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Bortezomib With Gemcitabine/Doxorubicin in Patients With Urothelial Cancer and Other Solid Tumors
This study is currently recruiting participants.
Verified by M.D. Anderson Cancer Center, December 2008
Sponsors and Collaborators: M.D. Anderson Cancer Center
Millennium Pharmaceuticals, Inc.
Information provided by: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT00479128
  Purpose

Primary Objective:

-Find dose pairs of Bortezomib & Gemcitabine/Doxorubicin that have acceptable posterior probability of toxicity (target 30%).

Secondary Objectives:

  • Define the dose limiting toxicities of the dose pairs found.
  • Choose a dose pair (an "MTD") for a future phase II expansion with patients having locally advanced or metastatic urothelial cancer.
  • Correlate extent of 20S inhibition with pharmacodynamic markers of p53 pathway activation, including p21 and TRAIL receptor DR5, in peripheral blood mononuclear cells (PBMCs).

Condition Intervention Phase
Solid Tumor
Urethral Cancer
Drug: Bortezomib
Drug: Gemcitabine
Drug: Doxorubicin
Phase I

Genetics Home Reference related topics: bladder cancer
MedlinePlus related topics: Cancer
Drug Information available for: Doxorubicin Doxorubicin hydrochloride Gemcitabine hydrochloride Gemcitabine Bortezomib
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title: Phase I Two-Dimensional Dose-Finding Study of Bortezomib in Combination With Gemcitabine/Doxorubicin in Metastatic Surgically Unresectable Urothelial Cancer or Other Solid Tumors

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • To find the highest tolerable dose of Gemzar (gemcitabine) and Adriamycin (doxorubicin) that can be given together with Velcade (bortezomib) in patients with urothelial cancer or other solid tumors. [ Time Frame: 3 Years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 80
Study Start Date: September 2006
Estimated Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental
Bortezomib + Gemcitabine + Doxorubicin
Drug: Bortezomib
0.8 mg/m^2 IV Over 3-5 Seconds
Drug: Gemcitabine
225 mg/m^2 IV Up to 90 Minutes
Drug: Doxorubicin
12.5 mg/m^2 IV Over 15-30 minutes

Detailed Description:

Gemcitabine and doxorubicin are designed to disrupt the growth of cancer cells, which causes cancer cells to start to die. Bortezomib is designed to enter cells and interfere with a substance found inside cells that is responsible for allowing cells to divide. This helps to kill the tumor cells.

Before you can start receiving the study drugs, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have a physical exam, including measurement of your vital signs (temperature, heart rate, breathing rate, and blood pressure), height, and weight. You will have a chest x-ray. You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). You will have an echocardiogram or a MUGA scan. These scans use sound waves to make pictures of your heart, which helps show how well your heart pumps blood. You will be asked to lie on your left side while a technician places a probe with gel on your chest to create images of your heart to determine the function and size.

Depending on the stage of the disease, you will have a computerized tomography (CT) scan and/or a bone scan. Blood (about 3 teaspoons) will be drawn for routine tests and for a pregnancy test (for women who are able to have children). You must have a negative blood or urine pregnancy test before starting the study. You will be asked if you would like to have a central venous catheter (CVC) line placed. A central venous catheter is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure.

If you are found to be eligible to take part in this study, you will receive doses of the study drugs based on when you join the study and how many people have started before you. Two (2) participants will be entered into each dose level. Additional participants may be added at a dose level if it is being well tolerated. The doses will increase until the highest tolerable dose is found.

You will receive the 3 study drugs on the first day of each cycle. You will receive gemcitabine for up to 90 minutes. Next you will receive doxorubicin over 15-30 minutes. Bortezomib will be given last over 3-5 seconds. Every 14 days is considered a study "cycle."

While on study, you will have a complete physical exam before each dose of study drugs. Blood (about 3 teaspoons) will be drawn to check bone marrow and kidney function each week during the first month. The study doctor may decide to draw blood more often, if you are having side effects to the study drugs. Your vital signs will be measured before you receive the study drugs and 1 hour after the infusion.

At the end of Cycle 3, your tumor status will be re-evaluated. You will have CT scans and a bone scan. Blood (about 2 tablespoons) will be drawn for routine tests.

You will be taken off study if the disease gets worse or intolerable side effects occur. If you have stable disease, you may continue receiving therapy as long as your physician feel you are benefiting.

Once you are off-study, you will receive a phone call every 6 months. You will be asked how you are doing, the status of the disease, and if you have had other treatments.

This is an investigational study. Gemcitabine, doxorubicin, and bortezomib are all FDA approved and commercially available. Their use in this study is considered investigational because they have not been approved in patients with urothelial cancer. Up to 80 patients will take part in this study. All will be enrolled at M. D. Anderson.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  2. Female patient is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie: a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study.
  3. All patients must: Have biopsy proven cancer (i.e. solid tumor) for which there is no standard therapy available. If prior history of ischemic heart disease or exposure to > 200 mg/m^2 of doxorubicin, patients must have a measured ejection fraction (either by MUGA, ECHO or ventriculography) of at least 45%. Have preserved hepatic function as shown by AST (SGOT) levels < 2 x the upper limit of normal and an INR (for patients NOT on anticoagulant therapy) of < 1.4. Have normal serum creatinine (<=1.5) or creatinine clearance (measured by Cockroft-Gault formula) of >= 20 ml/min.
  4. All patients must have measurable or evaluable disease. In general, liver and lung lesions should be at least 1 cm, and patients with node-only disease should have lesions of >/= 1.5 cm in greatest dimension. Patients with disease confined to bone may be eligible of a measurable lytic defect is present or a serum marker is elevated (>4 x ULN). The Study Chairman is the final arbiter in questions related to measurability. Patients with a three-dimensional mass or pelvic sidewall fixation on bladder examination under anesthesia are considered to have measurable disease.
  5. For the second stage of the Phase I trial, all patients must have histologic demonstration of metastatic or locally unresectable transitional cell carcinoma of the urothelium. Minor components (<50% overall) of variant such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or small cell change are acceptable. However, when these atypical histologies are dominant, other treatment approaches may be more appropriate, and such patients are not eligible.
  6. Zubrod performance status </= 2.
  7. Patients must have had at least one prior therapy to be eligible for either the first or second stage a) Patients are eligible with any number of prior regimens regardless of what those regimens contained (i.e. prior Bortezomib or combination gemcitabine and adriamycin is acceptable).

Exclusion Criteria:

  1. Patient has a platelet count of < 100 x 10^9/L.
  2. Patient has an absolute neutrophil count of < 1.2 x 10^9/L.
  3. Patient has >/= Grade 2 peripheral neuropathy within 14 days before enrollment.
  4. Patient has total bilirubin > 2.5 mg/dL.
  5. Patient has hypersensitivity to bortezomib, boron, mannitol, gemcitabine, or doxorubicin. Gemcitabine skin rash that be controlled by short course steroids is allowed.
  6. Female subject is pregnant or breast-feeding.
  7. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test (Unless there is reasonable certainty that beta-hCG is coming from the tumor). Pregnancy testing is not required for post-menopausal or surgically sterilized women.
  8. Patient has received other investigational drugs with 14 days before enrollment.
  9. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  10. Patients with significant atherosclerotic disease, as defined by: a) Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia or active conduction system abnormalities. Any prior ECG abnormality at Screening has to be documented by the investigator as not medically relevant. b) Symptomatic congestive heart failure. c) Claudication limiting activity and d) History of cerebrovascular events within the last year (including TIA).
  11. Patient have uncontrolled brain metastases or central nervous system disease.
  12. Patients with an active, or likely to become active second malignancy.
  13. Patients must be at least 6 weeks out from pelvic irradiation, and must not have more than 10% of bone marrow irradiated.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00479128

Contacts
Contact: Arlene Siefker-Radtke, MD 713-792-2830

Locations
United States, Texas
U.T.M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Arlene Siefker-Radtke, MD            
Sponsors and Collaborators
M.D. Anderson Cancer Center
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Arlene Siefker-Radtke, MD U.T.M.D. Anderson Cancer Center
  More Information

UT MD Anderson Cancer Center  This link exits the ClinicalTrials.gov site

Responsible Party: U.T.M.D. Anderson Cancer Center ( Arlene Siefker-Radtke, MD/Assistant Professor )
Study ID Numbers: 2006-0014
Study First Received: May 24, 2007
Last Updated: December 29, 2008
ClinicalTrials.gov Identifier: NCT00479128  
Health Authority: United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Solid Tumor
Bladder Cancer
Ureteral Cancer
Urothelial Cancer
Urethral Cancer
Renal Pelvis Tumor
Bortezomib
Gemcitabine
Doxorubicin
Gemzar
Adriamycin
Velcade
LDP-341
MLN341
PS-341
Gemcitabine Hydrochloride
AD
Hydroxydaunomycin hydrochloride

Study placed in the following topic categories:
Bortezomib
Urinary Bladder Neoplasms
Urogenital Neoplasms
Urologic Neoplasms
Doxorubicin
Signs and Symptoms
Urethral cancer
Urologic Diseases
Urethral Neoplasms
Gemcitabine
Pelvic Neoplasms
Urinary tract neoplasm
Bladder neoplasm

Additional relevant MeSH terms:
Antimetabolites
Anti-Infective Agents
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Antibiotics, Antineoplastic
Immunosuppressive Agents
Antiviral Agents
Pharmacologic Actions
Protease Inhibitors
Neoplasms
Neoplasms by Site
Radiation-Sensitizing Agents
Therapeutic Uses
Urethral Diseases

ClinicalTrials.gov processed this record on January 16, 2009