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

• ClinicalTrials.gov Identifier: NCT02710734
• Recruitment Status: Recruiting
• First Posted: March 17, 2016
• Last Update Posted: September 19, 2019
• Sponsor: Fox Chase Cancer Center
• Information provided by (Responsible Party): Fox Chase Cancer Center

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 (Clinical Trial)
• Estimated Enrollment: 38 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: February 24, 2016
• Estimated Primary Completion Date: April 2020
• Estimated Study Completion Date: April 2023

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 :

1. Metastasis-free survival (MFS) at 2 years. [ Time Frame: 24 months ]

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Rate of urothelial carcinoma recurrence in active surveillance patients [ Time Frame: 60 months ]
2. Overall survival and PFS of the entire cohort [ Time Frame: 60 months ]
3. toxicity during each treatment arm according to NCI CTCAE v 4.01 criteria [ Time Frame: 24 months ]
4. Proportion of patients with ≥cT1 disease after TURBT#2 [ Time Frame: up to 22 weeks ]
5. Proportion of patients requiring a cystectomy, either immediately after TURBT#2 or as salvage after surveillance or CRT [ Time Frame: up to 24 months ]
6. Endoscopic Tumor Quantification System score at each TURBT [ Time Frame: 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
7. Quality of life with neoadjuvant AMVAC and subsequent risk-adapted treatment [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts

Contact: Daniel Geynisman, MD; 215-214-1515; Daniel.Geynisman@fccc.edu

Locations

United States, District of Columbia

Washington Cancer Institute at MedStar Washington Hospital Center; Recruiting

Washington, District of Columbia, United States, 20010

Contact: Lambros Stamatakis, MD 202-877-8839 lambros.stamatakis@medstar.net

United States, Maryland

Johns Hopkins; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Jean Hoffman-Censits, MD 410-955-8893 jhoffm57@jhmi.edu

United States, Pennsylvania

Sidney kimmel Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19107

Contact: James Mark, MD 215-955-8874

Fox Chase Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19111

Contact: Daniel Geynisman, MD 215-728-4300 daniel.geynisman@fccc.edu

Principal Investigator: Daniel Geynisman, MD

Sponsors and Collaborators

Fox Chase Cancer Center

More Information

• Responsible Party: Fox Chase Cancer Center
• ClinicalTrials.gov Identifier: NCT02710734 History of Changes
• Other Study ID Numbers: GU-086; 15-1071 ( Other Identifier: Fox Chase Cancer Center IRB )
• First Posted: March 17, 2016
• Last Update Posted: September 19, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Fox Chase Cancer Center:

Urothelial

Additional relevant MeSH terms:

Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Urinary Bladder Diseases; Urologic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Doxorubicin; Methotrexate; Mitomycins; Mitomycin; Vinblastine; Antineoplastic Agents; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents; Folic Acid Antagonists