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

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ClinicalTrials.gov Identifier: NCT03617913
Recruitment Status : Active, not recruiting
First Posted : August 7, 2018
Last Update Posted : May 30, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

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.

Condition or disease Intervention/treatment Phase
Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall Stage II Bladder Cancer AJCC v8 Stage II Renal Pelvis Cancer AJCC v8 Stage II Ureter Cancer AJCC v8 Stage II Urethral Cancer AJCC v8 Stage III Bladder Cancer AJCC v8 Stage III Renal Pelvis Cancer AJCC v8 Stage III Ureter Cancer AJCC v8 Stage III Urethral Cancer AJCC v8 Stage IIIA Bladder Cancer AJCC v8 Stage IIIB Bladder Cancer AJCC v8 Urethral Urothelial Carcinoma Drug: Avelumab Drug: Cisplatin Drug: Fluorouracil Drug: Mitomycin Other: Quality-of-Life Assessment Radiation: Radiation Therapy Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the complete response rate of concurrent chemotherapy radiation treatment combined with avelumab for patients with muscle invasive bladder cancer.

SECONDARY OBJECTIVES:

I. To evaluate the safety and toxicity (adverse event profile) of concurrent chemotherapy radiation treatment combined with avelumab.

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

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

CORRELATIVE OBJECTIVES:

I. To explore biomarkers that may predict response to avelumab in the muscle invasive population.

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

III. 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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
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 : September 19, 2018
Estimated Primary Completion Date : November 13, 2019
Estimated Study Completion Date : July 31, 2025


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 Name: Quality of Life Assessment

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation




Primary Outcome Measures :
  1. Complete response [ Time Frame: At 6 months from registration ]
    A two-stage study design will be utilized. Expression of immune signatures by RNA-sequencing (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. Confidence intervals for the true success proportion will be calculated using the properties of the binomial distribution.


Secondary Outcome Measures :
  1. Incidence of adverse events per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: 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. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

  2. Patient-reported outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life questionnaire [QLQ]-30 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From registration to time of first documentation of progression or death from any cause, assessed up to 12 months ]
    Will be estimated using the method of Kaplan-Meier.

  5. Recurrence-free survival [ Time Frame: From documented complete response to the first documentation of recurrence, assessed up to 12 months ]
    Will be estimated using the method of Kaplan-Meier.


Other Outcome Measures:
  1. Relationship of PD-L1 (SP263 and SP142), CD8+ by immunohistochemistry [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03617913


Locations
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United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85054
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Parminder Singh Mayo Clinic

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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03617913     History of Changes
Other Study ID Numbers: MC1752
NCI-2018-01539 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1752 ( Other Identifier: Mayo Clinic in Arizona )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: August 7, 2018    Key Record Dates
Last Update Posted: May 30, 2019
Last Verified: November 2018

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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:
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Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Urethral Neoplasms
Ureteral Neoplasms
Kidney Neoplasms
Pelvic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Urethral Diseases
Ureteral Diseases
Kidney Diseases
Cisplatin
Fluorouracil
Mitomycins
Mitomycin
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs