High Risk Urothelial Carcinoma of the Upper Urinary Tracts, Muscle Invasive Bladder Cancer
Conditions
Keywords
bladder, cancer, invasive
Brief summary
Standard treatment for early stage bladder cancer is chemotherapy with methotrexate (M), vinblastine (V), adriamycin (A), and cisplatin (C) followed by surgical removal of any remaining cancer and the bladder with the intent of cure. The M V chemotherapy is usually given every 14 days with the AC given along each 28 days. This study looks at giving the same drugs at the same doses closer together, all drugs every 14 days, with the support of growth factor medication to promote growth of the white blood cells and platelets and allow chemotherapy to be finished sooner and surgery to be done sooner.
Detailed description
Primary Objective To assess the rate of complete response (pT0) at cystectomy or ureterectomy following preoperative dose dense MVAC (DD-MVAC) in patients with muscle invasive urothelial carcinoma of the bladder or high grade upper tract urothelial carcinoma. Secondary Objectives To assess the toxicity profile of DD-MVAC when given in the neoadjuvant setting: To define the number of patients who complete all three cycles of treatment without dose reduction, and to compare incidence of toxicity to the historical standard described by Grossman et al. To assess the 5 year overall and relapse free survival in patients who receive neoadjuvant DD-MVAC. To compare complete response rates between the following subgroups of study patients: Among bladder patients: Clinical N0 versus N1 (Appendix B) Among bladder patients: T2 stage without high risk features versus T2 with high risk features plus those with \> T2 stage. Three 14 day cycles of: Methotrexate 30 mg/m2 IV push or infusion over 2-3 minutes. Day 1 Vinblastine 3 mg/m2 Slow IV push or infusion over Day 1 Doxorubicin 30 mg/m2 Slow IV push or infusion over 15 minutes Day 1 Cisplatin 70 mg/m2 IV infusion over 4 hours Note: May divide dose over two sequential days (35 mg/m2/d x 2 days) if creatinine clearance 50-59 mL/min Day 1\* (or divided over Day 1 and Day 2) Pegfilgrastim 6 mg subcutaneous (SQ) 24-48 hours after completion of chemotherapy. Followed in 4-8 weeks by radical cystectomy/ureterectomy.
Interventions
DRUGsingle arm dose dense MVAC
standard doses of methotrexate, vinblastine, adriamycin, and cisplatin given every 14 days.
Sponsors
Fox Chase Cancer Center
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
* histologically confirmed urothelial carcinoma of bladder, ureter, or renal pelvis. T2-T4 and muscle invasion must be established by TURBT. Upper tract must be high grade. N0-N1 are eligible. * candidate for radical cystectomy, nephroureterectomy, or segmental ureterectomy with goal of cure. -\>/= 18 years old * ECOG performance status 0-1. * Adequate marrow and organ function. * May enter on therapeutic anticoagulation if it can be safely held during perioperative period. * No women of childbearing potential, pregnant or breastfeeding. * LVEF \>/= 50 % * Patients with history of other non-urothelial malignancies may enroll if: 1)no evidence of distant disease w/in last year. 2)No anticancer treatment for \>/= 1 year other than adjuvant treatment or treatment for secondary prevention. 3) Less than 360 mg/m2 lifetime dose of adriamycin. * ability to understand and willingness to sign written informed consent and HIPAA.
Exclusion criteria
* Intravesicular therapy w/in 4 weeks of study entry or those who have not recovered from adverse effects of such agents administered more than 4 weeks earlier. * Patients may not be receiving any investigational agents within 4 weeks of study entry. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to Methotrexate, Vinblastine, Adriamycin or Cisplatin or other agents used in the study. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects of cytotoxic chemotherapy. * Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cytotoxic chemotherapy. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. -. Patients who have undergone prior pelvic radiation are excluded due to risk of life threatening myelosuppression. * Patients who have received any previous systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response at Cystectomy or Ureterectomy Following Preoperative Dose Dense MVAC | Following completion of the 3rd/final cycle of chemotherapy (about week 9) by CT imaging and at time of surgery for pathologic response. | complete response rate (pT0), as defined by pathologic staging at cystectomy or ureterectomy, following neoadjuvant DD-MVAC chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Profile of Dose Dense MVAC Given in the Neoadjuvant Setting. | Ongoing throughout treatment at each MD visit every 14 days. | Defined by number of patients who complete all three cycles of treatment without dose reduction |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dose Dense MVAC standard doses of MVAC given every 14 days x 3.
single arm dose dense MVAC: standard doses of methotrexate, vinblastine, adriamycin, and cisplatin given every 14 days. | 54 |
| Total | 54 |
Baseline characteristics
| Characteristic | Dose Dense MVAC |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 28 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants |
| Age, Continuous | 65 years |
| Region of Enrollment United States | 54 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 40 |
| serious Total, serious adverse events | 22 / 40 |
Outcome results
Primary
Percentage of Participants With Complete Response at Cystectomy or Ureterectomy Following Preoperative Dose Dense MVAC
complete response rate (pT0), as defined by pathologic staging at cystectomy or ureterectomy, following neoadjuvant DD-MVAC chemotherapy.
Time frame: Following completion of the 3rd/final cycle of chemotherapy (about week 9) by CT imaging and at time of surgery for pathologic response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Dense MVAC | Percentage of Participants With Complete Response at Cystectomy or Ureterectomy Following Preoperative Dose Dense MVAC | 38 percentage of total participants |
Secondary
Toxicity Profile of Dose Dense MVAC Given in the Neoadjuvant Setting.
Defined by number of patients who complete all three cycles of treatment without dose reduction
Time frame: Ongoing throughout treatment at each MD visit every 14 days.
Population: Forty patients were evaluable for response as predefined in the protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Dense MVAC | Toxicity Profile of Dose Dense MVAC Given in the Neoadjuvant Setting. | All three cycles of chemotherapy were completed | 37 participants |
| Dose Dense MVAC | Toxicity Profile of Dose Dense MVAC Given in the Neoadjuvant Setting. | Discontinued chemotherapy | 3 participants |