Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Urethral Neoplasms

Ureteral Neoplasms

Kidney Neoplasms

Pelvic Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Urethral Diseases

Ureteral Diseases

Kidney Diseases

Transitional Cell Carcinoma

Urethral Cancer

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Fluorouracil

Avelumab

Cisplatin

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Mitomycin

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Antibodies, Monoclonal

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Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Alkylating Agents

Enzyme Inhibitors

Antineoplastic Agents, Immunological

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.

Quality-of-Life Assessment

Radiation Therapy

Parminder Singh

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.

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.

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

Phase II Study Evaluating Combination Chemotherapy + Radiotherapy (RT) With Avelumab in Muscle Invasive Bladder Cancer

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.

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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Mayo Clinic

Adverse Events were assessed at the end of every 14 day cycle during treatment, up to 12 cycles.

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.

Avelumab and Cisplatin IV

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

All participants registered were included in this analysis.

Parminder Singh, MD

All patients who registered and began protocol treatment are included in this analysis.

Proportion of Participants With Complete Response (At 6 Months)

All patients who were registered, received protocol treatment, and were assessed for adverse events were included in this analysis.

Adverse Events Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0)

All patients who were registered, treated, and completed the EORTC QLQ assessment at baseline and post-therapy were included in this analysis

Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-30

All patients who were registered, treated, and completed the EORTC QLQ assessment at baseline and post-therapy were included in this analysis.

Patient-reported Outcomes (European Organization for Research and Treatment of Cancer [EORTC] EORTCQOL-Muscle-Invasive Bladder Cancer Module [BLM]30

All patients who registered and were treated are included in this analysis.

Progression-free Survival

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.

Recurrence-free Survival

Relationship of PD-L1 (SP263 and SP142), CD8+ by Immunohistochemistry

Tumor Mutational Burden With Response to Concurrent Chemo- Radiation and Immunotherapy

Evaluate Whether Concurrent Chemoradiation and Immunotherapy After Maximal TURBT is Associated With a Decrease in Circulating Bim+CD11ahighPD-1+CD8+ T-cells and MDSCs.

Overall Study

Symptoms and General Pathology

Recurrence

Disease Attributes

Amino Acids

Erlotinib Hydrochloride

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Participants receive erlotinib hydrochloride PO QD for 3-5 weeks in the absence of disease progression or unacceptable toxicity. Within 24 hours of the last dose, participants undergo cystectomy.

Arlene Siefker-Radtke

This phase II trial studies how well erlotinib hydrochloride works in Treating participants with muscle invasive urothelial cancer or urothelial cancer that has come back. Drugs used in chemotherapy, such as erlotinib hydrochloride, 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.

PRIMARY OBJECTIVES:

I. To estimate the response rate (ie: pT0 rate) of patients with urothelial cancer treated with erlotinib prior to cystectomy.

SECONDARY OBJECTIVES:

I. To estimate the 4-year disease-free survival of patients with urothelial cancer treated with erlotinib prior to cystectomy.

II. To measure epithelial-mesenchymal transition (EMT) markers (E-cadherin, HER4, PDGFR-beta, vimentin, fibronectin) in pre- and post-treatment biopsies and correlate expression patterns with the biological responses measured below.

III. To quantify target inhibition, antiproliferation (KI-67), and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling \[TUNEL\]) in biopsies obtained from patients before, during, and after therapy.

IV. Interrogate membrane (phosphorylated EGFR) and downstream receptor signaling pathways (ERKs, AKT/mTOR, GSK-3beta) to provide further insight into whether or not a given tumor displays a biological response.

V. To correlate the changes in Ki-67 expression with changes in angiogenesis and angiogenesis related gene expression utilizing fluorescent tissue staining techniques that we have developed in the laboratory (such as two-color TUNEL, phosphor-receptor, and microvessel density.) VI. To profile messenger ribonucleic acid (mRNA) expression in pre- and post-treatment biopsies using Affymetrix arrays and correlate the changes observed with EMT, growth arrest, and apoptosis.

VII. To quantify EGFR copy number and correlate with changes observed with EMT, growth arrest, and apoptosis.

OUTLINE:

Participants receive erlotinib hydrochloride orally (PO) once daily (QD) for 3-5 weeks in the absence of disease progression or unacceptable toxicity. Within 24 hours of the last dose, participants undergo cystectomy.

After completion of study treatment, participants are followed up every 6 months for 1 year, then annually for 4 years.

Erlotinib Hydrochloride in Treating Participants With Muscle Invasive or Recurrent Urothelial Cancer

A Phase II Exploratory Study of Pre-Operative Treatment With Erlotinib (Tarceva) in Muscle Invasive or Recurrent Transitional Cell Carcinoma Requiring Cystectomy

The response rate is the number of patients with urothelial cancer treated with erlotinib prior to cystectomy. The response is defined as the absence of residual cancer in the surgical removed tissue (i.e., pT0). A responder is defined as a participant with the pathological stage of pT0 meaning that there is no evidence of disease.

M.D. Anderson Cancer Center

Toxicities were measured at weekly visit while on therapy using the NCI CTCAE v3.0.

Erlotinib 150 mg by mouth daily for 3 weeks followed by cystectomy within 24 hours of the last dose.

Pre-surgical Erlotinib Treatment

cTaN0

cT1N0

cT2N0

cT3aN0

cT3bN0

cT4aN0

Participants were staged clinically before treatment began. The T describes the tumor size; the larger the number is the more advanced the disease. The N indicates the lymphnode involvement; zero indicates that no lymph nodes were believed to be cancerous.

Three particpants withdrew from study treatment.

Clinical Staging

Participants were stagged clinically before treatment began. The T discribes the tumor size; the larger the number is the more advanced the disease. The N indicates the lymphpnode involvemnt; zero indicates that no lymph nodes were believed to be cancerous.

Dr. Arlene O. Siefker-Radtke,Professor, Genitourinary Medical Oncology

Number of Responders

Number of Non Responders

two participants did not take any eroltinib and three participants stopped erlotinib early due to intolerable side effects.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Avelumab in Combination With Fluorouracil and Mitomycin or Cisplatin and Radiation Therapy in Treating Participants With Muscle-Invasive Bladder Cancer	NCT03617913	Bladder Carcino... Stage II Bladde... Stage II Renal ... Stage II Ureter... Stage II Urethr... Stage III Bladd... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IIIA Blad... Stage IIIB Blad... Urethral Urothe...	Avelumab Cisplatin Fluorouracil Mitomycin Quality-of-Life... Radiation Thera...	18 Years -	Mayo Clinic
Erlotinib Hydrochloride in Treating Participants With Muscle Invasive or Recurrent Urothelial Cancer	NCT00749892	Recurrent Bladd... Recurrent Renal... Recurrent Urete... Recurrent Ureth... Stage 0a Bladde... Stage 0a Renal ... Stage 0a Ureter... Stage 0a Urethr... Stage 0is Bladd... Stage 0is Renal... Stage 0is Urete... Stage 0is Ureth... Stage II Bladde... Stage II Renal ... Stage II Ureter... Stage II Urethr... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IIIA Blad...	Erlotinib Hydro...	19 Years -	M.D. Anderson Cancer Center
Erlotinib Hydrochloride in Treating Participants With Muscle Invasive or Recurrent Urothelial Cancer	NCT00749892	Recurrent Bladd... Recurrent Renal... Recurrent Urete... Recurrent Ureth... Stage 0a Bladde... Stage 0a Renal ... Stage 0a Ureter... Stage 0a Urethr... Stage 0is Bladd... Stage 0is Renal... Stage 0is Urete... Stage 0is Ureth... Stage II Bladde... Stage II Renal ... Stage II Ureter... Stage II Urethr... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IIIA Blad...	Erlotinib Hydro...	19 Years -	M.D. Anderson Cancer Center
Avelumab in Combination With Fluorouracil and Mitomycin or Cisplatin and Radiation Therapy in Treating Participants With Muscle-Invasive Bladder Cancer	NCT03617913	Bladder Carcino... Stage II Bladde... Stage II Renal ... Stage II Ureter... Stage II Urethr... Stage III Bladd... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IIIA Blad... Stage IIIB Blad... Urethral Urothe...	Avelumab Cisplatin Fluorouracil Mitomycin Quality-of-Life... Radiation Thera...	18 Years -	Mayo Clinic

Spots Global Cancer Trial Database for stage ii urethral cancer ajcc v8