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
Conditions
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.
Interventions
Given PO
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Chicago
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 3 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and the sum must also demonstrate an absolute increase of at least 5mm, or unequivocal progression of existing non-target lesions, or the appearance of new lesions. Estimated at 3 months using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 3 years | Includes both complete responses (CR) and partial responses (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR) is defined as the disappearance of all target lesions (any pathological lymph nodes must have reduction in short axis to \<10 mm); Partial Response (PR) is defined as \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR. |
| Median Progression-free Survival (PFS ) Time | Up to 3 years | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and the sum must also demonstrate an absolute increase of at least 5mm, or unequivocal progression of existing non-target lesions, or the appearance of new lesions. Estimated using the Kaplan-Meier method. |
| Median Overall Survival (OS) Time | Up to 3 years | Estimated using the Kaplan-Meier method. |
| EGFR Expression Status | Baseline | These analyses were conducted using available archival formalin-fixed, paraffin-embedded sections from surgical specimens. Each sample was tested to determine whether there was EGFR amplification. |
| HER2 Expression Status | Baseline | These analyses were conducted using available archival formalin-fixed, paraffin-embedded sections from surgical specimens. Each sample was tested to determine whether there was HER2 amplification. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Presence of Tumor Micro Ribonucleic Acids (RNAs) Like miR-200 | Baseline | Relationship to 3-month PFS will be determined. |
| Epithelial to Mesenchymal Transition States | Up to 3 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Afatinib) - Phase II Study Patients receive afatinib dimaleate PO QD on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
afatinib dimaleate: Given PO
Enrolled as part of the main Phase II study | 23 |
| Treatment (Afatinib) - Molecularly Selected Cohort Patients receive afatinib dimaleate PO QD on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
afatinib dimaleate: Given PO
Enrolled as part of the molecularly selected cohort | 9 |
| Total | 32 |
Baseline characteristics
| Characteristic | Treatment (Afatinib) - Phase II Study | Total | Treatment (Afatinib) - Molecularly Selected Cohort |
|---|---|---|---|
| Age, Continuous | 67 years | 69 years | 70 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 31 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 20 Participants | 28 Participants | 8 Participants |
| Region of Enrollment United States | 23 Participants | 32 Participants | 9 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 18 Participants | 25 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 23 | 9 / 9 |
| other Total, other adverse events | 23 / 23 | 9 / 9 |
| serious Total, serious adverse events | 11 / 23 | 3 / 9 |
Outcome results
Primary
Progression-free Survival (PFS)
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and the sum must also demonstrate an absolute increase of at least 5mm, or unequivocal progression of existing non-target lesions, or the appearance of new lesions. Estimated at 3 months using the Kaplan-Meier method.
Time frame: 3 months
Population: Analysis population included those in the main Phase II study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Afatinib) | Progression-free Survival (PFS) | 5 Participants |
Secondary
EGFR Expression Status
These analyses were conducted using available archival formalin-fixed, paraffin-embedded sections from surgical specimens. Each sample was tested to determine whether there was EGFR amplification.
Time frame: Baseline
Population: The analysis sample included those in the main Phase II study. Two patients did not have a sample to analyze.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Afatinib) | EGFR Expression Status | 5 Participants |
Secondary
HER2 Expression Status
These analyses were conducted using available archival formalin-fixed, paraffin-embedded sections from surgical specimens. Each sample was tested to determine whether there was HER2 amplification.
Time frame: Baseline
Population: Analysis population included those in the main Phase II study. Two patients did not have a sample to analyze
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Afatinib) | HER2 Expression Status | 4 Participants |
Secondary
Median Overall Survival (OS) Time
Estimated using the Kaplan-Meier method.
Time frame: Up to 3 years
Population: Analysis population includes those in the main Phase II study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Afatinib) | Median Overall Survival (OS) Time | 5.3 months |
Secondary
Median Progression-free Survival (PFS ) Time
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and the sum must also demonstrate an absolute increase of at least 5mm, or unequivocal progression of existing non-target lesions, or the appearance of new lesions. Estimated using the Kaplan-Meier method.
Time frame: Up to 3 years
Population: Analysis population includes patients from the main Phase II study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Afatinib) | Median Progression-free Survival (PFS ) Time | 1.4 months |
Secondary
Overall Response Rate
Includes both complete responses (CR) and partial responses (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR) is defined as the disappearance of all target lesions (any pathological lymph nodes must have reduction in short axis to \<10 mm); Partial Response (PR) is defined as \>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.
Time frame: Up to 3 years
Population: Analysis population includes those patients in the main Phase II study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Afatinib) | Overall Response Rate | 2 Participants |
Other Pre-specified
Epithelial to Mesenchymal Transition States
Time frame: Up to 3 years
Population: This outcome measure was not assessed.
Other Pre-specified
Presence of Tumor Micro Ribonucleic Acids (RNAs) Like miR-200
Relationship to 3-month PFS will be determined.
Time frame: Baseline
Population: This outcome measure was not assessed.