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

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00749892
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 34
• Location: 1
• Arm: 1
• Actual Duration (Months): 137.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Bladder Urothelial Carcinoma; Recurrent Renal Pelvis Urothelial Carcinoma; Recurrent Ureter Urothelial Carcinoma; Recurrent Urethral Urothelial Carcinoma; Stage 0a Bladder Cancer AJCC v8; Stage 0a Renal Pelvis Cancer AJCC v8; Stage 0a Ureter Cancer AJCC v8; Stage 0a Urethral Cancer AJCC v8; Stage 0is Bladder Cancer AJCC v8; Stage 0is Renal Pelvis Cancer AJCC v8; Stage 0is Ureter Cancer AJCC v8; Stage 0is Urethral Cancer AJCC v8; 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 Renal Pelvis Cancer AJCC v8; Stage III Ureter Cancer AJCC v8; Stage III Urethral Cancer AJCC v8; Stage IIIA Bladder Cancer AJCC v8	Drug: Erlotinib Hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Exploratory Study of Pre-Operative Treatment With Erlotinib (Tarceva) in Muscle Invasive or Recurrent Transitional Cell Carcinoma Requiring Cystectomy
• Actual Study Start Date: Jun 10, 2008
• Actual Primary Completion Date: Jun 30, 2019
• Actual Study Completion Date: Nov 26, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (erlotinib hydrochloride) 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.	Drug: Erlotinib Hydrochloride; Given PO; Other Names: Cp-358,774 OSI-774 Tarceva

Outcome Measures

Primary Outcome Measures

1. Response Rate [Determined at the time of surgery or 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.

Secondary Outcome Measures

1. Estimated 4-Year Disease-Free Survival [4 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologic proof of urothelial cancer. This includes bladder cancer, in addition to other tumors of the urothelial lining including renal pelvis, ureteral, and urethral cancer. This group may include any patient requiring cystectomy, including patients with recurrent or extensive superficial disease (cTa-T1N0M0), CIS (carcinoma in situ), or muscle invasive disease (cT2-3aN0M0), whose tumor could not be completely removed at transurethral resection

• Patients with the following high-risk features: Micropapillary features (more than focal on pathology); Small cell carcinoma; 3-dimensional (D) mass on exam under anesthesia (EUA); Lymphovascular invasion; Hydronephrosis (unless in the opinion of the treating physician, this is not due to tumor); High grade (grade 3) tumors of the ureter, renal pelvis, or urethra, or tumors in these areas with radiographic abnormality large enough to recognize as an abnormal mass by computed tomography (CT) or magnetic resonance imaging (MRI) imaging; Direct invasion of the prostatic stroma or the vaginal wall (ie: cT4a disease) should be offered neoadjuvant cytoreductive chemotherapy (ie: cisplatin-based). Patients refusing or who are not considered candidates for cytoreductive chemotherapy may be considered eligible. Dr. Siefker-Radtke will be the final arbiter in determining eligibility for the trial

• Please note that the presence of variant histologic subtypes is acceptable, except in the case for small cell variant which is traditionally treated with cytoreductive chemotherapy. Patients with small cell who refuse recommended cytoreductive chemotherapy may still be considered eligible

• Patients must have an evaluation in the department of urology, and be deemed an acceptable surgical candidate

• Patients must NOT have clinical evidence of metastatic disease by either CT or MRI of the abdomen and pelvis, and chest x-ray. In the absence of a bone scan, patients should be free of bone pain and have an alkaline phosphatase < 1.5 x upper limit of normal (ULN) of the upper limit of normal, or a normal bone fraction of alkaline phosphatase. If these features are present, patients should have a bone scan and this should be interpreted as showing no evidence of metastatic disease in order to be eligible

• Patients, 18 years and older, must either be not of child bearing potential or have a negative pregnancy test within 2 weeks of treatment. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal

• Absolute neutrophil count (ANC) >= 1,000/ul

• Platelets >= 75,000/microliters

• Creatinine =< 2.0 x institutional upper limit of normal (ULN), or a creatinine clearance of > 30 ml/min as calculated by Cockroft-Gault or by 24-hour urine collection

• Bilirubin =< 2.5 x ULN

• Aspartate aminotransferase (AST) =< 5.0 x ULN

• Zubrod performance status (PS) =< 2

• Patients with second malignancies are eligible provided that the expected outcome from the second cancer is such that this will not interfere in the delivery of this therapy, or in doing cystectomy, and provided that the expectation of survival from any prior malignancy is reliably > 4 years

Exclusion Criteria:

• Acute hepatitis or known human immunodeficiency virus (HIV)

• Active or uncontrolled infection

• Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction =< 40%

• Prior therapy specifically and directly targeting the EGFR pathway

• Patients with interstitial lung disease

• Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s)

• Patients with metastatic or surgically unresectable disease are not eligible for this study. In addition, patients who do not agree to surgery are not eligible for this trial

• Patients who have received prior systemic chemotherapy or radiation therapy for urothelial cancer are not eligible. Any prior intravesical chemotherapy is allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Arlene Siefker-Radtke, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 11, 2009

More Information

Additional Information:

• MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00749892
• Other Study ID Numbers: 2007-0704; NCI-2018-01833; 2007-0704; P30CA016672
• First Posted: Sep 9, 2008
• Last Update Posted: Sep 10, 2020
• Last Verified: Aug 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urethral Neoplasms; Ureteral Neoplasms; Kidney Neoplasms; Pelvic Neoplasms; Recurrence; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	Recruitment began 6/9/2008 and concluded on 12/19/2011 in the medical clinic. Diagnosis of invasive transitional cell carcinoma in the bladder, upper tract or urethra tumors were required for participants who were candidates for cystectomy to be considered. Participants with high-risk features were generally excluded.
Pre-assignment Detail	Erlotinib treatment milestone: Three participants decided to not start the study medication.

Arm/Group Title	Pre-surgical Erlotinib Treatment
Arm/Group Description	Erlotinib 150 mg by mouth daily for 3 weeks followed by cystectomy within 24 hours of the last dose.
Period Title: Overall Study
STARTED	34
COMPLETED	31
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Pre-surgical Erlotinib Treatment
Arm/Group Description	Erlotinib 150 mg by mouth daily for 3 weeks followed by cystectomy within 24 hours of the last dose.
Overall Participants	34
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	8 23.5%
Male	26 76.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.9%
Not Hispanic or Latino	12 35.3%
Unknown or Not Reported	21 61.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 8.8%
White	30 88.2%
More than one race	0 0%
Unknown or Not Reported	1 2.9%
Region of Enrollment (participants) [Number]
United States	34 100%
Clinical Staging (Count of Participants)
cTaN0	1 2.9%
cT1N0	10 29.4%
cT2N0	17 50%
cT3aN0	1 2.9%
cT3bN0	1 2.9%
cT4aN0	1 2.9%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	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.
Time Frame	Determined at the time of surgery or cystectomy

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pre-surgical Erlotinib Treatment
Arm/Group Description	Erlotinib 150 mg by mouth daily for 3 weeks followed by cystectomy within 24 hours of the last dose.
Measure Participants	26
Number of Responders	8 23.5%
Number of Non Responders	18 52.9%

2. Secondary Outcome

Title	Estimated 4-Year Disease-Free Survival
Time Frame	4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Evaluated for 2 months once drug therapy started.
Adverse Event Reporting Description	Toxicities were measured at weekly visit while on therapy using the NCI CTCAE v3.0.
Arm/Group Title	Pre-surgical Erlotinib Treatment
Arm/Group Description	Erlotinib 150 mg by mouth daily for 3 weeks followed by cystectomy within 24 hours of the last dose.
All Cause Mortality
	Pre-surgical Erlotinib Treatment
	Affected / at Risk (%)	# Events
Total	0/31 (0%)
Serious Adverse Events
	Pre-surgical Erlotinib Treatment
	Affected / at Risk (%)	# Events
Total	5/31 (16.1%)
Blood and lymphatic system disorders
Decreased Neutrophils/Grabulocytes	1/31 (3.2%)
Endocrine disorders
Adrenal insufficiency	1/31 (3.2%)
General disorders
Fatigue	1/31 (3.2%)
Infections and infestations
Infection-wound	1/31 (3.2%)
Skin and subcutaneous tissue disorders
Rash	2/31 (6.5%)
Other (Not Including Serious) Adverse Events
	Pre-surgical Erlotinib Treatment
	Affected / at Risk (%)	# Events
Total	19/31 (61.3%)
Blood and lymphatic system disorders
Lymphopenia	5/31 (16.1%)
Decreased Neutrophils/Grabulocytes	2/31 (6.5%)
Gastrointestinal disorders
Diarrhea	6/31 (19.4%)
Skin and subcutaneous tissue disorders
Rash	15/31 (48.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.