Afatinib in Advanced Refractory Urothelial Cancer

Afatinib Dimaleate in Treating Patients With Advanced Refractory Urothelial Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Bladder Cancer; Stage III Bladder Cancer; Stage IV Bladder Cancer; Ureter Cancer; Distal Urethral Cancer; Proximal Urethral Cancer; Recurrent Urethral Cancer; Stage III Urethral Cancer; Stage IV Urethral Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: afatinib dimaleate

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Winship Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Health
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina - Lineberger Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (afatinib); Patients receive afatinib dimaleate PO QD on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Drug: afatinib dimaleate; Given PO; Other Names: Gilotrif; afatinib; BIBW 2992 MA2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 3 years
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.	Up to 3 years
Median Overall Survival (OS) Time	Estimated using the Kaplan-Meier method.	Up to 3 years
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.	Baseline
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.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of Tumor Micro Ribonucleic Acids (RNAs) Like miR-200	Relationship to 3-month PFS will be determined.	Baseline
Epithelial to Mesenchymal Transition States		Up to 3 years

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Peter O'Donnell, University of Chicago

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2017
• Primary Completion (Actual): April 4, 2024
• Study Completion (Actual): April 4, 2024

Study Registration Dates

• First Submitted: April 22, 2014
• First Submitted That Met QC Criteria: April 23, 2014
• First Posted (Estimated): April 24, 2014

Study Record Updates

• Last Update Posted (Actual): April 25, 2025
• Last Update Submitted That Met QC Criteria: April 24, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Disease Attributes; Urologic Neoplasms; Ureteral Diseases; Urinary Bladder Diseases; Urethral Diseases; Recurrence; Ureteral Neoplasms; Urinary Bladder Neoplasms; Urethral Neoplasms; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: 13-0540; P30CA014599 (U.S. NIH Grant/Contract); NCI-2014-00859 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); IRB13-0540; 13-0540/ 1200.171 (Other Identifier: University of Chicago)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No