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Risk Enabled Therapy after Neoadjuvant Immunochemotherapy for the Treatment of Bladder Cancer

Trial Status: Approved

This phase II trial studies the effect of nivolumab when given together with chemotherapy drugs in treating patients with muscle invasive bladder cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as the accelerated methotrexate / vinblastine / adriamycin / cisplatin (AMVAC) regimen, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Nivolumab in combination with the AMVAC chemotherapy regimen may help patients avoid or delay surgery and improve the quality of life and long term survival of patients with bladder cancer.

Inclusion Criteria

  • Male or female patients >= 18 years
  • Primary urothelial or predominantly urothelial carcinoma of the bladder confirmed from pathology report. Patients with some component of variant histology mixed with predominant urothelial carcinoma will be allowed. Upper tract urothelial carcinoma patients are not allowed
  • Urothelial carcinoma of the prostatic urethra in men is allowed
  • 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 multigated acquisition scan (MUGA) or echocardiogram (ECHO) within 6 months of study entry
  • Negative pregnancy test in women of child bearing potential within 24 hours of study registration. If the pregnancy test is positive, the patient must not receive protocol treatment and must not be enrolled in the study
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< institutional upper limit of normal (ULN). If a patient has known Gilbert’s disease, an elevated bilirubin is allowed
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X institutional ULN
  • Creatinine clearance >= 50 mL/min (calculated using the Cockcroft-Gault formula or measured with 24 hour urine collection)
  • Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document

Exclusion Criteria

  • Any component of small cell histology
  • Prior systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible. Patients who received immunotherapy for non-muscle invasive bladder cancer will be excluded
  • 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
  • Patients who have received doxorubicin based treatment in the past
  • 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 due to the potential for teratogenic or abortifacient effects of cytotoxic chemotherapy
  • Known human immunodeficiency virus (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 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
  • Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease. Use of steroids as pre-medication for contrast allergy prior to CT scans is permitted. It is acceptable to use steroids as pre-medication for AMVAC
  • History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
  • Prior treatment with CD137 agonists, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
  • Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrollment


Fox Chase Cancer Center
Contact: Pooja Ghatalia
Phone: 215-728-3889


I. To test whether an adaptive strategy of bladder preservation (using pre-specified tumor mutations and post-treatment clinical response) will not compromise long term oncologic outcomes (metastasis-free survival at 2 years).


I. To allow bladder preservation in selected patients using adaptive strategy post-neoadjuvant nivolumab and AMVAC.

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

III. To assess proportion of patients with > cT1 disease after neoadjuvant AMVAC and nivolumab.

IV. To assess overall survival and progression free survival for all patients.

V. To assess toxicity of neoadjuvant nivolumab and AMVAC therapy.

VI. To assess time from initiation of neoadjuvant therapy to surgery.

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.


I. To assess genomic and immune correlates.

II. To assess circulating free tumor deoxyribonucleic acid (DNA).

III. To assess and compare the epigenetic state of immune cells before and after therapy.

IV. To assess germline DDR (DNA damage repair) correlates.


Patients receive nivolumab intravenously (IV), methotrexate IV, vinblastine IV over 15 minutes, doxorubicin IV over 15-30 minutes, cisplatin IV over 1-2 hours, and pegfilgrastim subcutaneously (SC) on days 1, 15, and 29 in the absence of disease progression or unacceptable toxicity.

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

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Fox Chase Cancer Center

Principal Investigator
Pooja Ghatalia

  • Primary ID GU-176
  • Secondary IDs NCI-2020-12080, 20-1047
  • ID NCT04506554