Gemcitabine, Paclitaxel, Doxorubicin in Metastatic or Unresectable Bladder Cancer With Decreased Kidney Function

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00478361
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 40
• Locations: 2
• Arm: 1
• Duration (Months): 98
• Patients Per Site: 20
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving gemcitabine, paclitaxel, and doxorubicin together with pegfilgrastim works in treating patients with metastatic or unresectable bladder cancer or urinary tract cancer and kidney dysfunction. Drugs used in chemotherapy, such as gemcitabine, paclitaxel, and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Colony stimulating factors, such as pegfilgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving combination chemotherapy together with pegfilgrastim may kill more tumor cells. Chemotherapy drugs may have different effects in patients who have changes in their kidney function.

Condition or Disease	Intervention/Treatment	Phase
Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer	Drug: Gemcitabine hydrochloride; Drug: Paclitaxel; Drug: Doxorubicin hydrochloride; Drug: Pegfilgrastim	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Assess the efficacy of gemcitabine hydrochloride, paclitaxel, doxorubicin hydrochloride, and pegfilgrastim, in terms of response rate, in patients with metastatic or unresectable transitional cell carcinoma of the bladder or urinary tract and renal insufficiency.

SECONDARY OBJECTIVES:

1. Assess the safety and tolerability of this regimen in these patients. II. Determine the median time to progression in patients treated with this regimen.

2. Determine the median survival duration in patients treated with this regimen.

3. Assess the safety and efficacy of pegfilgrastim in these patients.

OUTLINE: This is a multicenter study.

Patients receive doxorubicin hydrochloride intravenous (IV) over 20 minutes, paclitaxel IV over 60 minutes, gemcitabine hydrochloride IV over 90 minutes, and pegfilgrastim subcutaneously on day 1. Treatment repeats every 14 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Gemcitabine, Paclitaxel, and Doxorubicin, With Pegfilgrastim for the Treatment of Patients With Metastatic Transitional Cell Carcinoma and Renal Insufficiency
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Gemcitabine, Paclitaxel and Doxorubicin Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 min; Doxorubicin 40 mg/m^2 IV over 20 min; treatment may repeat every 2 weeks for up to nine courses. Injection of Pegfilgrastim on day 1.

Drug: Gemcitabine hydrochloride; Gemcitabine 900 mg/m^2 IV over 90 minutes repeat every 14 days.; Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar ; Drug: Paclitaxel; 135 mg/m^2 IV over 1 hour; Other Names: Anzatax Asotax TAX Taxol ; Drug: Doxorubicin hydrochloride; Doxorubicin 40 mg/m^2 IV over 20 minutes; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: Pegfilgrastim; Subcutaneously injection on day 1.; Other Names: Filgrastim SD-01 GCSF-SD01 Neulasta SD-01 sustained duration G-CSF

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [Up to 12 weeks, or following completion 6 cycles of chemotherapy, respectively; the best response achieved within 6 cycles of starting chemotherapy used to calculate response rate.]

   The percentage of participants with either Complete Response (CR) or Partial Response (PR) in their disease burden based upon the rules of the Response Evaluation Criteria in Solid Tumors (RECIST). A participant with of all of the lesions disappearing is a CR. A participant with at least a 30 percent decrease in the measured lesions is a PR.

Secondary Outcome Measures

1. Overall Survival (OS) of Participants With a Continuous Complete Response, Partial Response and Stable Disease [Registration Date of each participant for up to three years or death whichever came first]

   The overall survival was determined by grouping participants based upon their response based on RECIST. The groups are Complete Response(CR): All the cancerous lesion disappear, Partial Response (PR): All the measured lesions decrease by at least 30 percent, and Stable Disease(SD): No significant change in the disease burden. OS of complete response or partial response participants were compared to the reference group of stable disease participants in a Hazard Ratio(HR). If HR is greater than 1, the experimental group has a better outcome than the reference group. If HR is less than 1, the reference group has the better outcome.

2. Safety and Efficacy of Same-day Pegfilgrastim [Up to 3 years]

   Determined the number of participants who had either a fever due to abnormally low level of neutrophils, a type of white blood cell, on the day of study drug treatment, or the participants who had the study drug treatment delayed due to an abnormally low level of neutrophils.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed transitional cell carcinoma (TCC) of the bladder, urethra, or upper urinary tract

• Mixed TCC and variant histologies (i.e., small cell, squamous cell, adenocarcinoma, or sarcoma) allowed if present in < 50% of the biopsy specimen

• Patients must sign an informed consent indicating that they are aware of the investigational nature of this study, in keeping with the policies of the institution.

• Measurable disease: may include radiographic detection of metastases in lymph nodes (>= 1.5 cm) or liver or lung (>= 1.0 cm) OR pelvic mass palpable on examination under anesthesia

• Creatinine clearance < 60 mL/min; no renal insufficiency that requires hemodialysis; no renal insufficiency that is reversible in patients with tumor confined to the primary site (i.e., that is potentially resectable with neoadjuvant chemotherapy)

• Zubrod performance status 0-2

• Platelet count > 100,000/mm^3

• Absolute granulocyte count > 1,500/mm^3

• Bilirubin =< 2.0 mg/dL

• Aminotransferases (AST and ALT) =< 2 times upper limit of normal

• Left ventricular ejection fraction (LVEF) > 40% OR normal electrocardiogram (EKG or ECG) and no history of cardiac disease

• All patients must be evaluated in the Department of Genitourinary Medical Oncology at

1. 1. Anderson Cancer Center or participating CCOP center prior to signing informed consent.

• No prior systemic chemotherapy including, adjuvant or neoadjuvant therapy

• Prior intravesicular chemotherapy allowed

Exclusion Criteria:

• No brain metastases

• Not pregnant or nursing

• No severe or uncontrolled infection

• No New York Heart Association class III-IV congestive heart failure, unstable angina, or history of myocardial infarction within the past 6 months

• No peripheral neuropathy >= grade 2

• No persistently uncontrolled diabetes mellitus

• No chronic liver disease

• No HIV positivity

• No other malignancy except nonmelanoma skin cancer unless disease-free for the past 3 years

• No overt psychosis, mental disability, or other condition that would preclude giving informed consent

• No known sickle cell disease

• No uncontrolled severe hypertension

• Renal insufficiency that requires hemodialysis or renal insufficiency that is reversible in patients with tumor confined to the primary site (i.e., that is potentially resectable with neoadjuvant chemotherapy).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ozark Health Ventures LLC dba Cancer Research for The Ozarks Springfield	Springfield	Missouri	United States	65802
2	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Lance Pagliaro, MD, BA, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00478361
• Other Study ID Numbers: 2005-0839; NCI-2009-00154; CDR0000544831; 2U10CA045809-17; NCT00477438
• First Posted: May 24, 2007
• Last Update Posted: Oct 9, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urethral Neoplasms; Kidney Neoplasms; Ureteral Neoplasms; Recurrence; Gemcitabine; Paclitaxel; Doxorubicin; Liposomal doxorubicin

Study Results

Participant Flow

Recruitment Details	Recruitment period: April 24, 2007 to November 10, 2011. All recruitment done within Community Clinical Oncology Programs (CCOP) medical clinics, specifically The University of Texas MD Anderson Cancer Center and the Ozarks Regional CCOP.
Pre-assignment Detail	One patient withdrew from the study without receiving treatment.

Arm/Group Title	Gemcitabine, Paclitaxel and Doxorubicin
Arm/Group Description	Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 minutes; Doxorubicin 40 mg/m^2 IV over 20 minutes; treatment may repeat every 2 weeks for up to nine courses. Subcutaneous Injection of Pegfilgrastim on day 1 or 2 of each course, after chemotherapy.
Period Title: Overall Study
STARTED	39
COMPLETED	39
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Gemcitabine, Paclitaxel and Doxorubicin
Arm/Group Description	Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 minutes; Doxorubicin 40 mg/m^2 IV over 20 minutes; treatment may repeat every 2 weeks for up to nine courses. Subcutaneous Injection of Pegfilgrastim on day 1 or 2 of each course, after chemotherapy.
Overall Participants	39
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72
Sex: Female, Male (Count of Participants)
Female	11 28.2%
Male	28 71.8%
Region of Enrollment (participants) [Number]
United States	39 100%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	The percentage of participants with either Complete Response (CR) or Partial Response (PR) in their disease burden based upon the rules of the Response Evaluation Criteria in Solid Tumors (RECIST). A participant with of all of the lesions disappearing is a CR. A participant with at least a 30 percent decrease in the measured lesions is a PR.
Time Frame	Up to 12 weeks, or following completion 6 cycles of chemotherapy, respectively; the best response achieved within 6 cycles of starting chemotherapy used to calculate response rate.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine, Paclitaxel and Doxorubicin
Arm/Group Description	Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 minutes; Doxorubicin 40 mg/m^2 IV over 20 minutes; treatment may repeat every 2 weeks for up to nine courses. Subcutaneous Injection of Pegfilgrastim on day 1 or 2 of each course, after chemotherapy.
Measure Participants	39
Number (95% Confidence Interval) [percentage of participants]	56.4 144.6%

2. Secondary Outcome

Title	Overall Survival (OS) of Participants With a Continuous Complete Response, Partial Response and Stable Disease
Description	The overall survival was determined by grouping participants based upon their response based on RECIST. The groups are Complete Response(CR): All the cancerous lesion disappear, Partial Response (PR): All the measured lesions decrease by at least 30 percent, and Stable Disease(SD): No significant change in the disease burden. OS of complete response or partial response participants were compared to the reference group of stable disease participants in a Hazard Ratio(HR). If HR is greater than 1, the experimental group has a better outcome than the reference group. If HR is less than 1, the reference group has the better outcome.
Time Frame	Registration Date of each participant for up to three years or death whichever came first

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine, Paclitaxel and Doxorubicin
Arm/Group Description	Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 minutes; Doxorubicin 40 mg/m^2 IV over 20 minutes; treatment may repeat every 2 weeks for up to nine courses. Subcutaneous Injection of Pegfilgrastim on day 1 or 2 of each course, after chemotherapy.
Measure Participants	39
Complete Response	0.25
Partial Response	1.09

3. Secondary Outcome

Title	Safety and Efficacy of Same-day Pegfilgrastim
Description	Determined the number of participants who had either a fever due to abnormally low level of neutrophils, a type of white blood cell, on the day of study drug treatment, or the participants who had the study drug treatment delayed due to an abnormally low level of neutrophils.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

Thirty-two patients (82%) received Pegfilgrastim immediately after chemotherapy on day 1 of the cycle.

Arm/Group Title	Gemcitabine, Paclitaxel and Doxorubicin
Arm/Group Description	Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 minutes; Doxorubicin 40 mg/m^2 IV over 20 minutes; treatment may repeat every 2 weeks for up to nine courses. Subcutaneous Injection of Pegfilgrastim on day 1 or 2 of each course, after chemotherapy.
Measure Participants	32
Neutropenic Fever	4 10.3%
Treatment Delay	0 0%

Adverse Events

Time Frame	Adverse event collection during therapy may continue for 12 weeks (6 cycles) with possible 3 additional cycles (6 weeks) beyond a documented complete response.
Adverse Event Reporting Description	AEs were graded by numerical score according to the NCI Common Terminology Criteria Adverse Events (CTCAE), version 4.0.
Arm/Group Title	Gemcitabine, Paclitaxel and Doxorubicin
Arm/Group Description	Paclitaxel 135 mg/m^2 intravenous (IV) over 1 hour; Gemcitabine 900 mg/m^2 IV over 90 minutes; Doxorubicin 40 mg/m^2 IV over 20 minutes; treatment may repeat every 2 weeks for up to nine courses. Subcutaneous Injection of Pegfilgrastim on day 1 or 2 of each course, after chemotherapy.
All Cause Mortality
	Gemcitabine, Paclitaxel and Doxorubicin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Gemcitabine, Paclitaxel and Doxorubicin
	Affected / at Risk (%)	# Events
Total	39/39 (100%)
Blood and lymphatic system disorders
Granulocytopenia	13/39 (33.3%)	13
Anemia	6/39 (15.4%)	6
Neutropenic Fever	4/39 (10.3%)	4
Gastrointestinal disorders
Mucositis	4/39 (10.3%)	4
General disorders
Fatigue	4/39 (10.3%)	4
Pain	3/39 (7.7%)	3
Investigations
Lymphopenia	3/39 (7.7%)	3
Leukopenia	8/39 (20.5%)	8
Thrombocytopenia	6/39 (15.4%)	6
Metabolism and nutrition disorders
Hyperuricemia	4/39 (10.3%)	4
Hyperphosphatemia	2/39 (5.1%)	2
Dehydration	2/39 (5.1%)	2
Hyperglycemia	4/39 (10.3%)	4
Hyponatremia	2/39 (5.1%)	2
Musculoskeletal and connective tissue disorders
Hand Foot Syndrome	2/39 (5.1%)	2
Vascular disorders
Deep Vein Thrombosis	2/39 (5.1%)	2
Other (Not Including Serious) Adverse Events
	Gemcitabine, Paclitaxel and Doxorubicin
	Affected / at Risk (%)	# Events
Total	34/39 (87.2%)
Blood and lymphatic system disorders
Anemia	32/39 (82.1%)	73
BUN	1/39 (2.6%)	1
Cardiac disorders
Sinus Tachycardia	1/39 (2.6%)	1
Atrial Fibrillation	1/39 (2.6%)	1
Acute Coronary Syndrome	1/39 (2.6%)	1
Chest Pain	1/39 (2.6%)	1
Ear and labyrinth disorders
Hearing Impaired	5/39 (12.8%)	6
Tinnitus	1/39 (2.6%)	1
Eye disorders
Watering Eyes	2/39 (5.1%)	2
Gastrointestinal disorders
Mucositis Oral	8/39 (20.5%)	14
Nausea	9/39 (23.1%)	12
Constipation	7/39 (17.9%)	8
Abdominal Pain	2/39 (5.1%)	5
Diarrhea	6/39 (15.4%)	7
Dry Mouth	2/39 (5.1%)	2
Dyspepsia	2/39 (5.1%)	2
Dysphagia	1/39 (2.6%)	1
Vomiting	1/39 (2.6%)	1
General disorders
Fever	3/39 (7.7%)	3
Edema Limbs	10/39 (25.6%)	12
Fatigue	17/39 (43.6%)	33
Gait Disturbance	2/39 (5.1%)	2
Hepatobiliary disorders
Hepatobiliary Disorders	1/39 (2.6%)	1
Infections and infestations
Vaginal Infection	1/39 (2.6%)	3
Skin Infection	1/39 (2.6%)	1
Injury, poisoning and procedural complications
Bruising	1/39 (2.6%)	1
Investigations
Platelet Count Decreased	13/39 (33.3%)	28
Creatinine Increased	26/39 (66.7%)	38
Alkaline Phosphatase Increased	6/39 (15.4%)	8
Carbon Monoxide Diffusing Capacity Decreased	1/39 (2.6%)	1
Cardiac Troponin I Increased	1/39 (2.6%)	2
White Blood Cell Decreased	5/39 (12.8%)	8
Neutrophil Count Decreased	4/39 (10.3%)	4
INR Increased	1/39 (2.6%)	1
Hemoglobin Increased	2/39 (5.1%)	3
Cholesterol High	3/39 (7.7%)	3
Phosphorus High	1/39 (2.6%)	1
Activated Partial Thromboplastin Time Prolonged	1/39 (2.6%)	1
CPK Increased	1/39 (2.6%)	1
Lymphocyte Count Decreased	2/39 (5.1%)	3
Weight Loss	1/39 (2.6%)	2
Aspartate Aminotransferase Increased	1/39 (2.6%)	2
Alanine Aminotransferase Increased	1/39 (2.6%)	2
Metabolism and nutrition disorders
Hypoalbuminemia	6/39 (15.4%)	7
Hyperkalemia	6/39 (15.4%)	6
Hypoglycemia	2/39 (5.1%)	2
Hyperuricemia	10/39 (25.6%)	10
Hyperglycemia	14/39 (35.9%)	18
Hypermagnesemia	2/39 (5.1%)	2
Hypophosphatemia	2/39 (5.1%)	2
Anorexia	11/39 (28.2%)	14
Hypernatremia	1/39 (2.6%)	1
Hypocalcemia	5/39 (12.8%)	6
Hypokalemia	3/39 (7.7%)	5
Hyponatremia	7/39 (17.9%)	8
Hypomagnesemia	6/39 (15.4%)	9
Glucose Intolerance	1/39 (2.6%)	1
Hypercalcemia	2/39 (5.1%)	2
Alkalosis	1/39 (2.6%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	2/39 (5.1%)	2
Flank Pain	3/39 (7.7%)	3
Arthritis	1/39 (2.6%)	1
Palmar-Plantar Erythrodysesthesia Syndrome	2/39 (5.1%)	2
Pain	11/39 (28.2%)	22
Muscle Weakness Lower Limb	1/39 (2.6%)	2
Muscle Weakness Left-Sided	1/39 (2.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin and Subcutaneous Tissue Disorders - Nodule	1/39 (2.6%)	1
Nervous system disorders
Peripheral Motor Neuropathy	2/39 (5.1%)	2
Peripheral Sensory Neuropathy	13/39 (33.3%)	17
Headache	1/39 (2.6%)	1
Dysgeusia	5/39 (12.8%)	5
Accessory Nerve Disorder	1/39 (2.6%)	1
Nervous System Disorders - Sensory	1/39 (2.6%)	1
Paresthesia	1/39 (2.6%)	1
Dizziness	1/39 (2.6%)	1
Psychiatric disorders
Depression	2/39 (5.1%)	3
Agitation	1/39 (2.6%)	1
Anxiety	2/39 (5.1%)	3
Insomnia	1/39 (2.6%)	1
Renal and urinary disorders
Proteinuria	4/39 (10.3%)	5
Hematuria	6/39 (15.4%)	8
Hemoglobinuria	2/39 (5.1%)	2
Bladder Spasm	1/39 (2.6%)	1
Urinary Tract Pain	1/39 (2.6%)	2
Urinary Frequency	3/39 (7.7%)	4
Urinary Incontinence	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/39 (2.6%)	1
Dyspnea	2/39 (5.1%)	2
Cough	3/39 (7.7%)	3
Nasal Congestion	1/39 (2.6%)	1
Pneumonitis	1/39 (2.6%)	1
Skin and subcutaneous tissue disorders
Skin and Subcutaneous Tissue Disorders - Redness/Irritation	1/39 (2.6%)	1
Dry Skin	2/39 (5.1%)	2
Alopecia	6/39 (15.4%)	6
Rash Maculo-Papular	2/39 (5.1%)	2
Social circumstances
Dehydration	1/39 (2.6%)	1
Vascular disorders
Hypertension	3/39 (7.7%)	3
Hypotension	1/39 (2.6%)	2
Thromboembolic Event	1/39 (2.6%)	1

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.