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Avelumab and Bladder-Directed Radiation in Treating Cisplatin-Ineligible Patients with Muscle-Invasive Bladder Urothelial Cancer

Trial Status: Temporarily Closed to Accrual

This phase II trial studies the side effects and how well avelumab works when given together with bladder-targeted radiation in treating cisplatin-ineligible patients with muscle-invasive bladder urothelial cancer. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons, or other sources to kill tumor cells and shrink tumors. Giving avelumab and bladder-directed radiation may work better in treating patients with muscle-invasive bladder urothelial cancer.

Inclusion Criteria

  • Histologically confirmed transitional cell (urothelial) carcinoma of the bladder that is invasive into the muscularis propria (>= T2 disease) within 6 months of enrollment date. The presence of variant histologies (squamous, adenocarcinoma, micropapillary, etc.) is allowed * Note: A prior diagnosis of non-muscle-invasive bladder cancer (=< T1) managed with transurethral resection with or without intravesicular therapy (now with muscle invasion) is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky score >= 60%
  • Life expectancy of greater than 1 year
  • Hemoglobin > 9 g/dL (conducted within 28 days prior to registration)
  • Platelet count > 100,000 per mm^3 (conducted within 28 days prior to registration)
  • Leukocyte count > 3,000 per mm^3 (conducted within 28 days prior to registration)
  • Absolute neutrophil count (ANC) > 1,500 per mm^3 (conducted within 28 days prior to registration)
  • Total bilirubin < 1.5 x upper limit of normal (ULN) (conducted within 28 days prior to registration) * For patients with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, direct bilirubin must be < 1.5 x ULN
  • Aspartate aminotransferase (AST) < 2.5 x ULN (conducted within 28 days prior to registration)
  • Alanine aminotransferase (ALT) < 2.5 x ULN (conducted within 28 days prior to registration)
  • Estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula (conducted within 28 days prior to registration)
  • Inability to receive cisplatin-based chemotherapy, as defined by creatinine clearance < 60 ml/min, ECOG performance scale (PS) =< 2, grade 2 or higher hearing loss, New York Heart Association (NYHA) class 3 or higher, neuropathy (grade 2 or higher), or patient refusal to receive cisplatin-based chemotherapy
  • Women of child-bearing age must have a negative serum pregnancy test at screening
  • Women of child-bearing potential and men must agree to use a highly effective method of contraception (hormonal or barrier method of birth control, or abstinence) beginning prior to study entry, for the duration of study participation, and for at least 30 days after last avelumab treatment administration if the risk of conception exists
  • Ability to start study treatment (first cycle of avelumab) within 1-8 weeks of the most recent pre-study transurethral resection of bladder tumor (TURBT)
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • Prior intravenous therapy for treatment of bladder cancer
  • Prior pelvic radiation
  • Any component of small cell histology in the bladder biopsy
  • Evidence of lymph node involvement or metastatic disease on computed tomography (CT) of the chest, abdomen, and pelvis. To be considered positive, a lymph node must measure > 15 mm in short axis. Bone scan is recommended in patients with bone pain or elevated alkaline phosphatase. Positron emission tomography (PET)/CT can be considered in patients with renal dysfunction who are unable to receive intravenous (IV) contrast
  • Clinically significant (i.e. active) cardiovascular disease: symptomatic congestive heart failure (>= New York Heart Association Classification class II), unstable angina pectoris, serious cardiac arrhythmia requiring medication, or cerebrovascular accident (CVA)/stroke/myocardial infarction (MI) (< 6 months prior to enrollment)
  • Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4.03 grade >= 3)
  • Breast feeding women who are unwilling to stop breastfeeding during treatment and for at least one month after the duration of treatment
  • Patients with known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
  • Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment
  • Current use of immunosuppressive medication, EXCEPT for the following: intranasal, inhaled, topical steroid, or local steroid injection (e.g., intra-articular injection); Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent; Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed
  • Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
  • Active infection requiring intravenous antibiotic therapy
  • History of another malignancy within 5 years prior to randomization except for: non-muscle-invasive bladder cancer (i.e., =< T1), completed resected basal cell or squamous cell skin cancer, completed resected carcinoma in situ of any site, or localized prostate cancer managed curatively with a non-radiation based approach
  • Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
  • Major surgery within the last 30 days (with the exception of TURBT)
  • Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid [RNA] if anti-HCV antibody screening test positive)
  • Prior organ transplantation including allogenic stem-cell transplantation
  • Patient is unwilling to stop (or wishes to start) taking herbal and natural remedies that may have immune-modulating effects during the study period
  • Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy grade =< 2, or other grade =< 2 not constituting a safety risk based on investigator’s judgment are acceptable
  • Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
  • Pregnant women are excluded from this study. Based on its mechanism of action. Avelumab can cause fetal harm when administered to a pregnant woman. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. Human IgG1 immunoglobulins are known to cross the placenta. Therefore, avelumab has the potential to be transmitted from the mother to the developing fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss. Therefore, potential risks of administering avelumab during pregnancy include increased rates of abortion or stillbirth. Advise females of reproductive potential to use effective contraception during treatment with avelumab and for at least one month after the last dose of avelumab


Beth Israel Deaconess Medical Center
Contact: Joaquin Bellmunt
Brigham and Women's Hospital
Contact: Kent William Mouw
Phone: 617-732-7948
Dana-Farber Cancer Institute
Contact: Kent William Mouw
Phone: 617-732-7948


I. To assess efficacy of the combination of avelumab and radiation in cisplatin-ineligible muscle-invasive bladder patients as measured by the complete clinical response rate at 3 months following completion of radiation.


I. To assess locoregional control, progression-free survival, and overall survival.

II. To assess patient-reported quality-of-life using (Quality of Life Questionnaire Core 30) QLQ-C30 and Functional Assessment of Cancer Therapy (FACT)-Bladder instruments at the following timepoints: baseline, end of radiation, and at each follow-up visit.

III. To explore the association of tumor PD-L1 expression, immune cell subsets, T cell receptor diversity, mutational status, immune-related gene expression signatures, circulating immune cell subsets, and plasma/urine cell-free deoxyribonucleic acid (DNA) with treatment response.


Patients receive avelumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Within 14 days of cycle 1 day 1 of avelumab, patients also undergo radiation therapy in the form of conventional radiation therapy or intensity-modulated radiation therapy (IMRT) over 10-15 minutes on Mondays-Fridays for 4-7 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up to 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Kent William Mouw

  • Primary ID 18-464
  • Secondary IDs NCI-2018-03623
  • ID NCT03747419