Erlotinib Before and After Surgery in Treating Patients With Muscle-Invasive Bladder Cancer

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00380029
• Collaborator: OSI Pharmaceuticals (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 27
• Location: 1
• Arm: 1
• Duration (Months): 97
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving erlotinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving erlotinib after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well erlotinib works when given before and after surgery in treating patients with muscle-invasive bladder cancer.

Condition or Disease	Intervention/Treatment	Phase
Bladder Cancer	Drug: Erlotinib; Procedure: Radical Cystectomy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the effect of neoadjuvant erlotinib hydrochloride on histopathological, molecular, and genetic correlates in patients undergoing radical cystectomy for muscle-invasive bladder cancer.

Secondary

• Determine the pathological complete response rate in surgical specimens from patients treated with this drug.

• Determine recurrence and progression rates after cystectomy (up to 2 years after surgery) in patients treated with neoadjuvant and adjuvant erlotinib hydrochloride.

• Determine 2- and 5-year disease-free, disease-specific, and overall survival rates in patients treated with this drug.

• Determine the safety of this drug in these patients.

OUTLINE: This is an open-label study.

Patients receive oral erlotinib hydrochloride once daily for 4 weeks. Patients then undergo radical cystectomy with curative intent. Within 12 weeks after surgery, patients resume oral erlotinib hydrochloride* once daily for up to 2 years in the absence of disease progression or unacceptable toxicity.

Note: *Patients who are candidates for adjuvant chemotherapy (e.g., found to have pathologic stage T3 (pT3), Node positive (N+) disease) do not receive erlotinib hydrochloride after surgery.

Tumor tissue is obtained at baseline (at the original or confirmatory transurethral resection of the bladder tumor) and at the time of cystectomy for analysis of drug-specific and tissue-based biomarkers by western blot, immunohistochemistry, and gene array techniques. Histopathological, molecular, and genetic correlates are analyzed to better understand the potential effects of the epidermal growth factor receptor (EGFR) inhibition in transitional cell carcinoma and to determine the effect of neoadjuvant erlotinib on gene expression. Tumor tissue is also evaluated by real-time polymerase chain reaction to confirm drug effects on expected targets and on EGFR expression, activity, and affected signaling pathways in the disease state and by microarray analysis to define expression phenotypes correlating with outcome, distinguish responders from nonresponders, and determine effects of drug treatment on gene expression in disease.

Patients are followed periodically for up to 5 years after surgery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Erlotinib (Tarceva®) in Patients With Muscle-Invasive Bladder Cancer Undergoing Radical Cystectomy
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Erlotinib erlotinib given before and after transurethral resection of a bladder tumor, TURBT

Drug: Erlotinib; Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression; Other Names: Tarceva ; Procedure: Radical Cystectomy; Will occur 4 weeks prior to dosing with erlotinib

Outcome Measures

Primary Outcome Measures

1. EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib [4 weeks before treatment and 4 weeks post treatment]

   Determine the effect of neoadjuvant erlotinib hydrochloride on histopathological, molecular, and genetic correlates in patients undergoing radical cystectomy for muscle-invasive bladder cancer. Gene expression of pre-treatment and post-treatment tumor samples were analyzed to define molecular determinants of response or resistance to epidermal growth factor receptor (EGFR) inhibition. Both in vitro and in vivo EGFR-associated signatures were evaluated on pre-treatment bladder tumors. Candidate molecular determinants of sensitivity to EGFR inhibition were characterized and examined for their ability to predict sensitivity to EGFR inhibitors in vitro.

Secondary Outcome Measures

1. Pathological Complete Response Rate [4 weeks]

   Determine the pathological complete response rate (P0 rate) after undergoing radical cystectomy (RC). Evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

2. Disease Recurrence and Progression Rates After Cystectomy [2 years]

   To determine disease recurrence/progression rates after cystectomy in patients treated with erlotinib

3. Overall Survival Rate [25 months]

   The number of patients who remained alive and with no evidence of disease at the mean (range) follow-up of 24.8 months (3.0-36.6).

4. Number of Subjects Experiencing Adverse Events [4 weeks - 2 years following surgery]

   The incidence of all toxicities observed during neoadjuvant and adjuvant treatment phase.Toxicity will be graded per the Common Terminology Criteria for Adverse Events (CTCAE) 2.0.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed muscle-invasive bladder cancer, meeting the following criteria:

• Clinical stage T2 disease

• No locally-extensive clinical stage T3 or T4 disease

• No metastatic disease (N+, M+) by physical exam or radiologic evaluation

• Must have undergone prior initial or confirmatory transurethral resection of the bladder tumor (TURBT)

• Candidate for and has agreed to undergo radical cystectomy with curative intent

• No non-transitional cell carcinoma histologies

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Granulocyte count > 1,500/mm³

• Platelet count > 100,000/mm³

• Bilirubin normal

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 times upper limit of normal

• Creatinine normal

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No contraindication to erlotinib hydrochloride or other tyrosine kinase inhibitors

PRIOR CONCURRENT THERAPY:

• No prior radiotherapy or systemic chemotherapy for bladder cancer

• Prior single-dose mitomycin C allowed at the time of TURBT

• Prior 6- or 12-week course of adjuvant intravesical Bacillus Calmette-Guerin (BCG) therapy with or without recombinant interferon alfa-2a allowed

• At least 4 weeks since other prior or concurrent radiotherapy, chemotherapy, or hormonal therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• OSI Pharmaceuticals
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Raj S. Pruthi, MD, UNC Lineberger Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UNC Lineberger Comprehensive Cancer Center

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00380029
• Other Study ID Numbers: LCCC 0521; P30CA016086
• First Posted: Sep 25, 2006
• Last Update Posted: Jul 19, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: stage II bladder cancer; transitional cell carcinoma of the bladder
• Additional relevant MeSH terms: Urinary Bladder Neoplasms; Erlotinib Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	27 patients were screened, 23 patients were consented to the study; three of these patients were not subsequently enrolled due to ineligibility (1) and patient decision not to enroll in the trial (2).

Arm/Group Title	Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib
Overall Participants	20
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	67.1
Sex: Female, Male (Count of Participants)
Female	5 25%
Male	15 75%
Region of Enrollment (participants) [Number]
United States	20 100%
Smoking Status (Count of Participants)
Current	7 35%
Former	10 50%
Never	3 15%

Outcome Measures

1. Primary Outcome

Title	EGFR Activation Signal (AKT2) Expression to Predict Sensitivity to Erlotinib
Description	Determine the effect of neoadjuvant erlotinib hydrochloride on histopathological, molecular, and genetic correlates in patients undergoing radical cystectomy for muscle-invasive bladder cancer. Gene expression of pre-treatment and post-treatment tumor samples were analyzed to define molecular determinants of response or resistance to epidermal growth factor receptor (EGFR) inhibition. Both in vitro and in vivo EGFR-associated signatures were evaluated on pre-treatment bladder tumors. Candidate molecular determinants of sensitivity to EGFR inhibition were characterized and examined for their ability to predict sensitivity to EGFR inhibitors in vitro.
Time Frame	4 weeks before treatment and 4 weeks post treatment

Outcome Measure Data

Analysis Population Description

Only patients with tumor samples with sufficient and high quality RNA were used to generate the in vivo signatures.

Arm/Group Title	Downstaged Tumors	Not-downstaged
Arm/Group Description	transurethral resection of a bladder tumor, (TURBT) tumors resected from participants treated with neo-adjuvant erlotinib which were considered to be downstaged ( pathologic tumor stage at cystectomy <pT2 and N0)	transurethral resection of a bladder tumor, (TURBT) tumors resected from participants treated with neo-adjuvant erlotinib which were considered to be not-downstaged ( pathologic stage at cystectomy >=pT2 or node positive (N1 or N2))
Measure Participants	6	15
Mean (Full Range) [fold change]	-0.29	0.128

2. Secondary Outcome

Title	Pathological Complete Response Rate
Description	Determine the pathological complete response rate (P0 rate) after undergoing radical cystectomy (RC). Evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib
Measure Participants	20
Count of Participants [Participants]	5 25%

3. Secondary Outcome

Title	Disease Recurrence and Progression Rates After Cystectomy
Description	To determine disease recurrence/progression rates after cystectomy in patients treated with erlotinib
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib
Measure Participants	20
Count of Participants [Participants]	4 20%

4. Secondary Outcome

Title	Overall Survival Rate
Description	The number of patients who remained alive and with no evidence of disease at the mean (range) follow-up of 24.8 months (3.0-36.6).
Time Frame	25 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib
Measure Participants	20
Count of Participants [Participants]	10 50%

5. Secondary Outcome

Title	Number of Subjects Experiencing Adverse Events
Description	The incidence of all toxicities observed during neoadjuvant and adjuvant treatment phase.Toxicity will be graded per the Common Terminology Criteria for Adverse Events (CTCAE) 2.0.
Time Frame	4 weeks - 2 years following surgery

Outcome Measure Data

Analysis Population Description

All patients enrolled received the full 4-week neoadjuvant course of erlotinib. 12 patients continued on erlotinib in the adjuvant phase for a mean (range) duration of 29 (5-84) weeks.

Arm/Group Title	Neoadjuvant Erlotinib	Adjuvant Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib	Patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression.
Measure Participants	20	12
Rash	15 75%	6 NaN
Anorexia	6 30%	0 NaN
Diarrea	6 30%	1 NaN
Fatigue	6 30%	2 NaN
Lower urinary tract symptoms	4 20%	0 NaN
Nausea	3 15%	0 NaN
Cough	3 15%	2 NaN
Dry skin	2 10%	1 NaN
Haematuria	2 10%	0 NaN
Vagal episode	1 5%	1 NaN
Stomatitus	1 5%	2 NaN
Pneumonitis	0 0%	1 NaN
Deep vein thrombosis	0 0%	1 NaN

Adverse Events

Time Frame	5 years
Arm/Group Title	Erlotinib
Arm/Group Description	erlotinib given before and after transurethral resection of a bladder tumor, TURBT Erlotinib: Erlotinib will be given at a dose of 150 mg per day for 4 weeks before undergoing planned radical cystectomy. In addition, patients will continue on erlotinib daily at a dose of 150 mg per day (qd dosing) for up to 2 years after surgery (beginning within 12 weeks of surgery) or until evidence of disease recurrence or progression Radical Cystectomy: Will occur 4 weeks prior to dosing with erlotinib
All Cause Mortality
	Erlotinib
	Affected / at Risk (%)	# Events
Total	11/23 (47.8%)
Serious Adverse Events
	Erlotinib
	Affected / at Risk (%)	# Events
Total	8/23 (34.8%)
Cardiac disorders
Cardiac ischemia/infarction	2/23 (8.7%)
Cardiovascular/Arrhythmia-Other (Abnormal EKG)	1/23 (4.3%)
Gastrointestinal disorders
Gastrointestinal-Other (Mallory-Weiss tear w/nausea, vomiting)	1/23 (4.3%)
Ileus (or neuroconstipation)	2/23 (8.7%)
General disorders
Death NOS- Unknown cause	1/23 (4.3%)
Infections and infestations
Infection without neutropenia	1/23 (4.3%)
Injury, poisoning and procedural complications
Thrombosis/embolism	2/23 (8.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal- Other (Parastomal hernia)	1/23 (4.3%)
Nervous system disorders
Syncope	1/23 (4.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	Erlotinib
	Affected / at Risk (%)	# Events
Total	23/23 (100%)
Blood and lymphatic system disorders
Hemoglobin	13/23 (56.5%)
Cardiac disorders
Ventricular arrhythmia (PVCs/bigeminy/trigeminy/ventricular tachycardia)	1/23 (4.3%)
Eye disorders
Glaucoma	1/23 (4.3%)
Gastrointestinal disorders
Abdominal pain or cramping	2/23 (8.7%)
Constipation	4/23 (17.4%)
Diarrhea	7/23 (30.4%)
Gastrointestinal-Other (Gastroesophageal reflux disease)	1/23 (4.3%)
Nausea	5/23 (21.7%)
Pain - Abdomen NOS	1/23 (4.3%)
Stomatitis/pharyngitis (oral/pharyngeal mucositis)	2/23 (8.7%)
Vomiting	2/23 (8.7%)
General disorders
Fatigue	8/23 (34.8%)
Pain-Other (Cramping - Hands/Feet)	1/23 (4.3%)
Pain-Other (Pain - rash induced)	1/23 (4.3%)
Infections and infestations
Infection with unknown ANC	1/23 (4.3%)
Infection without neutropenia	3/23 (13%)
Infection/Febrile Neutropenia-Other (Urinary tract infection - intermittent)	1/23 (4.3%)
Investigations
Alkaline phosphatase	4/23 (17.4%)
Amylase	1/23 (4.3%)
Coagulation-Elevated international normalized ratio (INR)	1/23 (4.3%)
CPK (creatine phosphokinase)	1/23 (4.3%)
Creatinine	6/23 (26.1%)
GGT (Gamma-Glutamyl transpeptidase)	2/23 (8.7%)
Lipase	1/23 (4.3%)
Lymphopenia	4/23 (17.4%)
Partial thromboplastin time (PTT)	1/23 (4.3%)
Platelets	3/23 (13%)
SGOT (AST) (serum glutamic oxaloacetic transaminase)	3/23 (13%)
SGPT (ALT) (serum glutamic pyruvic transaminase)	1/23 (4.3%)
Metabolism and nutrition disorders
Anorexia	10/23 (43.5%)
Bicarbonate	4/23 (17.4%)
Hyperglycemia	3/23 (13%)
Hyperkalemia	3/23 (13%)
Hypernatremia	2/23 (8.7%)
Hypoalbuminemia	5/23 (21.7%)
Hypocalcemia	7/23 (30.4%)
Hypoglycemia	1/23 (4.3%)
Hypokalemia	4/23 (17.4%)
Hypomagnesemia	8/23 (34.8%)
Hyponatremia	7/23 (30.4%)
Hypophosphatemia	1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/23 (4.3%)
Musculoskeletal-Other (Gout flare)	1/23 (4.3%)
Pain - Back	2/23 (8.7%)
Nervous system disorders
Dizziness/lightheadedness	1/23 (4.3%)
Neuropathy-sensory	1/23 (4.3%)
Syncope	1/23 (4.3%)
Taste disturbance (dysgeusia)	4/23 (17.4%)
Tremor	1/23 (4.3%)
Psychiatric disorders
Insomnia	1/23 (4.3%)
Mood alteration - Anxiety	1/23 (4.3%)
Mood alteration - Anxiety, agitation	1/23 (4.3%)
Mood alteration- Depression	3/23 (13%)
Renal and urinary disorders
Bladder spasms	1/23 (4.3%)
Dysuria	2/23 (8.7%)
Hematuria (in the absence of vaginal cleeding)	5/23 (21.7%)
Incontinence	1/23 (4.3%)
Renal/Genitourinary - Other (Dysuria)	1/23 (4.3%)
Renal/Genitourinary-Other (Candida urinary tract infection (UTI))	1/23 (4.3%)
Urinary frequency/urgency	12/23 (52.2%)
Respiratory, thoracic and mediastinal disorders
Apnea	1/23 (4.3%)
Cough	4/23 (17.4%)
Skin and subcutaneous tissue disorders
Alopecia	1/23 (4.3%)
Dermatology/Skin-Other (Reynaud's)	1/23 (4.3%)
Dermatology/Skin-Other (onychomycosis -on fingers -bilaterally)	1/23 (4.3%)
Dermatology/Skin-Other (Paronychia)	1/23 (4.3%)
Dermatology/Skin-Other (Boils on abdomen)	1/23 (4.3%)
Dermatology/Skin-Other (Cracked Lips)	1/23 (4.3%)
Dry skin	3/23 (13%)
Hand-foot skin reaction	1/23 (4.3%)
Pruritus	1/23 (4.3%)
Rash/desquamation	21/23 (91.3%)
Sweating (diaphoresis)	1/23 (4.3%)
Vascular disorders
Cardiovascular/Arrhythmia-Afib/tachycardia	1/23 (4.3%)
Hemorrhage-Other (Hemorrhoid)	1/23 (4.3%)
Hypertension	1/23 (4.3%)

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.