Avelumab in Combination With Fluorouracil and Mitomycin or Cisplatin and Radiation Therapy in Treating Participants With Muscle-Invasive Bladder Cancer

Sponsor
Mayo Clinic (Other)
Overall Status
Completed
CT.gov ID
NCT03617913
Collaborator
National Cancer Institute (NCI) (NIH)
2
3
1
22.2
0.7
0

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects of avelumab and how well it works in combination with fluorouracil and mitomycin or cisplatin and radiation therapy in treating participants with muscle-invasive bladder cancer. Monoclonal antibodies, such as avelumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as fluorouracil, mitomycin, 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 beams to kill tumor cells and shrink tumors. Giving avelumab with chemotherapy and radiotherapy may work better in treating participants with muscle-invasive bladder cancer.

Detailed Description

PRIMARY OBJECTIVES:
  1. To evaluate the complete response rate of concurrent chemotherapy radiation treatment combined with avelumab for patients with muscle invasive bladder cancer.
SECONDARY OBJECTIVES:
  1. To evaluate the safety and toxicity (adverse event profile) of concurrent chemotherapy radiation treatment combined with avelumab.

  2. To evaluate quality of life (QoL) at 1 year of concurrent chemotherapy radiation treatment combined with avelumab.

  3. To evaluate progression-free survival and relapse-free survival at 1 year with concurrent chemotherapy radiation treatment combined with avelumab.

CORRELATIVE OBJECTIVES:
  1. To explore biomarkers that may predict response to avelumab in the muscle invasive population.

  2. To evaluate the association of tumor mutational burden with response to concurrent chemo- radiation and immunotherapy.

  3. To evaluate whether concurrent chemoradiation and immunotherapy after maximal transurethral resection of bladder tumor (TURBT) is associated with a decrease in circulating Bim+CD11a^high PD-1+CD8+ T-cells and myeloid-derived suppressor cells (MDSCs).

OUTLINE:

Participants receive avelumab intravenously (IV) over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during radiation therapy (RT) and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, 6, 9, and 12 months.

Study Design

Study Type:
Interventional
Actual Enrollment :
2 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Study Evaluating Combination Chemotherapy + Radiotherapy (RT) With Avelumab in Muscle Invasive Bladder Cancer
Actual Study Start Date :
Sep 19, 2018
Actual Primary Completion Date :
Nov 14, 2019
Actual Study Completion Date :
Jul 27, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (avelumab, chemotherapy, radiation therapy)

Participants receive avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and 16-20 during RT and mitomycin IV on day 1 of course 3, or cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.

Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C
  • Drug: Cisplatin
    Given IV
    Other Names:
  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
  • Drug: Fluorouracil
    Given IV
    Other Names:
  • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
  • 5-Fluorouracil
  • 5-Fluracil
  • 5-FU
  • AccuSite
  • Carac
  • Fluoro Uracil
  • Fluouracil
  • Flurablastin
  • Fluracedyl
  • Fluracil
  • Fluril
  • Fluroblastin
  • Ribofluor
  • Ro 2-9757
  • Ro-2-9757
  • Drug: Mitomycin
    Given IV
    Other Names:
  • Ametycine
  • MITO
  • MITO-C
  • Mito-Medac
  • Mitocin
  • Mitocin-C
  • Mitolem
  • Mitomycin C
  • Mitomycin-C
  • Mitomycin-X
  • Mitomycine C
  • Mitosol
  • Mitozytrex
  • Mutamycin
  • Mutamycine
  • NCI-C04706
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Radiation: Radiation Therapy
    Undergo RT
    Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation
  • Outcome Measures

    Primary Outcome Measures

    1. Proportion of Participants With Complete Response (At 6 Months) [At 6 months from registration]

      Patients enrolled will have non-measurable disease based on imaging at baseline. Patients will be assessed for a response after 6 months of treatment using the results of a biopsy and cytology test. A complete response (CR) is defined as having a negative biopsy and negative urine cytology at 6 months from registration after finishing of concurrent RT and immunotherapy. Imaging of abdomen and pelvis confirming no systemic disease within 4 weeks of cystoscopy will be completed. The proportion of patients reporting a CR is reported here with confidence intervals for the true success proportion using the binomial distribution.

    Secondary Outcome Measures

    1. Adverse Events Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0) [Up to 12 months]

      The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. The number of patients reporting a grade 3+ adverse event regardless of attribution is reported here.

    2. Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-30 [Baseline to 12 months]

      EORTC QLQ-C30 is a 30-item patient-reported questionnaire. 28 of the 30 items are measured on a 1-4 scale (1=not at all; 4=very much) with the remaining two items (overall health and overall quality of life) scored on a 1-7 numeric analogue scale (1=very poor; 7=excellent). The recall period for the EORTC QLQ-C30 is one week. Changes from baseline will be statistically tested using paired t-tests, and standardized response means (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's (2002) adjustment) using Cohen's (1988) cut-offs: <0.20 = trivial; 0.20-<0.50 = small; 0.50-<0.80 = moderate; and >=/0.80 = large. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.

    3. Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] EORTCQOL-Muscle-Invasive Bladder Cancer Module [BLM]30 [Baseline to 12 months]

      EORTC QLQ-BLM30 is a 30-item questionnaire for patients with muscle invasive bladder cancer (T2, T3, T4a and T4b). The muscle-invasive bladder cancer module contains additional items assessing urostomy problems, problems associated with the use of a catheter, and body image. Changes from baseline will be statistically tested using paired t-tests, and standardized response means (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's (2002) adjustment) using Cohen's (1988) cut-offs: <0.20 = trivial; 0.20-<0.50 = small; 0.50-<0.80 = moderate; and >=/0.80 = large. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.

    4. Progression-free Survival [From registration to time of first documentation of progression or death from any cause, assessed up to 12 months]

      Progression-free survival is defined as the time from registration to the time of progression or death. This study will not use RECIST criteria to evaluate response or progression. The patients enrolled will have non-measurable disease on imaging and response will be evaluated with biopsy or cytology. Progression is defined as progression in T stage, N stage or M stage both clinically or radiologically. Histological confirmation of metastatic disease is at the discretion of the treating provider. The median time will be estimated using the method of Kaplan-Meier.

    5. Recurrence-free Survival [From documented complete response to the first documentation of recurrence, assessed up to 12 months]

      Recurrence-free survival is defined as the time from registration to the time of recurrence or death. Recurrence is defined as having histologically proven first appearance of muscle invasive bladder cancer, clinical evidence of metastatic disease, or treatment with radical cystectomy or radiation to the bladder, or death due to any cause after they were confirmed remission at 6 month evaluation. The median time will be estimated using the method of Kaplan-Meier.

    Other Outcome Measures

    1. Relationship of PD-L1 (SP263 and SP142), CD8+ by Immunohistochemistry [Up to 12 months]

      Association of Bim (BCL-2-interacting mediator of cell death) expression will be evaluated at using the baseline tissue specimen and explored in relation to 6 months post-registration response and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests.

    2. Tumor Mutational Burden With Response to Concurrent Chemo- Radiation and Immunotherapy [Up to 12 months]

      Association of Bim expression will be evaluated at using the baseline tissue specimen and explored in relation to 6 months post-registration response and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests. Expression of immune signatures by RNA-seq expression (using the baseline tissue specimen) will be evaluated at baseline and explored in relation to clinical outcomes such as progression-free survival, tumor response, and adverse event incidence using two-way tables and box plots and analyzed using Fisher's exact tests or logistic regression methods, as appropriate.

    3. Evaluate Whether Concurrent Chemoradiation and Immunotherapy After Maximal TURBT is Associated With a Decrease in Circulating Bim+CD11ahighPD-1+CD8+ T-cells and MDSCs. [Up to 12 months]

      Association of Bim expression will be evaluated at using the baseline tissue specimen and explored in relation to 6 months post-registration response and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests. Expression of immune signatures by RNA-seq expression (using the baseline tissue specimen) will be evaluated at baseline and explored in relation to clinical outcomes such as progression-free survival, tumor response, and adverse event incidence using two-way tables and box plots and analyzed using Fisher's exact tests or logistic regression methods, as appropriate.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Histologic proof of T2-T4a N0M0 (American Joint Committee on Cancer [AJCC] 8th edition) with predominant urothelial carcinoma. Mixed histologies are acceptable provided urothelial carcinoma is the predominant histology. Small cell urothelial carcinoma is excluded.

    • Cystoscopy with maximal TURBT performed =< 70 days of study registration. NOTE: Both completely resectable or partially resectable tumors are eligible as long as the treating urologist attempted complete resection. Exam under anesthesia needs to be performed and documented.

    • Absolute neutrophil count (ANC) >= 1500/mm^3 =< 28 days prior to registration.

    • Platelets (PLT) 100,000/mm^3 =< 28 days prior to registration.

    • Total bilirubin =< 1.5 upper limit of normal (ULN) =< 28 days prior to registration.

    • Aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement) =< 28 days prior to registration.

    • Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement) =< 28 days prior to registration.

    • Hemoglobin (Hgb) >= 9 gm/dl =< 28 days prior to registration.

    • Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft-Gault formula =< 28 days prior to registration.

    • Eastern Cooperative Oncology Group (ECOG) performance status (PS 0, 1, 2).

    • Ability to provide informed written consent.

    • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).

    • Life expectancy >= 6 months.

    • Negative serum pregnancy test done =< 14 days prior to registration, for women of childbearing potential only.

    Exclusion Criteria:
    • Patients with locally advanced unresectable (T4b) or metastatic urothelial carcinoma (N1M0-1) as assessed on baseline radiographic imaging obtained =< 70 days prior to study registration. The required radiographic imaging includes:

    • Abdomen/pelvis computed tomography (CT) or magnetic resonance imaging (MRI) scan

    • Chest x-ray or CT scan.

    • Patients with concurrent urothelial carcinoma and/or related variants anywhere outside bladder

    • NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.

    • A prior or concurrent malignancy of any other site or histology unless the patient has been disease-free for > 2 years prior to registration except for:

    • Non-melanoma skin cancer and/or localized prostate cancer (T2 a or b , Gleason < 3+4) or carcinoma in situ of the uterine cervix which has been adequately treated =< 2 years prior to registration

    • Or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =< 3+4, and prostate-specific antigen [PSA] =< 10 mg/mL, etc.).

    • Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies =< 4 weeks prior to registration, or who have not recovered from the side effects of such therapy.

    • EXCEPTION: Except single dose intravesical chemotherapy administered after TURBT.

    • Patients who have received prior therapy with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4, anti-TIM3) or immune co-stimulatory molecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed agents.

    • Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to registration, or who have not recovered from side effects of such procedure or injury prior to registration.

    • NOTE: Patients who have had minor procedures (i.e. TURBT) or percutaneous biopsies prior to registration are eligible.

    • Patients with history of cirrhosis, alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis.

    • Patient with history of prior solid organ or allogeneic bone marrow transplant.

    • Clinically significant cardiac diseases, including any of the following:

    • History or presence of serious uncontrolled ventricular arrhythmias.

    • Clinically significant resting bradycardia.

    • Any of the following =< 3 months prior to registration: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE).

    • Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication(s).

    • History of untreated human immunodeficiency virus (HIV)

    • NOTE: There is no requirement to screen patients for HIV. Patients with history of HIV infection are allowed if on effective highly active antiretroviral therapy (HAART) therapy and CD4 count more than 250.

    • History of active hepatitis B infection

    • NOTE: There is no requirement to screen patients for hepatitis B.

    • Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy.

    • NOTE: Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted. For questions, please consult the study chair.

    • Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol.

    • Pregnant or breast-feeding women.

    • Women of child-bearing potential, who are biologically able to conceive, and not employing two forms of highly effective contraception. Highly effective contraception must be used throughout the trial and up to 8 weeks after the last dose of study drug (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test =< 14 days prior to registration.

    • Fertile males not willing to use contraception, as stated above.

    • Patients unwilling or unable to comply with the protocol.

    • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.

    • 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] 5.0 grade >= 3).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Mayo Clinic in Arizona Scottsdale Arizona United States 85054
    2 Mayo Clinic in Florida Jacksonville Florida United States 32224
    3 Mayo Clinic Rochester Minnesota United States 55905

    Sponsors and Collaborators

    • Mayo Clinic
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Parminder Singh, Mayo Clinic

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Mayo Clinic
    ClinicalTrials.gov Identifier:
    NCT03617913
    Other Study ID Numbers:
    • MC1752
    • NCI-2018-01539
    • MC1752
    • P30CA015083
    First Posted:
    Aug 7, 2018
    Last Update Posted:
    Apr 8, 2021
    Last Verified:
    Mar 1, 2021
    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
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Period Title: Overall Study
    STARTED 2
    COMPLETED 2
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Overall Participants 2
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    65
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    Male
    2
    100%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    Not Hispanic or Latino
    2
    100%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    2
    100%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    2
    100%

    Outcome Measures

    1. Primary Outcome
    Title Proportion of Participants With Complete Response (At 6 Months)
    Description Patients enrolled will have non-measurable disease based on imaging at baseline. Patients will be assessed for a response after 6 months of treatment using the results of a biopsy and cytology test. A complete response (CR) is defined as having a negative biopsy and negative urine cytology at 6 months from registration after finishing of concurrent RT and immunotherapy. Imaging of abdomen and pelvis confirming no systemic disease within 4 weeks of cystoscopy will be completed. The proportion of patients reporting a CR is reported here with confidence intervals for the true success proportion using the binomial distribution.
    Time Frame At 6 months from registration

    Outcome Measure Data

    Analysis Population Description
    All patients who registered and began protocol treatment are included in this analysis.
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Measure Participants 2
    Number (95% Confidence Interval) [proportion of participants]
    0.5
    25%
    2. Secondary Outcome
    Title Adverse Events Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0)
    Description The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. The number of patients reporting a grade 3+ adverse event regardless of attribution is reported here.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    All patients who were registered, received protocol treatment, and were assessed for adverse events were included in this analysis.
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Measure Participants 2
    Grade 3+ Adverse Event
    2
    100%
    Grade 4+ Adverse Event
    0
    0%
    3. Secondary Outcome
    Title Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-30
    Description EORTC QLQ-C30 is a 30-item patient-reported questionnaire. 28 of the 30 items are measured on a 1-4 scale (1=not at all; 4=very much) with the remaining two items (overall health and overall quality of life) scored on a 1-7 numeric analogue scale (1=very poor; 7=excellent). The recall period for the EORTC QLQ-C30 is one week. Changes from baseline will be statistically tested using paired t-tests, and standardized response means (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's (2002) adjustment) using Cohen's (1988) cut-offs: <0.20 = trivial; 0.20-<0.50 = small; 0.50-<0.80 = moderate; and >=/0.80 = large. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.
    Time Frame Baseline to 12 months

    Outcome Measure Data

    Analysis Population Description
    All patients who were registered, treated, and completed the EORTC QLQ assessment at baseline and post-therapy were included in this analysis
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Measure Participants 0
    4. Secondary Outcome
    Title Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] EORTCQOL-Muscle-Invasive Bladder Cancer Module [BLM]30
    Description EORTC QLQ-BLM30 is a 30-item questionnaire for patients with muscle invasive bladder cancer (T2, T3, T4a and T4b). The muscle-invasive bladder cancer module contains additional items assessing urostomy problems, problems associated with the use of a catheter, and body image. Changes from baseline will be statistically tested using paired t-tests, and standardized response means (mean of the change from baseline scores at a given cycle, divided by the standard deviation of the change scores) will be interpreted (after applying Middel's (2002) adjustment) using Cohen's (1988) cut-offs: <0.20 = trivial; 0.20-<0.50 = small; 0.50-<0.80 = moderate; and >=/0.80 = large. Correlation between outcomes will employ Pearson and/or Spearman correlations at individual time points.
    Time Frame Baseline to 12 months

    Outcome Measure Data

    Analysis Population Description
    All patients who were registered, treated, and completed the EORTC QLQ assessment at baseline and post-therapy were included in this analysis.
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Measure Participants 0
    5. Secondary Outcome
    Title Progression-free Survival
    Description Progression-free survival is defined as the time from registration to the time of progression or death. This study will not use RECIST criteria to evaluate response or progression. The patients enrolled will have non-measurable disease on imaging and response will be evaluated with biopsy or cytology. Progression is defined as progression in T stage, N stage or M stage both clinically or radiologically. Histological confirmation of metastatic disease is at the discretion of the treating provider. The median time will be estimated using the method of Kaplan-Meier.
    Time Frame From registration to time of first documentation of progression or death from any cause, assessed up to 12 months

    Outcome Measure Data

    Analysis Population Description
    All patients who registered and were treated are included in this analysis.
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Measure Participants 2
    Median (95% Confidence Interval) [years]
    NA
    6. Secondary Outcome
    Title Recurrence-free Survival
    Description Recurrence-free survival is defined as the time from registration to the time of recurrence or death. Recurrence is defined as having histologically proven first appearance of muscle invasive bladder cancer, clinical evidence of metastatic disease, or treatment with radical cystectomy or radiation to the bladder, or death due to any cause after they were confirmed remission at 6 month evaluation. The median time will be estimated using the method of Kaplan-Meier.
    Time Frame From documented complete response to the first documentation of recurrence, assessed up to 12 months

    Outcome Measure Data

    Analysis Population Description
    All patients who were registered, treated, and were assessed as having a Complete Response (CR) are eligible for this analysis. This endpoint can only be analyzed if more than one patient is eligible.
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    Measure Participants 0
    7. Other Pre-specified Outcome
    Title Relationship of PD-L1 (SP263 and SP142), CD8+ by Immunohistochemistry
    Description Association of Bim (BCL-2-interacting mediator of cell death) expression will be evaluated at using the baseline tissue specimen and explored in relation to 6 months post-registration response and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Other Pre-specified Outcome
    Title Tumor Mutational Burden With Response to Concurrent Chemo- Radiation and Immunotherapy
    Description Association of Bim expression will be evaluated at using the baseline tissue specimen and explored in relation to 6 months post-registration response and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests. Expression of immune signatures by RNA-seq expression (using the baseline tissue specimen) will be evaluated at baseline and explored in relation to clinical outcomes such as progression-free survival, tumor response, and adverse event incidence using two-way tables and box plots and analyzed using Fisher's exact tests or logistic regression methods, as appropriate.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Other Pre-specified Outcome
    Title Evaluate Whether Concurrent Chemoradiation and Immunotherapy After Maximal TURBT is Associated With a Decrease in Circulating Bim+CD11ahighPD-1+CD8+ T-cells and MDSCs.
    Description Association of Bim expression will be evaluated at using the baseline tissue specimen and explored in relation to 6 months post-registration response and subsequently in relation to other clinical outcomes such as tumor response and adverse event incidence using two-way tables and analyzed using Fisher's exact tests. Expression of immune signatures by RNA-seq expression (using the baseline tissue specimen) will be evaluated at baseline and explored in relation to clinical outcomes such as progression-free survival, tumor response, and adverse event incidence using two-way tables and box plots and analyzed using Fisher's exact tests or logistic regression methods, as appropriate.
    Time Frame Up to 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Adverse Events were assessed at the end of every 14 day cycle during treatment, up to 12 cycles.
    Adverse Event Reporting Description Adverse Events were assessed at the end of every 14 day cycle during treatment, up to 12 cycles.
    Arm/Group Title Avelumab and Cisplatin IV
    Arm/Group Description Participants received avelumab IV over 60 minutes every 14 days for a total of 10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days after the first dose of avelumab, participants received 35 mg/m^2/day cisplatin IV starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or unacceptable toxicity.
    All Cause Mortality
    Avelumab and Cisplatin IV
    Affected / at Risk (%) # Events
    Total 0/2 (0%)
    Serious Adverse Events
    Avelumab and Cisplatin IV
    Affected / at Risk (%) # Events
    Total 1/2 (50%)
    Infections and infestations
    Sepsis 1/2 (50%) 1
    Other (Not Including Serious) Adverse Events
    Avelumab and Cisplatin IV
    Affected / at Risk (%) # Events
    Total 2/2 (100%)
    Blood and lymphatic system disorders
    Anemia 1/2 (50%) 2
    Gastrointestinal disorders
    Constipation 2/2 (100%) 14
    Diarrhea 1/2 (50%) 9
    Nausea 1/2 (50%) 1
    Proctitis 1/2 (50%) 1
    Vomiting 1/2 (50%) 1
    General disorders
    Fatigue 1/2 (50%) 13
    Pain 1/2 (50%) 7
    Investigations
    Neutrophil count decreased 1/2 (50%) 1
    Platelet count decreased 1/2 (50%) 1
    White blood cell decreased 1/2 (50%) 2
    Psychiatric disorders
    Insomnia 1/2 (50%) 1
    Renal and urinary disorders
    Hematuria 1/2 (50%) 2
    Urinary frequency 2/2 (100%) 25
    Urinary incontinence 1/2 (50%) 2
    Urinary retention 1/2 (50%) 2
    Urinary tract pain 1/2 (50%) 1
    Urinary urgency 2/2 (100%) 9

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Parminder Singh, MD
    Organization Mayo Clinic
    Phone 5072555123
    Email Singh.Parminder@mayo.edu
    Responsible Party:
    Mayo Clinic
    ClinicalTrials.gov Identifier:
    NCT03617913
    Other Study ID Numbers:
    • MC1752
    • NCI-2018-01539
    • MC1752
    • P30CA015083
    First Posted:
    Aug 7, 2018
    Last Update Posted:
    Apr 8, 2021
    Last Verified:
    Mar 1, 2021