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

NCT02710734 | Active Not Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: GU-08615-1071
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 4

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.

Conditions

Urothelial Carcinoma of the Bladder

Keywords

Urothelial

Outcome Measures

Primary Outcomes (1)

• Metastasis-free survival (MFS) at 2 years.

  24 months

Secondary Outcomes (1)

• Ability to complete of 3 cycles of neoadjuvant AMVAC and chemoradiation therapy with 5-FU and mitomycin C.

  Up to 37 Weeks

Other Outcomes (7)

• 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

Study Arms (4)

CRT

EXPERIMENTAL

Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then chemoradiation followed by TURBT#3

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

Surveillance

EXPERIMENTAL

Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then active surveillance

Drug: Methotrexate; Drug: Vinblastine; Drug: Doxorubicin; Drug: Cisplatin; Procedure: Transurethral Resection of Bladder tumor

Intravesicle therapy

EXPERIMENTAL

Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then intravesicle therapy followed by TURBT#3

Drug: Methotrexate; Drug: Vinblastine; Drug: Doxorubicin; Drug: Cisplatin; Procedure: Transurethral Resection of Bladder tumor

Radical Cystectomy

EXPERIMENTAL

Trimodality of Maximal TURBT#1 Followed by AMVAC and TURBT#2 and then cystectomy

Drug: Methotrexate; Drug: Vinblastine; Drug: Doxorubicin; Drug: Cisplatin; Procedure: Transurethral Resection of Bladder tumor

Interventions

Methotrexate DRUG

Administered Day 1 of each 14 day cycle for 3 cycles

CRT; Intravesicle therapy; Radical Cystectomy; Surveillance

Vinblastine DRUG

Administered Day 1 of each 14 day cycle for 3 cycles

CRT; Intravesicle therapy; Radical Cystectomy; Surveillance

Doxorubicin DRUG

Administered Day 1 of each 14 day cycle for 3 cycles

CRT; Intravesicle therapy; Radical Cystectomy; Surveillance

Cisplatin DRUG

Administered Day 1 of each 14 day cycle for 3 cycles

CRT; Intravesicle therapy; Radical Cystectomy; Surveillance

Intensity modulated radiation therapy (IMRT) RADIATION

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

CRT

Transurethral Resection of Bladder tumor PROCEDURE

Performed at before and after AMVAC and after chemoradiation and intravesicle therapy

CRT; Intravesicle therapy; Radical Cystectomy; Surveillance

5-FU DRUG

Continuous 24hr Intravenous infusion days 1-5 and 16-20 with radiation treatment

CRT

Mitomycin C DRUG

Intravenous on day 1 with radiation treatment

CRT

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Fox Chase Cancer Center: lead

Study Sites (4)

Washington Cancer Institute at MedStar Washington Hospital Center

Washington D.C., District of Columbia, 20010, United States

Location

Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Sidney kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

Related Publications (2)

• Geynisman DM, Abbosh PH, Ross E, Zibelman MR, Ghatalia P, Anari F, Mark JR, Stamatakis L, Hoffman-Censits JH, Viterbo R, Greenberg RE, Churilla TM, Horwitz EM, Hallman MA, Smaldone MC, Uzzo R, Chen DYT, Kutikov A, Plimack ER. Phase II Trial of Risk-Enabled Therapy After Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer (RETAIN 1). J Clin Oncol. 2025 Mar 20;43(9):1113-1122. doi: 10.1200/JCO-24-01214. Epub 2024 Dec 16.

  PMID: 39680823 DERIVED

• Jiang DM, Chung P, Kulkarni GS, James ND, Sridhar SS. Lack of Evidence Does Not Equal Lack of Benefit: Neoadjuvant Chemotherapy and Trimodality Therapy in Selected Patients with Muscle-Invasive Bladder Cancer : In response to: Dirk Bohmer and Arne Grun. Lacking Evidence to Recommend Neoadjuvant Chemotherapy and Definitive Radiotherapy in Muscle-Invasive Bladder Cancer. Curr Oncol Rep. 2021 Mar 3;23(3):36. doi: 10.1007/s11912-021-01035-9. No abstract available.

  PMID: 33660142 DERIVED

MeSH Terms

Interventions

Methotrexate; Vinblastine; Doxorubicin; Cisplatin; Radiotherapy, Intensity-Modulated; Transurethral Resection of Bladder; Fluorouracil; Mitomycin

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics; Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Mitomycins; Indolequinones; Quinones; Azirines

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2016
• First Posted: March 17, 2016
• Study Start: February 24, 2016
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2034
• Last Updated: December 24, 2024

Record last verified: 2024-12

Locations

US (4)