Bladder Cancer, Muscle-Invasive Bladder Carcinoma, Urothelial Carcinoma
Conditions
Keywords
Muscle-Invasive Bladder Carcinoma, Bladder Cancer, MIBC, urothelial carcinoma, bladder preservation
Brief summary
In this research study, investigators will assess whether it is feasible to use information from the genes of a tumor combined with evaluation of the tumor response to systemic therapy to determine if bladder sparing chemoradiation can be used or if surgery to remove the bladder, or radical cystectomy, is needed.
Detailed description
This is a single-center, early phase 1 pilot study in which investigators will assess whether it is feasible to use information from the genes of a tumor combined with evaluation of the tumor response to systemic therapy to determine if bladder sparing chemoradiation can be used or if surgery to remove the bladder, or radical cystectomy, is needed. Perioperative systemic therapy with surgical removal of the bladder or chemoradiation are standard treatments for muscle-invasive bladder cancer. The investigational part of this study is using specific information from the tumor and response to therapy to guide a standard-of-care treatment decision. The research study procedures include screening for eligibility, standard of care systemic therapy, cystoscopy with biopsy, Magnetic Resonance Imaging studies, either bladder sparing chemoradiation or surgical removal of the bladder, blood tests, urine tests, questionnaires, and follow up visits. Participation in this research study is expected to last for 2 years. It is expected about 20 people will take part in this research study. AstraZeneca Pharmaceuticals LP is supporting this research study by providing funding for the trial Predicine is supporting this research study by providing funding for the molecular testing and tests required for research purposes. Tufts University is providing funding for tests for research purposes.
Interventions
DRUGGemzar
Nucleoside metabolic inhibitor, 200 mg single-dose vial, via intravenous infusion per standard of care.
DRUGCisplatin
Platinum-based drug, 50 mg single-dose vial containing, via intravenous infusion per standard of care.
DRUGAdrucil
Antineoplastic antimetabolite, 500 mg single-dose vial, via intravenous infusion per standard of care.
DRUGMitomycin
Antibiotic, single-dose vials containing either 5, 10, 20, or 40 mg of mitomycin, via intravenous infusion per standard of care.
PROCEDURERadical Cystectomy
Surgical removal of the bladder
Sponsors
Dana-Farber Cancer Institute
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
* Patient must have signed written informed consent indicating understanding of the purpose of the study and willingness to participate prior to any protocol-related procedures, including screening evaluation. * Participants must have histologically confirmed cT2-cT4aN0M0 urothelial (transitional cell) carcinoma of the bladder. Mixed histology is acceptable as long as there is a majority component of urothelial carcinoma. * Availability of baseline archival tumor tissue obtained for molecular analysis and correlative studies * Age ≥ 18 years * Candidate for radical cystectomy * Cisplatin eligible * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Participants infected with human immunodeficiency virus on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * Participants with evidence of chronic hepatitis B virus infection with an undetectable HBV viral load on suppressive therapy, if indicated, are eligible for this trial * Participants with a history of hepatitis C virus (HCV) must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Participants with a prior or concurrent history of malignancy whose natural history of treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational protocol are eligible for this trial * Participants must have adequate organ and marrow function as defined below: * Leukocytes ≥3,000/mcL * Hemoglobin ≥9.0 g/dL * Absolute neutrophil count ≥1,500/mcL * Platelets ≥100,000/mcL * International Normalized ratio ≤1.5 x institutional upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN * Unless the patient is receiving anticoagulation therapy provided INR or PTT is within the therapeutic range of the intended anticoagulant * Total bilirubin ≤ institutional upper limit of normal (ULN) * This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician * AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN * Measured creatinine clearance ≥ 50 mL/min or calculated creatinine clearance 50mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: * Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) * Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) * Evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal female patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. * Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment. * Patient is willing and able to comply with the protocol for the duration of the trial
Exclusion criteria
* Patients with urothelial carcinoma of the ureter, urethra, or renal pelvis * Contraindication for bladder radiation * Inoperable primary tumor * Any previous systemic chemotherapy or radiotherapy for bladder cancer * Inflammatory bowel disease * Patients who are receiving or have received any other investigational agents within 6 months of study entry * Child-Pugh class C hepatic impairment * Receipt of the last dose of intravesical chemotherapy or biologic therapy ≤ 42 days (6 weeks) prior to the first dose of study drug for patients who have received prior intravesical chemotherapy or biologic therapy (e.g. BCG) * Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, unstable cardiac arrhythmia, symptomatic interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent * Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements * Pregnant women are excluded from this study because chemotherapy and radiation have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with chemotherapy, breastfeeding should be discontinued if the mother is treated with chemotherapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility Failure Rate (FFR) | Approximately 16 weeks after initiation of neoadjuvant chemotherapy | FFR defined as the proportion of participants that achieve feasibility failure. Feasibility is defined as the ability to derive interpretable information from ≥70% of evaluable patients from tumor genomics and/or transcriptomic studies before NAC plus mpMRI or cystoscopic evaluation and urine cytology to guide the patient toward an informed decision for bladder preservation chemoradiation vs. RC. Evaluable patients are those who initiate planned NAC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Complete Response (cCR) Rate | Approximately 16 weeks after initiation of neoadjuvant chemotherapy | The cCR Rate is the proportion of participants achieving cCR. Patients will be defined as having a cCR if there is no residual disease (of any stage) on cystoscopy/TURBT/urine cytology and no evidence of disease on mpMRI. |
| Bladder Preserving Rate | Approximately 24 weeks after initiation of neoadjuvant chemotherapy, at time of definitive therapy | Bladder Preserving Rate is defined as the proportion of patients who preserve their bladders employing this strategy |
| Median Bladder-Intact Disease-Free Survival (BIDFS) | Disease evaluated radiolagically after completion of cisplatin-based neoadjuvant chemotherapy and after definitive treatment with chemoradiation/radical cystectomy.In long-term follow-up,data collected every 3-6 months for 2 years or progressive disease. | Bladder-intact disease-free survival based on Laplan-Meier method is defined as the time from registration to the earlier of cystectomy, progression, or death due to any cause. Participants alive with an intact bladder and without disease progression are censored at date of last disease evaluation. |
| Recurrence Rate at 1 Year | Relevant to this endpoint is at 1 year | Recurrence rate defined proportion of participants were diagnosed disease recurrence. Disease recurrence is defined as time from completion of NAC to development of a new primary urothelial carcinoma, local recurrence, or development of metastatic disease. New primary urothelial carcinoma and local recurrence will be evaluated using cystoscopy and metastatic disease will be measured using RECIST v. 1.1. |
| Recurrence Rate at 2 Year | Relevant to this endpoint is at 2 year | Recurrence rate defined proportion of participants were diagnosed disease recurrence. Disease recurrence is defined as time from completion of NAC to development of a new primary urothelial carcinoma, local recurrence, or development of metastatic disease. New primary urothelial carcinoma and local recurrence will be evaluated using cystoscopy and metastatic disease will be measured using RECIST v. 1.1. |
| 1-Year Overall Survival (OS) | In long-term follow-up, participants were assessed every 6 months, up to 2 years. Relevant to this endpoint is the estimate at 1 year. | 1-year OS is a probability estimated using the Kaplan-Meier method; OS is defined as the time from study entry to death, or censored at date last known alive. |
| 2-year Overall Survival (OS) | In long-term follow-up, participants were assessed every 6 months, up to 2 years. Relevant to this endpoint is the estimate at 2 years. | 2-year OS is a probability estimated using the Kaplan-Meier method; OS is defined as the time from study entry to death, or censored at date last known alive. |
| Longitudinal assessment of quality of life using the Bladder Cancer Index | Data are collected baseline, after neoadjuvant chemotherapy, after definitive treatment (CRT/RC), during follow-up and off sutdy visit, with up to 2 years of follow up. | Bladder Cancer Index (BCI) data will be analyzed descriptively to characterize longitudinal changes in symptom severity and symptom interference across the prespecified study time points.. Exploratory analyses may assess BCI trajectories by molecular status, treatment response, and/or definitive treatment (chemoradiation therapy \[CRT\] versus radical cystectomy \[RC\]). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORCharlene Mantia, MD
Dana-Farber Cancer Institute
Outcome results
None listed