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

Status: Active

Description

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.

Eligibility Criteria

Inclusion Criteria

  • Male or female patients >= 18 years
  • Primary urothelial or predominantly urothelial carcinoma of the bladder
  • Histologic evidence of muscularis propria invasion
  • American Joint Committee on Cancer (AJCC) clinical stage T2-T3 N0M0
  • No radiographic evidence of lymph node positive disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (>= 15 mm short axis diameter); lymph node positive disease is defined as clinical lymphadenopathy on staging computed tomography (CT) or magnetic resonance imaging (MRI) greater than 1.4 cm in the short axis; if a lymph node is greater than 1.4 cm, it has to be biopsy proven negative for the patient to be eligible
  • No metastatic disease (M0)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, or 1
  • Left ventricular ejection fraction >= 50% by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) within 6 months of study entry
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutmic oxaloacetic transaminas [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
  • 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; patients who received radiation for prostate cancer are also excluded
  • Prior systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible
  • Has a known additional malignancy that has had progression or has required active treatments in the last three years; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer; a history of prostate cancer that was treated with surgery is acceptable, provided that the following criteria are met: stage T2N0M0 or lower; prostate specific antigen (PSA) undetectable for 1 year while off androgen deprivation therapy; patients on active surveillance for low grade prostate cancer are allowed to participate
  • 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, doxorubicin 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
  • Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Patients with hydronephrosis that has not been addressed with a documented assessment (i.e. normal glomerular filtration rate [GFR], no intervention necessary) or an intervention such as placement of a stent or nephrostomy tube

Locations & Contacts

District of Columbia

Washington
MedStar Washington Hospital Center
Status: Active
Contact: Lambros Stamatakis
Phone: 202-877-8839
Email: lambros.stamatakis@medstar.net

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: Active
Contact: Jean H. Hoffman-Censits
Phone: 434-287-2886
Email: Jhoffm57@jhmi.edu

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: Active
Contact: Daniel M. Geynisman
Phone: 215-728-3889
Email: daniel.geynisman@fccc.edu

Trial Objectives and Outline

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.

PRIMARY OBJECTIVE:

I. To evaluate the metastasis-free survival (defined as a recurrence of urothelial carcinoma that is > cN1 [more than one clinically suspicious pelvic lymph node] or surgically unresectable local recurrence [e.g., > cT4a] or M1 disease) at 2 years for all patients.

SECONDARY OBJECTIVES:

I. To assess the feasibility of combined modality therapy (CMT) in muscle invasive bladder cancer with neoadjuvant methotrexate, vinblastine sulfate (vinblastine), doxorubicin hydrochloride (doxorubicin), and cisplatin (AMVAC) followed by concurrent chemoradiation with intensity modulated radiation therapy (IMRT) and fluorouracil (5-fluorouracil) and mitomycin (mitomycin C) for patients after neoadjuvant cisplatin-based chemotherapy (NAC) who have residual non-muscle invasive bladder cancer (NMIBC), cT2 disease or no residual disease but also no mutations of interest.

II. To assess the rate of any urothelial carcinoma recurrence in active surveillance patients.

III. To assess overall survival and progression-free survival of the entire cohort.

IV. To assess toxicity during NAC and chemoradiation therapy (CRT).

V. To assess the proportion of patients with >= cT1 disease after NAC.

VI. To assess bladder preservation rates with neoadjuvant AMVAC and subsequent risk-adapted treatment.

VII. To assess the feasibility of an Endoscopic Tumor Quantification System.

VIII. To assess quality of life with neoadjuvant AMVAC and subsequent risk-adapted treatment.

IX. To assess genomic correlates and mutations in urinary cell-free deoxyribonucleic acid (DNA).

OUTLINE

Beginning within 2 weeks after the first TURBT, patients receive methotrexate intravenously (IV) over 2-3 minutes, vinblastine sulfate IV over 20 minutes, doxorubicin hydrochloride IV over 15 minutes, and cisplatin IV over at least 1 hour on day 1 (or days 1 and 2). Treatment repeats every 14 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning within 4 weeks after completion of chemotherapy, patients undergo second TURBT. Patients undergo IMRT on days 1-5 for over 6.5 weeks and receive fluorouracil IV continuously over 24 hours on days 1-5 and 16-20 and mitomycin per institution standard on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity. Beginning 6-12 weeks after completion of therapy, patients undergo final TURBT.

After completion of treatment, patients are followed up every 4 months for 2 years and then every 6 months for years 3-5.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Fox Chase Cancer Center

Principal Investigator
Daniel M. Geynisman

Trial IDs

Primary ID GU-086
Secondary IDs NCI-2016-00254
Clinicaltrials.gov ID NCT02710734