Afatinib in Advanced Refractory Urothelial Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well afatinib dimaleate works in treating patients with urothelial cancer that cannot be removed surgically and has grown after treatment with standard first-line chemotherapy. Afatinib dimaleate may turn off the function of the epidermal growth factor (EGF) and human epidermal growth factor receptor 2 (HER2) receptors, which may slow the growth of cancer cells or cause some of the cells to die.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine the 3-month progression free survival (PFS) rate in metastatic urothelial cancer patients receiving afatinib (afatinib dimaleate) who have progressed despite prior platinum-based chemotherapy. SECONDARY OBJECTIVES: I. To determine the overall response rate (complete response [CR] + partial response [PR]), median progression free survival, and overall survival for the same treated population. II. To determine whether tumor epidermal growth factor receptor (EGFR) and/or HER2 overexpression influences 3-month PFS in patients treated with afatinib. OUTLINE: Patients receive afatinib dimaleate orally (PO) once daily (QD) on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Official Title
-----------------
Afatinib Dimaleate in Treating Patients With Advanced Refractory Urothelial Cancer

Conditions
-----------------
Distal Urethral Cancer, Proximal Urethral Cancer, Recurrent Bladder Cancer, Recurrent Urethral Cancer, Stage III Bladder Cancer, Stage III Urethral Cancer, Stage IV Bladder Cancer, Stage IV Urethral Cancer, Ureter Cancer

Intervention / Treatment
-----------------
* Drug: afatinib dimaleate
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have locally advanced or metastatic urothelial cancer that is not amenable to surgical treatment Patients must have histologically or cytologically confirmed urothelial tract carcinoma; patients with urothelial carcinoma of the bladder, upper tract, or urethra are eligible Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan for the evaluation of measurable disease (Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]) Patients must have evidence of disease progression prior to enrollment All patients must have received a prior platinum-based chemotherapy regimen for treatment of urothelial cancer and must now be considered refractory to platinum-based chemotherapy; patients may have received the platinum-containing regimen either in the peri-operative or metastatic setting Patients may have received up to one line of prior systemic chemotherapy for recurrent/metastatic disease; if a platinum-based regimen was received both in the peri-operative setting and again in the metastatic setting, this will be considered 1 line of chemotherapy Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Absolute neutrophil count >= 1,000/mcL Platelets >= 100,000/mcL Hemoglobin >= 8.5g/dL Total bilirubin =< 1.5 institutional upper limit of normal (IULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X IULN Calculated creatinine clearance >= 30 mL/min by the modified Cockcroft and Gault Formula OR glomerular filtration rate >= 30 mL/min/body surface area (BSA) by Modification of Diet in Renal Disease or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula Women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Patients must have the ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients may not be receiving any other investigational agents Patients with untreated known brain metastases, or treated brain metastases that are clinically unstable Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements Women known to be pregnant Women who are breastfeeding and who are unwilling to stop breastfeeding prior to study entry Patients with known prior human immunodeficiency virus (HIV)-positive status on combination antiretroviral therapy are ineligible; known prior HIV-positive patients with CD4+ =< 500/mm^3 are ineligible (HIV testing is not required as part of this study) Pre-existing interstitial lung disease Inability to take oral medications Prior therapy with afatinib

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (afatinib)<br>Patients receive afatinib dimaleate PO QD on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. | Drug: afatinib dimaleate<br>* Given PO<br>* Other names: Gilotrif;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Estimated using the Kaplan-Meier method. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (CR + PR) |  | Up to 3 years | 
| Median progression-free survival (PFS ) time | Estimated using the Kaplan-Meier method. | Up to 3 years | 
| Overall survival | Estimated using the Kaplan-Meier method. | Up to 3 years | 
| EGFR expression status | Relationship to 3-month PFS will be determined. | Baseline | 
| HER2 expression status | Relationship to 3-month PFS will be determined. | Baseline |