participants |
| Arm B | Adverse Events | Neutrophil count decreased | 6 Number of Participants |
| Arm B | Adverse Events | Platelet count decreased | 5 Number of Participants |
| Arm B | Adverse Events | Serum amylase increased | 4 Number of Participants |
| Arm B | Adverse Events | White blood cell decreased | 2 Number of Participants |
| Arm B | Adverse Events | Hyperglycemia | 1 Number of Participants |
| Arm B | Adverse Events | Hyponatremia | 0 Number of Participants |
| Arm B | Adverse Events | Hypophosphatemia | 0 Number of Participants |
| Arm B | Adverse Events | Muscle weakness left-sided | 0 Number of Participants |
| Arm B | Adverse Events | Peripheral sensory neuropathy | 0 Number of Participants |
| Arm B | Adverse Events | Atrial fibrillation | 0 Number of Participants |
| Arm B | Adverse Events | Bladder spasm | 0 Number of Participants |
| Arm B | Adverse Events | Dyspnea | 1 Number of Participants |
| Arm B | Adverse Events | Other respiratory, thoracic and mediastinal disorders | 2 Number of Participants |
| Arm B | Adverse Events | Other skin and subcutaneous tissue disorders | 0 Number of Participants |
| Arm B | Adverse Events | Rash maculo-papular | 0 Number of Participants |
| Arm B | Adverse Events | Other surgical and medical procedures | 1 Number of Participants |
| Arm B | Adverse Events | Hypertension | 2 Number of Participants |
| Arm B | Adverse Events | Hypotension | 0 Number of Participants |
| Arm B | Adverse Events | Thromboembolic event | 1 Number of Participants |
| Arm B | Adverse Events | Hearing impaired | 1 Number of Participants |
| Arm B | Adverse Events | Diarrhea | 1 Number of Participants |
| Arm B | Adverse Events | Nausea | 1 Number of Participants |
| Arm B | Adverse Events | Other gastrointestinal disorders | 1 Number of Participants |
| Arm B | Adverse Events | Pancreatitis | 0 Number of Participants |
| Arm B | Adverse Events | Upper gastrointestinal hemorrhage | 0 Number of Participants |
| Arm B | Adverse Events | Vomiting | 1 Number of Participants |
| Arm B | Adverse Events | Fatigue | 0 Number of Participants |
Secondary
Duration of Response (DOR)
DOR was defined as the period measured from the date that evaluation criteria were met for CR or PR (whichever status was recorded first) until the date that recurrence or PD was objectively documented.
Time frame: Up to a maximum of 50 months
Population: Out of 23 subjects in Arm B, two subjects were not evaluable for efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Duration of Response (DOR) | 8.64 Months |
| Arm B | Duration of Response (DOR) | 6.51 Months |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from randomization until death or date of last contact.
Time frame: Up to a maximum of 53 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Overall Survival (OS) | 24.74 Months |
| Arm B | Overall Survival (OS) | 16.43 Months |
Secondary
Progression-Free Survival (PFS)
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. PFS is defined as time from registration until disease progression met by RECIST 1.1 or death from any cause.
Time frame: Up to maximum of 50 months
Population: Out of 23 subjects in Arm B, two subjects were not evaluable for efficacy analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Progression-Free Survival (PFS) | 9.4 Months |
| Arm B | Progression-Free Survival (PFS) | 8.57 Months |