Risk Enabled Therapy After Initiating Neoadjuvant Chemotherapy for Bladder Cancer (RETAIN)

Sponsor

Fox Chase Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02710734

Collaborator

(none)

Enrollment

Locations

Arms

215.3

Anticipated Duration (Months)

19.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this study is to evaluate a risk-adapted approach to the treatment of muscle invasive bladder cancer. Each baseline transuretheral resection of bladder tumor (TURBT) sample will be sequenced while proceeding with neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) chemotherapy. Based on the mutational profile and the post AMVAC TURBT findings, patients will be treated with active surveillance (experimental arm), or standard of care intravesicle therapy, chemoradiation or surgery. We hypothesize that this approach will lead to non-inferior metastasis-free survival at 2 years, while preserving the bladder and thus quality-of-life for a proportion of patients.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Carcinoma of the Bladder	Drug: Methotrexate Drug: Vinblastine Drug: Doxorubicin Drug: Cisplatin Radiation: Intensity modulated radiation therapy (IMRT) Procedure: Transurethral Resection of Bladder tumor Drug: 5-FU Drug: Mitomycin C	Phase 2

Detailed Description

This phase II trial studies how well maximal transurethral surgery (surgery performed with a special instrument inserted through the urethra) followed by accelerated methotrexate, vinblastine, doxorubicin hydrochloride, cisplatin, and radiation therapy work in treating patients with bladder cancer that has spread to the muscle. Drugs used in chemotherapy, such as methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving chemotherapy with radiation therapy may kill more tumor cells. Giving combination chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Study Design

Study Type:

Interventional

Actual Enrollment :

78 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Trial of Risk Enabled Therapy After Initiating Neoadjuvant Chemotherapy for Bladder Cancer (RETAIN BLADDER)

Actual Study Start Date :

Feb 24, 2016

Anticipated Primary Completion Date :

Feb 1, 2027

Anticipated Study Completion Date :

Feb 1, 2034

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CRT Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then chemoradiation followed by TURBT#3	Drug: Methotrexate Administered Day 1 of each 14 day cycle for 3 cycles Drug: Vinblastine Administered Day 1 of each 14 day cycle for 3 cycles Drug: Doxorubicin Administered Day 1 of each 14 day cycle for 3 cycles Drug: Cisplatin Administered Day 1 of each 14 day cycle for 3 cycles Radiation: Intensity modulated radiation therapy (IMRT) 2.0 Gy per fraction to the whole bladder plus a margin for a total of 32 fractions (64.0 Gy). Radiation will be administered from Monday to Friday Procedure: Transurethral Resection of Bladder tumor Performed at before and after AMVAC and after chemoradiation and intravesicle therapy Drug: 5-FU Continuous 24hr Intravenous infusion days 1-5 and 16-20 with radiation treatment Drug: Mitomycin C Intravenous on day 1 with radiation treatment
Experimental: Surveillance Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then active surveillance	Drug: Methotrexate Administered Day 1 of each 14 day cycle for 3 cycles Drug: Vinblastine Administered Day 1 of each 14 day cycle for 3 cycles Drug: Doxorubicin Administered Day 1 of each 14 day cycle for 3 cycles Drug: Cisplatin Administered Day 1 of each 14 day cycle for 3 cycles Procedure: Transurethral Resection of Bladder tumor Performed at before and after AMVAC and after chemoradiation and intravesicle therapy
Experimental: Intravesicle therapy Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then intravesicle therapy followed by TURBT#3	Drug: Methotrexate Administered Day 1 of each 14 day cycle for 3 cycles Drug: Vinblastine Administered Day 1 of each 14 day cycle for 3 cycles Drug: Doxorubicin Administered Day 1 of each 14 day cycle for 3 cycles Drug: Cisplatin Administered Day 1 of each 14 day cycle for 3 cycles Procedure: Transurethral Resection of Bladder tumor Performed at before and after AMVAC and after chemoradiation and intravesicle therapy
Experimental: Radical Cystectomy Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then cystectomy	Drug: Methotrexate Administered Day 1 of each 14 day cycle for 3 cycles Drug: Vinblastine Administered Day 1 of each 14 day cycle for 3 cycles Drug: Doxorubicin Administered Day 1 of each 14 day cycle for 3 cycles Drug: Cisplatin Administered Day 1 of each 14 day cycle for 3 cycles Procedure: Transurethral Resection of Bladder tumor Performed at before and after AMVAC and after chemoradiation and intravesicle therapy

Outcome Measures

Primary Outcome Measures

Metastasis-free survival (MFS) at 2 years. [24 months]

Secondary Outcome Measures

Ability to complete of 3 cycles of neoadjuvant AMVAC and chemoradiation therapy with 5-FU and mitomycin C. [Up to 37 Weeks]

Other Outcome Measures

Rate of urothelial carcinoma recurrence in active surveillance patients [60 months]
Overall survival and PFS of the entire cohort [60 months]
toxicity during each treatment arm according to NCI CTCAE v 4.01 criteria [24 months]
Proportion of patients with ≥cT1 disease after TURBT#2 [up to 22 weeks]
Proportion of patients requiring a cystectomy, either immediately after TURBT#2 or as salvage after surveillance or CRT [up to 24 months]
Endoscopic Tumor Quantification System score at each TURBT [24 months]
At each cystoscopic examination, the location and extent of tumor volume will be visually depicted and graded according to Endoscopic Tumor Quantification System
Quality of life with neoadjuvant AMVAC and subsequent risk-adapted treatment [60 months]
American Urologic Association (AUA) Symptom Index Score, Sexual Health Inventory for Men (SHIM) score or Female Sexual Function Index (FSFI) score

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female patients ≥18 years.
Primary urothelial or predominantly urothelial carcinoma of the bladder.
Histologic evidence of muscularis propria invasion.
AJCC27 clinical stage T2-T4a .
No radiographic evidence of lymph node positivity (N0) or metastatic disease (M0). Clinical lymphadenopathy on staging CT greater than 1.5 cm in short axis must be biopsy proven negative.
ECOG performance status 0, 1, or 2.
Left ventricular ejection fraction ≥ 50% by MUGA or ECHO within 6 months of study entry.
Normal organ and bone marrow function as defined:

Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN Creatinine Creatinine Clearance ≥ 50 mL/min (calculated using the Cockroft-Gault formula or measured with 24 hour urine collection)

Exclusion Criteria:

Any component of small cell histology.
Prior pelvic radiation therapy or patients who have undergone prior radiation to greater than or equal to 25% of the bone marrow within the past year are excluded due to risk of life threatening myelosuppression
Prior systemic chemotherapy; 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.
Prior or concurrent malignancy of any other site except for non-melanoma skin cancer, unless disease free interval ≥ 5 years.
Patients who have received experimental 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 (defined by current oral or intravenous antibiotic therapy), 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 with hydronephrosis that has not been addressed with an intervention such as placement of a stent.
Pregnancy & Women of Childbearing Potential

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington Cancer Institute at MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
2	Johns Hopkins	Baltimore	Maryland	United States	21287
3	Sidney kimmel Cancer Center	Philadelphia	Pennsylvania	United States	19107
4	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111